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Notebook - SleepNon24VLiDACMel - VLiDACMel therapy for entrainment of treatment-resistant sighted non24

SleepNon24VLiDACMel - VLiDACMel therapy for entrainment of treatment-resistant sighted non24

Foreword

This is an experimental protocol for 24h entrainment of treatment-resistant sighted non24.

This is a work-in-progress documentation of the author's self-experiment. Hence, it will continue to evolve over time. Check out later this document for updates.

This work takes an evidence-based approach based on a mostly clinical literature review when possible and self-experimental using a combination of sleep diary, manual data logging and automatic vitals monitoring where the data is lacking in the literature (sighted non24 is pretty rare after all). The goal being to design and assess the effectiveness of therapies to manage sighted non-24.

As of July 2020, the protocol is considered mature, as it reproducibly allows for a stable (but not constant) entrainment of the author's circadian rhythm to a 24h cycle. Furthermore, all the observed effects could be elucidated by previous studies, which provides a framework to predict how this therapy works in various scenarios. This experiment is also following the new approach of radical open science, where the experiments progress is publicly accessible at nearly all stages. What remains to be explored are the following points:

  • Milestone 1 (done July 2020): Complete this document to fully describe the therapy and the theoretical physiological pathways underlying it, as well as the practical details to adjust it on an individual basis.
  • Milestone 1.5 (done August-October 2020): Reproduce the shorter than 24h circadian period with very long bright blue light therapy. This would allow to adjust backwards the circadian rhythm (ie, sleep and wake up earlier) without having to freerun forward.
  • Milestone 2 (done October 2020): Assess the necessity of each step by elimination (ie, try to keep all steps but remove one at a time, if no effect then can permanently be removed). After this milestone, the protocol will be including only the minimal set of steps necessary for entrainment of the author's circadian rhythm.
  • Milestone 2.5 (done November 2020): Update document with critical findings from side notebook. All major aspects of the therapy (such a very long light therapy being more effective than brighter light therapy) were found to be strongly supported by previous (but unpopularized) research, and adequate references were added. Added a simplified protocol (set of rules, 2 pages). The protocol is now considered mature.
  • Milestone 2.6: Update document with more findings from side notebook.
  • Milestone 3: Systematization of the therapy by circadian rhythm monitoring using wearable devices. Just like diabetes became medically manageable when glucose and insulin monitoring devices could be made, there needs to be a device to monitor the circadian rhythm in order to properly time the therapies on a daily basis and monitor their effects as well as chaotic biological fluctuations.
  • Milestone 3.5: Reproduce the shorter than 24h circadian period with very long bright blue light therapy, continuously for several weeks, while monitoring vital signs and body temperature, in order to objectively assess the phase advance produced by very long bright blue light therapy.
  • Milestone 4 (partially done April 2021 - database is still being acquired and is not peer-reviewed): Publication of the database of vital signs and sleep logs for this self-experiment to allow for third-party review and analyses. Database may be published in a peer-reviewed journal. See the Wearadian project on GitHub for more details on the acquisition system and access to the database.
  • Milestone 5 (may never happen because no funding): rewrite this protocol more concisely and with references in academic style instead of hyperlinks (using Zettlr) for publication in a peer-reviewed journal.

The therapy protocol is 16 pages long at the moment. In addition to the therapy, there is also a TROUBLESHOOTING section towards the end of this document, which aims to answer the most common questions about the various therapies for non24 and clarify how they work and how to optimize them according to the current scientific knowledge. This section is much longer than the therapy outline, and hence it is written for the curious reader to further their knowledge and/or answer their questions about or around circadian rhythm disorders. Reading the Troubleshooting section is not mandatory, rather the reader is invited to search there in case of a specific question that is not answered in the therapy outline.

This therapy was designed to treat sighted non24. Since the tools influencing the circadian rhythm are the same for all humans (and actually most research was done on typical sleepers but are applicable for people with circadian rhythm disorders), some parts may also be applicable to DSPD with some changes (mostly that the goal of DSPD is to phase advance gradually, whereas non24 aims to freeze the circadian rhythm in place with a treatment-induced daily phase advance that counteracts the natural intrinsic daily phase delay). For ASPD, it may be possible to use the same tools too but timed at the opposite, under the phase delay part of the zeitgebers' PRCs (eg, being exposed to light therapy in the evening instead of at wake-up, as did Czeisler et al in a case study). Findings for individuals with a circadian rhythm disorder can also provide generalizable insights for typical sleepers as previous studies have done.

DISCLAIMER: this protocol is not scientifically peer-reviewed and not clinically validated. It was tested on a sample size of only 2 individuals with non24 since birth and under a controlled home environment. Hence this protocol cannot be formally recommended, it should still be considered experimental and maybe risky. If you do try, it would be at your own risk (please ask a physician to follow you at least!).

IMPORTANT HEALTH NOTE: this therapy cannot be used by individuals with epilepsy or macular degeneration or other retinal diseases or malformations (eg, aphakic people born without crystalline lens and pseudophakic who received intraocular lens implants), as these populations are at risk when using light therapy. It is also risky for people with motor disorders such as restless legs syndrome or periodic limb movement disorder as both bright light therapy and melatonin can independently increase melatonin levels which can trigger motor symptoms, however these symptoms should disappear following discontinuation of the therapy.

This document was first written by Stephen Karl Larroque in February 2020, from material collected since August 2019, and with substantial iterative updates over the years. Last update: October 2021.
ORCID: https://orcid.org/0000-0002-6248-0957

To print the document, select the text and right-click on it then select print (ensure the option "print selected text only" is checked), in order to remove the top navigation bar that can hide text on some pages.

Preface

My name is Stephen Karl Larroque. I am a researcher in the neuroscience of consciousness. I was born with the non-24 circadian rhythm disorder, got diagnosed the first time in my twenties, and it started to become impossible to ignore in my thirties. Facing the sparsity of knowledge and effective treatments for this disorder, this prompted the start working on my own to find evidence-based approaches to improve the management of this disorder, which ultimately led to the VLiDACMel protocol presented below. The non-24 disorder affects my lineage over at least 2 generations of direct ancestors (so I am the 3rd), which strongly suggests that it is of genetic cause, and hence will likely affect my future children.

Although I was not trained to work on this specific field of circadian rhythm science, and hence claim no authority, I found myself in the exceptional circumstances of being trained in the scientific method and specifically in biomedical science, and being afflicted by a disorder I could study with this method and by building on my predecessor's works.

This protocol as is presented in this document is publihed with no guarantee of any kind of medical use nor of safety, please regard it simply as informational content. I publish it in the hopes that such a protocol with a review of the previous evidence in the theory of circadian rhythm and circadian rhythm disorders combined with the preliminary results from my self experiment, with a clear set of rules that optimized the therapy's efficacy during this self-experiment, may help in the design of future experiments by other researchers and lead to a faster investigation and finding of new therapeutic avenues for circadian rhythm disorders.

The current document has multiple levels of reading depending on how much you want to invest time in reading its content:

  • a Simplified Protocol of VLiDACMel is presented as a set of rules for legibility. It contains the most crucial information, but lacks the subtleties of some parameters that can reduce the efficacy of the therapy.
  • a Quick 2 minutes VLiDACMel protocol which is even more concise, for those who just want a quickstart to the core elements necessary for entrainment.
  • For a more complete understanding of the protocol, the Full Protocol section outlines the entire protocol with links to the most important academic works that underlies it, as well as explain the various adjustment factors to optimize its efficacy.
  • Then, the Troubleshooting section presents an in-depth review of the science of circadian rhythm and circadian rhythm disorders, with all the links to the academic sources, this section and its subsections are primarily addressed to scientists or the very curious reader as it gets much more technical and requires the use of jargon, although the author tried to summarize in layman terms the key points in the opening paragraph of each subsection, and keeping the jargon at the minimum required for accuracy.

Although this document is primarily aimed at sighted individuals with a non-24 sleep-wake circadian rhythm disorder, it is also mostly applicable for other circadian rhythm disorders such as DSPD and night shift work disorder given the same biological pathways are involved and hence the same therapies are likely applicable, see the sections "Adaptations of this protocol for other circadian rhythm disorders (DSPD, nightshift workers)" for more specific instructions for each disorder. The information contained herein may also be partially or fully applicable to insomnia, given the strong links with circadian rhythm disorders.

Introduction

This document describes a protocol for the entrainment of sighted non-24, which was designed using an evidence-based approach from a scrupulous examination of previous research, and self-experimentation to determine the factors influencing therapy's efficacy or circadian rhythm (dis)entrainment.

Here are some sleep graphs of the early results from uing this therapy:

Zoomed out, here is my full sleep diary over 1 year, with the working therapy at the end:

The graph above shows a relatively stable entrainment over 2.5 months. As of December 2020, the author was entrained for 6 months, which is significantly much more than any published therapy protocol before. In comparison, all the author's previous attempts, most using published protocols, failed after 2 weeks to 1 month. The entrained (right part) of the graph was through the use of 1-2h of daily light therapy.

Here is the result with very long light therapy of more than 5h everyday for 10 days. This result is especially interesting as it was never observed before, with an inverse freerunning pattern: waking up 30 min earlier every day and up to 1h30 (one full ultradian cycle) earlier on the last day (which prompted the premature stopping of the self-experiment because this became uncontrollably too early):

This first experiment with very long light therapy (on the far right) was started on about the 3rd of June, after 1 more month of freerunning as can be seen during May. The very long light therapy resulted in a staggering reduction of circadian period tau under 24h at 23.5h on average and 22.5h the last day! Everything else was held constant (same melatonin intake time, same meal eating time, same daytime activities and environment), only light therapy duration was extended to reduce the circadian period under 24h. This very long light therapy experiment had to be stopped because of waking up way too early. See the Backward Cycling Therapy protocol below for more information.

Before this working therapy, the author tried: 1- melatonin only, 2- light therapy lamps + melatonin, 3- strict ketogenic diet only with timed meals (time-restricted feeding), 4- intermittent fasting (or even complete fasting for a few days), 5-carbs-only diet, and of course strict sleep hygiene, 6- chronotherapy, 7- chronotherapy with light therapy (ie, advancing light therapy 1h earlier than last target wake up time every 3 days). None of those therapies worked.

The latest working therapy protocol designed by the author, which worked for 2.5 months and reproduced for 4 months (still ongoing) at the time of this writing, is named VLiDACMel, which stands for:

  • Very long Light therapy at wake-up (after minimal core body temperature), the most important tool of this therapy,
  • Dark therapy in the evening,
  • Avoid eating Carbohydrates when Melatonin is high in the blood,
  • Take exogenous instant-release Melatonin timed before DLMO (measured via core body temperature or approximated via 3 days average of wake-up times).
  • And always curate a sleep diary to assess changes in the circadian rhythm phase and properly adapt the treatments and to assess the conditions to optimally sleep restoratively.

Concisely, this therapy is founded on the following 3 points:

  • Light exposure control: light therapy glasses Luminette at wake-up (or another light source of 500lux with optimized light angle to stimulate ipRGCs in the nasal retinal hemiregion) to phase advance and hence reduce circadian period (biological day duration). The exposure must be "very long", so use for 2-5h from wake up using relatively low intensity bright light of 500 lux. Exposure duration to light therapy can be modulated to fine-tune the wake-up time (ie, with longer exposure, the participant will wake up earlier and earlier), and this modulation is the primary way this therapy allows for flexible readjustment of the sleep schedule on a daily basis without having to freerun a full cycle again. Light therapy must always be combined with dark therapy in the evening (ie, avoidance of light exposure to avoid unwanted phase delay), by using blue light filters and dimming the brightness of any light emitting device/lamps (or use blue blocker sunglasses if environmental light sources cannot be controlled).
  • Sleep induction and consolidation by melatonin: use melatonin instant release pills, taken at a time calculated relatively to the individual's DLMO (not the bedtime), and avoidance of wakefulness inducing drugs such as caffeine. This both consolidates sleep (ie, ensures you sleep your full night and not wake up too early or in the middle of your night causing unwanted sleep deprivation) and phase advance (allow to sleep and wake up earlier). The effect of melatonin is additive with light therapy. This step can be temporary, as melatonin can be dropped later on if the user feels too drowsy during days after melatonin, but it's good to do at least for a few weeks at first to magnify the sleepiness feeling so that the user re-learns to recognize it.
  • Food timing and diet composition control: never eat after melatonin intake and reduce/minimize carbohydrates intake. In the experiment above, I was half the time under a strict ketogenic diet, and half under a balanced diet including carbs. The ketogenic diet is not necessary, but it can help at first before phasing it out.

Update on current findings of efficacy for this therapy:

The first threshold to consider any treatment potentially effective was set to 1 month of entrainment, entrainment being defined as an average wake-up time under 1 ultradian cycle (a time window of 1.5-2h), such as wake up between 9am and 11am. A secondary threshold to consider a treatment really effective is set to at least 6 months of entrainment, as evidenced by circadian rhythm measures (eg, core body temperature, not necessarily the sleep-wake patterns). A third threshold to consider a treatment effective and robust is set to at least 1 year of continuous entrainment, as to ensure the treatment allows robust entrainment despite seasonal variations in sunlight exposure and ambient temperature (ie, robustness against environmental variability).

As of April 2021, very long (5h-9h) bright light therapy plus dark therapy achieved threshold 1, and is investigated for the 2nd and 3rd thresholds. Melatonin alone passed the 1st threshold but not the 2nd.

As of August 2021, since late February 2021 the very long (5-9h) bright light therapy plus dark therapy protocol (ie, updated VLiDACMel protocol, with melatonin being optional and not used during this period) achieved thresholds 1 and 2 but failed the 3rd threshold. Indeed, the entrainment (ie, stabilized/frozen circadian phase) worked for ~7 months, whereas with no therapy entrainment (to sunlight) lasts 1 month maximum for the author. This is significantly better than no therapy, but still the entrainment is lost once or twice a year. It should be noted that the entrainment is not lost at once, but rather there is a slight remaining daily shift that accumulates over time and so the wake up time changed from 8am in late February 2021 to 4pm in late July 2021, so that the circadian phase was now akin to a DSPD pattern. The author then decided to freerun to become again more quickly in phase with the day-night cycle. This is still a failure since the entrainment couldn't be maintained fully stable. A potential improvement to this therapy may be by adjuncting a hyper photosensitizing drug, this will be explored in the future (there is a section about these drugs below in the Troubleshooting section).

In summary, the current state (as of August 2021) of efficacy of the VLiDACMel therapy is a maintenance of entrainment for 6-7 months for the author (compared to 1 month without). Anecdotal reports from other users suggest that some have obtained (much) better results, while others have reported worse (in general individuals with comorbidities that prevent the continuous use of light therapy or melatonin, such as RLS and PLMD). Elders seem to be more responsive (often, melatonin alone is sufficient for their entrainment) than younger individuals.

Quick 2 minutes VLiDACMel therapy protocol

A quickstart for those who don't have the time to read or don't need the details and references.

  • Find your circadian night. It's when you sleep more than 6h with little to no wake ups in the middle of the night (no fragmentation). If you have non-24, freerun until your circadian night happens close to the time you want to freeze your sleep-wake schedule. Naps are allowed. Write a sleep diary all the time to monitor your sleep patterns, and bring it to a circadian rhythm disorder specialist to get diagnosed and accommodations.
  • On wake up, use light therapy glasses such as Luminette v3 for 2-8h using the lowest or medium light intensity setting. No alarm clocks, just wake up naturally. Don't use light therapy lamps, only glasses. This is the most important element of this therapy.
  • 3-5h before your natural fall asleep time (this should equal 12-15h before your last wake up time), dim to the minimum or switch off lamps and screens, and filter blue light using blue light filter apps or use orange or red tinted blue blocker glasses (use UVEX or blue-laser safety glasses) and red light lamps. Use a lux meter app on a smartphone to confirm, you should see 0 lux at best, or at least less than 10 lux. Don't eat nor consume carbohydrated meals or drinks past this time. Never consume alcohol nor caffeine the whole day. You can take melatonin at the same time, dosage 0.3mg up to 3mg (or rarely more for some people), instant release and in blister packs. For some people, taking melatonin 12h before the natural wake up time is a good starting point, the effects should work the very same night, and it's possible to then modify the timing each day by increments of 30min until the sweet spot of maximal effect is found. If feeling drowsy during days after melatonin intake, you can reduce melatonin dosage or stop it once entrainment to light therapy works and only if you do not consume any stimulant (eg, caffeine in coffee or tea or energy drinks, ADHD medications, etc).
  • Contra-indications: If you have an ocular illness, ask your doctor before if you can use light therapy, otherwise melatonin can still be used. If after starting the therapy, motor dysfunctions appear or are worsened (eg, restless legs) then stop the whole therapy (both light therapy and melatonin) right now, and talk to your doctor about getting tested for a motor disoder (PLMD, RLS) or ADHD. If on the other hand you can sustain being under the sunlight, you will probably be fine.

Simplified protocol

This is a simplified version of the full protocol presented as a straigh-to-the-point set of rules, without the rationale nor the explanations, which may be easier to present the therapy to patients. See the Full Protocol and the Troubleshooting sections below for more detailed explanations and references.

Jargon

  • phase shift: earlier or later shift in the timing of the circadian rhythm and hence of the natural wake up and bedtime, with phase advance being earlier and phase delay later
  • biological or circadian night/day: relative day or night in phase with the individual's circadian rhythm (respectively low period and high period - core body temperature reflects the same trends). The biological/circadian night is the ideal time for the individual to get a long and reparative sleep, and inversely it will be very difficult to sleep during the biological/circadian day.

What results can be expected

  • Freerunning should stop or get slower for those with a long circadian period (ie, >26h). This means there won't be "night-walking" phases anymore, where you sleep during the day and are awake the whole night.
    • However, this therapy does not guarantee a constant sleep-wake schedule, which will likely remain highly variable from day-to-day in a 6h timeframe: one day you can wake up at 1pm, the next at 11am, the next at 2pm, the next at 9am (and feel sleepy at according times).
  • Longer sleep on average than without the therapy, and with a higher quality and less to no interruptions.
    • However, biphasic sleep (ie, "weird insomnia") and irresistible naps will still occur somewhat regularly, mostly at random.
  • Improved overall health, especially cognitive performance and mood.
    • However, mood swings and cognitive drops (ie, "zombie-like" states) will still happen somewhat regularly, mainly dependent on how long you slept earlier.

Preparations

  • Start to write a sleep diary (template) with the fall asleep time and wake up time, everyday, including naps. Continue to curate this sleep diary all the time, this is the most essential tool to self-monitor the circadian rhythm and better manage the disorder. Digital sleep diary such as Sleepmeter Free on Android are recommended as they also generate sleep charts, which are easier to monitor and diagnose by doctors.
  • Before starting the therapy: Freerun (ie, sleep when naturally tired and wake up without an alarm clock) until you wake up close to your ideal wake up time. The therapy will then freeze in place the circadian rhythm and sleep-wake schedule. Nap as much as needed to reduce as much sleep deprivation as possible, this improves the therapy's efficacy. This applies only for non-24, other circadian rhythm disorders such as DSPD should not freerun.

Start the VLiDACMel therapy

Other advices

  • Always put one's sleep first.
  • Plan how to handle sleepless nights:
    • Sleepless nights and premature wake ups will always continue to randomly happen due to non-24, as there is unfortunately an uncurable insomnia component.
    • It's important to plan what to do during these sleepless nights. Trying to sleep for hours, alone, in the dark, will only cause a loss of time, running thoughts and depressive feelings of powerlessness. Realizing that doing activities during sleepless nights is acceptable and even advisable is definitely the most important realization of people with non-24, as this reduces time spent in a depressive setting while allowing more time for activities.
    • A good strategy is to strike a deal with oneself to always put one's sleep first, but to allow to get up and do activities if unable to sleep for more than 30min. If you can't sleep and do not feel tired after 30min of trying, get up and do something. But whenever you feel tired, try to go back to sleep/nap as your top priority. If again it does not work after 30min, you can get back up and do activities. This is similar to the core tenets of sleep hygiene, do not stay in bed for too long if you cannot sleep.
    • Make sure to avoid getting exposed to bright light (ie, use dark therapy) during sleepless nights. Hence, screens are allowed, but only dimmed to the minimum and with a blue light filtering software.
  • Learn how to detect and handle sleep deprivation and circadian misalignment:
  • Are there other effective therapies? Maybe, but there are a lot that are not working or even detrimental. Check if these interventions are known to modify the core body temperature (search on google scholar or pubmed), if not they are likely ineffective to shift the circadian rhythm.
    • Some therapies may work better for some than others, but effective therapies have an objectively measurable effect on everybody. And of course there are therapies that have no effect at all for everybody.
    • If you hear someone claim they were treated with a miracle therapy, ask for how long and a proof such as a sleep diary. If they can't produce a sleep diary over at least 1 month post-treatment of a stable sleep pattern, consider the therapy ineffective unless more follow-up data is provided. Transient improvements are common due to how elastic sleep can be, but it does not last more than a few weeks if the therapy is ineffective.
    • Avoid benzodiazepines and non-benzodiazepines (Z drug) sleeping pills. They work for some weeks, then they stop working because of tolerance, and then if you stop you'll have an even worse insomnia, so that you'll be compelled to continue using them just to sleep as bad as you were before starting the sleeping pills. That's why current medical guidelines recommend the use of sleeping pills to be limited to 4 weeks maximum, to then be phased out for other alternatives such as melatonin. This applies to all sleep disorders, including insomnia. For circadian rhythm disorders, sleeping pills are never recommended and even disadvised.
    • Avoid studies using "self-reported sleep measures", as they are the worst and most inaccurate kind of measure. This usually refers to periodically asking the subject to say how much they think they sleep on average. This kind of self-reported, subjective measure is known to have very poor accuracy due to poor recall. Prefer studies using objective measures of sleep such as actigraphy and core body temperature, or at least a sleep diary.
  • As we grow older, we typically need more light therapy (due to lens darkening) and smaller dosage of melatonin (due to lower endogenous levels) to get the same effects.
  • Work on accepting the disorder. This will likely involve going through the grieving process of foregoing your previous life or comparison with the social expectations. But that doesn't mean passively suffering from the disorder, but rather to actively improve your management of it and organizing your life in a sustainable manner around it, putting your sleep needs first. For additional infos on the steps of the acceptance process, see the dedicated section below.

WIP: self-monitoring: core body temperature modulation is the core signalling way to propagate circadian rhythm changes throughout all body's cells. Can allow to monitor both the circadian rhythm, and optimally time melatonin and other therapies by observing their direct effect on the core body temperature.

This protocol should result after about 10 days in at least a significantly reduced daily phase delay, or even entrainment.

Following this protocol should not be exhausting, on the contrary, it requires that the participant is fully rested before starting and during the therapy, as sleep deprivation reduces the therapy's efficacy, hence alarm clocks should be avoided, as they not only reduce the therapy's efficacy but also mask the sleep-wake patterns and hence make individualized assessment and monitoring of sleep-wake patterns and therapeutic adjustments difficult.

Belief, strictness and self-discipline are not required. Only compliance to use the devices at the indicated time is necessary for the therapy to be effective. The goal is to get educated on how sleep works and what (external) factors can influence it, not wish it into working how we want. By controlling these factors, this allows to get some control over the sleep-wake patterns.

It's also crucial for the clinical practitioner to explain the complexity of this therapy and instruct the patient how to adapt it to his needs.

Full protocol

This therapy aims to allow for the entrainment of the circadian rhythm to a 24h cycle (ie, entrainment is the stabilization of the sleep schedule) for individuals with a non-24 circadian rhythm sleep-wake disorder (ie, a circadian period longer than 24h). The therapy works by first waiting for the circadian rhythm to naturally and progressively shift towards the ideal wake up time, at which point the therapy should be started to "freeze"/entrain the circadian rhythm in its current state. In practice, this works by using tools that will phase advance (ie, reduce the circadian period), their combination being additive. Since the individual's sleeping schedule does not necessarily follows the circadian rhythm, we will use the terms of "biological day" and "biological night" to refer to the day and night as defined by the circadian rhythm and hence the ideal sleeping schedule, not by the individual's current sleeping schedule.

A previous study found that a combination of melatonin and light therapy could entrain all 6 individuals with non-24, but with limited long term success. The protocol below attempts to address the long term issues by identifying the key parameters for successful entrainment and clarifying how to adjust the therapy on an individual basis to get the optimal results for long term entrainment and for the necessary day-to-day adjustments (eg, spectral composition and duration of light therapy, timing of melatonin, etc.), as well as adding new tools that were not explored before (such as food control).

The therapy was self-experimented by the author (34 years-old, formally diagnosed thrice over 10 years).

Disclaimer: The author thoroughly designed and self-tested this protocol after several failed variations. The author does not guarantee that this protocol will work for anyone else, or that all steps are necessary, but all steps laid down below were tested under many variations (by elimination and by changing parameters), and this is the only combination that was found to consistently work so far. Please keep in mind that if the protocol is only done partially (eg, skipping some steps), this may reduce the effectiveness (or not work at all). But even when all steps are followed, this may not work for some individuals. This protocol is shared in the hope it can be helpful for future research or to other individuals with non24.

Preparation phase

Two weeks before doing the therapy: sleep without alarms to fulfill your sleeping needs, and wait for your circadian rhythm to shift naturally until it's close to the target sleep schedule (particularly the wake up time):

  1. Sleep according to your own natural rhythm for 2 weeks. It is crucial to be well rested before starting the therapy, as this is necessary to reduce fragmentation in your sleep schedule and circadian rhythm by eliminating sleep deprivation, which was also shown to reduce light therapy effectiveness. Indeed, sleep deprivation can cause chronic insomnia as shown by Randy Gardner's experiment. If necessary, buy an eye mask and ear plugs to prevent external factors from disrupting your sleep.
  2. Write down your wake-up time and falling asleep time every day in a journal (use Sleepmeter on Android). This will serve 2 purposes: you can get a formal diagnosis from a specialized sleep doctor with 2 weeks of sleep logs showing a non24 pattern, and it also allows you to better know what affect your sleep and better know your own sleep patterns. Indeed, it's not uncommon that we overestimate the duration of our sleep, and for non24 individuals the daily phase delay (ie, it's often shorter than you think).
  3. Take this opportunity to get to better listen to your body and recognize the signs of sleepiness tiredness signalling your body is ready to sleep. It takes at least 2-3 days of good sleep (good duration AND circadian alignment) for the body to recover and feel fully working. For individuals with non-24, this can be a genuinely new experience to NOT feel sleep deprived, since they only lived under sleep deprivation before. It is extremely helpful to know what it's like to not be sleep deprived, and to learn to differenciate when you are sleep deprived and when you are not, as it will help in knowing when to adjust the treatments timing and dosage for you.
  4. After the 2 weeks, calculate the average wake-up time over the last 3 days. Subtract the sleep duration you need to feel the most refreshed after sleep (usually 7-8h for adults) + 2 hours from this average wake-up time to calculate the DLMO (dim-light melatonin onset). Example: if the average wake-up time over 3 days was 6am, and you need 7h of sleep to feel refreshed, your DLMO is at 6-7-2 = 9pm. Subtract 2-4 hours from this DLMO time to get the ideal time window to take melatonin. Using the previous example, the melatonin intake window would be between 5-7pm.
  5. Now, wait for your sleep to cycle and come close to the ideal time you would like to freeze in-place. Indeed, there is no proven way to cycle backward (ie, wake up earlier and earlier, also called phase advance), but if you phase delay enough (ie, sleep later and later, which happens naturally for people with non-24 and is called "freerunning"), you'll eventually reach the wake-up time you would like. If you are too eager and start the therapies while sleeping out of phase with your circadian rhythm, this will not work, may worsen your phase delay and increase sleep deprivation temporarily, and hence ultimately discourage you. Hence, it's crucial to be patient to wait for your biological night to be in phase with the actual night. This is usually noticeable as when the circadian rhythm is in phase with the day-night cycle, your sleep will be on average more restorative and longer. Start the next steps below when your wake-up time is around 2-4h before the ideal time you would like to wake up. Meanwhile, continue to write a sleep log.

Note: Be careful to track the biological night's sleep and using this sleep session as a reference for all the calculations in this protocol, and not the siesta (nap time). Humans circadian rhythms naturally have a biphasic sleep with 2 sleep gates : one for the biological night sleep, and one for the siesta about 12h later, but then when sleeping during the siesta only a half night (3-5h) can be slept at most. Since both sleep gates are regulated by the circadian rhythm, knowing the timing of one allows to estimate the timing of the other: for example, if the siesta happens at 6-7pm, the biological night (the other sleep gate) is at 6-7am. See the Biphasic sleep section for more info. A very good indicator to differenciate both types of sleep in practice is the sleep duration, as the siesta can only lasts for half (3-5h) of the biological night sleep (7-9h on average for adult humans). Also, humans are more prone to do a siesta if chronically sleep deprivated (but do not avoid the siesta if you are chronically sleep deprived, as this will allow to reduce the sleep pressure and increase the likelihood you sleep during your biological night on the next days). Furthermore, the biological night sleep duration is dependent on sleep pressure, so that as a rule of thumb, if an individual sleeps a siesta, this amount will be subtracted from the biological night sleep: for example, if you sleep for 4h during the siesta, you can only sleep 4h during the biological night sleep ; if you sleep 2h during the siesta, you can sleep 6h during the biological night sleep. It's the bedtime that will be delayed, not the wake up time (eg, if your biological night sleep is 6am-2pm, and you take a 4h siesta at 6pm-10pm, then you'll be able to sleep your biological night sleep at 10am-2pm, not 6am-10pm, due to reduced sleep pressure so you'll need more time to build it before being able to fall asleep).

Reminder: it is crucial to wait for your circadian rhythm to be in phase with the ideal timing you wish before starting the therapy, as otherwise the treatments will be mistimed and hence will not work or even make your sleep temporarily worse, as for example light therapy can increase sleep fragmentation if mistimed.

For researchers, technically this preparatory phase is akin to a combination of a multiple nap protocol and a constant bed rest protocol, in that sleep and naps are permitted ad libitum in order to reduce or eliminate the effect of sleep pressure and avoid masking by alarm clocks or other factors. However, some factors such as light exposure, food timing and social events are not controlled since this is done in the wild. For these factors, asking the patient to log them such as by using the Pevlog app can allow to take them into account when assessing the circadian rhythm from sleep logs or actigraphy.

Entrainment therapy

After the 2 weeks of natural sleep, use now this combination of therapies everyday, laid out here in chronological order of use during the day, and the major steps emboldened:

  1. Continue to write down a sleep diary of your sleep and wake up times, optionally along with any other information you think pertinent for your sleep. This is the swiss army knife of non-24 management: the sleep diary not only helps with diagnosis, but it's also crucial to properly time the treatments relatively to the circadian rhythm and spot early signs of transient (dis)entrainment and other changes in your circadian rhythm once you get entrained, so that you can react fast enough to adapt your therapy to stay entrained (eg, by increasing or shortening the light therapy's duration or melatonin timing or dosage). Due to the ever changing circadian rhythm in this disorder, it's necessary for individuals with the non-24 disorder to always maintain a sleep diary.
  2. Very long light therapy: use 500 lux bright light therapy at wake-up for 2-8h with an angle towards your nose to "freeze" your circadian rhythm by constant phase advance or even reduce circadian period to less than 24h. Also stops melatonin secretion and increases vigilance and mood. This is the strongest tool (zeitgeber) to manipulate the circadian rhythm, for both for the central clock (suprachiasmatic nucleus in the brain) but also for all peripheral clocks of all the organs throughout the body. Use light therapy glasses such as Luminette v3 or v2 for 2-8h directly as soon as you wake up. If you are in a dimly lit environment, start with the eyes closed for a few seconds to allow for the eyes pupils to contract, before opening your eyes for the rest of the session, this will reduce minor side effects of sudden bright light exposure such as dizziness. The longer the exposure, the proportionally more phase advance you will get (see also here). It's possible to increase the duration of light exposure to more than 5h (see also here), in which case you may wake up earlier and earlier (but be careful because the effect increases over time, being maximal at 10 days due to photic history, so you may end up waking up too early!). The lowest setting, 500 lux, is sufficient with the Luminette. In case of incomplete entrainment after 10 days, increasing the duration is more effective than increasing the intensity of light therapy, as the author of the present document self-experimentally arrived at the same conclusion before finding previously published validation, which means that this effect is so robust that it is noticeable and reproducible on an individual basis. This is likely because light intensity has a low saturation point (1000lux to 2000lux), whereas duration has none (no PRC dead zone). Longer exposure to bright light also eliminates biphasic sleep. In theory, longer exposure to light may be necessary depending on age, as the eyes lens (cristallin) are obscuring and acting as a blue-light filter with age (see also here), although in practice age does not affect the response to light therapy as only melatonin inhibition is impaired by age but not the circadian phase advance which remains the same, and with some studies showing that light therapy produce the same phase shifting effects regardless of age or sex.
  3. Optional: Timed big main meal, which is to take your main meal at the middle of your circadian rythm's day. This synchronizes your circadian rhythm thanks to your intestines regulation of the circadian clocks (it's the biggest producer of melatonin). You can eat a breakfast, but it should be relatively small, and there should be only one big meal during the day (eg, the sort of meal that you feel like you ate enough for the whole rest of the day - but be careful of not over-eating!). More than entraining your circadian rhythm, timing meals allows to avoid circadian misalignment, as eating food during your biological night or too close to it can impair several regulatory functions such as insulin and glucose. This is true not only for non24 and DSPD but also for typical sleepers as well, although the former may be even more at risk due to a mutation in melatonin type 2 receptor (MT2) which seems to be more prevalent in individuals with a circadian rhythm disorder.
    • Important: Reducing the quantity of consumed carbohydrates is highly beneficial in any case, as each 1% reduction improves the metabolism and reduces risks of obesity and metabolic disorders, including sleep, according to a meta-analysis. It's also an advised treatment to deal with postprandial sleepiness and particularly reactive hypoglycemia.
    • Timed big meals provide very little additional circadian stability apriori and it's disadvised for those who try to manage their weight, so it's not recommended to focus in this step, rather focus on light and dark therapy and melatonin, and simply avoid ingesting calories and especially carbohydrates during the circadian night.
    • Optionally, it's possible to follow a strict ketogenic diet with timed big main meal.
      • The ketogenic diet is not necessary for entrainment, but it allows to eliminate the effect of carbs (postprandial sleepiness, sugar crash) as well as disconnect the digestive clock with the brain circadian clock, hence it can ease entrainment. The effects will start only after you reach a ketosis state as indicated by the highest 2 levels on the ketostix (measurement bands of ketosis from urine). Following a strict ketogenic diet is kind of the extreme of the carbohydrate reduction treatment for postprandial sleepiness. A strict ketogenic diet, as defined for epilepsy treatment and diabetes management, is a diet with limited carbohydrates (<=50g of wet carbs (sugar+fibers), including <= 20g of sugar carbs per day), medium proteins and lots of lipids (fat). Proteins should be kept in limited amounts, as to not compensate for the lack of carbs by eating too much proteins, as proteins will get converted to carbs, preventing reaching the highest levels of ketosis as indicated by the last 2 colors on the ketostix.
      • In practice, the author of the present document observed the following phenomena during self-experimentation, which fits with recent research findings:
        • Desynchronization of the whole body circadian clock, which has two paradoxical effects in practice: 1- a faster daily phase delay during freerunning (1h of delay per day in the author's case, instead of 30min/day usually); 2- reduced daily phase delay (ie, shorter circadian period) during the entrainment phase. This may be explained by the preliminary evidence on mice showing that the ketogenic diet can modulates the body's circadian clock, so that under ketosis, food has an increased circadian rhythm resetting effect, by increasing the intestines time clock gene expression and switching off liver's time clock genes and melatonin secretion — in other words, the peripheral (ie, body) circadian clocks will rely more on the food timing, which is a lot easier to control than other zeitgebers, and with bigger meals having an increased resetting effect. Another study on mice also observed that the ketogenic diet induced a shorter circadian period and hence a phase advance.
        • DEPRECATED: Reduction of the sleep duration (by one ultradian cycle, so about 1h30-2h shorter sleep) while improving sleep quality (so there is no loss in sleep even though the duration is smaller, which eases the maintenance of a stable sleep by compensating the too long awake period of individuals with non24 by a shorter sleep), as also observed on a study on epileptic children under the ketogenic diet.
          • UPDATE 2021: although during the first ketogenic diet run (over 3 months) seemed to reduce sleep duration with no side effect, the second ketogenic diet trial over 3 more months 1 year later did not show similar benefits. The difference is that coke beverages (containing caffeine) were excluded in the second run. It seems the caffeine's effects remains well over one day and carry over to the next day, so that this is the likely cause of reduction of sleep duration in the first run. In the second run, when sleeping in circadian alignment, the author could sleep a full 8h night and a bit more. Hence, the ketogenic diet did not show any significant effect on sleep nor on dreams during the 2nd run, which means that the ketogenic diet does not appear to improve, nor impair, sleep. It can hence be used by individuals with the non-24 disorder for other purposes in parallel to an entrainment therapy (eg, the ketogenic diet may be part of a diabetes management therapy).
        • Reduction of hunger (eases the avoidance of the detrimental melatonin/insulin/carbs interaction in the biological evening).
      • If you choose to do a ketogenic diet, plan to start it ahead, at least 2 weeks before the rest of this protocol, as to have enough time for your sleep to adapt and stabilize with the new diet. Also make sure to use vitamins and minerals supplement, and salt a bit your homemade food, to avoid the risk of electrolytes insuffisance contributing to the dreaded keto flu. If the strict ketogenic diet shows efficacy to you for entrainment, you can later transition back to a healthy diet (such as the scientifically designed DASH diet as recommended by the NIH, and combine with the openfoodfacts.org search engine filtered by Nutri-Score and NOVA to find healthier food products in practice) with carbs in reduced quantities compared to your old diet, and you should also keep the benefits in insulin resistance reduction even after stopping the ketogenic diet (as long as you don't revert back to your old diet).
      • The ketogenic diet may also improve sleep indirectly by:
        • weight loss, as weight surplus is associated with obstructive sleep apnea and snoring, which may resolve with weight loss.
        • reducing digestive issues for individuals with irritable bowel syndrome disorder as it reduces or eliminates the intake of FODMAP, since they are specific kinds of carbohydrates, which are avoided in the ketogenic diet. In other words, there are no FODMAPs in lipids nor proteins, so the ketogenic diet is a good option for those with FODMAP allergy.
      • To learn more about the ketogenic diet both in theory and in practice, read this and this excellent reddit posts.
  4. Kickstart your melatonin secretion with a melatonin pill and hence sleep and help its consolidation, several hours before bedtime: take melatonin in instant release form, if possible sublingually dissolving tablets. The optimal efficacy of melatonin is dictated by two factors: 1. ingestion before DLMO, 2. dosage high enough or timing close enough to DLMO for exogenous melatonin in bloodstream to overlap with DLMO. The timing is crucial and requires some trial-and-error, as melatonin must be taken relatively to one's current circadian rhythm (ie, bedtime and wake up time), NOT the target bedtime contrary to what current regulations state. Indeed, it's necessary to take melatonin before the body starts producing it (called the DLMO point), and the body starts producing melatonin a few hours before you go to bed, as melatonin is one of the things that cause sleepiness feelings and allow to sleep a full night (sleep consolidation). The dosage does not change the magnitude of circadian phase shifting effect, so it can be as low as 0.1mg or up to 3mg, but only higher doses > 1mg (supraphysiological) can produce hypothermia (as also shown here), so that "nighttime increase in sleepiness was achieved only after administration of high doses" and doses such as 3mg are "more likely to produce a substantial phase shift" although this needs confirmation. However, dosage does matter for the timing of intake, as it's necessary for melatonin from pills to overlap with the natural endogenous melatonin secretion (DLMO), as to simulate an earlier dusk and trick the body into thinking it started producing melatonin earlier. Since higher dosages remain longer in the bloodstream (see also here), they provide more leeway in timing and produce effects even if taken very early, whereas lower dosages need to be taken much closer to DLMO (but never after - hence lower dosages require more accurate calculations of DLMO), hence higher melatonin doses (1-3mg) are likely easier to time for beginners. However, both the DLMO timing (60% have a DLMO outside the 2-3h before bedtime range) and the dosage (between 10-fold variability and 35-fold variability) required are highly variable between individuals. Although melatonin can shift the circadian rhythm via the type 2 receptors, its main purpose is to stabilize the circadian rhythm and consolidate sleep, hence to maintain the benefits from more efficient tools for phase advance such as light therapy. Melatonin is also a powerful antioxydant that reduces or eliminates the detrimental health effects of sleep loss, but this (receptor-independent extracellular) effect is only obtained with very high doses (8mg/kg/day for humans).
  5. Avoid eating and caloric drinks (especially carbs) melatonin is high in the blood, to prevent insulin inhibition and hyperglycemia before and during the circadian night and early circadian morning + avoid alcohol, as Panda et al also recommend in a review. Tthe pancreas has both insulin and melatonin receptors so that each one inhibits the other at the protein level. When melatonin is high, insulin is inhibited and if you eat, then glucose will remain high in your blood and cause a superficial diabetes throughout the night, as insulin is necessary to process glucose. Hence, melatonin impairs insulin production and glucose processing (even in typical sleepers), and insulin impairs melatonin processing. This may have detrimental effects on health as it's hypothesized to be one of the cause of chronic diabetes type 2 and obesity, and may also disturb the ability to sleep as the high blood glucose and hence available energy will cause the individual to feel more energetic past bedtime. Researchers suggest that this may be a biological safeguard mechanism to avoid hypoglycemia during the night since we spend a long time without eating while we sleep, and hypoglycemia can be very dangerous (diabetics often have this issue at night time), but this safeguard assumes that the individual do not eat when supposed to sleep by the circadian rhythm and melatonin rhythm.
  6. Prevent light from interfering with melatonin secretion by using dark therapy blue blocker sunglasses 3-5h before natural bedtime (start dark therapy when melatonin pills are ingested): light can suppress both melatonin and shift the circadian rhythm (independently of whether melatonin is suppressed, see also here and here). Both the intensity and color of light (see also here and here) matter in circadian rhythm shifting and melatonin suppression by modulating the ipRGCs receptors (see here for intensity, and here and here for color), hence you need to avoid bright lights in your biological evening, both by dimming down all lights, and by filtering blue light. Dark therapy is necessary to keep a robust gain from the other therapies, by ensuring there is no unwanted shift in your circadian rhythm by uncontrolled factors such as uncontrolled light exposure.
    • The author strongly recommends the UVEX glasses with SCT-Orange coating as blue light filters, they are very inexpensive and highly effective according to several independent reviews (see the dedicated section on Dark Therapy below). Use the UVEX Skyper if you want to hang outside with it, or the UVEX S0360X Ultra Spec if you want to use prescription glasses under, as the Ultra-Spec are big enough to fit prescription glasses under, but not the Skyper.
    • For reliable dimming in uncontrollable environment (eg, outside your home), a blue blocker SUNglasses such as UVEX amber glasses and manually tinted in black using VLT shading films for cars windows is a very easy way to do both dimming and blue light filtering in any environment without any hassle.
    • If you don't have access to such glasses, a more inconvenient and less reliable but working alternative is to modify the environment: dim down / switch off all lamps (including your computer screen intensity) and install blue light filters softwares on your computer (advised: LightBulb or f.lux) and smartphone (Twilight on Android). If you have a changing color LED lamp (eg, Living Colors), use it as a bed lamp by setting it to full red color (the blue LED should be switched off if you selected an appropriately full red color).
    • Why start the dark therapy 2-4h before target bedtime? Because melatonin takes 1-2h to produce drowsiness effects from its DLMO point, and it takes 1-2h for melatonin secretion to reach it's DLMO level from the moment it starts its production (or from when the light inhibition/exposure is stopped). Hence, the dark therapy should be started 2-4h before the natural bedtime. Whereas light therapy phase advances your circadian rhythm (ie, you wake up earlier), dark therapy prevents unwanted phase delays due to light exposure, which concretely makes you feel more fatigued at the wanted time.
  7. Optimize sleep preparations and quality:
  • For the ear plugs for sleep, the most comfortable are outer ear plugs in silicon such as Medigrade or Mack's. But they do not work well during winter, as the cold temperature makes it hard to stick to the outer ear. During these periods, switch to Howard Leight Laser-Lite (Honeywell 3301105) earplugs, which are very soft foam inner ear plugs, they are less comfortable than outer ear plugs but they are much more comfortable than any other type in the author's experience (a lot of brands and types were tested!). Nevertheless, it will regularly happen that the ears get itchy and so you can't stand having earplugs in your ears for the night, or unconsciously rip them off during your sleep. This is to be expected from time to time, but if it happens most of the time, try other brands/material of earplugs, and make sure to clean your ears with cotton tips before sleep.

  • Using music as a non-drug stimulant during the day can be a good strategy. However, earbuds will make it more likely to experience itchiness at nighttime, and it's more important to be able to use night time earplugs for sleep quality. An alternative is to use bone conduction headsets, which do not put anything in-ear. The sound quality is more mediocre than with earbuds though, but still good enough to enjoy, and there are several other major advantages: silent to others, and the ability to hear and react to every surrounding sounds since the ears aren't filled with earbuds. They are hence perfect for use at night or in silent environments. Bone conduction headphones can be used in combination with in-ear plugs. AfterShockz is the leader in bone conduction headphones, but mimicking brands at a much lower price are available with an acceptable audio quality. Tip: after each use, cross the branches so that the headphone keeps its tight fitting form to maintain good contact with the skin, which is necessary for good sound quality.
  • Mind the ultradian cycles (20 minutes "sleep gates" every 1h30) and the dopaminergic forbidden zone of sleeping. When you feel sleepy, you can expect this feeling to last only 20 min, and then to go away. The next sleep gate, where the tiredness feeling will reappear for 20 min, will be about 1h30 after the last gate. The gates aren't all equal, there is one with a maximum sleepiness feeling, and the others will have a reduced feeling. Trying to sleep at these 20min sleep gates allow to fall asleep fast, sleeping outside may be possible but will be more difficult. See the relevant subsection below for more information on sleep gates.
  • If you can't sleep (eg, missed the ultradian cycle window), then wake up or sit and do something else than trying to sleep until the next window to sleep.
  • Identify any factor that can impair your sleep and buy the necessary workarounds. Anything that can prevent disturbances on your sleep is well worth it. If it's too warm temperature, buy a fan. If it's mosquitos, buy an anti-mosquito net for beds and/or a anti-mosquito lamp.
  • We are the product of our environment. If your environment is not adequate for good sleep, such as noisy neighbors, no tools can completely fix it. Consider moving to another place if you can.
  • If you snore regularly, this means your airways are obstructed, and that your sleep quality is impaired. Regular snoring is never normal. Consider getting a sleep study for sleep apnea. Meanwhile, you can try:
    • to sleep more on your sides by removing your pillows (as we are more likely to snore on our backs). Indeed, position-related snoring is a known phenomenon and is why military soldiers keep their backpacks while sleeping during missions, to avoid sleeping on their backs which increases the likelihood of snoring and hence of giving their position to their enemies. Furthermore, tribal populations have shown that they sleep without any pillow but on their arms, hence on their sides, and the researchers noticed they have a much lower prevalence of musculoskelettal disorders in addition to no snoring issues.
    • to use nasal sprays to clean the airways before sleep. This is an advice given by a nurse in a sleep study, this claim needs to be tested and double-checked.
  • If you have other afflictions that impair your sleep or blatantly wake you up in the middle of your sleep, then treat them. This is especially important for comorbid disorders that have a circadian pattern (ie, they trigger more often during the circadian night, such as RLS and PLMD and night legs cramps). The VLiDACMel protocol prevents entrainment, but having a restful night requires more than entrainment, it requires uninterrupted sleep.
  1. Optional but strongly advised: take multivitamins and minerals, including vitamin B12, vitamin A and magnesium supplementation every mornings. B12 vitamin is known to amplify the magnitude of the circadian rhythm shift of light therapies (see also here) and B12 supplementation entrained a few individuals with non24 (see also here and here). Vitamin A is necessary to synthesize all opsins in the eyes, including the melanopsin pigment necessary for ipRGC cells and entrainment to bright light to work, hence it is necessary to ensure adequate levels of vitamin A, via supplementation if needed. Magnesium also affects the circadian rhythm (studies here and here). Vitamin D deficiencies can affect the circadian rhythm and it interacts with at least 2 clock genes, and vitamin D appears to inhibit melatonin, as the body does not expect to get exposed to Vitamin D unless there is skin exposure to sunlight with UVs, so that Vitamin D supplements should preferably be taken in the circadian morning rather than the evening to avoid fragmenting sleep. Vitamin B6 helps with serotonin and melatonin secretion. Supplements are not going to fix your circadian rhythm, but deficiencies can have a detrimental effect on it, although it's not always a fix as shown by the ineffectiveness of B12 in a placebo controlled trial on DSPD. These vitamin deficiencies may be caused by gut microbiota dysbiosis, such as bacterial overgrowth (ie, candida albicans). Furthermore, deficiencies in other vitamins and minerals may impact mood (eg, magnesium), neurology (eg, vitamin B6, B12) and the circadian rhythm (magnesium and B12), so by taking a multivitamins and minerals supplementation you eliminate these potential factors on your sleep easily. Plus, if you do a strict ketogenic diet, this supplementation will help avoid electrolytes imbalance (but you may also need to supplement in salt). For B12 supplementation, use cyanocobalamin form, as it can be converted by the body into both forms of B12 (methylcobalamin or adenosylcobalamin). Some Discord users with diagnosed chronic B12 deficiencies influencing their circadian rhythm reported the B12 shots are more effective than the pills. Vitamins B3 and B5 are necessary for the production of cortisol, the hormone that prepare the body to fight stress and which interacts with the circadian rhythm, and which release can be boosted with bright blue light therapy. Over supplementation in vitamin D may inhibit melatonin which is hypothesized to result from a cross side effect of vitamin D production, which is triggered by skin exposure to UV, so the eyes are often also concurrently exposed to bright light, so a inhibiting pathway between vitamin D and the circadian rhythm may have hence developed as a byproduct of light exposure, although other individuals with non-24 and DSPD reported that treating their vitamin D deficiency significantly improved their sleep and circadian rhythm stability, so it seems there needs to be not too little but not too much vitamin D to avoid impairing sleep.
    • Although optional for entrainment, vitamins and minerals supplementation can be necessary for some individuals in order to sleep, as in the author's case. Indeed, without supplementation over 40 days, the author experienced limbs swelling, hands cramps, muscular weakness and joints and chest and limbs pain, to the point where these symptoms prevented sleeping more than 1h30 in one go, which was of course unsustainable. These symptoms were signs of a peripheral neuropathy, due to vitamins or minerals deficiency. Although the exact deficiency could not be determined yet, it was likely a combination of genetic predisposition in Vitamin B12 deficiency (the author possesses the AG variant in the FUT2 rs602662 location), which is known to be capable of causing peripheral neuropathy (although other vitamins deficiencies can also be responsible — see also here), and a too restrictive diet (due to this experiment, a very precise diet was devised and used everyday to reduce the effect of food composition on the circadian rhythm). Vitamin-induced peripheral neuropathy is a serious disease that can cause permanent nerves damages. There are anecdotal reports from discord members with the non24 disorder that intravenous administration of vitamin B12 was much more effective than oral supplementation, similarly to how intravenous iron supplementation seem to be more effective at treating RLS than oral iron supplementation.
    • Leverage the increased availability of rare and specific products in online stores such as Amazon. Although these stores certainly have a detrimental impact on local commercial shops, there is certainly an advantage in allowing rare products to be available worldwide and able to reach the target audience, whereas before such specific products were impossible to obtain even in big cities.
    • The author took multivitamins everyday in the morning (at wake up or later if forgot) for the whole duration of the experiment.
  2. Plan out how to handle the sleepless nights and premature wake ups. Sleepless nights and premature wake ups will always continue to randomly happen due to non-24, as there is unfortunately an uncurable insomnia component, even when under an effective entrainment therapy. In fact, these sleepless nights and premature wake ups become even more apparent during entrainment, as it becomes clear it's not due to the circadian rhythm. Most individuals with non-24 lose invaluable time trying to desperately sleep for hours, without succeeding. Alone in the dark for hours, with nothing to do but think, this creates the perfect opportunity for the brain to generate running thoughts, as nobody is able to suppress all thoughts for hours. This can ultimately cause a depressive feeling of powerlessness. That's why the core of sleep hygiene is to avoid staying in bed if you can't sleep. Hence, it's important to plan what to do during these sleepless nights.
      • A good strategy is to strike a deal with oneself to always put one's sleep first, but to allow to get up and do activities if unable to sleep for more than 30min. If you can't sleep and do not feel tired after 30min of trying, get up and do something. But whenever you feel tired, try to go back to sleep/nap as your top priority. If again it does not work after 30min, you can get back up and do activities. This is similar to the core tenets of sleep hygiene, do not stay in bed for too long if you cannot sleep.
      • Make sure to avoid getting exposed to bright light (ie, use dark therapy) during sleepless nights. Hence, screens are allowed, but only dimmed to the minimum and with a blue light filtering software.
      • Although not a therapy per se, planning out how to handle sleepless nights is definitely the most liberating realization for individuals with non-24. Being unable to sleep is already a huge handicap, but losing this time altogether by not doing any activity is even worse. Being sleepless does not mean you are not allowed to enjoy yourself and the activities you like.

Continue this combination of therapy strictly (respect the hours and use melatonin and light therapy everyday!) for at least 10 days. Indeed, because of carry-over effects such as photic history and gut microbiota adaptation, it takes several days to a few weeks for the body to adapt to both light and dietary (including melatonin) changes. This means that when starting a circadian rhythm therapy, it will take about 10 days for the full effects to be seen, and it will take as much time when stopping the therapy for the effects to wear off. But you should already see some effects a few days in, such as mood and vigilance boost from the first use of light therapy, and some circadian rhythm phase advance after 2 days of light therapy.

In practice, the first week you should see a reduction of your phase delay, and the next week your circadian rhythm (in particular your wake-up time) should be somewhat stable, and it will get more stable along time as you continue with the therapy. The time windows need to be respected, but a slight change of +-30min from day to day is OK in my experience (eg, taking melatonin 30min later or earlier, and there is more room for food timing as long as you do not eat past the melatonin intake time).

In case there is some unexpected event and you miss the therapy one day or use an alarm clock to wake up to get to an appointment, keep in mind that long napping is allowed and advised, as it reduces most of the health issues that sleep deprivation causes.

It should be emphasized that it is crucial that all the non-optional steps should be followed for the therapy to be effective, at least at first. Indeed, this therapy combines multiple approaches to increase the likelihood and robustness of entrainment. Once entrainment is achieved, the patient can try to eliminate some steps as they see fit if they can stay entrained. Indeed, some patients with a less treatment-resistant form of non-24 can be entrained with solely using melatonin pills, others with the ketogenic diet alone, and others with light therapy glasses alone as evidenced by several anecdotal patients accounts.

Monitoring

  • To optimize dark therapy, you can use a free "lux meter" app on your smartphone, with the screen directed at the light source to check the light intensity (lux). Lux varies with placement, orientation and distance, so it is important to orient the light sensor on the smartphone screen (usually at the top) directed at the light source, at eye level and at the distance you will usually be from the lamp. What lux intensity is low enough for dark therapy? The lower the better, but below 40lux should be fine, below 20 lux is great. If a light source (eg, lamp) is too intense, try playing with distance by placing the light source further from where you will be in your room when you'll use the lamp. If you have a Luminette, you can calibrate your lux meter app by measuring the Luminette 3 settings, the readings should be 500 lux, 1000 lux and 1500 lux. Remember that light intensity is only one factor, the other being the light color, which should be as red as possible (to reduce/eliminate blue and green colored light). Spectral sensors exist but not in smartphones unfortunately so just use your eyes: if a light source is red, it's fine; if it's yellow, it's good enough but not ideal.
  • body temperature monitoring as a proxy for the circadian rhythm even when not sleeping or sleeping in circadian misalignment (eg, such as when using alarm clocks due to appointments/work), in which cases the sleep diary is unreliable but temperature monitoring is reliable to reflect the circadian rhythm. TODO: expand this section when milestone 2 is completed.

Safety-Risk analysis

Limitations

Although this therapy can allow for a robust entrainment, entrainment can still be lost under some circumstances, which reminds us that this is not a cure:

  • During winter, the shortening and intensity reduction in sunlight can cause a desynchronization. Increasing the duration of artificial light therapy may compensate but may not be sufficient.
  • Any illness lasting for more than a week is likely to cause a desynchronization. Some acute severe diseases can as well. Anesthesia also impairs the circadian rhythm. Restless Legs Syndrome (PLMD), PLMD and night legs cramps can also significantly impair sleep and indirectly cause a loss of entrainment, especially since their acute (painful) symptoms show a circadian pattern, which means they are more likely to appear during the circadian night, which naturally push the individual to sleep outside of their circadian night.
  • The effect of artificial bright light therapy on the circadian rhythm is variable on a day-to-day basis due to various factors (eg, sunlight exposure in addition to artificial light, and artificial light exposure in the evening, other environmental factors). Hence, light therapy may start producing less phase advance than expected and required at some point, even if the user did not change their usage. This would cause a progressive desynchronization. Likewise, light therapy may start producing more phase advance than expected, and this would cause a desynchronization as well. If noticed early enough, this can be adjust by varying the duration of exposure to light therapy, but in practice it's difficult to assess what direction the desynchronization is happening, as the primary sign is a reduction of sleep duration and efficiency (ie, more fragmentation, lower restorative quality), which provides no information about whether it's because the circadian rhythm shifted later or too much earlier. The introduction of wearable monitoring devices could tremendously improve, or solve, this issue.
  • For some individuals, the therapy can be too effective and cause a too short sleep, by phase advancing the wake up time too much compared to the fall asleep time. Here are some tips to reduce the therapy's effectiveness.
  • Why is it so hard to treat non-24, and why does it seem like non-24 require much longer or intense light therapy to be temporarily entrained, whereas DSPD seem to require much less? There are logical reasons to assume this holds true, because of the differences in the therapeutic goals. DSPD need a phase advance, which can always be achieved with light therapy, the intensity and duration only modulating how much phase advance is obtained. Non24 on the other hand aims for entrainment, which also involves phase advance but what is required is a stable phase advance, and this changes everything. If stable phase advancing cannot be achieved, it doesn't matter how much phase advance you get, you won't be entrained. https://www.reddit.com/r/DSPD/comments/pvsfjy/comment/hec7o5h/?utm_source=share&utm_medium=web2x&context=3

Of course, a combination of multiple factors (eg, getting sick during winter) increases drastically further the likelihood of losing entrainment compared to any single disturbance.

Recommended equipment


Equipment for circadian rhythm entrainment

  • Light therapy tools: Luminette 3 (229€). Will be the primary treatment AND a calibration tool to evaluate other light emitting devices (to avoid them during dark therapy). It has a 30-days money back warranty (+ of course a 2 years warranty for defects in European Union), so you can test it for a month to see if it affects your circadian rhythm (it should work under 2 weeks of daily use), and if not you can send it back for free.
  • Dark therapy tools:
    • If the expected use is only to filter evening/night time artificial light: Blue blocker glasses such as UVEX with the SCT Orange coating glasses (there are multiple models: Skyper, Astro OTG, Protégé and Ultra-spec 2000, the latter being the best model to wear with other glasses below) ;
    • If the expected use is to filter daytime sunlight, whether indoors or outdoors: wrap-around blue blocker sunglasses such as hair removal laser safety amber/red tinted glasses filtering wavelengths in the range 400-550nm (example), as these laser safety glasses are made to ensure protection against the much more dangerous lasers and hence also include a VLT (light dimming) filter in addition to a color wavelength filter.
      • Complement: use blue light filtering softwares such as f.lux or LightBulb on computers and Twilight on smartphones, in addition to screen dimmers such as Nelson Pires Dimmer v2 on Windows or Twilight on Android smartphones.
      • Complement: buy RGB smart LED bulbs that can be controlled by wifi or a remote. These can usually be programmed to automatically switch to a dimmed red light at a specific time every day, hence automating dark therapy at home. One inexpensive example is Yeelight 1S, which costs about 15 euros to 20 euros apiece.
      • Alternative: Add clip-on or VLT shading films to dim down light sources, these can be added on any normal glasses, but usually they do not filter much and do not adapt well.
      • Optional: SwitchBot automatic curtains opener. SwitchBot is a brand that specializes in domotic automatization of non connected furnitures. The automatic curtains opener is programmable with a smartphone app and has several variants depending on the type of fixture: U-rail, I-rail or rod, and it has an optional solar panel to avoid the need to recharge. It is relatively affordable, at about 80 euros one device, plus 20 euros for one solar panel. This can be a great alternative to sunrise lamps, or be useful to automatically take care of pets.
  • Melatonin instant-release <= 3mg. The author of this document strongly recommends the sublingual Valdispert Melatonin 1.9mg Instant Release (mirror) (it's the one with pure melatonin only, not the one with "4 actions" because of including other compounds). This will help with stabilizing the circadian rhythm at the time you wish and feel sleepiness. Always prefer sublingual (orodispersible in french) tablets with no other compound than melatonin (besides of course a few conservative or flavor additives that are always present), as sublingual pure melatonin tablets are of higher quality in general, particularly for over-the-counter melatonin.
    • Another person with non-24 recommended "Vitality NUTRITIONALS" which are sublingual instant release melatonin like Valdispert's, distributed by VitaminExpress www.vitaminexpress.org Made in the Netherlands, dosed at 1.5mg. However this is a bottle, not packaged in individually sealed blister pack, hence this may degrade after a week of opening the bottle. Another untested product is Chronobiane 1mg.
    • In UK, Pharma Nord Melatonine 3mg (not Melatonin Complex) was licensed in the UK for the treatment of jet lag, and hence should be appropriate for circadian rhythm disorders too.
    • In the USA, there are only a few recommendable pure sublingual melatonin tablets in blister packs. One is Major Melatonin Tablets, 3 mg, 100 Count as sold by Walmart, another is webber naturals Melatonin 3 mg - 15 Tablet Blister Pack sometimes sold in 2 packs (30 days = 1 month). Alternatively, search for "melatonin blister pack sublingual tablet" or if no blister pack is available, at least search for "melatonin usp sublingual" (the USP label being a self-validation process). Do not worry about instant release or prolonged release, both should work anyway and if you take a sublingual tablet, it can only be an instant release since it's the coating that makes a prolonged release, hence prolonged release melatonin is always presented as an ingestible pill that will dissolves slowly in the guts. The author did not try these products. Another product is Herbatonin 0.3mg, also in blister packs.
  • Optional: DNA testing using Nebula Genomics, if MT2 receptor mutation, then also need to control food/glucose and melatonin mixup?
  • Optional: smart alarm / chronobiological alarm clock, such as Sleeptracker Pro watches (discontinued) or FitBit which can vibrate when it detects that the user is in a light sleep stage via actigraphy, it's very efficient to forcefully wake up despite sleep deprivation. Indeed, humans are highly sensitive and alert to touch and vibration, much more than sound. In addition, waking up during a light sleep stage is highly effective as to the user it feels like they are already awake when the alarm triggers, so that they are much less likely to fall back asleep or snooze. The window of detection of the light sleep stage is configurable, usually the default is 30min, which means that at the earliest, the smart alarm triggers 30min before the programmed alarm time if a light sleep stage is detected, and at worst at the programmed alarm time if no light sleep stage is detected. The combination of both features (smart alarm + vibration) is hence highly effective to wake up, and has the distinct advantage over sound that it doesn't bother partners living close by or in the same bed (which would induce sleep deprivation for them, a common but avoidable side effect that partners of individuals with circadian rhythm disorders often experience). However, they do not fix sleep deprivation so the tiredness and cognitive impairments will still appear during the day. Alternatives include Axbo and Sleep As Android app on Android smartphones (but apps are less accurate than wearables). Avoid faradic stimulation (electrically induced pain) devices such as Pavlok which are not supported modern science and will only increase sleep deprivation and pain. Combine with napping whenever possible to reduce sleep deprivation.

Recommended tools for circadian rhythm disorder management

  • Sleepmeter Free on Android and its widget, to log a sleep diary and generate sleep charts. Just tap the Sleepmeter Widget before sleep and tap again when you wake up, it will record your sleep timing and duration, and optionally you can add tags and comments after if you want to add more infos for yourself. In early 2021, Sleepmeter mysteriously disappeared from the Play Store and the developer is unresponsive to sollicitations, but the app can still be downloaded on APK Pure, its widget also.
    • Sleepmeter Free can also be used on computers (Windows, MacOS and Linux) via BlueStacks 4, an Android emulator. Simply install BlueStacks, then download Sleepmeter Free APK (APK = installation file for Android app), and simply double click on the downloaded APK. BlueStacks should automatically install the app and it should show up in "My Games" tab inside BlueStacks.
    • Paper alternative: the AASM sleep diary / sleep graph template is recommended (mirror here).
    • Alternative opensource free electronic diary with a similar tapping system: https://andrew-sayers.github.io/sleep-diary/
    • Another alternative opensource electronic diary for Android is Plees-Tracker: https://github.com/vmiklos/plees-tracker
    • Another alternative for Windows PC computers is SleepChart, by the developer of SuperMemo, who has non-24. The main advantage of this app is the ease to input data from a paper sleep diary for example, simply click on the chart to draw the sleep graph.
    • Alternative: For sleep tracker wearables users such as Fitbit wristbands, the data from these sensors can be converted to a sleep graph using Kizari's tool: https://sleepcharter.z13.web.core.windows.net/
    • Alternative: For individuals with sleep apnea, the CPAP machine may be able to record usage data, which can then be converted to a sleep diary using the opensource tool OSCAR, as was done by DSPD reddit member EarendilStar.
    • Alternative: Sleep Diary Dashboard by Andrew Sayers, another wonderful opensource tool that can convert various sleep diary formats including Sleepmeter, Plees-tracker and custom excel sheets into a generic sleep diary format and then generate a standard medical sleep report to present to doctors.
    • Alternative: not free, but this is a baby tracker which can generate a nice sleep graph but also tracks other things such as meal times, etc: Huckleberry.
  • Lux meter apps on smartphones. Any free lux meter app will do, what matters is the light sensor included in the smartphone, but nowadays most light sensors mimic pretty well the eyes responsivity to bright light, so the measurement is quite accurate between 5 lux to 30k lux usually.
  • Online Actogram by Barrett Davis, an opensource preliminary python tool to potentially massively screen for circadian rhythm disorders using browser's history (examples here).
  • Noice, an opensource multisounds whitenoise generator for Android. I recommend enabling a mix of pink noise, brown noise and a natural noise (such as gentle raindrops) to efficiently mask out external noises. Other opensource white noise generators include Chroma Doze and White Noise Plus for Android.
  • HabitLab to ease sleep hygiene (reduce disruption from social apps).
  • LightBulb, an opensource blue light filter and brightness dimmer for Windows
    • An alternative on Linux is GammaStep, which automatically change the gamma (brightness and color) of the screen depending on your surroundings (acquired from the webcam). An awesome idea that partially automates dark therapy.

Wearable circadian rhythm monitor

TODO: This section is a work-in-progress, come back later for updates.
Although there is currently a "wearables revolution", it is still hard to find devices that can continuously (24/7) record vital signs with a sufficient quality (sampling rate, low noise) to be considered adequate for research or medical purposes. However, there are a few, which we could use and determine as adequate for the purpose of ambulatory circadian rhythm monitoring, potentially by the patients themselves.

The two major sensors that are the most informative to monitor the circadian rhythm are the temperature sensors and the ECG (with an accelerometer). The total for one iButton and a Polar H10 is less than 200 euros, and these devices will last for several years.

The following is a practical, hands-on summary for the more complete setup instructions found in the Wearadian project: https://circadiaware.github.io/wearadian/docs/SleepNon24BiologicalMeasures.html

Usage advices: A critically important technique to properly wear these devices is to move them regularly to let the skin breathe, so as to avoid rashes (caused by sweat and warmness but not allergies since they are made of cotton and silicon), it's necessary to move the sensors (and belt) up and down to slightly different body sites to let the skin breathe. Hence, the sensors should be moved at least twice a day (once at wake up, once before sleep), and they should also be moved as soon as there is a feeling of itchiness. For example, the chest belt can be placed above the solar plexus during the day, and below (overlapping with the belly) before sleep and for the duration of the night. Cleaning the sensors and belt with a tissues imbibed with alcohol everytime after shower and every half week is also a good practice.
Also, it's important to avoid any wearable that requires the use of medical tape or sticky gel patches/electrodes, as they may feel comfortable at first but will invariable produce a skin reaction after some time (usually a few days). For continuous wear, it's necessary to use wearables that can be in contact with the skin without any adhesive, such as by strapping a belt.

  • Strong recommendation: GreenTEG CORE, can record core body temperature non invasively using the innovative Dual-Heat-Flux Method (a method that allows to sense the temperature 2-4cm below the skin, whereas iButtons only sense skin temperature). If you want a single device to improve your management of your circadian rhythm disorder, this is the best tool. It allows to monitor the circadian rhythm though the core body temperature fluctuations, with no impact of the sleep-wake schedule, which means that it can allow to observe a non-24 or DSPD pattern without having to write a sleep diary and even under restricted sleep. Costs about 300€, comes with a chest strap (no need for medical tape), battery lasts 6 days. An advantage is that it shows in Bluetooth on a smartphone app the last 2 days of core body temperature history, so it's easy to quickly check the core body temperature even on the go. The data is synced to a cloud server whenever the history tab in the smartphone app is opened at least once every 48h, and then the whole history can be accessed there. The data can be exported for free too (sampling resolution is one sample per 5 minutes with the standard license, but there is a research license for a 1Hz sampling resolution at 999CHF, the price for the CORE Research including both the lifetime subscription and the device itself with a chest belt and sticky patches. — the research license is unnecessary for practical use, all past research used a 5 or 10min resolution). At the time of this writing (November 2020, first B2B sale on May 2020, public sale opened in January 2021), this is the first and only commercially-available wearable core body temperature sensor using heat flux technology.
    • Advantages: easy to use (measures readable on smartphone app and cloud web app), easy to wear, reliable measures of the circadian rhythm, robust to bias (ie, environmental factors do not affect its measures).
    • Disadvantages: lags behind the current circadian rhythm phase by 1 or 2h.
    • Interpretation tips: when core body temperature is high, the body expects to be awake, when the temperature is low, this is the circadian night when it expects to be asleep. When the circadian night starts, there is a steep decrease in core body temperature. A slower but steady increase in core body temperature precedes the body's wake up. When core body temperature starts increasing, bright light therapy can be started. When the circadian night starts as reflected by a steep fall of temperature, continue dark therapy (it should be started before as bright light will prevent or delay the steep decrease in core body temperature). Take into account that core body temperature usually lags behind the true current phase of the circadian rhythm (ie, if you notice a steep decrease at 11pm, then you can expect the next day to be tired and able to sleep at 10pm instead of 11pm because of the lag). Read the section "Core Body Temperature Monitoring" below for an extended tutorial.
    • Tips for usage:
      • Avoid using sticky-based patch or tape-based wearable, prefer wearing the CORE with a Polar Pro chest belt, as adhesives will worsen irritation and are thus inadequate for continuous 24/7 long term wearing. The Polar Pro chest belt is flexible, contrary to the default chest belt provided with the CORE, which is both more comfortable and improve skin contact and hence more accurate measures.
      • Current CORE model cannot sustain 24/7 wearing with a chest belt due to a conceptual defect that makes the outer ring (that serves as a stabilizer/support) break after 3 months of use. A workaround is to use velcro, with a hooks-type vecro auto-adhesive patch placed on the center of the CORE, and a hooks-and-loops-type velcro band attached around the chest belt's band (just attach the hooks-and-loops-type velcro to itself to form a ring around the chest belt). Then simply attach the CORE's velcro onto the chest belt velcro. This is better than stitching the velcro on the chest belt as the chest belt fabric is flexible and stitching in it would fragilize its structure and reduce its durability. With this velcro-to-velcro workaround, all the mechanical pressure is supported by the CORE body instead of the outer ring, which is much more robust, and also there is less pressure since the outer ring is not clipsed on the chest belt anymore, the CORE can move much more freely with the skin. If the velcro is placed properly, the CORE can even be better positioned and in better contact with the skin than with the normal setup. See the following figure describing this whole setup: https://github.com/Circadiaware/wearadian/blob/main/docs/schemas/greenteg-core-velcro.svg
      • For instructions on how to connect to the cloud server, to export data and to interpret your core body temperature data in regards to your circadian rhythm phase, please read the section "Core Body Temperature Monitoring" towards the end of this document (navigate using the navigation bar at the top left).

  • Wrist skin temperature sensor for circadian rhythm phase assessment: Maxim Thermocron iButton DS1925EVKIT (Starter kit including one DS1925L iButton and the DS9490R and DS1402D-DR8+ connectors to retrieve the iButton's data on computers via USB as a CSV file). Cost: about ~$100. If DS1925L is unavailable, can also use DS1922L but the internal memory and battery are much shorter (4 years for DS1925L with 5min sampling rate (setup 300s in the config), 6 months for DS1922L for 2min sampling rate). The iButton does not need to be recharged, but unfortunately once it runs out of battery, it cannot be replaced (although there is one academic paper which shows how to replace an iButton's battery, but this is not an official instruction, do it at your own risk, and of course the device will be much less airtight after).
    • Advantages: this is a cheaper alternative to GreenTEG CORE. Wrist skin temperature has no delay, it shows the current state of the circadian phase, whereas core body temperature lags behind by a hour or two due to thermoregulation lag.
    • Disadvantages: rarely painful on the wrist especially when using a brand new cotton sport wristband until it loosen with use, clunky software suite (no smartphone app, transfert is wired via USB, need to export to CSV and then plot yourself the data or use Circalizer), prone to bias (the cotton wristband insulates the iButton from environment but still skin temperature can be biased by a lot of environmental factors, and it's just more noisy by nature compared to core body temperature).
    • Interpretation tips: opposite of the core body temperature: a steep increase of wrist skin temperature signals the start of the circadian night, while a slow decrease signals its end and the start of the circadian morning and day. There is no time lag. The data needs to be smoothed because it is very noisy.
    • Tips for usage:
      • Buy a cotton sports wrist band such as is used for tennis ("sweat bands"). The Under Armour wristbands are recommended, they exist in various lengths, even tiny ones which are great during summer.
      • Buy also velcro stripes (hooks type, not loop) with adhesive, to glue on the iButton and then attach it on the inside of the cotton sports wrist band (the velcro hooks will hook well on the cotton as it naturally forms loops).
      • How to wear: Wear the cotton wristband + iButton on the non-dominant arm, and place the iButton on contact with the skin, positioned at about the middle of the width of the arm to be on the radial artery. Technically, the radiar artery runs from the wrist to the elbow's interior, so you can place the iButton anywhere on the length of the forearm. In fact, you should regularly move the wristband up and down your forearm, to avoid the sweat and warmth accumulation from itching and damaging the skin (move twice a day at least, and whenever it's itching). If necessary, the wristband can be placed on the dominant arm for some time if you need the non-dominant one to rest.
      • This setup provides true 24/7 skin temperature monitoring setup, as the iButton DS1925L can last 4 years with its integrated battery (then need to buy another one or can try to manually replace the battery as some researchers have done).
      • Data need to be transferred to a computer every 6 months (for the DS1925L, the interval is much smaller with DS1922L, about 10 days), and the device memory (mission) needs to be reset, otherwise it will stop recording new records.

  • ECG (heart rate and heart rhythm) + 3-axis accelerometer (chest actigraphy): Polar H10. Costs about 80€. Comes with a chest strap. Battery: 16.5 days with one button (CR2320) battery.
    • Advantages: ECG is useful to assess sleep quality and discriminate out of phase sleep (ie, naps) vs in phase sleep sessions (ie, biological night sleep sessions), by observing the heart rate. ECG is also useful to evaluate some health parameters especially cardiac, and can allow to pre-screen for further assessments by a cardiologist using ECG devices with more channels. The accelerometer can be used as an actigraphic diagnostic tool, although being on the chest means it is less accurate than on the wrist (as laying down can be sufficient to appear as being asleep). The accelerometer can foremost be used to regress motion artefacts.
    • Disadvantages: Wearing a chest belt can be uncomfortable until you get accustomed to it (although if you wear the GreenTEG Core then you are already wearing a chest belt), require a phone that is always connected to the ECG (ie, you will likely need to buy a dedicated phone and wear it at all times), storage consumption (ECG generates a LOT of data).
    • Interpretation tips: Heart rate is generally higher during high wakefulness phases of the circadian rhythm, and lower during the circadian night. Posture also plays a role, with laying down decreasing the heart rate (just like core body temperature), but not as much as the circadian night. Heart rate variability may also be interesting to observe but this needs to be calculated manually.
    • Tips for usage:
      • The Polar H10 chest strap sensor was selected because it's the only chest strap ECG available with a long battery (2 weeks!), and all other consumer devices can only capture heart rate. Furthermore, chest strap ECG is more reliable for long-term ECG acquisition than wet electrodes or other systems, because there is no wires and hence chest strap ECG is the only ECG technology reliable enough to capture ECG during motion (ie, cheststrap ECG is robust to motion artifacts), as motion is unavoidable in continuous 24/7 use (and especially during the biological night for sleep acquisition!).
      • The Polar H10 sensor needs to be paired via Bluetooth to a smartphone, and an app needs to be used at all times to record the ECG (because only heart rate can be stored on the internal memory). No cloud service registration required, all data is stored locally.
      • Use the Polar Sensor Logger app on Android by Jukka Happonen to log both the ECG and accelerometer data with the sampling rate of your choice (up to 200Hz/8G for the accelerometer and 130Hz for the ECG). It also saves the Heart Rate in a separate CSV file, and the extra columns represent the RR-interval in milliseconds. The timestamp format is in nanoseconds and the epoch is 1.1.2000. Note that the app requires both bluetooth and location (GPS), hence to save battery, the phone can be set to Plane mode and wi-fi can be disabled, everything can be disabled except bluetooth and location, and the screen can be turned off during data collection. Data is stored in realtime in csv files in the sensorDataLogs folder at the device's root, so that even if the logging is interrupted due to a bug or the device being out of battery, the last logging session won't be lost.
        • Note that although the app can work with only bluetooth, it won't be able to seek and automatically reconnect to the Polar H10 sensor in case of disconnection without location (GPS) enabled.
        • Also to ensure automatic reconnection, it's necessary to enable the dual Bluetooth stream/pairing on the Polar H10 after each change of battery (the memory is flushed then) using the official Polar Beats app. Note that this app requires enabling wi-fi temporarily (in addition to Bluetooth and GPS location) to pair with the Polar H10. This can be a good opportunity to also disable GymLink and ANT+ to extend the H10's battery life.
        • It might be a good idea to buy a dedicated Android phone with a long battery, which can allow to continuously record up to 10 days with a single charge (the generated data with accelerometer set to 100Hz and 2G is 400KB/min total for accelerometer+ECG+Heart Rate, so this makes for 6GB for 10 days, or 17GB/month, or 200GB/year of data, so it all fits in any modern smartphone's internal memory).
          • Using as a bluetooth receiver the Realme 6i and its 5000mAh battery (cost about 170 euros), the battery consumption rate is 10%/24h, hence up to 9-10 days can be acquired with one full charge.
          • To achieve this and avoid background app kill, the Realme 6i with Android 10 needs to be setup as follows: set Background Processes Limit to 4 instead of standard limit in Developers Options ; disable Do Not Disturb mode ; in battery optimizations options (specific to Realme UI), disable all optimizations except for screen optimizations and standby optimizations ; finally, launch the Polar Sensor Logger app and Lock it (show the list of apps and then click on the 3 dots in the corner to see the Lock option), then launch the acquisition, setup 100Hz/4G for the accelerometer, then click on the Graph tab and click on the Pause button (after checking that the graphs were alright). Now switch back to the Main tab and you can turn off the screen and let the acquisition run. The data will be continuously saved in CSV files in the sensorDataLogs folder, even if the app or phone crashes at some point.
        • Alternative to get an even longer battery bluetooth receptor: make an Arduino-based bluetooth low energy (BLE = BT 4.0) logger to microsd card. Some developers already made heart rate loggers for Arduino and Polar H7 chest bands (see also here and here), but not the ECG, although the SDK is open so that should also be possible to do.
      • Using the Polar Beat app, the H10 sensor can be configured to have a dual Bluetooth stream, so that it can send data to two different devices/apps simultaneously. This can be used advantageously to concurrently continuously record the ECG data on one device, and use another device (the day-to-day smartphone) for when you want to visualize your current heart rhythm in real-time. To do this, install the Polar Beat app, pair the sensor, then go to the settings, click on the sensor and the sensor's options will show up, and then you can enable the "2 BLE receptors" option.
      • Combined with the EliteHRV Android and iOS app, the Polar H10 can be used for breathing relaxation exercises (fundamental resonance breathing etc), and also be used as a biofeedback tool.
      • Big advantage of this setup compared to others: it really allows for continuous ECG, since there is no need to transfer data to restart a new session, as the phone's memory is used and it's vast. So only the smartphone's battery is the limitation, but it can be recharged while the acquisition continues, and even the data can be transferred concurrently using FTP or similar apps. This is a true 24/7 continuous ECG monitoring setup.
      • Main limitation: a receiver bluetooth smartphone needs to ALWAYS be in range to capture the data. Since the bitrate necessary to transfer ECG is quite high, and the signal is greatly attenuated by going through objects, it's easy for the ECG signal to be lost. Fortunately, the Polar Sensor Logger app by Jukka Happonen was kindly updated following the author's feedbacks to automatically reconnect on signal loss, as long as GPS is enabled (due to a limitation of how Bluetooth is managed by Android OS).

Innovations of this protocol

  • Does not require prior sleep deprivation nor behavioral constraints (ie, a "strict sleep schedule"), which was shown to reduce the effectiveness of light therapy and has highly deleterious consequences.
  • Allows not only for entrainment but for sleep schedule correction by waking up earlier and earlier by using very long light therapy with the duration as a variable of adjustment. This allows to adjust the wake up time after entrainment, which no other therapy on non24 could achieve a constantly earlier wake up, the subjects having to freerun until they get in phase again with their ideal sleep schedule, which is highly impractical.
    • A previous study by Czeisler's team conducted a study in 2012 on 14 healthy men with a very long bright light therapy regimen of 5-8h of bright light exposure everyday for 5 days, which allowed them to achieve 8h of phase advance on average. This landmark and unfortunately poorly known study shows the viability of very long bright light therapy to produce significant phase advances in a short time span on the human circadian rhythm, in line with a subsequent study by the same lab and the current document's author's experiments results, which were found independently before finding these sources. However, one difference is that Czeisler's study required a concomittant sleep restriction scheme with a behaviorally progressively advanced wake up time (ie, using an alarm clock), whereas the present protocol does not. Also, the present protocol is the first to use very long bright light therapy as a treatment for circadian rhythm disorders. Another difference is the use of Luminette, a portable light therapy device, instead of constraining the patient to a light-filled room. A final difference is that the experiment spanned only one week, whereas for circadian rhythm disorders it's crucial to ensure stability of the new sleep-wake schedule over the long term.
  • A step-by-step comprehensive multi-system approach to entrain not only the central clock but also key peripheral clocks, and with multiple treatments with complementary effects to increase the likelihood and robustness of successful entrainment. The goal is to gain control of as many important zeitgebers as possible, while staying implementable in an at-home setting by non medically trained patients.
    • Another multi cases study also provided a combined therapy with melatonin and bright light therapy timed relatively to the circadian rhythm phase of non24 patients. However, as in nearly all studies, this was combined with sleep restriction (ie, forced progressively earlier wake up time by an alarm clock) which reduces effectiveness of light therapy, and hence is likely the reason of the high relapse rate. However, the study does not describe meals timing.
  • A focus on exogenous factor that can shift the circadian rhythm while accounting for endogenous specificities (eg, photosensitivity, timing of light therapy and melatonin relatively to current circadian rhythm phase, etc). Mental states and behaviors are disregarded as the author found them irrelevant.
  • Designed for at-home use in a realistic setting, not in a controlled lab environment.
  • Conception of an at-home circadian monitoring protocol, similarly to diabetes insulin and glucose monitoring devices, for the patient to make informed decisions and adequately time the therapies.
  • A complete cohesive therapy that can be directly applied in the clinical setting or at home under medical supervision. All the necessary tools and the margin of adjustments (eg, light therapy duration) are described along with the scientific justifications. All other currently available therapies only use one or 2 tools at most and with very precise values for the parameters as the purpose was to study their effects, there is no currently available protocol to use in the clinical practice.
  • Easier to implement and follow but also more flexible for the patient in practice than other combination therapies (see also here).
  • Low burden diagnostic and monitoring solution through temperature for the patient, more applicable in practice.
  • Designed and assessed for long-term use, whereas most circadian shifting interventions are only monitored for one week up to one month rarely.

Associated dataset

A continuously updated dataset covering experiments prior and during this protocol is available including a continuously maintained and annotated electronic sleep diary continuously and a record of a set of vital parameters including core body temperature (via dual-heat-flux method), skin temperature (via Thermocron iButtons), 6-axis actigraphy (using Axivity AX6), light intensity and spectral composition (using in-house recorder, open hardware details to be published) and ECG. This public dataset is available at https://github.com/lrq3000/non24article/tree/master/analysis . It will continue to be expanded as the experiment progresses over time, in order to provide for an as exhaustive as possible view of an individual's circadian rhythm. MRI (3T structural, functional and diffusion) and 30x whole-genome sequence are available upon request by academics.

Going further

  • Join an online community to share coping tips and tricks or just your complaints. Medical doctors recommendations do not cover coping tips, that's why patients communities can be very helpful. The r/N24 subreddit is a good place to start. There is also a chatroom on Discord.

Experimental variants of this therapy

This section contains variants of the VLiDACMel therapy repurposing the same tools and principles but for other aims.

Backward cycling therapy

WIP section: this is a work-in-progress, the content may change at anytime. Please consider this section to be experimental and requires further testing and validation.

The VLiDACMel therapy can be slightly modified to cycle the circadian rhythm backward, in other words to produce so much phase advance that the non-24 individual will wake up earlier and earlier (instead of later and later naturally). In fact, a previous study by Czeisler et al in 2012 did the same with a 5-8h/day regimen of bright light therapy, which achieved 8h of phase advance under 5 days. However, this was never tested before on individuals with non-24, no therapy ever demonstrated such a significant phase advance in their core body temperature. But in the current document's author's experience, this is possible.

To do so, use the VLiDACMel therapy as indicated above for entrainment, and modify the following points:

  • Use a very long duration of exposure to blue light therapy glasses, such as 5h or more during summer and 8h or more during winter solstice. This is the key component to cycle backward, increase the duration as much as needed, with longer duration allowing for a nearly proportionally increased phase advance and hence faster backward cycling.
  • Expect to sleep less than the full night, because the fall asleep time (melatonin onset) shifts with a delay whereas the wake up time (melatonin offset) instantly reflects the new circadian rhythm phase shifted by light therapy. But it can still be expected to sleep more than when completely out of phase (ie, for adults who on average need 7-8h of sleep, the user of this therapy can expect to still be able to sleep 6-7h/day if they find they can monitor when their circadian rhythm night is and follow their sleep schedule along).
    • To reduce the delay between melatonin onset and melatonin offset, one can use melatonin pills 1-2h before the estimated start of the circadian night. Taking exogenous melatonin this late will not result in a circadian phase advance, but this is already taken care of by very long light therapy. Instead, exogenous melatonin is here used very close to the expected fall asleep time to induce sleep a bit earlier and consolidate sleep.
  • Avoid eating meals several hours before the biological night. Since it's difficult to estimate especially during backward cycling since the circadian night will be always moving, ideally the user should rather eat a breakfast and lunch (can be eaten later, in the middle of the day, instead of just a few hours after breakfast) and completely skip dinner. This will help avoid digestive issues and the melatonin-insulin-carbohydrates interaction that can slow down the backward cycling and fragment sleep.
  • Always prioritize reducing sleep deprivation, as it significantly reduces light therapy and melatonin efficacy: if the individual slept less than 1 ultradian cycle away from what they ideally need should be considered sleep deprivation (eg, if ideal sleep duration is 7-8h, then any sleep session less than 6h is sleep deprivation as it is 1 ultradian cycle = 1h30 to 2h less than ideal sleep duration). If sleep deprived, always take a nap whenever possible to reduce sleep deprivation. The individual can start light therapy after, and for as long as they stop light therapy 3-4h before their (estimated) circadian night. In the author's experience, having trying both avoiding naps and doing naps whenever possible, the latter always improved the backward cycling therapy and made it much faster. Use a sleep eye mask and ear plugs to isolate from environmental sleep disturbances such as sound noises.
  • If wearing a body temperature monitoring wearable, avoid bright light and eating if wake up earlier than the end of the circadian night. Wait until the circadian night ends (core body temperature raises above the lower phase, limb temperature: lowers below higher phase).

From preliminary results, the author observed a possibility to backward cycle 1 to 2h/day by using 9h during winter solstice and 5h/day in February. At the time of this writing, the author tried this strategy 5 times and it worked 3 times. However, for the 2 failed attempts, it still allowed to entrain the circadian phase to a stable schedule.


Effect of very long bright light therapy (6-8h/daily) using Luminette v3 on the sleep-wake pattern. On the right, we can see the backward cycling effect thanks to the great phase advance produced by bright light therapy.

A reddit member of the N24 subreddit also reported similar results with 6-8h of artificial bright light therapy daily using Luminette, see here for a chart.

Daylight simulation, an extreme but simpler bright light therapy protocol

This variant protocol is an extreme form of bright light therapy, where we don't just do artificial light therapy to complement sunlight, but to replace it completely. In other words, using this variant, we are not reliant on sunlight anymore for entrainment. This may be a potential strategy to overcome the loss of entrainment during winter and the reduced sunlight exposure, as happens commonly to individuals with non-24 and DSPD. Timing light therapy administration with this protocol is also easier.

Instructions:

  • Simply do at least 5h of light therapy, but closer to 10h is better, during the 14h of wakefulness after wake up, as these 14h are your circadian day. Light therapy can be started and ended at any time during these 14 hours. The hours after 14h of wakefulness are to be assumed to be the circadian evening and night, when dark therapy needs to be used instead (ie, staying in the dark, dimming all light sources and filtering blue and green colors to keep red or orange lights).
  • If we don't care about the exact timing of the circadian night and wake up time but we just want a stable, consistent sleep schedule, this variant can be started right away, at any point in the circadian phase, no need to wait to be in phase.

This is what the author of the present document is using, and has used several times in the past. This allows to "freeze" the circadian rhythm in place at any timing, it can hence allow non-24 individuals to mimic any chronotype, such as ASPD, morning lark, evening owl, or even DSPD. There are also side benefits such as mood and energy level increases thanks to the anti-depressant effects of bright light exposure, which increase productivity compared to freerunning, even when the circadian rhythm is frozen in an extreme DSPD-like chronotype (eg, sleeping at 8am and waking up at 4pm). This does not however fix all issues and energy levels dysregulations and irrepressible naps/siesta, nor the weird insomnia phenomenon, nor the reliability of the therapy and variability of wake up time is still an issue (ie, the wake up time will still vary in a 1-3h window between different days, but will not delay further, it will remain in this window).

Phase-delay bright light therapy (true chronotherapy)

WIP section: this is a work-in-progress, the content may change at anytime. Please consider this section to be experimental and requires further testing and validation.

WARNING: Avoid this protocol if you have DSPD! Indeed, there may be a possibility for some individuals that freerunning can't be stopped once it is started, since there are some case reports of individuals with DSPD turning into Non24 after doing (behavioral) chronotherapy! Phase-delay bright light therapy works differently but still has the same effect of causing a freerunning, albeit more controlled, so that the same risks likely apply!

In the case the entrainment fails at some point and freerunning restarts, it is possible to use bright light therapy in the circadian evening and night, instead of the circadian morning and day, to accelerate the daily phase delay and hence the freerunning period. This can be advantageously used to reduce the periods in inverse phase with the day-night cycle (ie, nightwalking) and restart the VLiDACMel entrainment therapy earlier.

This is in effect what behavioral chronotherapy was designed to do, but unsuccessfully in practice, as sleep deprivation does not affect the circadian rhythm but only the sleep homeostat, so that the freerunning observed with chronotherapy can only be caused by the uncontrolled and inoptimal exposure to sunlight. Indeed, sunlight rise time and intensity cannot be controlled. Whereas here with bright light therapy in the evening and night, the circadian rhythm is directly manipulated at the optimal timing to cause a (near) maximal phase delay. There is another major difference: whereas chronotherapy relies on willful sleep deprivation by staying later and later everyday by sheer will, this tiresome procedure is unnecessary with phase-delay bright light therapy, as the circadian rhythm will shift thanks to the exposure to bright light, the individual can simply sleep whenever they feel tired. They should feel tired later and later everyday, with no effort required. In addition, they can use this additional time when they still feel energized to do activities and hence productivity loss is reduced contrary to chronotherapy.

To summarize the steps of phase-delay bright light therapy:

  • Get exposed to bright light during the circadian evening and the first part of the circadian night. Do not continue in the second part as there are risks of getting exposed after the minimum core body temperature point, which would phase advance (instead of phase delay, because of exposure before the minimum core body temperature point, as is the objective here).
  • Avoid pulling all-nighters (complete sleep deprivation), instead, try to nap during the circadian siesta and sleep during the second part of the circadian night (ie, partial sleep deprivation, since exposure to bright light during the circadian evening and first part of the circadian night necessarily reduces the sleep window opportunity, as only the second part of the circadian night can be slept, and in addition melatonin is inhibited which delays sleep onset and impairs sleep quality). Keep in mind that total sleep deprivation is not necessary to shift the circadian rhythm, napping during the circadian siesta and sleeping during the remainder of the circadian night are allowed, this won't slow down the freerunning since sleeping (or not) has no effect on the circadian rhythm. Keep in mind that when naps are done, the sleep homeostat gets partially reset, so that it can be expected that the sleep session during the next circadian night will be shorter.
  • (Optional, do this for faster freerunning but at the expense of impaired mood and decreased daytime energy): avoid bright light, including sunlight, in the circadian morning and day, ie, do dark therapy during the circadian day. Circadian rhythm shifting is kind of a zero-sum game: the phase delay obtained by being exposed to bright light during the circadian evening and night will be reduced by the phase advance obtained during the circadian morning and day, hence a greater phase delay can be obtained by reducing phase advances.
  • Stop when your wake up time is a few hours before your target ideal wake up time. Eg, after 10 days of phase-delay bright light therapy, I will be waking up at 4am, whereas I would prefer 7-9am. But I stop before to have some days for the photic history of evening bright light therapy to wear off, otherwise I may overshoot the time I target.

At the time of this writing, the author tried this strategy 3 times and it worked everytime, allowing for a systematically faster cycling back into phase with the objective day-night cycle compared to waiting for the natural phase-delay freerunning (no therapy) to achieve the same. However, this procedure is discouraged as it is unknown whether it can have any lasting effect on the circadian rhythm, or make it more difficult to stay entrained afterwards. In theory, since entrainment therapy is not permanent, phase-delay bright light therapy should not be permanent either, but given the potential risks it would be better to conduct trials first before recommending this therapy. Anecdotally, the author of this document could successfully switch to the VLiDACMel entrainment therapy right after 2 weeks of phase-delay bright therapy, with the entrainment building up over about 10 days as usual.

Mood, energy and motivation regulation

If what matters to you is not the time at which you are entrained but your productivity, whatever time you sleep or are awake, then light therapy can always be used, even through the periods when there is some freerunning (eg, winter). Indeed, several studies and systematic reviews demonstrated that bright light therapy is as effective as antidepressants to regulate mood and motivation. Furthermore, several studies demonstrated that sleep deprivation and circadian misalignment independently cause depressive-like symptoms in healthy individuals. Blue light therapy also reduces the circadian siesta dip performance decrease and triggers cortisol production, one of the major hormones of wakefulness.

Hence, even when blue light therapy cannot achieve complete entrainment, it can still allow to be productive thanks to its mood, energy and motivation regulating effects.

In the present document's author's experience, the two most important factors for motivation and mood regulations are:

  1. long bright light exposure
  2. sleeping sufficiently long every day (and in circadian alignment)

For example, if sleeping long enough but without exposure to bright light (eg, freerunning but staying mostly indoors), then the individual will stay in a motivation-less zombie-like state most of the time and is more likely to need to sleep during the siesta (ie, biphasic sleep). If exposed to long bright light but not sleeping sufficiently long or in circadian misalignment, the individual will retain some if not most motivation although it can be variable and with variable mood, napping can then be necessary to recover sufficient energy levels to work. Only when both conditions are satisfied can motivation be fully restored.

TROUBLESHOOTING

This section aims to answer several common and less common but crucial questions about circadian rhythm disorders and the potential treatments. The content in this section aims to be a short version of the most crucial details I have accumulated in my more complete 200+ page document, which you can read if you would like further information or details. Note this section also includes information that is not present in the 200+ document.

There are two kinds of solutions usually: either change your environment, or wear gadgets to isolate from the environment. This guide focuses on wearables, because although the results may be similar, wearables are much more comfortable and controllable, and hence more reliable than modifying the environment. Indeed, it's much easier to just put on your light therapy glasses and do your things such as preparing yourself for work, than standing in front of a light therapy lamp for 1-3h without doing anything else. You can even bring your light therapy glasses with you to work and use it while commuting if you don't have enough time beforehand.

Also, wearables are a lot less expensive than older solutions. A proper light therapy setup used to cost thousands of dollars to get enough lux (most cheap lamps don't provide enough lux unless you are literally on the nose with the lamp). Nowadays, light therapy glasses cost only $100-200. For other things such as dark therapy, blue blocker glasses cost only $10. That's why for example we prefer an eye mask and ear plugs instead of using cardboard on the window and soundproofing the walls. We also prefer using blue blocker sunglasses and light therapy glasses such as Luminette instead of advising to buy bright light neon fixtures that you'll need to setup up all around your house at the correct orientation for you or to go outside for a walk early in the morning: it's far easier to just put some glasses on your nose when your alarm rings.

General informations about the non24 disorder


What is the non24 sleep-wake circadian rhythm disorder?

Non24 is a severe and rare circadian rhythm sleep-wake disorder (CRSWD) with no cure currently known. A hallmark of circadian rhythm disorders is experiencing difficulties or inability to follow socially acceptable sleep schedules in the long run. Non24 can appear since birth or later in life, as the circadian rhythm changes with age. Although very common in blind individuals (two thirds are affected), it also affects more rarely some sighted individuals. It is a very disabling, debilitating disease characterized by an inability to sleep and wake up on a 24-hour schedule, and which impacts not only sleep but also wakefulness, hence why this disorder belongs to the family of circadian rhythm sleep-wake disorders. Indeed, if untreated, this disorder produces constant sleep deprivation which compounds with circadian misalignment, which in turn causes during wakeful periods: near constant brain fog, reduced cognitive abilities, slower reaction time and health issues such as cardiovascular diseases and metabolic disorders such as diabetes and obesity. This is in addition to the social exclusion directly caused by this irregular schedule. This worsen comorbid organic and mental disorders such as autism, adhd and depression. Unfortunately, no cure is known, and management therapies rarely work, with some commonly prescribed treatments such as benzodiazepines (sleeping pills) and modafinil worsening the condition and its associated chronic sleep deprivation, which in turns can cause chronic insomnia.

Although all humans naturally have a non24 circadian rhythm when in isolation from external timecues (~24.2h), the non24 disorder presents a necessary and unpreventable freerunning (ie, their circadian night delays later and later, which in practice means they wake up later and later each next day) despite exposure to external timecues (ie, zeitgebers, such as sunlight). Indeed, humans circadian clock, which defines different periods of activities such as the circadian day for wakefulness and the circadian night for sleep, is usually synchronized with the objective day-night cycle, mostly via sunlight, but in individuals with non-24, the circadian clock cannot align and hence the circadian night and day are ever shifting and misaligned with the objective day-night cycle. In practice, this means that individuals with non-24 cannot control not only their ideal sleep time, but (more problematically) neither their body's wake up time, even when they try to control their bedtime. If they do sleep earlier, they will simply take a nap that will be shorter and less restorative than a circadian night sleep (eg, often lasting only 2h — which is one ultradian cycle — even if they sleep during the objective night). Likewise, if they try to sleep later, they will wake up at their natural wake up time, no matter how short their sleep is (eg, if their current circadian night is from 8pm to 4pm, sleeping at midnight will see them incontrollably wake up at 4pm anyway, for a total sleep duration of 4h, which can appear to the untrained eye to be a form of insomnia, when it simply is the consequence of sleeping in circadian misalignment). These principles are governed by the generic sleep processes all animals share, but they are more apparent with circadian rhythm disorders such as non-24 due to the circadian misalignment with the day-night cycle.

The clinical signs characterizing the non-24 disorder is to experience days longer than 24h (with some having an extreme form with days longer than 32h) with longer wakefulness periods than typical sleepers experience (eg, 8h of ideal sleep duration and 18h of wakefulness period instead of 16h). The circadian night duration can be of similar length to typical sleepers of the same age group or there can be hypersomnia, although individuals with non-24 often sleep less than they need to due to sleep restriction because of circadian misalignment or social/work obligations. Although the non-24 disorder is often just described as "having a day longer than 24h", this is a layman description of a lengthened circadian period, the latter being the scientifically accurate description of non-24, as it is the lengthened circadian period that in turns increases the length of the behaioral sleep-wake period. In practice, the sleeping pattern can be highly variable and unpredictable from one day to the next, even in the absence of external disturbances, due to naturally reoccurring endogenous transient changes in the circadian rhythm, scientifically termed "relative coordination and transient (dis-)entrainment", as sleep bouts can happen at any random unexpected times, as well as experiencing premature wake-ups. A common example experienced by individuals with non-24 is to see their circadian rhythm delay faster when they are awake at night than when they are awake during the day (ie, see the "relative coordination" phenomenon). This shows that the circadian rhythm is always changing, and hence, a "steady freerunning sleep pattern" should not be expected but rather an average freerunning pattern with chaotic noise and disturbances. Non-24 is sometimes incorrectly labelled as a chronotype, when more accurately, non-24 is precisely the lack of any chronotype, as the timing of the circadian night progressively changes all the time and will revolve around the clock, covering all possible timings after a while. Since non-24 is the lack of a preferential chronotype, there cannot be a concurrent diagnosis of another chronotype (such as DSPD) as this would be antinomic to the very definition of non-24, although the individual may be temporarily/transiently entrained to a schedule during specific and limited periods of time due to relative coordination or medical therapy, or appear as a delayed or an irregular sleep-wake pattern when restricted by duties and alarm clocks.

Although there exists a few therapeutic options for management, there is no cure and a sizeable part of this population appears to be treatment-resistant, especially those with some comorbidities that interact with the circadian rhythm and contraindicate melatoninergic therapies, such as RLS and PLMD.

Since their circadian rhythm, and hence ideal sleep period as dictated by their biology, is often in mismatch with societal needs and the day-night cycle, individuals with non-24 are often chronically sleep deprived. At first, disregarding their circadian rhythm will cause the same symptoms as for jet lag: foggy thoughts, headaches, digestive issues, daytime tiredness, chronic fatigue, insomnia (inability to sleep when allowed to). If this circadian misalignment continues for years, more serious health issues can appear as for night shift work disorder, such as cardiovascular diseases, cancer as well as severe depression among other diseases that can be caused or worsened by severe chronic sleep deprivation and circadian misalignment.

Maintaining social obligations can worsen the symptoms of individuals with non-24, as this can not only lead to further sleep deprivation worsening all cognitive and mood capacities, but also additional disruption of their circadian rhythm from external cues (eg, unwanted light exposure mistimed with their circadian rhythm) depending on the time of the activity. Having non-24 is not inherently unhealthy, but trying to restrict sleep to fit into social expectations is, due to the chronic circadian misalignment and sleep deprivation. Furthermore, research has demonstrated that it's crucial to sleep in phase with one's own circadian rhythm, especially during childhood, to prevent the development of other diseases, such as metabolic disorders.

Unfortunately, even without social obligations, individuals with non-24 have no means of monitoring reliably their circadian rhythm, and hence often sleep in circadian misalignment and hence sleep too little. This makes them live in a nearly always exhausted state, only waiting for the next opportunity to sleep (since they cannot sleep just whenever they wish to due to the homeostatic sleep pressure and circadian process regulating the sleep-wake schedule), and when they finally fall asleep at a random unexpected time, they often get a sleep too short to be reparative, waking up prematurely because of sleeping in circadian misalignment, so that they continue to be exhausted and the cycle repeats. Hence, individuals with non-24 are often prone to undersleeping due to the lack of circadian rhythm monitoring tools, and sometimes oversleeping in proportion with the time they last spent awake or when sleeping in partial alignment with the circadian rhythm. On top of these endogenous issues, their sleep can often be impaired by external disturbances such as noise, sunlight, warm temperatures. Although there are unavoidable social constraints on sleep when living in society, it is worth noting that forcing someone else to wake up repeatedly despite knowing they need to sleep is physical and mental abuse, and is as such an established and practiced torture method.

Non24 and other circadian rhythm disorders are invisible diseases, with sleep-shaming being a common occurrence. Sleep shaming is due to the general public's misconceptions about how sleep works, which is not specific to sleep disorders but also affects typical sleepers doing night shifts. This also affects typical sleepers working on usual 9-5 office hours, with an endemic chronic sleep loss due to voluntary bedtime restriction to fit in the 24h society, which was termed "social jet lag". More generally, the general ableism culture does not help with the recognition of chronic diseases. This even leads some scientists, who clearly lack an expertise in circadian rhythm science, to suggest to avoid prolonging the work career of evening chronotypes, despite the latter being much more manageable than non-24. Michael Reed wrote for Metro.co.uk an excellent first-hand account of what it's like to live with the non-24 circadian rhythm disorder. See also this Youtube video by Leslie Exp: Non-24 Hour Sleep-Wake Disorder: My Experience.

Although non24 can be easily diagnosed with clear guidelines, medical and in particular psychiatric misdiagnosis is unfortunately a common iatrogenic occurrence for individuals with a circadian rhythm disorder, including for children, which can be very distressing and cause further harm. Indeed, although being so common that the non-24 disorder is the norm for blind individuals, the awareness about the existence of this disorder is still very low among the public, even more so for sighted non-24. That's why November 24th was chosen as the International Non-24 Disorder Awareness Day, with the "Think Zebras" theme of the 2015 edition as a reference to the common but error-prone medical saying to "diagnose common diseases first", as this has the unfortunate side consequence of increasing the rate of misdiagnosis of rare diseases such as non-24.

Often, non-24 is a multifactorial and complex disorder, which means that it is suspected to be in a similar class of disorders as autism, where multiple causes can lead to developing a non-24 disorder. This is also hinted at by the fact that some individuals are born with the disorder inherited from parents, such as is the case for the author of this document, while others seem to develop it later in life (although this may be due to misdiagnosis in childhood).

Are circadian rhythm disorders real diseases and disabilities?

Are non-24 and other circadian rhythm disorders considered to be disabilities?

Technically, non-24, among with other circadian rhythm disorders, are "lifelong untreatable pathology of the circadian time structure" which are functionally chronically affecting the individual in their everyday life and tasks to an extent that is in the accepted definition of what is a disability. Some authors argue for another definition of disability, in that since these disorders are currently not curable (only merely manageable for some individuals), these treatment-resistant individuals with a circadian rhythm disorder should be recognized as disabilities. And even for those who are responsive, having effective management therapies does not change the fact that circadian rhythm disorders are lifelong disabilities with no cure that require constant management and merit accommodations.

Is non-24 and other circadian rhythm disorders diseases?

Although there is no generally accepted definition on what constitutes a disease, one definition consists in conditions that can be improved with treatments, which is the case for circadian rhythm disorders. Another consensual approach to defining what constitutes a disease is whether the condition is included in a well established medical corpus of diseases, such as in the World Health Organization's International Classification of Diseases, which is the case for both non-24 and DSPD as well as other circadian rhythm disorders. Yet another definition is whether the condition reduces life expectancy or increases the risk of fatal outcomes, such as cardiovascular diseases or car accidents or cancer, which is again the case for circadian rhythm disorders (see more details below in the relevant section on "Health issues of a circadian rhythm disorder"). Finally, another common definition is whether it significantly impairs day to day functions and the possibilities to get employed, which is evident given the testimonials from individuals with non-24 and DSPD (including for business owners, not just employees).

Non-24 is a well established disease, this is not a "fashion illness", as it is recognized internationally as a disability by the World Health Organization's International Classification of Diseases (WHO ICD) since ICD-9 (1975 see also here) and up to the latest ICD-11 as of this writing. The WHO ICD is the international standard for the classification and billing of all diseases and disorders. Essentially, if it's in the WHO ICD, it's a disease. You don't need to know what the WHO ICD is or how it works, but your doctor should (and if they don't, run away!).

The WHO ICD codes of non-24 for each version are as follow:

  • ICD-9-CM: 327.34—"Circadian rhythm sleep disorder, free-running type"
  • ICD-10-CM: G47.24—"Circadian rhythm sleep disorder, free running type"
  • ICD-11: 7A63—"Non-24 hour sleep-wake rhythm disorder", "Circadian rhythm sleep-wake disorder, non-entrained disorder type", "Circadian rhythm sleep-wake disorder, non-24 hour type"

There are similar codes and recognition for DSPD (ICD-10 code: G47.21). See for example this french redditor who got their DSPD officially recognized by their country's social security system or this other one.

Organic vs non-organic in DSM, recognized and billable in ICD-10. TODO: update the above using: https://www.reddit.com/r/N24/comments/h8tnco/does_it_make_sense_to_try_to_get_a_diagnosis/

Sighted non-24 is considered an orphan disease (a rare and commercially unattractive disease). Non-24 is also included in Orphanet and NORD classifications of orphan and rare diseases respectively. It is a billable disease in all countries where ICD-10 or DSM is used for billing medical disorders, and hence open to disabilities accomodation, especially in USA under the Disabilities Act.

Disabilities recognition and accommodations should be available in most countries in the world, as 164 countries ratified the United Nations' Convention on the Rights of Persons with Disabilities (CRPD), although these disabilities rights are often poorly communicated about or are slow to be implemented by governments despite the convention existing since 2006 (see also here). Reading the convention is highly recommended to disabled individuals to understand their rights, and easy read versions are available here and here. The list of countries that ratified the convention can be found here. However, since this is only a convention, not a law, and hence not legally binding, it amounts to a commitment that states who ratified it make towards their citizens. The convention can however be part of a legal argument and may be considered by judges, but it cannot constitute the sole argument and it may be ignored. The convention can also potentially be a legally binding argument in constitutional courts. Note also that several countries made laws to implement the convention when they ratified it, such as Belgium, so it is worth looking at national laws to see if there are some that are in link with the CRPD.

Given that the AASM, the leading american and worldwide scientific organization on sleep science, has published a position statement in 2021 stating that "sleep is essential to health", with an importance on par with healthy nutrition or physical exercise, that was endorsed by more than 25 medical, scientific, patients and safety organizations, there is a case to be made that sleep disorders can qualify as disabilities, as without accommodations this would amount to deny the individual from his right to live healthily.
(NB: It could maybe even be argued that discrimination based on sleep patterns can be similar to preventing access to facilities by not providing adapted access to people with mobility issues, with both being inherent and hardly changeable with current technology.)

At the individual level, non-24 brings many burdens that undoubtedly qualify it as a disability. On a personal level, living with a chronic disease such as non-24 is extremely straining. Being unable to do what others can do not only easily but unconsciously, such as sleeping, is hard to accept and live with, which requires a long grief process, as the individual must grieve the loss of their past self and future plans.

On a professional level, employment is certainly more difficult to access for those with a non morning chronotype, such as DSPD and non-24, which could be framed as a chronotype discrimination. This discrimination has very real and far reaching consequences at a societal level, impacting all citizens beyond those with a different chronotype. There is no better example than healthcare, where the morning chronotype mindset ("the early bird catch the worm") reigns supreme, which is barring entry to medical candidates who get rejected because of their chronotype or circadian rhythm disorder. This is unfortunate, as healthcare is always necessary, day and night. Currently, clinical workers with non-evening chronotypes are required to work during their biological night, which is likely the reason why iatrogenic events (medical errors) and accidents are occur more often during night shifts compared to daytime healthcare. Having workers with an evening or night (DSPD) chronotype would allow to reduce these errors as these workers would be at their peak efficacy during night shifts, just like morning chronotypes have their peak during daytime. This example shows that with increased awareness and integration of different chronotypes into the workforce, costs and accidents can be reduced and productivity increased, at little to no cost for society or the company, as this simply requires accounting for the staff chronotypes and offering alternative organizations (eg, remote or recorded meeting sessions, asynchronous communication between teams by e-mail - which is already the case between dayshift and nightshift staff). Due to the detrimental health effect of shift work on misaligned circadian rhythms and the decreased performance and increased risk of work accidents, some scientists call to match employees chronotypes to shift work positions (see also here). Indeed, a study demonstrated that aligning work schedules with chronotypes allowed for clinically significantly improved workers sleep and mood, including 0.5h more sleep on work days and 1h less social jet lag, and that evening chronotypes better tolerated frequent night shifts. In 2021, a large-scale study demonstrated that mismatching the work schedule with the individual's genetical chronotype led to decreased well-being and increased anxiety and depression, in line with a previous study showing that mismatching chronotype and work schedule leads to a much more variable sleep schedule and increased circadian misalignment. Unfortunately, night shift schedules are still poorly regarded, despite their necessity in our 24/7 society and whether they are the result of occupational requirements or the endogenous rhythm of the individual. Furthermore, employers often apply a chronotype discrimination for their hiring process, by looking for morning owl chronotype individuals even when the job schedule is at night. This ideological prejudice of the immorality of night schedules can be traced back centuries ago up to modern day, despite being disproven by several studies, with immorality increasing when the subject needs to perform a task when in circadian misalignment, regardless of the genetic chronotype (source studies here).

Smart business owners with wide office hours (ie, night shift) or where teleworking is possible could flexibly organize employees schedules based on their circadian alignment to optimize production and reduce work accidents, with "sleepiness surpassing alcohol and drugs as the greatest identifiable and preventable cause of accidents in all modes of transport", as indeed driving accidents are much more likely for night shift workers with a misaligned circadian rhythm. Preliminary evidence indeed suggests that aligning the work schedule of shift workers with their circadian rhythm can reduce health issues and increase productivity. Indeed, morning larks perform badly and lack attention in the evening or worse at night (despite subjectively thinking they have the same performance), whereas night owls perform better in the evening and DSPDs during the night. Furthermore, non-evening chronotypes working on nightshift often suffer from depression as a result of the mismatch between their work schedule and their circadian rhythm and also the lack of bright light exposure as accounts from nightshift workers show, whereas individuals with DSPDs instead are more than happy to get such jobs. Hence, with some societal recognition and work culture evolutions, the variety of chronotypes could be leveraged to ensure optimal work conditions and productivity in our already 24/7 society. And it rather strikes as peculiar that in our 24/7 society, where everything is expected to be available at all time, the society as a whole reject the very people who makes this omnidisponibility possible.

Here is a saddening compilation of personal stories of adults with DSPD who had to drop out of school or their work career due to missing accommodations and recognition of their DSPD disorder. All fields of work, and all education degrees, including healthcare, are affected.

The challenge to employment and schooling is far greater for non-24, which can be considered as a non-chronotype, with no preferential and stable sleep-wake schedule, it changes from one day to the next. Since there are hardly any job, even with accomodations, that can allow for unplanned flexible schedules, which would require minimal to no social interactions (ie, clients business relationships, work meetings, etc.), it's highly likely that most individuals with non-24 remain unemployed for most of their lives. Furthermore, although societal awareness of different chronotypes could certainly reduce or eliminate most issues for DSPD and similar delayed disorders, it would not help non-24 employment, as the issue with non-24 is the lack of any regular schedule and hence of any possibility to predict, in addition to the consequent constant sleep deprivation due to unpreventable sleep interruptions by external factors making energy levels and cognitive performance (and risk of accidents) highly variable from one day to the next. Hence, although employment data are lacking, it is safe to assume given the volume of testimonies that most individuals with non-24 remain unemployed. Indeed, there are only a handful of jobs where a constantly shifting schedule would be an advantage, such as NASA's Mars monitoring missions which require ideally a martian schedule of 24.6h, and maybe healthcare with an adapted rotating schedule with smaller increments. On the off chance that someone with non-24 lands a job with a typical 9-5 daytime work schedule, they will end up missing more and more appointments as time goes by and their circadian rhythm continues to shift and hence are more and more unable to sleep when required, then doing overwork to try to compensate, to finally end up either burnout by the overwork or by the sleep deprivation (or a combination of both). Making one's own company is not any better, as although the office hours are certainly more flexible, the necessary customer relationship will still dictate a mostly diurnal working schedule. Working with remote companies will also enforce a regular although delayed working schedule, which again cannot fit with the non-24 circadian rhythm disorder.

In addition to these employment issues, individuals with non-24 can be qualified as unlucky. The most obvious reason is the acquisition of, or being born with, an crippling inheritable chronic disorder that is non-24. But beyond that, individuals with non-24 get much less opportunities than those with a 24h circadian rhythm: they are (almost) never there at the right time. Opportunities are mostly a product of interpersonal connections, which means that the more interpersonal interactions one can get, the more likely they will get opportunities. Hence, these opportunities happen mostly when most of the rest of the world is awake. Mechanically, the always changing schedule of non-24 bars the individual from a lot of these opportunities to only the short period of time (days/weeks) where the individual's circadian rhythm is in phases with the day-night cycle of their timezone (or timezone of interaction if working remotely). This lower probability of experiencing opportunities due to the always changing mismatched circadian rhythm is what makes individuals with non24 objectively unlucky.

It's crucial to understand that constraining someone with non-24 to fit within a fixed schedule does not just imply they will sleep less than optimally, as for typical sleepers, but that they will not sleep or so little this will be unsustainable healthwise. Sleep is an essential need for all living animals to survive, just like food and water. Hence, accommodations are not a convenience to increase the quality of life, they are a necessity for individuals with non-24 to live and preserve their dignity as human beings. Unfortunately, it is unclear what accommodations are required, since flexible schedules still need to be planned in advance and hence cannot accommodate the chaotic schedules of non-24, and the same goes for appointments and meetings. Asynchronous work and schooling, whenever needed depending on the current circadian phase of the individual, may be a potential, but partial, accommodation.

Even at home, circadian rhythm disorders are very debilitating. Due to the mismatch with social expectations, the individuals are drastically limited as to which activities they can carry out at night without bothering neighbors or violating laws about night noise, or simply by the opening hours of commodities and services. Some patients describe this situation as being "encaged" and "walking permenanently on eggshells", with computers with internet access being their only daily window to a lively world.

For a more in-depth discussion about non-24 and disabilities, watch this excellent video by Leslie Exp (textual script here) and this critique of the 24/7 society by Johnathan Crary (summary here).

Finally, seeking the help of disabilities associations can be very fruitful, these associations can help with the formalities to get the disability recognized and they likely won't judge the patients.

TODO: add info about remote work from: https://www.reddit.com/r/N24/comments/jewt6z/what_accommodations_have_you_successfully_got/

Diagnosis and sleep diary

Knowing the accurate diagnosis allows the patient to better understand their constraints and adapt their lifestyle around it to improve by themselves their quality of life and alleviate unwarranted guilt. This also opens the access of the patient to more therapies and to accommodations, which are crucial to reduce the impact of the illness on their quality of life.

How can I get diagnosed of non-24 or DSPD?

Two things are needed: a sleep diary over 2 weeks of freerunning (unrestricted sleep, no alarm clock), and to know that non-24 and DSPD are recognized as diseases in the WHO ICD.

Curating a sleep log is the basic and most essential tool for the diagnosis and management of any circadian rhythm disorder, especially for individuals with a non-24 disorder as their sleep schedule constantly changes. The curation of a sleep diary (also called a sleep log) is hence not only strongly recommended for diagnosis, but should also be continually done even long after as a self-management tool. Writing a sleep diary consists of writing when we fall asleep and when we wake up, including naps, for at least 2 weeks for diagnosis, and preferably to continue after for self-management. More exhaustive sleep diaries also include the bedtime (so that the sleep latency, aka the time taken to fall asleep, can be estimated) and the standing up time (ie, at what time the individual gets out of bed), as well as the timing of various compounds such as melatonin, caffeine, alcohol, etc. This sleep diary will not only be helpful to you to better understand your sleep patterns (ie, determine the circadian misalignment), but also can be used for diagnosis with a sleep specialist according to the official USA (executive summary here) and UK guidelines and also is necessary to correctly time the only few treatment options (see also here and here and here) that exist currently, as sleep diaries are reliable estimators of the circadian rhythm. Indeed, due to the unstable nature of the sleep schedule of individuals with non-24, it may be necessary to adjust the timing of the therapies from day-to-day, or sometimes reduce/increase the dosage (eg, of melatonin) or duration (of light therapy). Curating a sleep diary does not only allow to keep track of bedtime and wake up times, but also of sleep duration, which is a strong predictor of cognitive performance and mood during the day, as well as sleep pressure the next day/night, as too little sleep strongly indicates sleep deprivation, whereas a too long sleep indicates the body attempted to correct for previous sleep deprivation. Interestingly, a sleep diary over at least 2 weeks but preferably longer as a management tool is also the gold standard assessment of insomnia, hence sleep diaries should be systematically be requested in any sleep study updated to the latest medical guidelines.

It is crucial to try to write the sleep diary, at least for some weeks, with an unrestricted sleep schedule (no alarm clocks nor appointments requiring to forcefully wake up at a specific time). Indeed, restricted sleep will not only hide the freerunning pattern characteristic of non-24, but can also cause sleep deprivation which may produce chaoticity in the sleep patterns. It is also crucial to log all sleep sessions, including naps, however short they are.

The author strongly recommends the app Sleepmeter Free on Android (mirror) and its widget to write a digital sleep log which will produce nice sleep graphs that are easier for humans to read and hence for doctors to diagnose. It can also be installed on a computer using the Bluestacks emulator. A paper sleep diary is also fine, and there are plenty of templates available online, but the AASM sleep diary / sleep graph template is recommended (mirror here). A sleep graph such as with this template or software is much preferable over simply writing the fall asleep and wake up times, as a graph is much more legible for observers including sleep doctors, this will drastically reduce the rate of misdiagnosis. Write down your last sleep session as soon as you wake up, to avoid forgetting the accurate timing after you go on with your day. Other standard sleep diary templates (but not sleep graphs) include the Consensus Sleep Diary and its 3 variants.

Once you have a sleep diary over at least 2 weeks, or preferably 1 month or more to get a clearer pattern, look for a sleep specialist experienced with circadian rhythm disorders or a chronobiology clinic (not a sleep clinic) to diagnose your circadian rhythm disorder, preferably a chronobiologist with a background in neurology. Alternatively, psychiatrists with a well established research experience in circadian rhythm science, and hence who also are chronobiologists, can also diagnose non24. Sleep clinics often only test for sleep apnea and narcolepsy, not circadian rhythm disorders, although they should according to guidelines. Sleep specialists cover a wide range of background, but pneumologists, psychiatrists, psychologists and psychotherapists should generally be avoided unless they have a recognized experience in circadian rhythm disorders as they are highly prone to misdiagnosis and mistreatment due to systematic issues in the practice of psy* clinicians, such as the unfounded "secondary" classification of sleep disorders and circadian rhythm disorders¹. Indeed, sleep disorders, including insomnia and circadian rhythm disorders, should always be treated as they rarely resolve on their own and always with specific treatments for the sleep disorder, irrespective of any co-morbid psychological condition, which is why the DSM-5 dropped the terms "secondary" and "primary" insomnia to only keep "insomnia disorder", as the assumption that sleep disorders stem from psychological disorders (ie, is secondary to psychological disorders) is not supported by empirical evidence for the reasons reviewed here. Pneumologists focus on sleep apnea, and while it's good to be tested for this too, these clinicians usually disregard circadian rhythm disorders. Indeed, most sleep clinics will only test for sleep apnea and narcolepsy, ignoring any circadian rhythm disorder as a side effect (see also here), despite there being no evidence supporting this view, as indeed the comorbid circadian rhythm disorders usually do not resolve with sleep apnea treatments, both disorders appear to require independent therapies.

To find a chronobiologist doctor, who will be properly trained or experienced with circadian rhythm disorders, the Circadian Sleep Disorders Network patients association curates a list of chronobiology doctors from recommendations by previously diagnosed DSPD and non-24 patients:

https://www.circadiansleepdisorders.org/doctors.php

An especially excellent chronobiology center for non-24 diagnosis is the Centre for Chronobiology in Basel, Switzerland, they should be recommended especially for children diagnosis.

If you find a competent doctor who could diagnose you with a circadian rhythm disorder and isn't on this list please send the Circadian Sleep Disorders Network association an email to add your doctor in the list, this will help your future peers.

If in this list there is no doctor in your area, either travel to one if possible or if really too far, try to look by yourself for a specialist in circadian rhythm disorders. A good method is to look for scientific publications using scholar.google.com and then contact the authors that are in your region (eg, local university or hospital).

If you find a properly trained doctor who successfully diagnose you, make sure to ask them to write down a description of your diagnosis and an accommodation letter describing how it impairs your daily functioning, this will help later on to continue to get your treatment (eg, melatonin) if your doctor goes out of business and you need to find someone else, and to get disability recognition and work/school accommodations. Indeed, given that these disorders are uncurable, accommodations will become a necessity at some point, and asking for it as soon as you get your diagnosis will save you a lot of trouble later on.

Whichever doctor you meet, specialized or not, they should never shrug off your sleep issues as a side issue. It is a primary disorder that always requires independent treatment (it's NOT secondary to another psychological issue). Patient generated health data should always be considered by clinicians, including your sleep diary.

If the doctor you meet is not considering your complaint seriously, mention that non-24 is recognized by the WHO ICD. This stands for the World Health Organization's International Classification of Disease. The WHO ICD is the international standard for the classification and billing of all diseases and disorders. Basically, if it's in the WHO ICD, it's a disease. You don't need to understand what the WHO ICD is or how it works, but your doctor should (and if they don't, run away!).

The WHO ICD codes of non-24 for each version are as follow:

  • ICD-9-CM: 327.34—"Circadian rhythm sleep disorder, free-running type"
  • ICD-10-CM: G47.24—"Circadian rhythm sleep disorder, free running type"
  • ICD-11: 7A63—"Non-24 hour sleep-wake rhythm disorder", "Circadian rhythm sleep-wake disorder, non-entrained disorder type", "Circadian rhythm sleep-wake disorder, non-24 hour type"

You can also mention that the non-24 is not rare at all in blind people, as it's estimated that 2/3rd of blind people suffer from non-24. It's rarer in sighted individuals, but this is the same disorder. So if your doctor ever saw a blind individual, chances are they had non-24 (although they were likely undiagnosed if your doctor doesn't know about non-24...).

Unfortunately, with sighted non-24 being a rare orphan disorder, the standard care pathway is often made more difficult by untrained clinicians than it should be. This is unfortunately a common issue with chronic illnesses, even those that are not rare (see for example r/ChronicIllness), but the rarity causes additional struggles.

¹ Indeed, both sleep disorders such as insomnia and circadian rhythm disorders are often ignored and left untreated as these fields assume that sleep issues are secondary to other psychiatric disorders, which means that the psy practitioners will try to diagnose and treat any other disorder except the sleep issues. This distinction was criticized as being unfounded and detrimental to the patients' proper treatment since at least 2001 for insomnia and more recently in 2020 for circadian rhythm disorders, but the unfounded primary/secondary insomnia distinction still perseveres in the clinical practice, so it's unlikely that there will be any change soon for circadian rhythm disorders either. See the subsection about misdiagnosis below for more information.

Diagnosis methods for circadian rhythm disorders

This section describes more technically the diagnostic methods and tools for non-24, which are also applicable with little adaptation to other circadian rhythm disorders such as DSPD.

Circadian rhythm disorders are common in the clinical practice, despite being underdiagnosed. Nevertheless, diagnosis is theoretically easy and inexpensive. According to the latest medical guidelines, sleep diaries over at least 2 weeks are the main diagnostic tool for circadian rhythm disorders (see also here) and insomnia (see also here) as explained in the previous section. However, due to potential masking biases, it is recommended to curate a longer sleep diary over at least 1 month or even more, until a clear pattern emerges.

Specifically, non-24 is characterized by staircase-like freerunning circadian phase and sleep-wake pattern typical of non-24, whereas DSPD is characterized by a delayed but relatively stable circadian phase and sleep-wake pattern especially during week-ends for workers (social jet lag) or every days if sleep is not restricted. In practice, it's necessary for the patient to sleep unrestricted (no alarm clock, going to sleep when feeling tired and waking up naturally) over at least 2 weeks, and preferably longer as relative coordination to sunlight can mask the freerunning pattern by creating an illusory and temporary entrainment and to continue monitoring and manage the sleep disorder whenever there is a relapse, as is recommended for insomnia.

Although current medical guidelines only state freerunning over 2 weeks as the sole and sufficient criteria to diagnose non-24, the current document's author recommends to use a stricter criterion:

Proposed non24 diagnosis criteria: Given either a sleep diary or circadian phase proxy measures (melatonin sampling, core body temperature) over at least 2 weeks, if a freerunning pattern is observed despite periodic zeitgebers exposure and unrestricted sleep opportunities, then this should be sufficient to diagnose non24.

Indeed, all humans naturally freerun when left in a completely dark environment void of zeitgebers, especially light. But if the individual is exposed to zeitgebers on a daily basis, especially sunlight, and still display a freerunning pattern (eg, with alarm clocks), then this demonstrate a robust freerunning drive resistant to zeitgebers exposure and hence this condition would clearly demonstrate an endogenous non-24 disorder.

The AASM states in its latest meta-analysis of behavioral therapies for insomnia some of the reasons why sleep diaries have become the standard assessment tool for sleep disorders, preferred over behavioral questionnaires, as sleep diaries allow for a more accurate tracking of the sleep patterns and also allow to measure a wide array of sleep metrics and their daily variability:

> In the study of insomnia treatments, nighttime sleep and insomnia symptoms are most commonly measured with daily sleep diaries,29 which capture information about the timing of sleep (bedtime, rise time) in addition to individual sleep parameters, such as sleep latency (time to fall asleep initially), wake after sleep onset (WASO; duration of nighttime wakefulness), and early morning awakenings (waking in advance of the desired rise time) that are commonly the primary symptoms targeted in insomnia treatments. Additional summary metrics commonly derived from daily sleep diaries include total sleep time and sleep efficiency (total sleep time/time in bed*100%). Daytime napping/sleeping behaviors are also commonly tracked in daily diaries when delivering treatment. The primary advantage of sleep diaries is that they allow for the daily collection of information on nighttime symptoms, making them less subject to recall bias than questionnaires. Treatment effects are most commonly assessed with aggregated mean-level changes in individual sleep diary parameters across time, generally every 1 or 2 weeks, but increasingly, the variability of these parameters across days is also being viewed as clinically important.

In other words, humans are very bad in estimating their own sleep patterns without an adequate measurement instrument. We are prone to overestimating the amount of time we spend asleep and underestimate the time spent in bed awake trying to sleep.

As written earlier, the clinical signs characterizing the non-24 disorder is to experience days longer than 24h, with longer wakefulness periods than typical sleepers experience (eg, 8h of ideal sleep duration and 18h of wakefulness period). Hence, patients complaining of a "too long day" and of "sleeping later and later" should tip the clinician on to proceed to instruct the patient to curate a sleep diary in order to assess the presence of a circadian rhythm disorder. It is important to do a differential diagnosing by recognizing and excluding other circadian rhythm disorders, such as delayed sleep phase disorder (DSPD) with a delayed sleep schedule but not abnormally long wakefulness period nor sleep period, hypersomnia with a longer sleep period but standard wakefulness period duration, and advanced sleep phase disorder (ASPD) with an earlier sleep schedule (much rarer and usually only observed in elders). Other sleep disorders such as sleep apnea should also be investigated, as treating them can improve or more rarely resolve the circadian rhythm disorder, although a diagnosis for a sleep disorder does not preclude the diagnosis of a circadian rhythm disorder, they are not mutually exclusive.

TODO: add figure showing prototypical sleep graphs for each circadian rhythm disorder.

A longer sleep diary with no constraint on sleep is preferred, as the non-24 disorder can be missed or misdiagnosed with DSPD due to sleep restriction and relative coordination (transient entrainment) to sunlight or other zeitgebers. However, for the trained eye, it can be possible to suspect non-24 with a restricted sleep schedule, see for example this figure kindly provided by Kieran Wood and annotated by the current document's author:


This is an actigraphic sleep graph of a sighted non24 individual over 4 months, acquired using a Samsung Galaxy Watch wearable sports band. The individual's freerunning period is ~27min, which means that a full circadian revolution is completed under ~2 months. We can see the staircase-like pattern typical of freerunning during the period of unrestricted sleep. On both sides, we can see restricted sleep patterns. On the left, there is a period of restricted sleep, starting in phase with the day-night cycle for about 1 month, and progressively becoming chaotic as the individual's circadian rhythm continued to freerun and become out of phase (up to being in total opposition) with the day-night cycle during the 2nd month. However, due to the sleep restriction (work commitments, which required using alarm clocks), the freerunning pattern of the circadian rhythm was masked and hence is not apparent in the sleep pattern, but it was still happening and was expressed as chaotic sleep patterns during the out of phase period, with alternating patterns of short sleep (duration < 5h), hypersomnia (>9h), drastically varying fall asleep and wake up times by several hours, and missed sleep (all-nighters). The alternance between "stable" sleep for one period and chaotic sleep for the other period is a sign of (restricted) non24 disorder. The period of chaotic sleep is usually accompanied by other health symptoms such as more frequent illnesses. Although this graph was generated out of actigraphic data, the same patterns can be observed on manually curated sleep diaries.

Such a restricted schedule may appear as a very slow freerunning phase on the surface (ie, 1h of phase delay per month), but there are gaps, nights without any sleep, that must not be ignored. Very very slow freerunning phase delay is unheard of, this is most likely an estimation error, as in this case as demonstrated by the much faster freerunning phase delay when unrestricted (~25h) but without sleep gaps. More likely, the masking due to the restricted wake up time makes it look like the delay is very slow, but in fact the circadian phase is running around the clock. There are a few potential reasons:

  • When the fall asleep time seems to "reset" backward suddenly, it's because of the sleep pressure buildup due to accumulated sleep deprivation.
  • Another thing that is happening is that the siesta, which start is 12h apart from the circadian night start, also delays progressively forward, until it matches with the current sleep schedule. Assuming a 45min of daily phase delay, this would mean that a full freerunning cycle is completed under 32 days, and half a cycle, a 12 hour shift, is completed under 16 days. This means that every 16 days, the individual can sleep at, let's say, 3 am, at first because of alignment with the circadian night, then 16 days later at the same time because of alignment with the siesta (but then the duration is limited to about 5h), then 16 days later it's again in alignment with the circadian night, etc. In-between, the subject cannot sleep at 3am, but will either sleep later or not sleep at all if too much in circadian misalignment with either the circadian night and the siesta (ie, trying to sleep in the middle between both, during the wakefulness period of the circadian phase).
  • Finally, there is the effect of relative coordination which can increase or slow down the freerunning phase delay.

The above demonstrates that while the staircase pattern is typical of freerunning, it is not necessarily observable as it can be masked, despite the presence of the non-24 disorder. The staircase pattern is also insufficient to diagnose non24. Indeed, any human can freerun when isolated from zeitgebers influence. Hence, the proper diagnosis of non24 must also take into account whether the individual is exposed to zeitgebers, and still freeruns, and also if the individual sleeps better while freerunning than when not. A reliable measure is the sleep duration. Individuals who freerun but do not sleep well while doing so are likely not non24, and may rather be experiencing a temporary freerunning period consequently to a loss of entrainment, as it can regularly happen to DSPD individuals, especially during seasons changes (ie, winter, DST time change, etc).

This review outlines a standardized approach to diagnose circadian rhythm disorders solely from sleep diary and patient history.

Alternatively, medical-grade actigraphy can be used for diagnosis (see also here), although this does not replace a polysomnography. Consumer-grade actigraphy (eg, fitbit) cannot be used for diagnosis, but clinicians should still take into account patient-generated health data to investigate further.

In the clinical setting, dim-light melatonin onset (DLMO) salivary sampling is the gold standard, preferably over a period of time longer than 24h, and diagnosis is done just like for sleep diaries by looking for a specific pattern (freerunning, delay, advance, etc), but this test is unfortunately seldom used due to constraints and cost (see also here), most clinics not being equipped to do that and this procedure not being reimbursed by health insurances in most European countries, and hence can be a high financial burden for the patient, with an estimated cost of up to $US10 per sample to assay in 2003. It is also highly cumbersome for the patient, as it requires the patient to be maintained in a dim lit environment to avoid melatonin suppression by light and with samples being taken every 30 min to 1h during at least 6h at night but preferably >= 24h especially for circadian rhythm disorders since the rhythm can be variable between days, causing further sleep disruptions. Hence, individuals' DLMO remain largely undetermined in the clinical setting. However, DLMO can be reliably estimated from sleep diaries, especially when using the sleep midpoint or wake up time. An alternative is to measure melatonin metabolites (6-sulfatoxymelatonin) from urine (see also here). Most currently available objective diagnostic methods are of a high burden to the patient.

Sometimes, salivary sampling over 24h is proposed at home with a home kit (see also here, recommended in this clinical review on DSPD in children). This setting is a very great proposition, but the instructions sometimes fail to account for circadian rhythm disorders. To properly do a home test of salivary sampling, you need to test every x hours as instructed (if you have 12 sampling units, you do one sample every 2h) over 24h, and you need to stay in a black room all day long. Hence, you need to prepare up beforehand, try to do a test day & night without using the sampling kit yet but measure the lux: cover light sources including sunlight as much as possible, check with an lux meter app on Android or iPhone to check that your room is illuminated with less than 10lux during daytime - and of course it's forbidden to light up any artificial light source at any time during 24h! Indeed, to be representative of your circadian rhythm and not have any masking artifact, it's necessary to stay in a dark room during the whole sampling period (usually 24h) as any light source, even low light such as a computer screen, can inhibit melatonin, and here you want to sample your natural melatonin rhythm free of any confounding factor that could influence or inhibit it, especially light.

Clinicians should be aware of the limitations of DLMO sampling, especially that DLMO will vary for a few weeks after melatonin discontinuation. Hence, if the individual is already using melatonin, DLMO sampling should be scheduled no earlier than 4-6 weeks after the patient stopped melatonin intake.

For example, the excellent Centre for Chronobiology in Basel offer at-home melatonin sampling kits, with a protocol involving 8 samples throughout the day and night while staying in a darkened environment, over 2 days that are one week apart (which makes for 16 samples in total), for a cost of about 230 euros in 2021. This melatonin sampling protocol allows to objectively assess a phase delay between the timing of the circadian night sampled on the first day versus the second day a week later, and hence objectively confirm a freerunning circadian rhythm (not just the sleep-wake pattern) and hence a diagnosis of non-24. Hopefully, this testing protocol for non-24 can get generalized in the future, the design is very elegant and efficient.

Novel very promising diagnostic methods that could be faster or used at home include non-invasive core body temperature monitoring which should be the most accurate measure of the circadian rhythm given that body temperature modulation is how cells clocks are synchronized to the circadian rhythm throughout the body, wrist skin temperature monitoring. New non-invasive devices based on heat-flux (zero-heat-flux and dual-heat-flux) technology allow to non-invasively monitor the circadian rhythm continuously, which would allow for a cheaper objective assessment of circadian rhythm disorders such as non-24, as the device can then be re used, and could easily be sent at home for a week for the patient to collect the data themselves. Heat flux devices include the 3M Spot-On (zero-heat-flux) and GreenTEG CORE (dual-heat-flux). The difference between zero heat flux and dual heat flux is that dual heat flux uses two heat flux sensors and consumes much less energy, making it perfect for wearables, whereas zero heat flux needs to be plugged to an electrical outlet due to the higher energy consumption. Core body temperature can be used for diagnosis similarly to sleep diaries, by looking at the patterns of the low phases (freerunning, delayed phase, advanced phase, etc), with the advantage of being less biased by the sleep homeostat, behavior and other factors compared to sleep diaries.

Another novel and very promising diagnostic method is testing the pupil's contraction reflex speed in response to bright white light, which was found to be a reliable discrimination method for DSPD, by assessing the response of both the ipRGC cells but also the cones and rods to bright light. There is however evidence that the pupillary light response (PLR) to bright white light is not necessarily linked with objective sleepiness, the latter being closely linked to circadian dysregulations. An alternative is to test the PLR to only blue light, often called the circadian light, exposure, which is the cause of the maximum post-illumination pupil response (PIPR) test, which can be done either after blue light exposure with varying light intensities or via a chemically induced photosensitivity test. However, these methods are not yet officially accepted for medical diagnosis, and their novelty makes them hard to find at a local clinician in practice.

In the future, a blood test may also allow to diagnose circadian rhythm disorders as accurately as melatonin sampling, but since melatonin levels are only an imperfect proxy to measure the circadian rhythm (see also here), the blood test, just like melatonin sampling, can get a negative result for some individuals who do have a circadian rhythm disorder, but when the test is positive, it can be expected to be accurate, and hence provide a less expensive alternative to melatonin sampling for medical practitioners inexperienced with circadian rhythm disorders.

Sleep clinics offer to do a sleep study, which consists of a set of tests usually including polysomnography, either at home with a home kit or at the clinic (the latter meaning it's necessary to sleep at the clinic). A sleep study allows to mostly assess if there is a sleep disorder and especially sleep apnea and narcolepsy, but they rarely investigate circadian rhythm disorders since they are done only for one night, and circadian rhythm disorders are only revealed in multi-days patterns of sleep. According to a sleep lab technician (see also here), circadian rhythm disorders are not usually assessed during sleep studies as they are considered a diagnosis of exclusion from sleep studies, which is unfortunate since circadian rhythm disorders are a separate clinical entity that is not mutually exclusive with other sleep disorders and can be as disruptive. It is not uncommon for individuals to have both sleep apnea and a circadian rhythm disorder such as DSPD or non-24, and the treatment of sleep apnea usually does not improve the circadian rhythm disorder.
In addition, due to the "first night effect" (ie difficulty in sleeping in an unfamiliar environment), activity and sleep based measures won't be reliable since they only reflect the participant's sleep and hence will be majorly biased by the first night effect, they can only be used if the participant sleeps at home or multiple nights at the clinic and the first night's measures are discarded. Furthermore, sleep clinics often have a defined schedule, so the patient has to fit in and come to sleep only under specific hours, which may not align with the patient's circadian rhythm's current phase, prevent the patient from sleeping when allowed to by the staff and appointment time, although sometimes some sleep clinics can agree to accommodate different schedules so it's worth asking.
Hence, at-home sleep studies are more indicated to diagnose circadian rhythm disorders, and they can also diagnose sleep apnea if present, and this eliminates the risk of not sleeping during the sleep study (the "first night effect"). The only advantage of at-clinic sleep study is to allow to differenciate between the different kinds of sleep apnea (obstructive sleep apnea - where the respiratory tract is mechanically obstructed - versus central sleep apnea - where the cause for sleep apnea is neurological). The best course of action in case of suspected circadian rhythm disorder is hence to first make the patient write a sleep diary, then if a sleep study is required to eliminate other causes of sleep disorders such as sleep apnea, an at-home sleep study should be done first and then only if sleep apnea is detected, an at-clinic sleep study can be done to discriminate the type of sleep apnea.
Doing an at-clinic sleep study as a first indication is a nonsence for circadian rhythm disorders which can only logically result in a lot of misdiagnoses or null results. There is one exception, being at-clinic sleep studies including melatonin sampling and body temperature monitoring under a constantly dim-lit environment, as they can be reliable measures of the circadian rhythm in a one night clinical setting, whereas activity and sleep quality based measures such as EEG, polysomnography or actigraphy cannot (at least in one night). In addition, melatonin and body temperature reflect the circadian rhythm even when not sleeping, so the first night effect has negligible impact on these, but these measures are reliable only when in a constantly dim lit environment, as light can suppress the circadian rhythmicity. However, even with melatonin sampling or body temperature monitoring, a one-night sleep study can only diagnose a delay in circadian phase, hence diagnose DSPD, but not the non-24 disorder since by definition the non-24 disorder needs to display a freerunning pattern over several days. Hence, if a sleep study is required, prefer to conduct it over several days and at-home. Also make sure to ask for an at-home clinic that can be activated by the patient before sleep (and not with a preset time window where the patient needs to sleep - which is unfit to diagnose circadian rhythm disorders in particular non-24).
Note that sleep clinics are fundamentally different from chronobiology clinics, the latter being specialized in treating circadian rhythm disorders, and are hence a good choice for individuals with non-24. But they are rare.

To interpret the results of a sleep study with polysomnography, please refer to this excellent tutorial aimed to primary care physicians but written clearly enough to be interpretable for the general public.

Multiple Sleep Latency Test (MSLT) is the oldest vigilance test. It is often conducted during sleep studies. This test is mostly used to diagnose narcolepsy and sometimes insomnia, but it has no diagnostic value for circadian rhythm disorders, especially since it does not account for the circadian rhythm: indeed, the test consists in monitoring how long it takes for the subject to fall asleep in "conducive conditions" during the period of observation which usually lasts 7h. Ideally, this period should happen during the individual's circadian night, but there is no indication in the MSLT standards to do that. For example, if the MSLT test was to be conducted during the day, all typical sleepers would fail the test and be diagnosed with insomnia since they would take more than 15 min.

At first, you may have to be screened for sleep disorders of respiratory cause such as sleep apnea. Priori to that, you can yourself do a self-screening using a snoring detection app. The author strongly suggest to use Do I Snore Or Grind app on Android (it also detects sleep stages using sound and/or actigraphy on bed - although the accuracy is debatable). If you cannot find such an app for your device, a simple audio recorder will do, then look at the waveform to find the most loud events recorded during your sleep. Indeed, snoring is always a sign of a respiratory disorder, so if you score high on snoring, this may indicate an issue such as sleep apnea, but it is not necessarily the case, so snoring just indicates that further tests at a medical facility are necessary. However, if you score low or no snoring on several days (as it's normal to snore a bit from time to time), then it's unlikely you have a respiratory sleep disorder. Once you got screened for a respiratory sleep disorder and got a negative result, you need to ask your GP to be referred to a sleep specialist to be tested for "non-respiratory sleep disorder", or better a circadian rhythm disorder, although specialists of circadian rhythm disorders are much rarer than more general sleep specialists. It may be more difficult to get to a sleep specialist depending on the country you live in and whether you need to be referred or whether you can go directly. The UK falls in the first category, you can follow these instructions. For other countries such as France, you may be able to search a sleep specialist by yourself and go directly.

Experimental simpler self-screening procedure

This produce of diagnosis was devised by this document's author, it was not yet tested nor peer-reviewed.

If you don't have a sleep diary nor the possibility to do a sleep study in a sleep clinic, here is a self-screening procedure:

  • Just try going to sleep when you are tired and avoid alarm clocks for one or two weeks if possible. If not possible, try to focus on weekends sleep, when you can sleep in.
  • Your natural wake up time is the best indicator of where is your circadian night.
  • After a few days without an alarm clock it should either:
    • stabilize to a late, afternoon time if you may have DSPD.
    • keep on shifting later and later if have non24. This is an average over a week, the change can be more chaotic from one day to the next.
  • How to ensure that you slept in circadian alignment with the circadian night and hence that the estimation is accurate:
    • Pay attention to the duration of your sleep sessions, if they last less than 5h30 (assuming your optimal sleep duration is 7-8h, otherwise calculate the minimal duration of a circadian night sleep = your optimal sleep duration minus one ultradian cycle which last about 2h ; eg, on average for adults, 8h of optimal sleep needed - 2h = 6h minimum duration for a sleep session to be considered in circadian alignment with the circadian night) and are not fragmented nor interrupted and there is no 2-4h nap during the rest of the day/night, then this is strongly indicative of a sleep in circadian misalignment with the circadian night, and can suggest a circadian rhythm disorder.
    • Falling asleep faster is a good sign you are sleeping more in circadian alignment within your circadian night.
  • Naps are allowed, but this will reduce the duration of your main circadian night sleep, and can delay the fall asleep time, but the natural wake up time will remain unchanged and hence a good estimator. The rule of how it works is that we generally cannot sleep more than the optimal duration we need under 24h. So if you need 8h of sleep daily optimally, then you can either sleep 8h at once during the circadian night, or 8h minus the duration of naps you did the rest of the day for a combined total of 8h of sleep over 24h. And if you sleep only outside of the circadian night (ie, circadian misalignment), the maximum duration will be 8h minus one ultradian cycle of 2h = 6h over 24h.

If the result of this procedure is that you may have non24 or DSPD, consider trying to get a formal diagnosis by professionals (see the sections above).

Additional signs of a potential circadian rhythm disorder:

  • irrepressible daytime sleepiness, this is a strong sign.
  • taking a long time to fall asleep, more than 45min, regularly. When sleeping in circadian phase, falling asleep should take less than 30min, and usually it takes less than 10-15min.

Early detection of non-24 in toddlers and infants

As of this writing, there is no documented cases of non-24 in toddlers and infants in the scientific and medical literatures. This does not mean that non-24 cannot affect young children, it just means there is no known information on this question. Hence, there is currently no clinicial who would be willing to diagnose non-24 in a toddler or infant, given there is no medical guideline or even just documented case on how to handle this rare scenario. Nevertheless, given that non-24 can have a genetic inheritance such as in the author's case, it is arguable that non-24 can appear very early. But is it detectable?

A few parents who were suspecting non-24 kindly provided some very valuable data on their toddler and infant's sleep patterns. The author is very grateful for their kind data sharing, with the hopes this will allow researchers and clinicians provide better medical support for infants with non24. The data was anonymized per the common standards in clinical research. Please note the data displayed below is exclusive, this is the first ever documented cases of potential non-24 in toddlers and infants. Feel free to reuse the data, following the requirements of the open-source license that cover this entire documentation.



Top image: One month sleep diary in a 1 year old girl toddler with potentially a non24 sleep disorder. The sleep graph was generated with the smartphone app Huckleberry. Travelled between July 17 midnight until July 22 noon but in the same timezone. The source is from private communications, the parents wished to remain anonymous. Bottom image: Sleep graph from a sleep diary of a typically sleeping baby from 3 months old to 17 months, collected by u/jitney86. For comparison purposes, only the right side of the right sleep graph will be here considered (ie, at around 1 year of age, when the sleep stabilizes in a triphasic sleep pattern).

In both cases, we can observe how both toddlers experience a daily occurring major block of long sleep, which is likely aligned with the circadian night, and several shorter bouts of sleeps, which are naps periods. Interestingly, in both cases, there seem to be on average 2 naps periods in addition to the major long sleep period, hence a triphasic sleep pattern. We can observe that not only does the long sleep period (the circadian night) of the presumably non-24 toddler gets inexorably delayed every days, revealing a characteristical staircase pattern typical of the non-24 disorder, but the nap periods also appear to be delayed as well.


Six months double-plot sleep diary made in a spreadsheet of a 4 year old girl infant (turned 4 year old about in the middle of the graph). The x axis (hour) is duplicated to allow to better observe the sleep pattern, as is commonly done in studies of non24. Right-click on the image and choose "Open image in a new tab" to see in full resolution. The blue colored sections represent the sleep pattern under a prescribed therapeutic protocol by sleep doctors, which involved sunlight therapy, melatonin and sleep restriction. During this period, the girl infant cognitively regressed, losing all the developmental progress obtained so far by the parents since the diagnosis of non24 and allowing their children to sleep in freerunning, and the infant suffered from severe narcolepsy-like daytime sleepiness, falling asleep whenever the infant wasn't stimulated (eg, just going to the toilets and coming back, the infant was asleep in plain day). This daytime sleepiness was a clear sign of severe sleep deprivation. The parents decided to stop the protocol and allowed again their infant to sleep as they need, with a freerunning pattern. The developmental progress was then restored and resumed. According to the parents, the daily freerunning delay is on average 45 min, except when the circadian night overlaps with the objective day period, then the freerunning accelerates due to relative coordination with sunlight. The M label in some cells represent the time of exogenous melatonin intake. The source is from private communications, the parents wished to remain anonymous.

Just like the previous one, this sleep graph reveal a clear staircase-like sleep pattern, very typical of the non-24 disorder and its freerunning circadian rhythm phase. But here the child is older, hence with a more consolidated sleep, with much rarer naps at ~4 years old than the child above at ~1 year old. This graph also allow us to observe the sleep pattern over a much longer period of 6 months, which demonstrate how the freerunning sleep pattern is quite stable over time, repeating indefinitely at approximatively equal periods. The sleep disruptions due to environmental disturbances or social (school) requirements are also apparent, especially during the phases when the circadian night is opposite to the day-night cycle (ie, the child sleeping during the day).

The child was also diagnosed with autism, and her cognitive development tremendously progressed when her freerunning sleep was left unrestricted (ie, sleeping whenever she needed to, including naps), which brought praises from the medical staff. The naps also progressively disappeared (this can be already observed towards the end of the above sleep graph, and the trend continued beyond), as the circadian rhythm and sleep processes matured, in line with what can be observed in typically sleeping children. The impressive cognitive development and the natural reduction in naps at the expected age suggest that, at least in this case, letting the child sleep according to their circadian rhythm (including naps) contributed to their natural cognitive and sleep development, contrary to what could have been assumed.
Nevertheless, this is in line with previous research. Indeed, it is now widely recognized that "poor sleep exacerbates problematic daytime behavior", especially for children and adolescents with severe symptoms associated with ASD, as sleep patterns predict with a 81% accuracy worsened behavior in individuals with low-functioning autism. Sleep deficits also lead to difficulties in communication, as well as increased restrictive and repetitive behaviors. The American Academy of Neurology published guidelines in 2020 to recommend to systematically screen autistic individuals for sleep issues, and for sleep to be a primary target of treatment as a major way of improving the quality of life and the symptoms of autism. A 2018 review even suggested that autistic children should be profiled based to design better targeted interventions. Sleep issues are indeed highly prevalent with individuals with ASD: 44% to 83% of children and adolescents with ASD have sleep issues.

These two sleep graphs provide the first recorded evidence that the non-24 circadian rhythm sleep disorder is potentially detectable very early in life, potentially even towards the end of the 1st year of life in toddlers.

Unfortunately, some clinicians confuse non-24 in toddlers and infants with an irregular sleep-wake pattern, which is common for very young toddlers in the first 3 months of life, when the circadian rhythm has not yet matured. But even then, the major, long sleep period in phase with the immature circadian night can be clearly separated from the daytime fragmented sleep-wake periods (ie, lots of daytime naps):


A sleep graph for an even younger infant from 3 days old to 3 months old, showing a irregular sleep pattern due to an immature circadian rhythm system. By u/AtmosChemist.

Although data is lacking for children this young, given the evidence collected above about the non-24 pattern clearly appearing as a staircase-like pattern of the long sleep period, it can be argued that the same staircase-like pattern may appear in sleep diaries or actigraphy logs of even younger children, regardless of the daytime sleep-wake fragmentation.

Although all sleep graphs above were generated manually by the parents curating a sleep diary for their children, it's alternatively possible to use actigraphy to record children's sleep-wake patterns, by attaching the actigraph on their chest using a chest strap, as it is not possible to attach it on their arms since they are so small. This harmless procedure is common in medical studies. However, only clinical-grade actigraphs should be used, since commercially available actigraphs, and even some clinical-grade actigraphs, are unable to reliably record daytime naps, which can explain why most studies on children sleep do not account for naps, and hence they are also unreliable to detect the circadian night of children with non-24 when their phase is opposite to the objective day-night cycle.

Some practitioners, when treating a toddler or infant with non24, prescribe sleep or nap restriction, ie, avoiding naps or even restricting sleep. This is a very unfortunate and uninformed decision that impairs the child's cognitive and neurological development. Indeed, it was demonstrated that napping toddlers retain learnt spatial information, whereas toddlers who remain awake forget. Memory consolidation is crucial in the child's development, as it precedes lexical development, and is mostly done during sleep. But sleep also affects semantic development, since infants who napped, but not those who remained awake, could remember 1.5h after the learning event what was the precise word meaning and moreover how to classify new category exemplars they did not see before, demonstrating a capacity for generalization that infants who avoided naps could not. Another study demonstrated that naps promoted abstraction in language learning of infants, another high level cognitive capacity. In fact, a study shown that 3-years-old infants could only remember a visual stimuli, a cartoon face, 1.5h-2h after presentation only if there was a period of sleep/nap in-between, even if short, hence the authors concluding that even short naps are beneficial for infants memory development (and likely other cognitive functions). Chronic sleep loss impairs neurodevelopment and incurs neuronal loss, especially if from a young age. In summary, sleep including naps is necessary for children's neurocognitive development. Sleep and nap restriction should hence be avoided. It's worth noting that most of the studies promoting sleep restriction on children were using imprecise actigraphs or behavioral questionnaires, which were so imprecise they couldn't record daytime naps.

Why detect a circadian rhythm disorder so early in life? Early detection of disease is well established to be the main method to obtain more favorable outcomes. Despite widespread assumption that children may outgrow their sleep issues, there is no evidence of that for either non-24 or DSPD, as of course the presence of these disorders in adults demonstrate they do not necessarily disappear with age. An unaccommodated and untreated circadian rhythm disorder cause chronic sleep deprivation and chronic circadian misalignment, both having serious detrimental effects on the health of adults and even more severe effects on the development of children. Chronic sleep loss impairs neurodevelopment and incurs neuronal loss, especially if from a young age. Chronic sleep deprivation increases the risk of cardiometabolic diseases, even in children. Chronic sleep deprivation greatly impairs academic performance of children and teenagers. Growth hormones are mainly released during sleep, so that it can be expected that chronic sleep deprivation may stunt height growth. Innovative thinking and flexible decision making to adapt to new situations and find new solutions, crucial skills for academic success, are drastically impaired by sleep deprivation. Indeed, sleeping allows to find innovative mathematical solutions and patterns compared to individuals who do not sleep during the time gap between problem presentation and restitution (see here for a layman presentation). Even if the patients have comorbid diseases, clinicians should be cognizant about sleep disruption complaints, especially with children and teenagers, as sleep disruption worsen all risks of comorbidities. It is hence no surprise the AASM released a recent (as of 2021) scientific statement emphasizing sleep as essential to health, especially for children. Indeed, sleep medicine researchers previously called for the recommendation of systematically assessing pediatric sleep disturbances using standardized scales.

Quantifying parameters of a non24 case

(TODO: work-in-progress)
The major characteristic to quantify a non-24 pattern is to calculate the circadian period/length (tau), which is informally the length of the internal day and night for an individual with non-24.

Formula to calculate the circadian period: tau = average of daywise differences of midpoint of sleep or wake up times + 24h.

Step-by-step calculation of the circadian period:

  1. From a sleep diary, write down the midpoint of sleep for each day. The midpoint of sleep is calculated as latest wake-up time - earliest fall asleep time.
  2. Start from the latest date, and calculate midpoint_n - midpoint_n-1 (ie, subtract the midpoint time of the day before the last day from the midpoint time of the last day). Then continue with the other days similarly, ie: midpoint_n-1 - midpoint_n-2, etc. You will end up with a serie of n-1 values, which represent the daily freerunning delay, which is the amount of phase shift observed between each day.
  3. Calculate the median of this serie. This gives the median daily freerunning delay, aka median daily phase shift. An average works too but is more sensitive to noise.
  4. Finally, add 24h to this average. This should end up with a value greater than 24h if there is a non-24 pattern.

The above is the ideal, most accurate way to calculate the circadian period. It requires data over at least 2 weeks with unrestricted sleep (ie, no alarm clock).

There are other simpler methods to calculate the circadian period:

  • By doing the same calculation as detailed above but using the wake up times of the longest sleep session each 24h instead of the midpoint of sleep, as the wake up times are easier to collect.
  • By counting the duration of a full freerunning cycle: allow the individual with non24 to make a complete around-the-clock freerunning course and record a sleep diary during this whole period. This means that the individual must wait until they record a sleep session for which the wake up time is close to the wake up time that happened at the start of the freerunning course. In other words, count the number of days it takes for the individual to do a full freerunning cycle, the sleep diary is there to know more precisely when the freerunning course is completed. Then, the circadian period is simply 24h + 24h/(the number of days that separate the two sleep sessions). For example: if it takes 12 days to do a full freerunning course, the individual's circadian period is: 24 + 24/12 = 26h circadian period length. The disadvantage with this method is that if the individual has a short circadian period (ie, 24.3h to 25h), and hence a long freerunning cycle, they will have to wait a long time before being able to calculate their circadian period.
  • By calculating the difference between 2 wake up times at least 2 weeks apart (or longer for more accuracy). This method is much less accurate than the others above as it is more prone to noise since there is no averaging, so the estimated period is very imprecise and can change a lot when using different time points (ie, days). The wake up times need to be less than 24h apart, ie, less than a full freerunning cycle between these two timepoints. To calculate: circadian-period = 24h + (last-wake-up-time - earliest-wake-up-time) / number-of-days-between-the-two-timepoints. For example, let's say the circadian phase shifted from 8am to 2pm over the course of 12 days. The circadian period can be calculated as follows (note: 2pm represented in 24h format as 14h): 24h + (14h - 8h)/12 days = 24.5h. Tip: for a much increased accuracy, select only the sleep sessions that are long enough, ie, with a duration close to the ideal sleep duration needed by the individual (look at the excerpt below for reference of average sleep durations by age). This is because a long sleep session is likely an indication of a sleep in phase with the circadian night, so that there is more confidence that a long sleep session does represent the circadian phase of the circadian night at the time, and not a circadian misaligned sleep session that happened only thanks to the sleep homeostat.
  • By calculating the difference between the number of internal days versus the number of objective days. This method was devised by reddit member u/non-24 and explained here (and here).

(TODO: average sleep durations per age ref: https://pubmed.ncbi.nlm.nih.gov/29073412/
> Results: The panel agreed that, for healthy individuals with normal sleep, the appropriate sleep duration for newborns is between 14 and 17 hours, infants between 12 and 15 hours, toddlers between 11 and 14 hours, preschoolers between 10 and 13 hours, and school-aged children between 9 and 11 hours. For teenagers, 8 to 10 hours was considered appropriate, 7 to 9 hours for young adults and adults, and 7 to 8 hours of sleep for older adults.
>
> Conclusions: Sufficient sleep duration requirements vary across the lifespan and from person to person. The recommendations reported here represent guidelines for healthy individuals and those not suffering from a sleep disorder. Sleep durations outside the recommended range may be appropriate, but deviating far from the normal range is rare. Individuals who habitually sleep outside the normal range may be exhibiting signs or symptoms of serious health problems or, if done volitionally, may be compromising their health and well-being.)

Hypersomnia and non24, which we could classify as a subcategory of non24, is when the non24 disorder is not caused by a too long period of wakefulness, but when the sleep period is too long for a 24h day.
To know if hypersomnia, (TODO: check criteria, is it sleeping more than 12h?)

Severity can be considered to be proportionate to the length of the circadian period, as indeed stronger phase advance therapies are required to offset more the longer the period. In practice, it can be assumed (and from anecdotal feedback) that periods up to 26h are likely responsive at least partially (although this does not mean that full entrainment can be reached with current therapies). Periods of more than 28h are likely too wide to be responsive enough to current treatments (this does not mean that they are not responsive, but that the phase advanced benefit from currently available therapies are likely not enough to reach any satisfactory reduction of the circadian period, which anecdotally match with the feedback received in private communications). Extreme periods of 30+h are usually associated with intensive past use of benzodiazepines and other strong psychotropic medications, and/or alcohol, and/or RLS/PLMD (which symptoms can be triggered/worsened by melatonin and hence indirectly by bright light through photic history's increase of melatonin). There appears to be a sweet spot for periods of about 25h-26h, as this represents an average daily freerunning delay of 1h to 2h, which means that the individual goes through a complete phase reversal (ie, a 12h shift, which means going from wakefulness during the day to during the night and vice versa) every 1 to 2 weeks, which according to private communications feedbacks and public posts on reddit seem to allow for a better quality of life as they can expect to be able to resume typical daytime activities every 1 to 2 weeks, alternating with 1 to 2 weeks of nocturnal activities. This rapid-but-not-too-rapid cycling allows them to find consistency in the alternance of this schedule. Indeed, slower circadian periods such as 24.5h cycle phase reverse about every 1 month, which means they cannot do typical daytime activities for a full month, and is especially problematic with work (severe chronic sleep deprivation may be powered through for 1 to 2 weeks, but not a full month). Faster circadian periods more than 28h cycle so fast that they complete a phase reversal under less than half a week.

Medical misdiagnoses

How to detect and avoid a misdiagnosis?
The greatest early sign of misdiagnosis is the dismissal of sleep diaries by a doctor. If the doctors you met shrugged off the sleep diary, or the sleep clinic where you had your sleep study did not include a 2-weeks sleep diary, then that's a clear sign they are not properly trained to diagnose circadian rhythm disorders, as sleep diaries over at least 2 weeks are the standard method to diagnose insomnia since 2008 and circadian rhythm disorders according to american and british guidelines. Furthermore, the american guidelines on patient-generated health data (PGHD) using consumer-grade sleep technology such as fitbit or sleep diaries state that this data should be used to (at least) open dialogue with the patient, that the clinician should understand the data and that "clinicians should recognize the patient's use of consumer sleep technology as a commitment to focus on sleep wellness". In other words, handing over your sleep diary of at least 2 weeks should be sufficient for any properly trained sleep specialist to diagnose you if you have a circadian rhythm disorder, should be considered an indication of your motivation to get better, and should certainly never be shrugged off (see for example these unacceptable patient experiences, with general practitioners denying specialized testing despite adequate data). If this happens to you, seek counseling from another medical professional.

Although there is an official diagnosis criterion according to the AASM (simply to have a sleep diary over at least 2 weeks showing a freerunning pattern), the author is convinced this criterion is both too vague and too restrictive. Indeed, it is too restrictive as it doesn't account for people who constraint their sleep schedule and hence can't freerun, and too vague because all humans can freerun given an environment devoid of timecues, the specificity of non-24 is that freerunning (and the cyclical inability to sleep and wake up) happens continuously despite environmental timecues (ie, zeitgebers).

Causes of misdiagnoses: psychology misdiagnoses
Circadian rhythm disorders are often misdiagnosed (see also here), which can cascade and leads to unnecessary distress despite being easily diagnosable and may lead to inappropriate prescriptions of psychoactive drugs. Most often, the misdiagnosis is confusing non-24 or other circadian rhythm disorders for DSPD, since this is the most commonly known circadian rhythm disorder in non specialists fields of medicine, but misdiagnoses of inexistent psychiatric disorders is also common. Misdiagnosis and medication errors are frequent and the most common types of medical errors. A psychological misdiagnosis (such as psychosomatic disorder, medically unexplained symptoms, or others as seen below) worsen these issues, as this can have dramatically detrimental consequences for the patient with a rare disease such as non-24, as they already wait an average of 4.8 years to be diagnosed, and a psychological misdiagnosis delays 2.5 to 14 times longer the proper diagnosis of their chronic rare disease, according to a survey of 12,000 European patients, with this delay being harmful for a majority of patients. Psychological misdiagnosis does not affect only new and rare diseases but also well-documented physical diseases such as epilepsy. This was sadly illustrated in a horrible case of iatrogenic (medical) mistake from both psychiatry and psychology practitioners on a 14-year-old boy as reported in this study:

> A 14-year-old male was referred for sleep disorder assessment with the complaint of daytime sleepiness and lack of motivation. [...] During the 4 years before referral, the patient suffered from major functioning difficulties including conflicts with teachers, parents, and peers. He was described by a licensed child psychologist as being extremely introverted with severe narcissistic traits, poverty of thought, and disturbed thinking, including thoughts with persecutory content and self-destruction that led to a paralyzing anxiety, anhedonia, social isolation, and withdrawal. [...] Two years before referral, the patient dropped out of school and was sent to an inpatient child psychiatry center. Three months of psychiatric evaluation yielded diagnoses of atypical depressive disorder with possible schizotypal personality disorder. He was described as sleepy and passive, especially in the mornings. The patients psychiatrist suggested further assessment, including assessment of sleep disorders. [...] Failure to make a correct diagnosis led to psychological distress and personal turmoil for a boy whose sleep disorder was easily diagnosable and treatable with melatonin. [...] Greater awareness of sleep disorders may prevent psychiatric misdiagnosis of treatable sleep-wake schedule disorders.

The misdiagnosis of sleep disorders is also much more frequent in children, as historically, sleep disturbances in children have largely been ignored by the psychomedical field.

As demonstrated by this case, misdiagnosis of sleep disorders (here non-24) as a psychological disorder is common, especially of schizotypical, schizoid or schizophrenic disorders. Indeed, two major items of the schizo* spectrum are dissociative symptoms such as depersonalization/derealization (see also here and here), and social isolation, both being also caused by severe chronic sleep deprivation due to sleep disorders. Add on top the specific difficulties of non-24, such as the nightwalking phases during which the individual will be exclusively living at night and sleep during the day for months, which necessarily leads to social isolation due to the mismatch of the individual's sleep-wake schedule with the rest of the world and cause feelings of being "disconnected from reality" which are perfectly normal as they were also experienced by typical sleeper archeologists such as Siffre during their "expériences hors du temps" in caves disconnected from external interactions and zeitgebers for months. Furthermore, episodes of depersonalization and derealization are extremely common in the general population, as 26% to 74% experience them at some points in their lifetime according to a systematic review (see also here). For healthy, typical sleeper participants, 52% experience dissociative symptoms including depersonalization and derealization after 24h to 48h of acute sleep deprivation according to a systematic review. Despite the normalcy of these feelings, and the challenged unproven assumptions that dissociative disorders cause sleep disorders in response to trauma, whereas empirical evidence demonstrate the opposite to be true as shown by the excellent works of Dr. Dalena van der Kloet (see also here), the mere evocation of these feelings by the patient is a recipe for a misdiagnosis of a schizotypical disorder by psy* clinicians, regardless of the chronicity and context of their occurrences.

Unfortunately, although these effects of sleep deprivation are well documented, most psychiatrists and psychologists are unaware of this knowledge about sleep, even when they practice in a sleep clinic. Even in the rare instances they are, they tend to focus on treating the psychological symptoms (assumption of an intrapsychic cause), assuming this is the cause of the sleep disorder. However, the results of a recent systematic review state that sleep disorders often precede psychological disorders symptoms onset, they persist even when psychological disorders are well controlled and hence that "sleep problems require independent attention irrespective of co-morbid conditions". Unfortunately, psy* clinicians are unlikely to consider sleep disorders as anything other than secondary to psychological disorders contrary to the evidence, as otherwise they would be unable to provide any service to their insomniac patients. This kind of misdiagnosis also happens at sleep clinics, since they often have psychiatrists and psychologists in their staff.

These misdiagnoses are unfortunate, as an accurate diagnosis of their medical condition allows circadian rhythm disorders sufferers from being relieved from the "humiliation" and social guilt of their self-perceived "bad behavior", which can dramatically improve their and their family's wellbeing.

These misdiagnoses, especially psychological ones, are often due to a failure in adequately testing the potential hypotheses. For example, studies on "paradoxical insomnia" always fail to test the circadian rhythm, and a reddit member even reported the sleep clinicians, after misdiagnosing non24 as paradoxical insomnia, argued that testing for a circadian rhythm disorder was unnecessary as it was useless. It's surprising some clinicians consider that getting an appropriate diagnosis for a condition that is partially treatable, versus another condition that is not, is useless.

In practice, avoid psychiatrists, psychologists and psychotherapists when looking for a clinician to diagnose a sleep disorder, as they will rather favor intrapsychic explanations and hence diagnose and treat psychological disorder (even if there is none) rather than the sleep disorder. Furthermore, avoid any clinician recommending sleep deprivation, chronotherapy or any form of sleep deprivation such as avoiding naps, as sleep restriction is never a treatment for sleep deprivation, just like dietary restriction is never a treatment for malnutrition. Timing therapies to an absolute/fixed target bedtime or wake up time instead of relative to the current circadian phase (eg, natural bedtime and wake up time) is a red flag too, as it is a fundamental error no sleep chronobiology expert would do, it's literally nonsensical given how zeitgebers work (ie, PRC curve).

Causes of misdiagnoses: medical procedure and cognitive errors
All fields of medicine are plagued by systematic procedure and cognitive errors that can lead to misdiagnoses. Although studies on this topic are sparse, especially for mistreatments and prognosis, several authors could identify the most common errors that account for misdiagnoses.

Among systemic errors, the lack of education on the latest findings in sleep medicine is certainly a major factor:

  • An important factor to consider is that the clinical practice (medicine) lags on average 17 years behind translational research. Note this is an average! The paper shows the intervals for various domains, and in some cases the clinical practice can be "221 years" behind the current scientific knowledge! This is why the consensus found in scientific papers can seem very remote, even opposite at times, to the clinical practice (eg, insomnia being wrongly assumed to be secondary to psychological disorders).
  • In the case of sleep medicine, this lag is verified. Historically, sleep disturbances have been largely ignored by the psychomedical field, missing unique opportunities for improved health outcomes. Even nowadays (as of 2021), "education about sleep and sleep disorders is lacking in medical school curricula, graduate medical education, and education programs for other health professionals" according to the AASM (see also here), which the AASM recommends to change by teaching sleep health as a prominent element since a young age at school and up to medical school curricula. As the authors write: "A multi-nation survey of medical schools found that the average amount of time spent on sleep education is just under 2.5 hours, with 27% responding that their medical school provides no sleep education."
  • More generally, there seems to be a lack of adequate training in the medical cursus for the handling of chronic illnesses, and the public is now discovering this at large now that they experience the widespread long covid chronic illness.
  • Gender also plays a role, since women are much more likely to be discharged without a physiological illness diagnosis but instead with a "junkbin diagnosis" such as anxiety or stress (TODO: add refs). For example, sleep apnea has historically been underdiagnosed in women.
  • "Iatrogenesis is the fifth leading cause of death in the world. There are about 5%–8% of deaths due to adverse drug reactions worldwide. [...] Among the European Union Member states, WHO concluded that the healthcare-related errors occur in 8% to 12% of hospitalizations." https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6060929/
  • The medical work culture is not tolerant of chronic illnesses in their workforce, which removes profiles who could provide a interesting transversal contribution to the field. See for example the reddit r/DisabledMedStudents. More specifically, there are lots of complaints from medical students with DSPD, despite DSPD med students being ideal to work night shifts, but the prevalent dogma is that med students should work the day, and those who work the night are expected to be available day and night (see r/NightShift).

Another major factor is chronic sleep deprivation and the "no sleep culture as a badge of honor" in the clinical workplace:

Developing health literacy to avoid misdiagnoses and improve health outcomes
Hence, it is necessary for people with a circadian rhythm disorder to be resilient and develop their health literacy as recommended by medical organizations in order to navigate the information and circumvent the potential misdiagnoses they may encounter during their journey to get medical help for the diagnosis and management of their condition. Indeed, it was demonstrated by several studies across various subpopulations that people that have more understanding of their health and medicine have better health outcomes (see also here). Online forums have plenty of anecdotes of life-saving self-diagnoses. Hence, monitoring of one's own symptoms and vital signs, as well as reading about one's own (suspected) ailment ought to be recommended to the patients, and these patient-generated data should be taken into account by the medical practitioners.

Indeed, excluding patients' personal knowledge from medicine is not scientific but scientism which impairs the medical practice and ethics:
> Medical scientism is the imperative to define and achieve all medical goals through science. This imperative manifests in numerous ways and is particularly evident in the objective−subjective dichotomy, whereby objective knowledge is viewed as superior and subjective knowledge is regarded as inherently suspect. In this paper, we argue that medical scientism is flawed because it only recognizes what we call general and explicit knowledge and excludes what we call tacit and particular knowledge. This exclusion is epistemic, in that tacit and particular knowledge may be implicitly recognized by scientism, though not as genuine knowledge but as some modulating factor in the application of scientific knowledge (from a Kuhnian perspective [Kuhn 1996]; this is because recognizing tacit and particular knowledge as valid knowledge would undermine the foundational assumption of the scientistic paradigm that the quality of knowledge is related to the extent and rigour of its justification). Such factors, which are invoked through terms like clinical expertise or patient preferences, we suggest are more accurately described as valid and necessary forms of medical knowledge, with features that distinguish it from the knowledge science delivers. We argue that the exclusion of tacit and particular knowledge impairs our ability to achieve medicine’s goals, primarily because these knowledge forms are essential to doing medicine and secondarily because the overemphasis of general-explicit knowledge distorts our perceptions of what legitimate medicine should be. These impairments relate to a range of domains of medical practice, from the reasons supporting one treatment over another through to health policy and even to the legitimacy of different kinds of ethical arguments. [...] Scientism, we argue, excludes tacit and particular knowledge and thereby distorts "clinical reality" and impairs medical practice and medical ethics.

Paradoxically, the clinician's personal knowledge is often used to guide diagnostic and theurapeutic courses, regardless of their (lack of) evidence base, which is usually termed "clinical lores".

TODO: also read Michel Foucalt on history of medicine and how it was used to control populations as part of "biopolitics", term that he coined.

Why can't people with non-24 simply sleep when needed? Why trying to do so causes a chaotic sleep?

Sleep is not a matter of personal preferences. Humans cannot control the circadian rhythm by will, that is a common misconception and the root cause of ineffective treatments. Otherwise, if sleep control by will was possible, sleep disorders such as insomnia and non24 would not exist. Night shift would not lead to chronic insomnia and major health issues such as cancer. Humans cannot control their circadian rhythm by will, just like they cannot control their insulin levels by will, as they both are biological processes.

However, we can manipulate our insulin levels to some extent by controlling our carbs intake, just like we can manipulate our circadian rhythm to some extent with external tools such as zeitgebers (eg, bright light and melatonin). But not by will. That is a common misconception about sleep and the major cause of improper management and lacking development of proper tools to manage sleep disorders. This major realization underlies the VLiDACMel protocol, after countless of failed attempts with various will-based schemes (eg, chronotherapy), only the use of external tools allowed some degree of manipulation of the circadian rhythm.

The intuition that sleep is controllable is only natural, as the circadian rhythm is deeply hidden and often imperceptible. When everything works, it's only natural to think it's easy. But there are a few cases where anyone can experience circadian disruptions and hence the existence of their own circadian rhythm: jet lag and night shift work. Indeed, anyone travelling between timezones will feel restless for days/weeks, having difficulties falling asleep at the local night time, until magically after a few days/weeks we become accustomed. That's because of the circadian rhythm progressively readjusting, which takes some time. If we could sleep whenever we wanted/needed, jet lag and night shift work disorder wouldn't exist. Now imagine being constantly jet lagged, as if your body never recovers from jet lag after a travel, and you can get an idea of what non-24 and other circadian rhythm disorders (eg, DSPD, night shift work) are like.

When someone tries to sleep outside of their circadian rhythm to meet social obligations, this means that they then have to rely only on the second sleep process, the sleep pressure (process S of Borbély's model), to be able to initiate sleep while fighting the natural sleep propensity induced by the circadian rhythm (process C). Since the circadian rhythm continues to periodically cycle in the background, it will periodically enhance the ability to sleep (too early or too late compared to the individual's social constraints), which will compound with the sleep pressure and produce alternating periods of hyposomnia (sleep deprivation because of social constraints preventing sleep initiation when the circadian rhythm allows it) and then hypersomnia (because of the accumulated sleep debt that will magnify the circadian rhythm). Adding in the ultradian gates to sleep, this all combines into producing a chaotic sleep pattern, where the individual with a circadian rhythm disorder or doing night shifts will alternate between sleeping little to none one day, and then crash into bed for a very early and long night of sleep the next day because of the huge sleep debt, and this alternating cycle will repeat until the body can't take it anymore.

Hence, an individual with non-24 who tries to maintain socially acceptable schedule will necessarily restrict their sleep, which will only cause more sleep deprivation and chaoticity in their sleep patterns (and hence reduce their ability to plan appointments, which makes this whole approach highly counter-productive. As this study explains:

> The pattern of sleep disruption experienced by patients with the disorder does not always present as a shift in sleep timing each day. A majority of individuals will attempt to maintain sleep at a socially normal time. As a result, some individuals will produce a sleep pattern with the nocturnal sleep episode expanding and contracting as they move in and out of phase and with the build up and pay-back of homeostatic sleep pressure. Due to the pleomorphic variation in patient's sleep timing, a review of sleep history may not reveal a clear cyclic pattern to indicate the presence of N24HSWD. These more subtle cyclic changes are termed “relative coordination” and often require an expert to review.

People with no circadian disturbances often advise to "just try to sleep at the time you need". More formally, this is a form of sleep hygiene, the oldest treatment for insomnia. However, AASM guidelines since 2008 and in a 2021 systematic review state that sleep hygiene is not supported as a single therapy, it is not sufficient to improve sleep disturbances, which should not come as a surprise given the above info on how the circadian rhythm orchestrates sleep.

The use of sleeping pills is also inappropriate for non-24: "The circadian basis of N24HSWD distinguishes it from other sleep-wake disorders, and therefore use of hypnotics and stimulants to address the sleep and sleepiness symptoms, respectively, is not appropriate."

When you sleep outside your circadian phase, it's the sleep pressure that you will then use to sleep. The first day you can't sleep so you'll sleep late, but since your sleep is restricted you'll wake up with some residual sleep pressure, so the next day you'll sleep early because you'll have today's sleep pressure, plus yesterday's residual. This day you'll sleep a long night, maybe even too early and too long. Bu the next day the vicious loop starts again: can't sleep until late because your biological night is delayed compared to the objective night, so you'll keep some residual sleep pressure at wakeup, etc...

If your biological night is just a bit delayed, let's say a few hours at most, you can sustain like that for a long time although it's unhealthy and straining. But if your biological night is a lot later, let's say into the day, then you'll accumuate too much sleep pressure debt to repay in one night, and so you'll keep residual sleep pressure and eventually just collapse with a behavioral sign thad resembles hypersomnia or narcolepsy.

Hence, a pattern of chaotic sleep is likely a sign of oscillation of sleep pressure. This suggests that chaotic sleep can simply be caused by sleeping outside of one's own biological night as defined by the circadian rhythm. This is not specific to individuals with circadian rhythm disorders, but it more often happen to them due to their circadian rhythm being out of phase with social obligations.

TODO: add graphic and sourcecode of model reproducing a chaotic sleep pattern from simply: process C, process S, ultradian cycle, exogenous sleep onset constraint: only outside of process C (can define anytime to see what happens when can sleep in the process C), endogenous sleep onset constraint: addition of all processes must reach a certain threshold for sleep to occur (hyposomnia, can't sleep) + high threshold when sleep onset is irresistible (hypersomnia). Sleep onset is not deterministic but is probabilistic. Generate graphs with various values for these parameters, should reproduce non24 pattern with chaoticity. Can extend the usefulness of the model by learning with viterbi the hidden parameters from real sleep logs to make a predictive model and estimate the parameters on an individual bases (may help in differenciating different subkinds of non24 and adapt therapies accordingly, ie some may have a stronger process S than others compared to process C). ADDENDUM: meanwhile, there was a post on reddit ELI5 that more or less describe the same idea in more layman terms.

Health issues of a circadian rhythm disorder

Keep in mind that ignorance doesn't shield from detrimental health effects. But knowledge may allow to overcome.

Why do we need to sleep?

It's common to hear among insomniacs claims that one sustained a month without sleeping at all, while another didn't sleep in years. This is false. Dangerously false.

The world record for the longest sleep deprivation is held by Randy Gardner, who could stay awake for a little more than 11 days straight with the help of friends and families keeping him awake, until he had to stop for health reasons. Indeed, he was on the verge of dying, plainly. After achieving his world record, this "good sleeper" according to his own words became a very severe insomniac ("unbearable insomnia"), being unable to sleep more than a few hours in a single session for decades. His extremely prolonged sleep deprivation streak left his sleep process dysregulated for decades, making him publicly state that he regreted his world record. He is not the only one, before him, Peter Tripp did a similar experiment, which shown that sleep deprivation detrimental effects on health and cognition appear much earlier, as soon as the next day without sleep.

Indeed, it's now well established by systematic reviews that sleep deprivation causes hallucinations, depersonalization, derealization and delusions.

However, contrary to what was previously assumed by scientists, sleep deprivation kills not because of the brain, but because of the guts: indeed, sleep primary function is to clean up and relieve the oxydative stress from the guts that is produced by ingested food, the greatest source of reactive oxydative species (ROS). These ROS elements accumulate in the guts, and sleep cleans them up. In the absence of sleep (or melatonin), ROS continues to accumulate unchecked and leads up to a swift death. The brain has nothing to do with sleep deprivation induced death, it's irrelevant whether the brain sleeps (or secrete melatonin) or not, what matters is only whether the guts are cleaned up.

Due to the paucity of research, and because sleep and the circadian rhythm are highly conserved vital biological processes throughout evolution and species indicating that the same results should apply to all organisms, other health issues involving circadian misalignment and sleep deprivation were included, similarly to what was done by other studies. For example, a very close model of non-24 (endogenous disorder) is chronic jet lag disorder (exogenous disorder) as experienced by flight staff, and a similar model to DSPD (endogenous) would be night shift work disorder (exogenous).

The AASM published a position statement in 2021 affirming sleep as an essential need, just like food and water, for all humans and especially children (see also here for a vulgarized article):

> Healthy sleep is as important as proper nutrition and regular exercise for our health and well-being, and sleep is critical for performance and safety. It is the position of the AASM that sleep is essential to health, and we are urging educators, health care professionals, government agencies, and employers to prioritize the promotion of healthy sleep.

They further state four points to implement:

> * Sleep education should have a prominent place in K-12 and college health education, medical school and graduate medical education, and educational programs for other health professionals.
> * During patient visits, clinicians should ask about sleep patterns and symptoms of sleep and circadian rhythm sleep-wake disorders, and hospitals and long-term care institutions should improve sleep environments.
> * To enhance health-related outcomes, public health and workplace interventions should focus on good sleep, and habits that assist people in achieving healthy sleep should be actively supported.
> * To better understand the relevance of sleep for public health and the implications of insufficient sleep to health inequalities, more sleep and circadian research is needed.

Overview of health risks of circadian disruption and sleep deprivation

Why modify your circadian rhythm? What are the health costs of free-running, circadian disruption/misalignment or chronic sleep deprivation?

Sleep is a highly conserved functionality throughout the animal kingdom, despite the dangerosity for animals to sleep and be defenseless against predators. All species also have a "profound drive to maintain a regular sleep-wake cycle" (ie, circadian alignment), with disruptions having wide reaching detrimental effects in performance, safety and health. On a scale of urgency of importance for survival, sleep deprivation kills in a few days, whereas food in a few weeks. Hence, both sleep and circadian alignment must serve at least one or several vital purposes.

Everybody has a set period to sleep, even typical sleepers: those who have a night shift job but can't sleep a full night during the day have shift work disorder. The difference with (endogenous) circadian rhythm disorders as that the individual's circadian rhythm is different from the socially acceptable norm. Those who can't sleep as early as socially acceptable have Delayed Sleep Phase Disorder (DSPD), and those who have a sleep period that changes everyday have non-24. In all of these cases, including shift work disorder, sleeping outside of the biological night leads to detrimental health issues. Indeed, everybody can wake up at any time for some time at the expense of sleep deprivation, but doing so for too long or too regularly will invariably lead to death.

The primary issue with having a circadian rhythm disorder is obviously the huge chronic sleep deprivation that is constantly induced by the social jetlag (ie, the attempts to constraints to social expectations/requirements for work, family, hobbies, etc). Chronic sleep deprivation is a major health issue, not only for circadian rhythm disorders, as most people in modern society are sleep deprived (social jetlag), although usually not to the extent and frequency that individuals with a circadian rhythm disorder experience. There are plenty of resources showing how harmful and dangerous sleep deprivation is, and is one of the rare disorders that can directly and swiftly cause death if too prolonged or too chronic. Circadian misalignment, also called chronodisruption, was also shown to lead to a higher mortality in general.

According to the AASM and CDC:
> Chronic inadequate sleep and untreated sleep problems, according to the study’s authors, are associated with an increased risk of cardiovascular disease, diabetes, obesity, occupational accidents, and motor vehicle collisions.
>
> According to the CDC and the Maternal and Child Health Bureau, 34.1 percent of children, 74.6 percent of high school students, and 32.5 percent of adults in the United States do not get enough sleep on a regular basis. As a result, one of the aims of Healthy Individuals 2030, which sets 10-year, quantifiable public health goals for the United States, is to help people get adequate sleep.

A large-scale epidemiological cohort study on the UK BIOBANK found the following factors that increase the risk of heart failure (summary here):

  • 34% higher in those reporting daytime sleepiness — in other words chronic sleep deprivation.
  • 17% higher in those with frequent insomnia,
  • 12% higher in those who had a short sleep (slept less than 7 hours daily),
  • 8% higher in later risers — note however that the authors did not control for the individuals' circadian misalignment with their job's hours, which is likely the main factor for health and not the chronotype per se. This result was barely significant when controlling for other factors.

What is impressive about this cohort observational study is that the first 3 effects were highly significant independently of other factors across 3 different models: age, gender, alcohol intake, medication, diabetes, hypertension, even the first 10 genetic principal components, etc. (see Table 1 legend). This shows these effects are very strong, the only exception being the morning lark chronotype with a very weak p-value across models and getting weaker with better controlled models, barely reaching significance on the most controlled Model 3 (p-value = 0.04, whereas for the most lenient Model 1 p-value = 0.002). Another similar study found that "poor sleep efficiency and long wake after sleep onset" increase the risk of cardiovascular diseases. Given that daytime sleepiness and brain fog are very common for people with circadian rhythm disorders, this is a serious risk to consider for this population. Another study on the same dataset but investing healthspan reduction from a variety of mortality causes that are related to sleep found similar results.

This increase in the risk of heart failure, as well as the variety of other diseases caused by sleep deprivation, is likely primarily caused by the increase in oxydative stress, in other words cellular damage, which is the primary purpose of sleep as evidenced by a landmark 2020 study. Indeed, the authors found that prolonged sleep deprivation causes death by the accumulation of reactive oxydative species, in other words a buildup of cellular damage. During sleep, there is a widespread release of strong antioxydative agents such as melatonin which cleans up and keep under control the oxydative damage and inflammation, especially in the digestive system (the primary source of oxydative damage due to food ingestion). Indeed, it is now strongly suspected the core pathway of sleep-deprivation-induced damages is via increased oxidative stress and inflammation. For instance, a study on mice found that continually phase advancing (chronic jet lag) mice by 6h/daily led to a 4.2x increased death rate (89% versus 21% in unshifted mices), which is in practice what individuals with non-24 experience when they restrict their sleep to fit into a typical schedule without entrainment therapies.

Sleep disruption was found to affect cognition and mood in the short-term in otherwise healthy adults, and on the long-term increase the risks of virtually all physiological illnesses including metabolic disorders, cardiovascular diseases, diabetes and colorectal cancer:

> In otherwise healthy adults, short-term consequences of sleep disruption include increased stress responsivity, somatic pain, reduced quality of life, emotional distress and mood disorders, and cognitive, memory, and performance deficits. For adolescents, psychosocial health, school performance, and risk-taking behaviors are impacted by sleep disruption. Behavioral problems and cognitive functioning are associated with sleep disruption in children. Long-term consequences of sleep disruption in otherwise healthy individuals include hypertension, dyslipidemia, cardiovascular disease, weight-related issues, metabolic syndrome, type 2 diabetes mellitus, and colorectal cancer. All-cause mortality is also increased in men with sleep disturbances. For those with underlying medical conditions, sleep disruption may diminish the health-related quality of life of children and adolescents and may worsen the severity of common gastrointestinal disorders. As a result of the potential consequences of sleep disruption, health care professionals should be cognizant of how managing underlying medical conditions may help to optimize sleep continuity and consider prescribing interventions that minimize sleep disruption.

A non-managed circadian rhythm disorder such as non-24 results in all 4 of the issues above, suggesting that unmanaged circadian rhythm disorders such as non-24 likely significantly increases the risk of cardiovascular complications. Indeed, the cardiometabolic system shows a clear circadian component, and the suprachiasmatic nucleus (SCN) "innervates the heart and other organs involved in hemodynamic control, such as kidney, vasculature and adrenal, via a multisynaptic pathway, probably including direct projections form the SCN to the paraventricular nucleus of the hypothalamus (PVN)" (see also here for an updated review).

Although we do not have data for non-24 specifically, there is some data about evening chronotypes, which we can infer to share similar albeit lesser chronic sleep deprivation. Evening chronotypes are 5 times more likely than morning larks and intermediate chronotypes to retire early on a disability pension. It's likely much worse for non-24.

Sleep deprivation, which is likely the root cause of most of the issues above, can either be resolved by free-running or by being entrained, the latter being very difficult if not impossible to reach for most non24 at this stage of scientific knowledge. So is free-running enough to live heathily? Unfortunately, that's unlikely.

Indeed, free-running means that there is an almost constant environmental-circadian misalignment (ie, misalignment between the individual's circadian rhythm and the day/night cycle). But the production of some hormones, such as melatonin, is dependent on the external day/night cycle. Melatonin is produced most at night, as it is inhibited by bright light. Hence, a free-running individual is likely to have reduced levels of melatonin due to unwanted inhibition by light exposure.

What are the consequences of melatonin reduction? Well, melatonin is a strong (maybe the strongest) anti-oxydant in the body. It is also immunomodulatory. Hence, a lack of melatonin is linked in animal models with various diseases and immunodepression.

Furthermore, mistimed eating when melatonin is at high levels in the body has been linked with metabolic dysregulations, and even directly caused diabetes in an animal model, without any other change of any other factor (TODO: add links to refs). Hence, both the lack of melatonin and the mistiming of melatonin with other factors such as food can produce detrimental effects on health, whether or not the individual is sleeping enough by free-running. (But of course these risks are far lower than what chronic sleep deprivation causes, so health-wise it's preferable to freerun rather than suffer from sleep deprivation, but it's also preferable to be entrained than to freerun, if of course an efficient treatment is possible for the individual).

Hence, supplementation of melatonin serves two purposes: to both supplement to overcome the lack of melatonin, and help with entrainment which directly reduces unwanted inhibition of melatonin by light. Would an oral supplementation of melatonin be enough to reduce the rate of diseases due to circadian misalignment and/or sleep deprivation? Likely yes, but it depends on the dosage: a study on animals shown that totally sleep-deprived animals could survive if supplemented orally (or intraveinously) with melatonin, and it's known that blind individuals have a much lower rate of cancers which is hypothesized to be because of higher melatonin levels since their melatonin is never inhibited by light, and since then melatonin was shown to indeed reduce cancer progression. Future trials are needed to know the proper dosage and how much benefits can be expected in humans, see the section on Melatonin below for more infos about the few already conducted trials (such as on sepsis and cancer).

Beyond sleep deprivation and melatonin reduction, circadian misalignment reduces our immunological response. Indeed, the circadian rhythm modulates the immunological response, especially the macrophages, as a 2021 study found. This means that our immunological system works better during our biological day, but worse at night so we are more likely to get ill or more severe diseases at night. For example, an individual with a circadian night happening in the day, as is always the case for DSPD and cyclically for non-24, means that if these individuals try to force themselves to stay awake during the objective day, they will be more prone to getting infections, contrary to typical sleepers who would be more vulnerable during the objective night since their circadian night happens during the objective night. This also means that even without sleep deprivation, sleeping in circadian misalignment increases the risks and severity of illnesses. This finding shows that individuals with circadian rhythm disorders are more prone to infections when they try to follow a typical sleep-wake schedule. The authors also found that the circadian rhythm mechanisms in the cells are much more complex than previously thought, with their study showing one of these new mechanisms, and suggesting that there is likely much more to discover on the ways the circadian rhythm controls the immunological system. Hence, it is crucial to sleep in phase with the circadian rhythm, as "the latest research has demonstrated that life habits coherent with the internal clocks should be adopted, especially during childhood, to prevent metabolic diseases." For instance, it was found that shift workers were 2 to 3 times more likely to get infected by COVID-19, with the highest odd being for those who performed irregular/rotating night shift work.

> Most immunological functions, from leukocyte numbers, activity and cytokine secretion undergo circadian variations, which might affect susceptibility to infections. The intensity of symptoms and disease severity show a 24 h pattern in many immunological and allergic diseases, including rheumatoid arthritis, bronchial asthma, atopic eczema and chronic urticaria. This is accompanied by altered sleep duration and quality, a major determinant of quality of life. Shift work and travel through time zones as well as artificial light pose new health threats by disrupting the circadian rhythms. Finally, the field of chronopharmacology uses these concepts for delivering drugs in synchrony with biological rhythms. https://doi.org/10.1186/s12948-018-0080-0

NB: chronopharmacology dates back to at least 1973 or 1971.

Furthermore, beyond general health damages, chronic sleep deprivation and circadian misalignment drastically increase the risk of transportation and work accidents, with sleepiness being the major cause of preventable accidents in all modes of transport, surpassing alcohol and drugs. Indeed, drowsy driving due to even slight small sleep deprivation, such as staying awake for 1-3h later than usual, is more dangerous than driving drunk.

The potential therapeutic benefits of circadian-based medical interventions, or at least medical interventions integrating the circadian rhythm in their protocol, are such, not only for circadian rhythm disorders but for all pathologies beyond sleep, that well established researchers are confident of the advent of "circadian medicine" as a crucial step forward in future medicine.

A classification of the health risks of circadian rhythm disorders

Unfortunately, the potential health issues of free-running non-24 or DSPD sleeping according to their natural schedule remain unexplored in the medical scientific literature. But we do have indirect evidence from extrinsic circadian rhythm disorders, such as night shift disorder or jet lag disorder, which are much more common. We can define 4 different broad classes of health risks related to circadian rhythm disorders:

Sleep deprivation, usually chronic (ie, regularly experienced)
Sleep deprivation happens when not sleeping enough, and it becomes "chronic" when it happens regularly. Sleep deprivation not only has major impacts on health that majorly increases all-cause mortality, including by cardiovascular diseases and cancer (see also here), and can even lead to sudden death by cardiac arrhythmic arrest through oxidants accumulation in the body, particularly, but not only (see also here and here), for those with obstructive sleep apnea (see also here), and sleep deprivation is now a primary target of treatment for the modern comprehensive approach for cardiac diseases prevention. The influence of subqualitative sleep on cardiovascular risks is so important that the American Heart Association acknowledged the issue since its 2016 guidelines and aims to run public health campaigns on the importance of sleep for cardiac health. The increase in cardiovascular risks also affects children, and it may be dependent on predisposition to metabolic syndromes. It can also curb the benefits of diet or lifestyle changes and it impairs the evaluation of risks by causing an overly optimistic bias. Sleep loss majorly impairs the immune system. Sleep and the immune system are interacting bidirectionally: severe infections can cause sleep deprivation, and a shorter sleep impairs the immune response to infections and inflammations so that the risk of infections is increased and vaccines efficacy is decreased by directly decreasing the number of antibodies produces, since sleep promotes their production. During the COVID-19 pandemic, short sleep was assessed as a risk factor for more severe symptoms, and scientists suggested that requiring longer sleep prior and after vaccination may be an effective and inexpensive way to increase a COVID-19 vaccine's efficacy. Furthermore, again with COVID-19, each 1-hour decrease in sleep was associated with 12% higher odds of infection (see also here). Indeed, sleep deprivation can alter the DNA, RNA and proteins. An informal survey reported that half of COVID-19 long-haulers complained about new sleep disturbances. All these risks also affects children and teenagers ("general pediatric population") and lead to poor academic performance. Since sleep deprivation reduces light therapy effectiveness, a vicious cycle can appear where chronic sleep deprivation impairs the very therapies that could reduce sleep deprivation. Chronic sleep deprivation has a dose-dependent cumulative effect on cognitive impairment: sleeping 4h per night is worse than 6h per night, and the impairment will only increase day by day, even though subjectively the individual doesn't feel more sleepy than on the first day sleep deprivation started. Compared to partial sleep deprivation (eg, 4h), total sleep deprivation (0h for 3 days) results in a "disproportionately large" neurobehavioral impairment. Hence, fixing sleep deprivation by allowing the individual to sleep according to their natural sleep schedule or by napping (or to another schedule with entrainment) should be a primary target for general health improvement. Ironically, chronic sleep deprivation can cause treatment-resistance chronic insomnia as suggested by the Randy Gardner case, or even lifelong psychoses and personality changes even after recovery sleep as shown by the Peter Tripp's case (although he lost his job due to the payola scandal and not due to the lasting effects of sleep deprivation), which shows that all-nighters can only worsen the condition. Personality makes little difference, but if anything and if you believe in the psychological concept of personality, extroverts performed worse after sleep deprivation than introverts. Interestingly, it seems that partial chronic sleep deprivation requires more time for cognitive recovery than total sleep deprivation. A neuroimaging fMRI study found that sleep deprivation affects differentially various brain regions, with decreased activation in the posterior cerebellum, right fusiform gyrus and precuneus, and left lingual and inferior temporal gyri, and increased activation in the bilateral insula, claustrum and right putamen. A neuroimaging review details that the DMN in particular demonstrates significant alterations under sleep deprivation, including decreased connectivity between the anterior and posterior cingulate gyrii of the DMN and a degraded connectivity segregation with the external awareness network, which is the type and areas of connectivity that is impaired in disorders of consciousness. Chronic sleep loss impairs neurodevelopment and incurs neuronal loss, especially if from a young age, hence the necessity for accomodations of children with sleep disorders as chronic sleep deprivation can not only stunts cognitive performance, but pave the way for the development of neurological disorders. Sleep deprivation impairs auditory attention cognitive performance (see also here and here). Sleep deprivation causes more impairments and damages than just the loss of the benefits of sleeping. Three nights of consecutive, chronic sleep loss of just a few hours per day was sufficient to significantly impair mood and cognitive functions. Multitasking is impaired by sleep deprivation, as well as innovative thinking and adaptation to new situations (flexible decision making). Medical students' judgment and reaction time are also impaired by sleep deprivation.

Unfortunately, chronic sleep deprivation has been much less studied than acute sleep deprivation, and it remains mostly unknown the full extent of sleep-deprivation-induced damages, especially neuronal, and the potential for recovery, if any. The authors also note:

> The basic scientific findings regarding sleep loss have not yet been routinely applied in the clinic. [...] Sleep abnormalities are robustly observed in every major disorder of the brain, both neurological and psychiatric. Sleep disruption merits recognition as a key relevant factor in these disorders at all levels, from diagnosis and underlying aetiology, to therapy and prevention. More collaborative work between basic and clinical scientists in the field will be necessary to accomplish this goal. Notably, the answers to all these questions have perhaps never been more pressing considering the professional, societal and clinical implications that continue to scale in lockstep with the precipitous decline in sleep duration throughout industrialized nations.

Circadian misalignment
This is when you sleep the duration you need, but outside of your biological night. The detrimental health effects is well known and experimented worldwide every year because of daylight saving timezone (DST) changes, causing an increase of 8% in strokes, an increase of depression disorders and of car accidents due to decreased vigilance, and 25% increased rate of cardiac arrests, all due to one single hour of sleep lost after the timezone change. The most common type of circadian misalignment, social jet lag, which happens weekly in the transition between weekends to weekdays, is likely the reason why the vast majority of cardiac arrests happen on Mondays (or in other words, due to the sudden circadian misalignment and slight sleep deprivation after the week-end). Sleep-wake cycle is the most robust output rhythm of the circadian system, is significantly affected by neurodegenerative disorders, and may precede them by decades, and hence emerging evidence suggests that circadian disruption (ie, non24, shift work) may be a risk factor for these neurologic disorders. Circadian misalignment alone can lead to life-threatening cardiac arrhythmias (without sleep deprivation) and increases general cardiovascular risks. Circadian misalignment is associated with increased risk of metabolic syndromes such as diabetes and obesity as shown by epidemiological studies, prompting the renaming of metabolic syndromes as Circadian Syndromes, as circadian misalignment can actually directly cause diabetes in mice (see the section about Food and metabolic syndromes for more information). Several studies have demonstrated a clear circadian regulation of the cardiometabolic system, with strong evidence suggesting circadian disruptions "may impact cardiometabolic and overall health", with for example a study finding "a 4% increased risk of ischemic stroke for each 5 years of shift work" (see also here and here). There is now a general consensus in the scientific medical community that circadian misalignment is a major risk factor for metabolic disorders, independently from sleep deprivation (see here, here, here). Furthermore, circadian misalignment is the major cause of accidents by far, as "sleepiness surpasses alcohol and drugs as the greatest identifiable and preventable cause of accidents in all modes of transport [...] industrial accidents associated with night work are common, perhaps the most famous being Chernobyl, Three Mile Island, and Bhopal." The IARC, the highest authority on defining probable causes of cancer, recognizes that "circadian disorganization" in night shift work is a "probable carcinogen in humans" (group 2A) (see also here). Circadian misalignment, in particular with aberrant light exposure, can also cause major cognitive, learning and mood impairment. Circadian misalignment affects wounds healing, with wounds happening during the biological night healing more slowly than those during the day. Circadian misalignment in women is associated with disturbances in menstrual function, particularly menstrual irregularity and longer menstrual cycles and may increase the risk of breast cancer. Circadian misalignment is not only observed in non-24 and DSPD but also night shift work disorder and social jet lag. The reduction of light exposure can worsen mood since bright light exposure has antidepressant effects. Sleep apnea is known to be a major cause of cardiovascular death, but it interestingly shows a marked circadian rhythm, with more deaths by sleep apnea during the biological night, whereas for other cardiovascular deaths it's rather during the day. Circadian misalignment also reduces the immunologic system and hence may increase the risk of infections such as COVID-19 and its severity. It was further found that shift workers were 2 to 3 times more likely to get infected by COVID-19, with the highest odd being for those who performed irregular/rotating night shift work. Circadian misalignment due to aberrant light exposure or melatonin inhibition is associated with increased breast cancer rates, and inversely timezones where melatonin is less inhibited by light such as the Arctic zones have lower rates of breast cancers. Circadian misalignment (chronodisruption) caused by chronic melatonin inhibition/deficiency due to urban artificial lighting increases the risk of cancers. Breast cancer survivors have a shorter disease free interval in metastatic breast cancer if bedtimes are misaligned with their circadian rhythm according to a meta-analysis. The disruption of cellular-level functional clocks has been evidenced by biologist as a pathway that can cause cancers, and in practice a 2020 systematic review found moderate grade evidence that shift work and long work hours increase the risk of (breast) cancer and strokes. Circadian dysregulation can cause metabolic disorders including non-alcoholic fatty liver disease (NAFLD - the most common liver disease worldwide), and circadian realignment may improve NAFLD. Circadian misalignment is associated with digestive pathologies such as constipation and irritable bowel syndrome. The cognitive impairment induced by circadian misalignment can be objectively observed neurologically with a reduced default mode network's functional connectivity in night owls. Circadian misalignment can also affect proper administration of medication (chronopharmacology), since depending on the time of administration, a drug can have more potent and beneficial effect, whereas at the wrong time (usually during the circadian night), a drug may have more adverse effects (see also this talk). Neurologically, chronic circadian disruption impairs temporal lobe's and especially hippocampal neurogenesis (see also here), which explains the wide range of cognitive funcitons impairements observed in chronic jet lag and circadian rhythm disorders, such as decreased performance, memory, reaction time and depressive symptoms, with an estimated 6.5 years of cognitive decline in long-time shift workers compared to age-related controls, which persists for 5 years after conclusion of shift work. Ample evidence from animal studies strongly suggest that circadian rhythm disorder underlies several psychological disorders, such as major depression, anxiety and schizophrenia. Circadian disruption is common (20%) among survivors of traumatic brain injuries such as car accidents, and is a primary target of treatment as it can "precede, exacerbate or perpetuate many of the other sequelae". A study on mice demonstrated premature aging and prediabetic profiles in circadian misaligned mices (see also here). The circadian rhythm and sleep regulate the blood brain barrier notably by increasing endocytosis and re-equilibrium of metabolites, which may be relevant for brain cleanup and sleep inertia.

Hormonal suppression (especially melatonin) by unwanted/uncontrolled light exposure
Given the wide range of protective actions of melatonin on all cells in the body, unwanted inhibition of endogenous melatonin by bright light exposure during the biological evening and night is a serious health issue. This can happen without circadian misalignment because of artificial lighting, as it often happens for night shift work. There is some evidence that the lack of light exposure and reduced melatonin secretion may be the cause of the increase in breast cancer due to circadian misalignment. It's difficult to discriminate what is due to melatonin inhibition or what is due to circadian misalignment as this field of medical research is still in its infancy, so apriori the health risks associated with circadian misalignment should be considered to overlap those of hormonal, especially melatonin, suppression.

Cognitive impairments, social isolation and accidents
Sleep deprivation impairs the ability to suppress unwanted thoughts especially when presented with reminders and hence to multitask. Sleep deprivation largely impairs attention, but not reasoning abilities. Drowsy driving is responsible for a million crashes and 500 000 injuries each year in the USA, with "sleepiness surpassing alcohol and drugs as the greatest identifiable and preventable cause of accidents in all modes of transport". Indeed, driving with even the slightest sleep deprivation is akin to driving drunk with alcohol: even slight small sleep deprivation, such as staying awake for 1-3h later than usual, leads to more cognitive disruptions than 0.05% of blood-alcohol level, which is considered a "drunk state" in most European countries (see also here), hence "a drowsy driver may be as dangerous as a drunk driver". A review found an almost linear increase in accident risk in shift workers beyond 8h of work. There is a 15x increase in driving accident risk for truckers after more than 13h awake compared to the first hour. Cognitive performance and memory, including short-term and long-term memory formation and recall, are greatly diminished when occurring out of phase with the natural circadian rhythm, and can even manifest as other cognitive deficits. Catastrophic industrial accidents associated with night work are common, including Chernobyl and the space shuttle Challenger catastrophic accidents were mostly attributed to poor judgment consecutive of chronic sleep deprivation induced by extended night shiftwork (see also this video). Crew accidents due to sleep deprivation is also common in aviation and military and responsible for hundreds of millions of material loss (see also here, here). The Navy started in 2021 to acknowledge sleep deprivation as a major issue and pledged to try to find new solutions to better manage it. Sleeping allows to find innovative mathematical solutions and patterns compared to individuals who do not sleep during the time gap between problem presentation and restitution (see here for a layman presentation).

Sleep fragmentation
Sleep fragmentation, which can be caused by melatonin deficiency or sleep disturbances such as noise and unwanted exposure to bright light, can cause various impairments. Sleep fragmentation impairs motor skills learning. Sleep fragmentation is associated with more periods of unconscious wakefulness, also called cortical arousal, which may increase the risk of premature death and cardiometabolic diseases. Sleep fragmentation is one of the primary factors increasing the likelihood of delirium in hospitals' intensive care units' (ICU) patients, along with aberrant bright light exposure (see also here and here), with some scientists even suggesting that the expression of delirium is very similar to sleep deprivation. Sleep disturbances can have a very strong detrimental effect on sleep efficiency, sleep quality and the circadian rhythm especially when there is unwanted exposure to bright light, that can carry over several days after the disturbances happened.

Note that non24 likely has worse health prospects than DSPD, due to the increased frequency and magnitude of circadian misalignment and potential of chronic sleep deprivation.

TODO: add content from https://www.reddit.com/r/DSPD/comments/h8och2/i_sleep_between_9am_and_16pm_every_day_i_this/fuw6h3k and https://www.reddit.com/r/N24/comments/hqz5ix/does_n24_have_long_term_effects_on_health/fy25ppz

For more detailed information on the risks of sleep deprivation and circadian misalignment, this great review is recommended:
> Baron KG, Reid KJ. Circadian misalignment and health. Int Rev Psychiatry. 2014;26(2):139-154. doi:10.3109/09540261.2014.911149 . URL: https://pubmed.ncbi.nlm.nih.gov/24892891/

Depression, anhedonia, running thoughts and social isolation

Although a lesser known fact, depression, anhedonia (lack of pleasure and will, feelings of being empty) and social isolation are normal part of circadian rhythm disorders, and especially in non24 where they appear cyclically depending on the current phase (nightwalking) and season (winter is worse).

> In anhedonia, both wanting and liking are muted.
Source of the quote.

Although prevalence data is sparse for sighted non-24, depression appears to be a common comorbidity similarly to other sleep disorders, as this 2005 study of 57 sighted non-24 participants cohort found that 34% of them also suffered from depression after the onset of non-24.

Both a single night of sleep deprivation and lack of bright light exposure or aberrant exposure in the biological night (see also here) independently cause depressive symptoms such as anxiety and moodiness in non depressive, healthy individuals, with the combination likely causing even greater distress. There is a two-fold risk of developing depression when chronically sleep deprived. Severely sleep deprived individuals "manifest an anxious, depressed, negative cognitive-affective set". Plenty of evidence from animal studies strongly suggest that chronic circadian disruption likely cause depressive symptoms such as anhedonia and memory impairements as well as anxiety and psychological disorders such as major depression, regardless of sleep deprivation. A large-scale study using the UK BioBank dataset found a causal link between the genetical chronotype and circadian misalignment on depressive and generalized anxiety disorder symptoms, explaining why morning owls on a day job have higher well-being, whereas intermediate chronotypes and night owls who constantly defy their circadian rhythm (body) clock suffer from lower well-being and increased anxiety and depression, in line with previous studies (see here and here). Sleep disorders during childhood are robustly associated with a modest increase in the risk of early onset of major mental mood and psychotic disorders in teenagers and young adults. Sleep deprivation has been linked to an increased risk of suicide in a systematic review. Although some psychologists claim (REM) sleep deprivation may treat depression, most studies were not properly controlled, and a 2021 systematic review only found 9 controlled studies to review, from which it appears that sleep deprivation only has a temporary and often non-significant effect on depression, but it can increase 4x the risk of transition to mania. Since sleep deprivation and circadian misalignment independently cause depressive symptoms, it has been established that on the first day of the work week, the day with the most social jet lag due to the transition from weekend to work days, is the most likely time for suicidal posts on Reddit, which interestingly enough mirrors the increase of cardiac arrest, both pointing to circadian misalignment as the likely main cause.

In fact, there is a study by Soomi Lee et al that precisely modeled with mathematical equations how mood and cognitive impairments are related to chronic sleep deprivation:

> Daily negative affect increased and positive affect decreased in curvilinear fashion as the number of consecutive sleep loss increased. For example, daily negative affect increased (linear), but the rate of increase decelerated as the number of consecutive sleep loss increased (quadratic). Results were consistent for the number and severity of physical symptoms. For negative affect and the severity of physical symptoms, cubic effect was also significant such that the rate of increase accelerated again in the days most distal to baseline (no sleep loss).

In addition, sleep deprivation impairs the ability to suppress unwanted thoughts (ie, increases racing thoughts) especially when presented with reminders (see also here and here), which can partially explain the higher propensity of sleep deprived individuals to anxiety. Indeed, neurologically, sleep deprivation impairs sensory gating and reduces P50 suppression, in other words sleep deprivation reduces inhibition of irrelevant information, which leads to racing thoughts and human errors and accidents. Furthermore, a CBT-i study by Harvey et al shown that instructing the insomniac patients to suppress their thoughts before sleep (more technically called "suppression of presleep cognitive activity") led to a worsening of the sleep issues, with an increased sleep latency and reduced sleep duration. Hence, having racing thoughts before sleep is in fact be a consequence of sleep deprivation, rather than the cause, and treating by suppression the running thoughts does not help and even worsen the insomnia. Actually, scientists even think sleep deprivation may be the root cause explaining the dissociative symptoms as observed in schizophrenia and schizotypical disorders as well as PTSD, although there is no link with non-24 for the moment, it just further supports that running thoughts are a common symptoms of all diseases causing chronic sleep deprivation. Another study found both running thoughts and dissociative symptoms increased after sleep deprivation.

Practical tip: signs of anhedonia include lack of appetite, lack of motivation and lack of pleasure. If this is caused by sleep deprivation or circadian disruption, anhedonia should resorb in the following days. Otherwise, if this persists, this may be a sign of major depression and should be investigated with a clinician.

Not only does sleep deprivation cause depressive symptoms, sleep deprivation is also literally and objectively painful, with modest changes in sleep quality tremendously increasing pain experience. Indeed, this study, focusing on the neurological basis of sleep deprivation magnified pain, found that even small sleep disruptions can cause major increases in pain the subsequent day while also decreasing reactivity and quality of decision-making:

> Sleep loss increases the experience of pain. [...] Here, we demonstrate that acute sleep deprivation amplifies pain reactivity within human (male and female) primary somatosensory cortex yet blunts pain reactivity in higher-order valuation and decision-making regions of the striatum and insula cortex. Consistent with this altered neural signature, we further show that sleep deprivation expands the temperature range for classifying a stimulus as painful, specifically through a lowering of pain thresholds. Moreover, the degree of amplified reactivity within somatosensory cortex following sleep deprivation significantly predicts this expansion of experienced pain across individuals. Finally, outside of the laboratory setting, we similarly show that even modest nightly changes in sleep quality (increases and decreases) within an individual determine consequential day-to-day changes in experienced pain (decreases and increases, respectively). Together, these data provide a novel framework underlying the impact of sleep loss on pain and, furthermore, establish that the association between sleep and pain is expressed in a night-to-day, bidirectional relationship within a sample of the general population. More broadly, our findings highlight sleep as a novel therapeutic target for pain management within and outside the clinic, including circumstances where sleep is frequently short yet pain is abundant (e.g., the hospital setting).

This is on top of the objective worsening of comorbid conditions and of general health by sleep deprivation, so that sleep deprivation increases pain both objectively and subjectively. And indeed there is an interaction, as a review found that not only sleep deprivation does increase pain perception (hyperalgesia), it also decreases the effect of pain medication such as opioid and serotoninergic analgesics:

> Chronically painful conditions are frequently associated with sleep disturbances, i.e. changes in sleep continuity and sleep architecture as well as increased sleepiness during daytime. A new hypothesis, which has attracted more and more attention, is that disturbances of sleep cause or modulate acute and chronic pain. Since it is well-known that pain disturbs sleep the relationship between the two has since recently been seen as reciprocal. To fathom the causal direction from sleep to pain we have reviewed experimental human and animal studies on the effects of sleep deprivation on pain processing. According to the majority of the studies, sleep deprivation produces hyperalgesic changes. Furthermore, sleep deprivation can interfere with analgesic treatments involving opioidergic and serotoninergic mechanisms of action. The still existing inconsistency of the human data and the exclusive focus on REM sleep deprivation in animals so far do not allow us to draw firm conclusions as to whether the hyperalgesic effects are due to the deprivation of specific sleep stages or whether they result from a generalized disruption of sleep continuity.

Sleep deprivation also causes social isolation, as individuals who are sleep deprived feel much less comfortable with other people being physically close to them. Chronic insomnia also decreases the ability to feel empathic with others emotions such as sadness and fear and also happiness. Combined with the sleep deprivation induced anhedonia, this results in a decreased engagement and enjoyability of interpersonal relationships, as was already well established for insomniac patients. To its extreme, sleep deprivation also causes paranoia, which drastically impairs communication. Paranoia being likely experienced at least a few times during the lifespan of any individual with untreated non-24. These neurocognitivo-social isolating processes compound with the mistimed wakefulness schedules of non24 individuals which further worsen the issue by making it very difficult to plan and attend to social appointments and events. This effect of sleep deprivation on social isolation seems unidirectional, as social loneliness does not impair sleep, hence treating the social isolation is unlikely to improve sleep.

Sleep deprivation is an underappreciated strong factor of interpersonal conflicts: frequency of interpersonal conflicts in romantic relationships increases with sleep deprivation, and are more often resolved when both partners are well rested, and these effects are not explained by stress, anxiety, depression, lack of relationship satisfaction, or by partners being the cause of poor sleep. According to David Randall's book Dreamland about the "no sleep" culture in military and military studies done on sleep deprivation, which may be inaccurate but there is no other sources to check given the type of sources used, air force pilots had a different vocal pattern when sleep deprived, being often unable to speak loudly to be understood and with a monotone speech that lacked emphasis on key words. Another military study was conducted on the cooperation of military duo's ability to planify and communicate together after sleep deprivation, which shown they most often were unable to succeed, whereas their sleeping counterparts could, which shows that sleep deprivation also affects professional interpersonal communications and collaboration even under highly trained and rigorous environments.

Furthermore, sleep deprivation largely impairs attention, but not reasoning abilities. Sleep deprivation also makes the patient "forget their life" as it impairs autobiographical memories.

Especially during the nightwalking phase, when completely out of phase with the day-night cycle, and the winter season, with longer nights and shorter days, the combination of sleep deprivation and lack of exposure to bright light is a perfect recipe for anhedonia and social isolation. Combined with the necessity to live on eggshells, the individual can justifiably feel like they are encaged.

The author also noticed that these cognitive and mood disruptions can go both ways in practice: often the effect of sleep deprivation is mood depressive, but sometimes there are maniac-like phases, hence chronic sleep deprivation can cause bipolar-like episodes, which may explain why it was hypothesized, but since then refuted, that non-24 was associated with the bipolar disorder.

These effects of sleep deprivation on cognition are in many respects similar to the cognitively disruptive effects of alcohol, with one sleepless night being analogous to 0.10% of blood-alcohol level, much beyond the drunk driving threshold in most European countries, with similar impairments in judgment and other cognitive functions:

> Staying awake for just 17 to 19 hours straight impacts performance more than a blood-alcohol level of .05 percent (the level considered legally drunk in most western European countries). This level of impairment slows an individual's reaction time by about 50 percent compared to someone who is well rested. Twenty-four hours of continuous wakefulness induces impairments in performance equivalent to those induced by a blood-alcohol level of 0.10 percent, beyond the legal limit for alcohol intoxication in the United States. Source

It is hence not surprising that sleepiness is the major cause of preventable accidents by far in all modes of transport, surpassing alcohol and drugs. Hence, a circadian rhythm disorder also limits the transportation possibilities, which further increase isolation and impairs the possibilities of getting hired, as most work positions require independent car transportation. Hence, "a drowsy driver may be as dangerous as a drunk driver". A review found an almost linear increase in accident risk in shift workers beyond 8h of work.

There is strong evidence sleep issues cause anxiety, and modest evidence circadian rhythm disturbances can cause anxiety.

Mood and cognitive dysregulations are not just limited to practical abilities, as one night of sleep deprivation drastically impairs innovative thinking and flexible decision making, in other words, sleep deprivation impairs the ability to "think outside the box" to find new solutions and adapt to new situations (see here for a layman presentation). Likewise, sleep deprivation impairs multitastking ability, in other words, when sleep deprived, there is a tendency to hyperfocalize on one task.

Often, this set of cognitive and mood disturbances are expressed by the patients as "feeling like a zombie". It's crucial not only for the clinical practitioners to recognize these signs associated or caused by sleep deprivation, but also to teach the patient how to recognize them too, in order for them to avoid risky situations (such as driving while sleep deprived, or taking important decisions - delaying to a later time after recovering some sleep is a sound strategy).

More precisely, this systematic review provides prevalence figures of the cognitive impairements due to sleep deprivation:

  • Hallucinations (visual, auditory and somatosensory) for nearly all participants in all studies, appearing after 24h to 48h of sleep deprivation.
  • Mood changes (including anxiety and irritability) for 76% of the participants in 16 studies, usually appearing under 24h (very fast!). These are followed by "depression, apathy alternating with euphoria, anger, and hostility within 45 h without sleep".
  • Disordered (running) thoughts, confusion, and bizarre behavior (14 studies, 66%), usually appearing on the 2nd day of sleep deprivation, and get to their worst from the 5th day on.
  • Dissociation including derealization and depersonalization (11 studies, 52%), usually appearing after 24-48h.
  • Delusions (9 studies, 42%), usually appearing on the 3rd day of sleep deprivation, and get to their worst from the 5th day on.
  • Distortions in the sense of time (4 studies, 20%).

These impairments are gradual, so that paying attention to these symptoms allows to know when it's crucial to get some sleep asap: "Initially, participants tend to question the veracity of the deceptive perceptual phenomena. With the passing of time and persistence of symptoms, there is a gradual acceptance that these events might be real, which precedes the appearance of full-blown delusional explanations."
Furthermore, for some participants, it took days up to weeks for the cognitive impairments to fully resolve, although usually sleeping at least 50% of the total time spent awake was sufficient.

Indeed, recognizing and remedying to sleep deprivations may allow to better manage, or even prevent, co-morbid psychiatric disorders: "given that ‘depression is announced by sleep disturbances’ (van Moffaert, 1994, p. 9), future research should explore whether an early intervention targeting sleep disturbance may prevent the development of depression (Ford & Kamerow, 1989). [...] In addition, future research should explore the utility of advising patients who have had a previous depressive episode to review relapse prevention strategies or to make an appointment with their clinician whenever they experience an ongoing sleep disturbance. In other words, relapse rates may be reduced if patients are taught to view insomnia as a signal to initiate preventative action."

Although the above review on sleep deprivation signs was done on acute, continuous sleep deprivation, the same is likely applicable to chronic sleep deprivation, but it depends on the amount of daily sleep deprivation. Indeed, a study comparing 0h, 4h, 6h and 8h of sleep "doses" demonstrated that the "neurobiological impairment" is proportional to the amount of daily sleep deprivation, so that the shorter the nights, the more frequent the impairments.

Despite a previously long held belief, morning larks do not display higher morality standards than later chronotypes such as night owls. Rather, studies have shown (see a summary here) that individuals are more susceptible to cheating when performing their tasks during their circadian night, in other words when they are in circadian misalignment. Indeed, morning larks were more susceptible to cheat during the objective night, whereas night owls were more susceptible to cheat in the early morning.

All these cognitive impairments are supported by neuroimaging studies, which found impairments in the DMN connectivity both within and in its segregation with the external awareness network, as well as impairments in the functional connectivity of the amygdata (emotions), the thalamus (memories), the dorsolateral prefrontal cortex and anterior cingulate cortex (consciousness and incentives processing), with conversely an increase of connectivity between the amygdala with the posterior cingulate cortex and the precuneus, denoting an increase in emotionally-directed behaviors. The authors also note that not all brain functions changes are maladaptive, some preserve task performance and are hence clearly compensatory and adaptive, but the extent and limitations of these adaptive strategies remain poorly characterized (ie, they are likely often overestimated by those experiencing or professing chronic sleep deprivation).

There is fortunately no quick and easy solution, as nothing can replace sleep, but some strategies may specifically help improve cognitive and mood disturbance in complement to sleep recovery:

How to reduce the health issues of sleep deprivation and circadian misalignment

WIP: TODO: add references

Obviously, an ideal scenario to reduce the health issues due to sleep deprivation and circadian misalignment would be to eliminate them in the first place through robust entrainment. Indeed, some authors suggest it is sensible to treat the circadian misalignment and chronic sleep deprivation potentially underlying some cardiometabolic diseases using zeitgebers therapies such as light therapy and melatonin.

Unfortunately, that is not always possible, as the therapies do not work for everyone or they are under conditions that prevent them from optimally using therapies (eg, they must use an alarm clock to get to work). What can be done then? Here are a few practical tips:

  • As advised for night shift work disorder, who experience similar issues and risk factors, the most adequate strategy to reduce the risks involves avoiding multifactorial causes of sleep disruptions including the "suppression of melatonin secretion by ALAN [bright light in the biological evening], sleep deprivation, and circadian disruption".
  • Always respect your circadian rhythm as much as possible. This means to strive to sleep during your circadian night, and put aside other matters. This in effect put your sleep first, as anyone should do.
  • Avoid at all cost activities, especially those requiring a high focus and are prone to accidents (eg, car driving), during your circadian night. If you really need to move during your biological night, prefer to ask someone else to drive or take public transportation.
  • Take medication during your biological day, avoid during biological night as they will be less effective and have more side effects (see chronopharmocology). Similarly, injuries and wounds heal better during the biological day than during the biological night.
  • Avoid eating during your circadian night, as melatonin will inhibit insulin which itself will inhibit your body's capacity to process carbohydrates and so you will be in hyperglycemia all night, which is highly suspected to cause metabolic disorders such as diabetes and obesity and fatty liver disease.
  • If at wake up you feel your heart pounding in your chest or head, this is tachycardia. If it happens when you get out of bed, this may be postural orthostatic tachycardia. In any case, this is a sign you are at increased risk of cardiovascular issues, so try to sleep more or take a nap as soon as you can. If not possible, avoid activities or situations that can further cause cardiovascular issues, such as exercise or fast movements (and some temperature settings?).
  • Supplement in vitamins to reduce deficiencies due to lack of exposure to sunlight and potential deficiencies due to chronic sleep deprivation such as vitamin D and vitamin B12. In the future, high doses of melatonin may be an avenue to drastically reduce the detrimental health issues of sleep deprivation due to its strong antioxydative properties, but it remains unclear what dose in humans would allow to reach the required extracellular concentration of melatonin to benefit from these antioxydative properties.

There are also a few very promising therapeutic avenues that are still experimental and thus not yet available for patients, as we do not even know the adequate dosage to achieve these effects on humans, but still the research is very promising:

Should all individuals with non-24 get entrained to be more healthy, or is freerunning acceptable? Well, freerunning for sure is much better than restricted sleep, as at least the sleep deprivation - the most acute health impairment - is reduced. However, even under freerunning, there will always be some degree of sleep deprivation and circadian misalignment, as it is impossible to completely control all environment factors such as unwanted sunlight exposure during the biological evening when nightwalking, or ambient temperature and ambient noise, all of which contribute to impair sleep. Hence, entrained non-24 likely is a more healthy state than freerunning non-24.

Interestingly, the periodicity of freerunning and restricted non-24 is also reflected in the periodicity of immunodepression, with individuals with non24 falling more often ill during their nightwalking phase than when they are in phase with the day-night cycle. Hence, being often but periodically ill, or regularly feeling daytime drowsiness, may be strong signs of chronic sleep deprivation.

How to monitor my entrainment progress?

One of the most difficult things for someone with a non-24 circadian rhythm disorder is to find when their biological night is, as it changes all the time and with high variability and sometimes chaotically.

To see if your circadian rhythm is stabilizing to a constant time, or just to find where your biological night is when freerunning, it is possible to use your sleep diary. But do not monitor your bedtime nor your falling asleep time (sleep onset), as they are both unreliable markers of the circadian rhythm and the DLMO. In other words, you can sleep more or less late with more or less variation while your circadian rhythm stays stabilized - the opposite is true, your bedtime can be regular but your circadian rhythm can still freeruns.

A much better measure is your wake up time (sleep offset), which is correlated with the DLMOff and is hence a much better marker of the circadian rhythm. This was demonstrated on both typical sleepers and DSPD. In fact, the wake up time is tightly coupled with the core body temperature, which is the core signalling pathway of circadian rhythm synchronizations throughout the body (see the Zeitgebers section for more infos). In other words, if your wake up time stays constant, this is a strong indication that you are entrained.

But the wake up time can sometimes be variable due to the random occurrence of "weird insomnia" (likely biphasic sleep) or external disturbances. An even better circadian rhythm marker is the midpoint of the sleep period(s) (see also here and here). This was also demonstrated in both typical sleepers and DSPD.
Let's say you usually sleep at 1.30am and wake up at 9.30am. The midpoint is the sleep onset time + average of (sleep onset/falling asleep - sleep offset/wake up) divided by 2 = 1.5+((9.5-1.5)/2) = 5.5 = 5.30am .
Let's now say that the next night, you experience a biphasic sleep, so you sleep earlier at midnight but wake up at 5am and then sleep again between 9am and 11am. If we look only at the wake up time, it looks like you woke up 1h30 later than usual, but if we calculate the midpoint, we get: 0 + (11-0)/2 = 5.30 = 5.30am . This is exactly the same midpoint time as usual, so in fact even if the sleep was biphasic, the circadian rhythm did not change, and you will likely be able to sleep at the same time as usual on the next night.

There are also a few other signs you may indicate that you are sleeping under your biological night:

  • if your sleep onset latency is reduced, ie, when you get to bed, you fall asleep faster than usual. In my case, I used to never take less than 30 min to fall asleep, usually it took 1 or more hours, but after entrainment it consistently took me less than 15 min, and usually under 5-10 min, to fall asleep from getting to sleep.
    • Tip: If it takes longer to fall asleep, either you are not sleeping in your biological night, or you missed the ultradian cycle window and need to wait for the next one (see below the ultradian cycle section). Accumulated sleep deprivation (eg, pulling an all-nighter) can also make it more difficult to sleep because of dopamine build-up.
  • if you wake up on your own without an alarm or disturbance but didn't sleep long, then it's likely you are not sleeping in your biological night, but are rather doing a nap. Duration, along with the wake up time, is a very good indicator of sleeping inside one's own biological night.
> Results: The panel agreed that, for healthy individuals with normal sleep, the appropriate sleep duration for newborns is between 14 and 17 hours, infants between 12 and 15 hours, toddlers between 11 and 14 hours, preschoolers between 10 and 13 hours, and school-aged children between 9 and 11 hours. For teenagers, 8 to 10 hours was considered appropriate, 7 to 9 hours for young adults and adults, and 7 to 8 hours of sleep for older adults.
>
> Conclusions: Sufficient sleep duration requirements vary across the lifespan and from person to person. The recommendations reported here represent guidelines for healthy individuals and those not suffering from a sleep disorder. Sleep durations outside the recommended range may be appropriate, but deviating far from the normal range is rare. Individuals who habitually sleep outside the normal range may be exhibiting signs or symptoms of serious health problems or, if done volitionally, may be compromising their health and well-being.)
Source: https://pubmed.ncbi.nlm.nih.gov/29073412/
  • if your hunger and stools are more or less at the same time every day, that's a good sign your digestive system adapted to the entrainment, since these metabolic cues are linked to the circadian rhythm and directly to the suprachiasmatic nucleus. Since the digestive system is responsible for most melatonin secretion, this is certainly an important factor.
    • Furthermore, if you are entrained, you should not feel hungry late into the night. If you feel hungry so late, it's a sign your digestive system at least is not entrained, since the digestive system also follows a circadian rhythm (but its own) which should "sleep" too at night.
  • if you experience brain fog (aka performance reduction or sleep inertia), try to use light therapy, particularly blue light which is more effective at reducing brain fog and increasing vigilance. Bright light in the morning is well known to not only inhibits melatonin but also have antidepressant properties. In practice, this should clear up the brain fog under 30min to 1h of blue light therapy, as brain fog is likely due to melatonin residues in the blood stream, which can be inhibited most effectively by blue light. If the brain fog sustains all day long, then it may be a sign of circadian misalignment (ie, sleeping all your needed hours but outside of your biological circadian night). Note also that even under entrainment, it may take a few weeks before the all day brain fog disappears, the time for the digestive system to adapt (since it is the major producer of melatonin).
  • Weight loss without changing your diet or exercise can be an indication you are sleeping in phase (circadian alignment), and on the opposite weight gain a sign of circadian misalignment, since circadian misalignment is strongly associated with metabolic syndromes (see "circadian syndrome").

In the future, it may become possible to more precisely monitor our circadian rhythm with the help of wearable core body temperature sensors (see the section on Core Body Temperature and also the Wearadian project on GitHub).

Circadian rhythm disorders: body, brain or mental disorders?

Although there is a common misconception that circadian rhythm disorders are either neurological or psychological (as reflected in the DSM and ICD-10 classifications TODO: update with precise classif G vs F), hence stemming from dysregulations in the brain or thoughts, this can only be qualified as incorrect.

Summary: There is now considerable evidence that circadian rhythm disorders are associated and worsened by a delayed peripheral circadian clock (ie, the digestive system 's clock including the liver and intestines), so it's much more likely a whole body disorder. It's even now considered to be associated with metabolic syndromes such as diabetes, so much so that some researchers call for a name change to "circadian syndrome". Another evidence is that sleep is more a product of the body than of the brain, as it mainly serves to clean up the oxydants in the intestines. Another hint that circadian rhythm disorders are not psychiatrical nor neurological conditions but rather whole body conditions is the fact that usually very effective psychiatric interventions such as cognitive behavioral therapy (CBT) are ineffective for DSPD and other circadian rhythm disorders.

For a more argumented study of this question, let's tackle it step-by-step.

Can circadian rhythm disorders be psychologically caused or manipulated?

Summary: no, sleep disorders, including circadian rhythm disorders and insomnia, cannot be caused by a psychological disorder. This is an archaic belief that is not supported by evidence nor the current medical guidelines. Sleep disorders require their own treatment, independently from possibly co-occurring psychological disorders.

Although almost all humans have a naturally non-24 circadian clock (~24.2h according to the NIH), and hence can freerun in the absence of external time cues, as shown by the "expériences hors du temps" done by several speleologists or the modern variants of forced desynchrony protocol or nap paradigms, not everyone can follow a non-24h schedule, with morning larks having the most difficulties to adapt to other schedules (see also here and here). And even when individuals can follow a non-24h schedule, it is not a painless experience (see also here). Work schedule experiments on the NASA crews monitoring Mars mission, where the trained crew was tasked with following a non-24h martian sleep-wake schedule to better monitor the robotic missions, ended up with the crew rebelling and dropping the schedule as they felt it was unbearable ("broken"), after a single month! As the authors noted:

> The authors attributed this result to the high motivation of the crew, although motivation has limited ability to override circadian and homeostatic regulation of alertness and performance and is, in fact, subject to these influences itself.

Hence, the non24 circadian rhythm sleep wake disorder is characterized not only by a freerunning sleeping pattern, but by the fact that it is unpreventable and incontrollable (ie, no obvious and easy to fix cause). Just as any other humans, the circadian rhythm cannot be overriden simply by motivation.

How do we know for sure that motivation cannot override the circadian rhythm? Because we can objectively measure the circadian rhythm using physiological variables (eg, core body temperature, melatonin levels), and whether factors affect it.

Psychologically changing one's circadian rhythm is different from forcing oneself to sleep out of phase (ie, constaint the sleep schedule, in other words circadian misalignment). All individuals with non24 do constraint their sleep schedule at some point and sleep under a circadian misaligned time. But without changing the circadian rhythm, this only leads to a circadian misaligned night of sleep, sleeping outside of one's biological night, which causes a short and subquality sleep accumulating sleep deprivation if reproduced repeatedly, as is shown by the fact that depression was more prevalent with the circadian DSPDs, and other health issues as described in another section above. Likely, the behavioral DSPD did not sleep optimally when their night was delayed later but would sleep better if they were going to bed earlier, whereas circadian DSPD consistently report that their sleep deprivation subsides as well as various other health and cognitive improvements when they sleep under their biological delayed night, and accumulate sleep deprivation when they try to sleep earlier.

If we reduce the assumption of a psychological cause, but simply that psychological therapies may change the circadian rhythm, we end up with the theory of circadian plasticity and chronotherapy, for which there is absolutely no proof of effectiveness currently (see the dedicated Chronotherapy section). Furthermore, usually effective therapies for psychiatric conditions, such as the cognitive behavioral therapy (CBT), have shown no efficacy for circadian rhythm disorders. To summarize, there is currently no proof an entrained person can become freerunning by psychological intervention only without modifying the exposure to zeitgebers. And inversely, none that an individual with non 24 or another circadian rhythm disorder can become entrained or sustain stable phase advances with a psychological intervention only, which is why chronotherapies are not recommended by the AASM guidelines.

Furthermore, it remains highly controversial whether the mind can modify the biology. An often cited example is the placebo effect, but according to a Cochrane systematic review, placebo only affects subjective feelings, without modifying any objective measure. In other words, placebos (and noceabos) can help see things differently (eg, subjectively feel less pain), but not modify how the body works nor cure a disease (nor cause a disease). The placebo effect being the most studied and best proved psychologically induced effect, it's doubtful whether the circadian rhythm can be influenced by psychological factors at all. Firstly because the core circadian rhythm signalling pathway is body temperature modulation, for psychological factors to modify the circadian rhythm they would have to modify body temperature, which was never evidenced experimentally so far (whether motivation, psychological stress or placebo). Furthermore, the chronic sleep deprivation induced by circadian rhythm disorders is not a subjective feeling: it is a real and highly dangerous health issue that can be objectively measured and which requires adequate treatments. The concept of psychological stress being a possible cause for most disorders stems from the psychoanalytical field, rooted in hysteria renamed to conversion syndrome and later to psychosomatic syndrome. The problem with the theory of psychological stress causing other disorders is that this is mostly based on measures of cortisol, which can also be modified (much more strongly) by sleep deprivation, and hence those studies are often confounded by the fact they often do not account for sleep duration, as sleep disorders and circadian dysregulations have been historically widely ignored by psychological studies.

The circadian rhythm plays an essential biological role: the survival chances of all living creatures are depedent on their synchronization to the external day-night cycle, whether it is to get food and regulate temperature or to flee from predators. The circadian rhythm modulates not only the core body temperature as a way to synchronize clocks throughout all cells of the body, but also regulates most body organs functions and even RNA transcriptions. The circadian rhythm is hence a biological vital function, just like blood glucose levels or insulin. Psychological factors hence likely have as much influence on the circadian rhythm as they have on diabetes, which is little to none. An analogy would be to ask whether a diabetic individual could control their glucose and insulin blood levels simply by motivation and will (or any kind of psychological therapy). The answer would obviously be no. The analogy with diabetes is not fortuitous, there are strong ties that are found between metabolic syndrome disorders such as diabetes and circadian rhythm disorders (see "circadian syndrome" or the food zeitgeber section below).

A variant of the psychological argument for circadian rhythm disorders is to cite the increase in blue light exposure in the evening due to computer and smartphone screens use. While it is true that blue light from screens can cause unwanted circadian delays and should be managed as part of an appropriate dark therapy, this cannot be used as evidence that circadian disorders are *only* due to screens misuse. One simple counter-argument is that if this argument was true, all computer scientists would have a DSPD or non-24 disorder, which is clearly not the case. Furthermore, the non-24 disorder was medically recognized in 1977, before the advent of ubiquitous screens exposure. There is obviously an intrinsic component, as per the currently accepted medical definition, that makes the circadian rhythm of some people less robust to entrainment than others (or more prone to unwanted circadian shifts by uncontrolled factors), and hence being intrinsic is a hallmark of circadian rhythm disorders. Unwanted circadian shifts are merely a side consequence of the disorder.

Circadian rhythm disorders are sometimes qualified as being "idiopathic" (ie, of spontaneous and unknown cause) is only a temporary placeholder label, as the number of idiopathic diagnoses decreases over time as technology and knowledge progress, and as such some authors recommend to more properly prefer the term of "cryptogenic disorder" (disorder of yet unknown cause) instead of "idiopathic disorder" (spontaneous appearance - which can be misleading as it can suggest that disorders and diseases can have no physiological cause). As this other review for a dermatological condition states: "The more competent we are in etiological identification, the less idiopathic cases are found", which goes on to show this is a generic process happening in all medical domains.

Hence, there is currently no proof that circadian rhythm disorders can be caused or manipulated through psychological factors, and actually there is evidence of the opposite, which is that sleep disorders and circadian dysregulations actually often precede the appearance of other physiological or psychological symptoms, and the complete management of psychological disorders do not improve the sleep disorders, prompting scientists to recommend to always investigate and treat sleep and circadian rhythm disorders independently of any psychological condition. The same statement was also pronounced two decades prior for insomnia (see also here).

Can circadian rhythm disorders be neurological disorders, or a body disorder?

Since circadian rhythm disorders aren't psychologically caused, it must be a neurological disorder, right? Not necessarily, and there is some strong evidence that it's not.

Here are four arguments that contradicts the hypothesis of a brain disorder, and rather suggest that circadian rhythm disorders are body disorders:

  1. Firstly, the circadian rhythm is not solely defined by the suprachiasmatic nucleus (SCN) neurons in the hypothalamus, since there are actually molecular clocks in every organs and cells, and furthermore astrocytes arguably play an important role.
  2. Secondly, the vast majority of melatonin is produced outside the brain. Even if the pineal gland is cyclically secreting melatonin following the SCN inputs and is hence usually qualified as the "master clock", this is a highly arguable statement since the gastrointestinal tract secretes 2 orders of magnitude (at least 400x!) more melatonin in response to food than the SCN. Furthermore, even after pinealectomy, melatonin levels still increase in a dose-dependent manner (ie, proportionally) to oral intakes of melatonin in animals, just like for animals with their pineal gland, and it even restores an entrained circadian rhythm, showing that extrapineal producers of melatonin, likely the digestive tract, are producing and managing most of the circulating melatonin.
  3. Thirdly, the SCN is unnecessary for circadian shifting. Indeed, the effect of light, the strongest zeitgeber, on shifting the circadian rhythm is not impacted by the destruction of the SCN. Furthermore, a subsequent study shown that the ipRGC cells are sufficient to cause circadian rhythm and body temperature shifts without the need for the SCN, which shows that the non-visual effect of light on the circadian rhythm is independent from the SCN. Hence both the pineal gland and the SCN, the two major brain structures related to circadian rhythm modulation, are not required for circadian rhythm modulation and entrainment.
  4. Fourthly, chronic sleep deprivation (often caused by circadian rhythm disorders) causes death not through the brain but through the whole body via the accumulation of ROS in the guts (see the great abstract video or also the Inverse vulgarization article). This can be rescued (avoided) using anti-oxydants targeting the guts (through food or gene overexpression), but not when targeting neurons in the brain. It lends further credence to the consideration that the guts is a "2nd brain".
  5. Fifthly, the circadian clock and the cell cycle are coupled, which means that the circadian clock is a core regulator of all cells cycles throughout the body. By accounting for the other discoveries, this means that body temperature controls the cells cycles through the circadian clock modulation. This is another strong supporting evidence for the hypothesis that circadian rhythm disorders are bodily disorders, not just brain disorders.
  6. Sixthly, core body temperature modulation is the primary way that circadian rhythm changes are signalled across all cellular clocks throughout the body, with temperature being modulated by bright exposure through the SCN, although another study shown that the SCN is in fact unnecessary as the ipRGC cells are sufficient to control the body temperature changes. Likewise, melatonin causes a reduction in core body temperature reduction proportionally to the dose, and endogenous melatonin levels are inversely coupled with peripheral (limbs) temperature (heat transfer to limbs is a way to reduce core body temperature, so increasing limbs temperature actually decreases core body temperature). Temperature being the primary signalling pathway of circadian clock changes and synchronization especially via melatonin was already suspected since at least 2007 since supraphysiological melatonin doses were known to cause hypothermia, and it was even earlier hypothesized in 2000 that temperature may be a 3rd signalling pathway and potential treatment approach after light and melatonin. Given that humans, like most mammals, are homeothermic, which means that it's crucial for their survival that their core body temperature is always maintained inside a very specific range, and hence that body temperature control is automatic and unconscious (ie, an individual cannot manipulate their temperature by will) and is very robust to ambient temperature changes, this shows that the circadian rhythm is a very deeply ingrained and automatic biological process that is both uncontrollable without external means, and affecting the whole body.

Hence, circadian rhythm disorders should more properly be qualified as body disorders, instead of neurological or psychological, as both of the latter conveys a large understatement and misunderstanding of the whole-system interactions underlying circadian rhythm disorders, and focusing on brain structures such as the SCN that are in fact unnecessary for circadian rhythm modulation.

Accepting circadian rhythm disorders are whole-body disorders does not mean that there is not a neurologic component, since of course there is given that light exposure is the strongest zeitgeber and is mediated from the eyes' ipRGC cells through the brain to then the rest of the body via core body temperature modulation and melatonin levels inhibition. However, this strongly indicate that a neurocentric approach is insufficient to fully understand and treat these disorders. In practice, this means that treating the brain (master clock) without the body (peripheral clock in the digestive system) will be at least suboptimal or even ineffective.

Circadian rhythm disorders bear strong similarities, or even links according to recent findings, with metabolic syndrome disorders such as diabetes. Hence, it is likely safe to think of circadian rhythm disorders in similar terms as diabetes: a body disorder with some neurological component, which is both varying with endogenous but majorly with exogenous (external, environmental) factors.

What causes circadian rhythm disorders such as non-24?

Although the cause of sighted circadian rhythm disorders such as non-24 certainly is not psychological but physiological (either neurological or bodily) as explained above, the causes are currently poorly understood.

For blind individuals, the loss of pathways to conduct the signal from the eyes' ipRGC cells (the ones that are intrinsically photoreceptive and responsible for the shift in our circadian rhythm and the inhibition of melatonin) is the reason most of them suffer from the non24 circadian rhythm disorder. But for sighted individuals (whether DSPD or non-24), it's unlikely these pathways are lost as most studies found these pathways to be intact in sighted individuals.

Some scientists suggest it can be a genetic mutation in clock genes, as indeed the circadian rhythm is mostly inherited through genes. If this is correct, then circadian rhythms should be inherited among siblings and descendents, and hence diagnosis of one member should prompt the testing of close family relatives. This is the case of the author of the present document, as there is a clear lineage at least 2 direct ancestors above, and anecdotal reports from other individuals with non-24 suggest this is not an isolated case (see here).

There is also an age effect, as some of these disorders can appear later in life, especially DSPD, with a delayed circadian rhythm phase being common at adolescence compared to childhood. However, this does not always resolve as shown by various testimonials from individuals with DSPD. Furthermore, there is no evidence that freerunning, the characteristical circadian pattern of non-24, can appear later in life and resolve on its own with age, contrary to the delayed phase. Indeed, a delayed phase is fundamentally different from an ever shifting phase.

Other scientists suggest there may be a functional or anatomical dysregulation in the brain, particularly the suprachiasmatic nucleus or the pineal gland. There is also some anecdotal evidence (see also here) that damages to the pituitary gland may cause a non-24 circadian rhythm pattern rarely. However, it appears clear that the circadian rhythm is regulated not by a single locus but by a network of brain structures, or even body organs, each with their own clocks interacting and contributing to the overall circadian clock. Hence, it seems unlikely these disorders can be caused by one single point of failure, it's more likely they are the result of a complex set of dysregulations, as happens for other complex disorders such as autism and schizophrenia.

Can these disorders be anthropogenic? The major difference nowadays (since the industrial revolution, see also here) is NOT where we sleep, but where we spend our awake time: whereas in 1800s almost everyone (90% of americans) worked out in fields, nowadays they work in offices, as by 87% of americans spend their wake time indoors, in places which sometimes do not even have windows and with reduced light exposure both in light intensity, spectral composition and duration (see also here). Hence their circadian rhythm is only entrained by artificial lights. The exact same thing they use in the evening at home, which delays their circadian rhythm.

Hyposensitivity to zeitgebers such as light may be a factor, as indeed the sensitivity to zeitgebers is highly variable for everyone, with a 50-fold variability among typical sleepers. The opposite, hypersensitivity to zeitgebers, may also cause circadian rhythm disorders.

Another possibility that was observed in studies is that exposure to an aberrant pattern of light exposure diminishes its effect on the circadian rhythm. A simple example to illustrate: if a human is placed in a room exposed 24/7 to bright light, with no variation whatsoever in the light intensity or color, light exposure will have less and less effect on their sleep over time (except on melatonin which will still be inhibited - melatonin inhibition is decoupled from circadian rhythm shifting). Hence that's why for light therapy to be effective, it needs to be combined with dark therapy, ie, the avoidance of bright light (especially blue and green) in the biological evening.

Finally, sleep deprivation is known to reduce the effect of zeitgebers such as light on our circadian rhythm, so if an individual is chronically sleep deprivated, zeitgebers (and light therapy) won't work, hence why it's important to feel rested before starting to use them and to continue from benefitting from their use.

Hence, there are both intrinsic (genetical hyposensitivity) and extrinsic (environmental) factors that can be at play in causing circadian rhythm disorders, and furthermore these factors are not exclusive, so that it's likely that multiple factors are at play (complex disorder) and with different causes producing the same phenotype (polygenic disease).

It is the author's conviction that, at the most fundamental level, circadian rhythm disorders are in fact disorders of body temperature homeostatic regulation.

Why do circadian rhythm disorders exist?

Anthropology of sleep dates circadian rhythm diversity back to the hunter-gatherers tribes, where it is hypothesized that the various chronotypes allowed to always have someone on guard at any time. This "sentinel hypothesis" seems verified with another study on modern tribes, showing that even nowadays their members have a wide variety of chronotypes, so that the tribe has someone awake at nearly all times to stand guard (only 18 min was left unguarded over 24h).

Chronotype repartition among the general population is known to follow a bell shaped curve, in other words a gaussian distribution, which strongly suggests a random and natural variability. In other words, the repartition is normal (in the mathematical sense), no two individuals have the exact same chronotype/circadian rhythm, and it's ingrained in our biological, genetic code. Indeed, it is estimated that ~40% of sleep disorders are inherited, and 46% to 70% of the circadian rhythm is genetically inherited, with minor influence from environmental factors, with similar heritability for the propensity to regularly do a siesta. In fact, heritability of the circadian rhythm is so strong that it was shown that rats kept in the dark for generations maintained the same circadian rhythm, which strongly suggests that behavioral exposure to light patterns cannot affect the circadian rhythm between generations (neither negatively - by bad habits - nor positively - by following an entrainment therapy, children likely won't benefit from genetic improvements). The repartition of chronotypes in the general population is about 30% of morning larks, 40% of night owls and the rest in-between (see also this informal review). Circadian rhythm disorders such as DSPD or non-24 are not accounted in these statistics, and are likely on the tails of the bell-shaped curve ("extreme" chronotypes). This biological diversity is further supported by some evidence that prehistoric mammals were likely all nocturnal to avoid the oversized reptilian predators that were the dinosaurs, and only later some mammals, including humans, switched into bright light vision (see also here for a layman summary).

Occupation does not seem to play a role, since most computer scientists do not have the non-24 disorder desite extensive use of screens, and 75% of the total workforce is estimated to have been involved in shift work and night work in industrialized countries. However, there is one study on animals which suggest that exposure to even very dim light during the circadian night can significantly lengthen the circadian period to an extreme non-24 pattern, although this would need to be reproduced to be confirmed.

Preliminary evidence from migrating birds suggest that the lessening of the robustness of circadian rhythm entrainment may be a natural way to allow some individuals to be more sensitive to external zeitgebers and hence more easily adapt to new environments. If this hypothesis is correct, this would mean that individuals with a circadian rhythm disorder may in fact more easily adapt to different timezones and length of day/night when the zeitgebers (particularly artificial light and food) are controlled, and play a crucial role in the survival of the species. This hypothesis is further strenghtened by findings from the "expériences hors du temps" during which humans live in an environment completely isolated from environmental timecues such as in a cave. During one of these experiments involving two individuals for about one month, one could readily adapt to a 28h/day sleep-wake pattern and core body temperature profile, demonstrating that their circadian rhythm also adapted, whereas the other one could not and stayed entrained to a 24h/day schedule as demonstrated by the core body temperature profile. Of note, after the end of the experiment, the individual who entrained to a 28h/day schedule had additional difficulties to re-entrain to a 24h/day schedule, which extent is left unreported unfortunately.

> The ease with which some people can adjust their habits to an alteration of phase or cycle length is thus no evidence against an endogenous rhythm, and the difficulty experienced by others is in favor. Perhaps the most striking of such evidence is that obtained by Kleitman (131) in the Mammoth Cave of Kentucky with 2 subjects living there on (‘days” of 28 hr. The temperature and wakefulness rhythms of one adapted readily but those of the other did not, so that at the midpoint of every week they were exactly out of phase; the poor adaptor was not constrained into feeling sleepy even by the presence of a soundly sleeping companion, nor into wakefulness by a wakeful companion. All influences, social and environmental, were working one way, but he maintained his 24-hr rhythmicity for the whole 32 days. Perhaps even more striking, the other subject, who adapted well, showed some persistence of a 28-hr sleep-wakefulness rhythm after emerging. A similar persistence of a 24-hr sleepiness rhythm is recorded in some, but not all, subjects living on a 220hr day (26, I 50). A phase shift, a common experience for travelers, is more easily accomplished: Sharp (226), studying a community of six men who altered their phase by I2 hr under almost ideal conditions, records a minimum of 2 and a maximum of 9 days before they were sleeping satisfactorily again. The regularity of sleep in Arctic communities was much the same during the continuous darkness of winter, the alternation of light and darkness around the equinoxes, and the continuous daylight of summer (220), both in the working population and in convalescent patients in a hospital.

Another hypothesis is that having non-24 individuals allow to have always awake watchers to guard the community, at anytime of the day and night, to ward off impromptu predators.

A related hypothesis is related to the new finding that the Earth's rotation, and hence day-night cycle, has not always been of 24 hours (see also here and here and here), as they rather were 23.5h and progressively increased to 24h by 2.3ms each century. With cataclysmic environmental changes, it may also happen that the rotation duration may lengthen further in the future too. Hence, having in the genetic pool a diversity of circadian rhythm lengths different to 24h (ie, non-24) can increase the survivability of a specie in case of such a catastrophic cataclysmic event.

Hence, it's becoming increasingly apparent that endogenous circadian rhythm disorders are due to natural diversity with the purpose of increasing the survival chances of a community. Unfortunately, with the modern society expectations rooted in agriculture, chronotypes other than morning larks are at a disadvantage and suffer from social jet lag, despite the majority having an intermediate or night owl chronotype (see also here).

See also: Anthropology of sleep: Worthman, C. M. (2008). After dark: the evolutionary ecology of human sleep. In Evolutionary medicine and health (pp. 291-313). Oxford University Press.

Prevalence and demographics of sighted non-24

Non24 is very common in blind individuals, with an estimated 2/3rd of blind people having the non24 disorder. Other estimates such as in the visually impaired Japanese population found that 33% had a circadian rhythm disorder, with the most common being the non-24 disorder affecting 26.8%, followed by ASPD (3.8%) and DSPD (2.5%). Given the rarity - or wide misdiagnosis rate - of non24 in sighted individuals (ie, sighted non-24), there is currently no reliable estimate of its prevalence, although there are some indirect evidence that can allow a vague estimation.

Sleep disorders are highly prevalent, as it is estimated that the "worldwide prevalence of sleep disorders is about 50% with even higher occurrence in psychiatric population", and is increasing over time. The apriori most common type of circadian rhythm disorder, Delayed Sleep Phase Disorder (DSPD), is much more prevalent than previously thought, accounting for 10% of all sleep disorders and is often misdiagnosed as sleep-onset insomnia, hence about 5% of the worldwide population by combining with the previous figure. Relatively to the global population, a genetics study by Dr. Alina Patke estimated that potentially 0.6% of the population is carrying a gene mutation CRY1 that may cause Famillial DSPD (ie, inheritable DSPD). However, sighted non-24 is undoubtedly much rarer than DSPD, although it is not uncommon for non-24 to be misdiagnosed with its better known counterpart DSPD.

The most direct evidence, but non-statistical, of the prevalence of sighted non-24 comes from a survey done by the Circadian Rhythm Disorders Network association (mirror). They found that out of all the respondents who declared to have a circadian rhythm disorder, between 29% to 33% declared to have sighted non-24, and at least 19% had a medical diagnosis of sighted non24, which is much higher than any previous estimate. However there are some limitations. To quote them:

> With careful questioning we could also get a rough estimate of Non-24 prevalence in sighted people, which we suspect (from our survey—see next paragraph) is considerably higher than generally believed. Currently there is almost no evidence of the prevalence of sighted Non-24 and limited evidence for the prevalence of ISWD, mostly based on its occurrence in the context of other conditions such as head injury. (We do have good estimates of the number of Non-24 cases in the totally blind population.)
> In our survey, 29% of respondents with CRDs believe they have Non-24. Some may have misunderstood the definition of Non-24. But of the people diagnosed with a CRD by a medical professional, 19% were diagnosed with Non-24. Our sample is biased by self-selection—people with Non-24 are more likely to have major problems with their lives and be more likely to participate in our survey. Still, the results suggest that the prevalence of Non-24 is much higher than is generally recognized.

Hence, if the results of this survey are valid, which needs to be verified by future better controlled studies, sighted non-24 may account for at least 1/4th of all the circadian rhythm disorders (accounting only the medical diagnoses) and up to 1/3rd of all circadian rhythm disorders if we account for the self-diagnoses.

Sighted non-24 seem to often occur, or at least gets noticed, at teenage: "The onset of non-24-hour sleep-wake syndrome had occurred during the teenage years in 63% of the cohort, and the mean ( +/-SD) period of the sleep-wake cycle was 24.9 +/- 0.4 hours (range 24.4-26.5 hours). The mean sleep length of the patients was 9.3 +/- 1.3 hours, and 44% of them had a sleep length of between 9 and 10 hours. Psychiatric disorders had preceded the onset of non-24-hour sleep-wake syndrome in 16 patients (28%); of the remaining 41 patients, 14 (34%) developed major depression after the onset of non-24-hour sleep-wake syndrome." From this 2005 study of 57 participants cohort. There is indeed evidence for neuroendocrine changes during adolescence that can affect the circadian rhythm.

How to explain non-24 to others?

Explaining what is non-24 to other people who don't have it, whether they are relatives or acquaintances, can be quite difficult as circadian rhythm disturbances are usually not comprehended by typical sleepers.

The best way to explain is your way to explain, and it's your choice whether you want to explain or not.

However, keep in mind that most people won't be able to understand, as sleep is such a covert process that most do not realize how much sleep and the circadian rhythm regulate their daily life, and thus, sleep disorders are beyond their comprehension. This is well evidenced by the experience of night shift workers, who, despite being typical sleepers required to modify their sleep-wake schedule to accomodate their work needs, experience the same difficulties in explaining their situation and their issues being recognized by their day-time colleagues and hierarchy. This is not helped, and even partially caused, by the prevalent no-sleep culture, a modern view with sleep being disregarded as a convenience, when it is an essential need.

Nevertheless, here is a list of suggestions to build your own explanation if you want to:

  • Having non-24 is like having to wake up 1h earlier everyday for the rest of your life, just to get to work on time and do your groceries, otherwise the world leaves you behind. This means that regularly you'll wake up and go through your day without any sunlight at all, for weeks at a time, until eventually you see sunlight again. You have to plan all your activities with relative time. Also regularly you'll wake up 3h earlier, sometimes 1h later, there's a lot of randomness between days.
    • To drive the point home for the recalcitrants, and if you're brave, you can call your boss/colleagues/relatives at the same shifted time relative to your biological night. For example if they can't stop calling you when you just went to sleep 2h earlier, you can call them at 2am and go over the points they wished to discuss. This method is plebiscited by r/nightshift workers on reddit.
    • Here is a variation of this approach including a figure, courtesy of u/sprawn :
> It is very difficult to describe N24 to people. Most people tend to think they themselves "don't get very much sleep." And when you describe N24, they think that you "never sleep." Or they might think you "sleep all the time." You describe it, and then they might say, "Oh yeah, I like to sleep in, too!" They just don't get it. One trick I attempt is to show them a graphic like the one below.
>
> Imagine this is your work schedule. At first they are excited. Oh Great! Noon to 8pm! That's easy. Even the first week seems do-able to them. After the first weekend, they begin to understand. Wait! I can't get to work at 5AM! And then 4AM the next day. No one could do that! And that's when I say, "This is what a 'normal' work or school schedule is for me." What I want to say is, "Oh, it's okay. Take some melatonin, and you'll be fine…" By week three, hopefully they can imagine how impossible it would be to live like this. Forcing yourself to sleep earlier and earlier.
>
> If they are imaginative, they can come to an understanding of just how difficult that life would be. They think, "Maybe I could handle the first three weeks. Maybe I could use coffee and naps to make this work for a little while." But they will eventually see that sustaining an insane schedule like this (for years) is impossible.
  • Non-24 is like being permanently jet-lagged. My internal timezone changes everyday to an unknown timezone. The change is not constant but chaotic, so it is impossible to accurately predict when to sleep. It affects all aspects of general health and can cause cardiovascular diseases and diabetes, especially when chronically sleep deprived since this disease prevents from sleeping. For some it causes throwing up, dizziness, random fainting, car accidents, sudden cardiac arrest and strokes, and a lot of other very not fun ailments. Just like jetlag, but all the time, everyday of your life.
  • Non-24 is like diabetes before the discovery of insulin: there is no monitoring tool for the circadian rhythm, and we are not sure what causes these disorders nor how to improve them. Using light therapy and melatonin is like taking insulin regulating drugs for diabetics, but here it's regulating the circadian rhythm since our body can't do it properly. Health consequences of unmanaged non-24 are similar to diabetes, leading to cardiovascular diseases such as arrhythmias and even to diabetes and obesity.
  • Even with a working treatment, social and unexpected events makes it difficult to follow the therapy. Just like for diabetics, it's hard to go out while not being able to eat or drink anything because it can kill you with a stroke. Similarly, even when entrained with a working therapy, we would likely have to forego evening and night social events. That's unfortunately the price we have to pay for a stably managed sleep.
  • Non-24 causes chaotic wake up and drowsiness, I cannot plan when I will be awake or asleep.
  • I have a chronic illness that affects my ability to sleep, and for which no cure is known yet.
  • Everybody has a set period to sleep, even typical sleepers: those who can't sleep during the day have shift work disorder, those who can't sleep as early as socially acceptable have DSPD, and those who have a defined sleep period that changes everyday have non-24.
  • For work: I cannot know beforehand when I will sleep and wake up. On top of that, I don't know when I will be productive, as every other day the illness causes a zombie-like state between wakefulness and sleep.
  • If an alarm clock could cure an illness, it wouldn't be an illness.
  • Living with non-24 is living a life in alternance: one month you are good, one month you hibernate and get ill and are fatigued and late and depressed all the time.
  • Living with non-24 is like having a rotating day and night shift work but with no off days whatsoever, including on week-ends.
  • Living with non-24 is a very solitary life, it's like COVID-19 quarantines but for the whole life instead of just a few months. Everything, every errands, every appointments need to be carefully planned and weighted given the health risk.
  • Non-24 is like working a rotating night-and-day schedule that changes all the time. No week-end, no vacations, it's all the time. (And I'm not even paid for that.)
  • An excellent accurate depiction of DSPD was written in this couple's story in the Modern Love column of the New York Times, which was later accurately adapted in the TV series Modern Love S2.2 on Amazon Prime. The story mentions the fairy tale called The Day Boy and the Night Girl, which can also be seen as a depiction of DSPD. This isn't a depiction of non24, but it is very rare to find accurate depictions of circadian rhythm disorders in video media, this can provide a valuable and easy to share and watch medium to family and friends for them to understand what a circadian rhythm disorder is.
  • Here are more suggestions (mirror).

What are effective treatments for circadian rhythm disorders?

Circadian rhythm science is still in its infancy, and hence there are a lot of unknowns and gaps in the scientific knowledge. Therefore, patients are often left to their own device, and not understanding exactly how their disorder works, they try various treatments and approaches that can illusorily appear effective in the short-term but in fact lose any positive effect pretty fast, and can even cause more harm in the mid to long term. Clinicians also often verse into the same pitfalls, with the hope of helping their patients, but given the lack of practical guidelines, they are also left just like their patients to process by trial-and-error.

There is theoretically a simple way to determine if a therapy is effective to manage circadian rhythm disorders: if a treatment can directly shift the circadian rhythm phase, it's effective. Since the circadian rhythm cannot be measured, core body temperature profile over 24h can be used as a proxy since it is strongly coupled with the circadian rhythm. If a treatment cannot shift the circadian rhythm phase nor modify the core body temperature profile, it's ineffective and useless for circadian rhythm disorders (although these treatments can still be helpful for other comorbid issues or disorders).

Hence, if you would like to try other therapies not described in the present document, you can first check the academic literature to know if these interventions change the core body temperature. If they do, it's likely the intervention can shift the circadian rhythm, but if it can't change the core body temperature, it's almost certain it can't shift the circadian rhythm either.

For example:

  • Light therapy, melatonin, and any zeitgeber, can demonstrably and objectively shift the circadian rhythm phase and change the core body temperature profile, hence they can be used as effective management therapies for circadian rhythm disorders, including non-24. See the next section for more infos on zeitgebers.
  • Sleep hygiene, chronotherapy and CBT-i have never been demonstrated to shift the circadian rhythm phase nor to change the core body temperature. They are ineffective to treat circadian rhythm disorders, and should never be attempted as a first-line treatment. Although sleep hygiene can obviously help in other areas, using it as a first-line treatment for circadian rhythm disorders is like advising an alcoholic to eat healthily. Yes it can be a more healthy lifestyle, but this procedure is irrelevant in the context of this clinical entity.

Logically, in accordance with a recently growing body of scientific evidence, another alternative are drugs that increase photosensitivity. Since light therapy affects directly the circadian rhythm and core body temperature, anything that increases the sensitivity to light will also indirectly affect the circadian rhythm, but only when combined with light therapy.

Hence, to summarize, the only drugs that help are those which either directly affect the core body temperature eg melatonin, or sensitivity to light such as antidepressives and ADHD medications. Marijuana and psychedelics cannot manipulate the circadian rhythm. Our body needs a very stable core body temperature to ensure survival, so it's extremely difficult to affect it (humans are endotherm and homeotherm). Manipulating core body temperature is the key to manipulate the cercadian rhythm, but the very safety focused homeostatic processes that safeguard the stability of our core body temperature and hence our survival is also what hinders our ability to manipulate the circadian rhythm.

In practice, this becomes a bit more difficult: how can we know whether a procedure can shift the circadian rhythm? There are mostly two ways:

  • Either look at past academic literature, although there are conflicting results and often false positives, so it requires some training to discern what is viable and what is not.
  • Either test on yourself and measure the effect on your own individual case. There are multiple avenues:
    • The measurement can simply be a sleep diary, but this medium can suffer from high variability so it should be considered as partially unreliable. One way to overcome this is to maintain the sleep diary for a longer period of time (eg, months), to ensure the procedure is consistently effective (and it's not a coincidence with relative coordination - see the section below).
    • A more experimental but more reliable and objective method is to record the core body temperature or wrist skin temperature. See the wearables section for more information.

Accommodations for non-24


Disability rights and disability recognition

The very first step to get accommodations with non-24 is to get to learn about your disability rights in your country.

Disabilities recognition and accommodations should be available in most countries in the world, as 164 countries ratified the United Nations' Convention on the Rights of Persons with Disabilities (CRPD), easy read versions are available here and here, and the list of countries that ratified the convention is here. You may choose to use your rights or not, but it is crucial you do the formalities to get acknowledged and to get offered these possibilities if you need them. Do them while you are still able to, because when you will need them, you may be in the incapacity to fulfill the steps or may be in a dire financial situation.

In practice, to get disability recognition is not easy, the eligibility criteria are usually quite harsh, so that only the most debilitating illnesses are eligible (contrary to what the convention states...), but non24 usually meet them.

First you need to estimate how many days you can (not) work per week, and check your country's eligibility threshold for disability. Usually it's around 2/3rd of disability required at minimum for recognition. There are also othes eligibility criteria you need to check, but the productivity handicap threshold is the most important. Then you need a medical report / accommodation letter from your sleep specialist describing your difficulties with the illness and how it affect your ability to work, and most important of all, write their (or your) estimation of your productivity handicap, eg, can't work more than 2 days per 7 days due to the illness without accommodations. This doesn't mean that you can't work more with accommodations, in fact the accommodations are ther to allow you to be more productive, with rn adapted environment to your condition. Of course, it's necessary first to be medically diagnosed, so if that's not the case yet, check the informations in the Diagnosis section in this document.

Now with the medical accommodation letter, you can check how is the administrative process and the forms needed in your country to ask for a disability recognition. You can also ask for financial help if you need it, but even if you just ask for a disability recognition, this should at least allow you to ask for work accommodations or even financial access to work help (eg, tax reductions for your employer) which would already be tremendously helpful.

The other sections below describe specific practical accommodations that either you (the patient/employee) or the employer can be reasonably expected to implement. Indeed, the disability rights only guarantee "reasonable accommodations", which is subject to interpretation. It's hence a good idea to check what previous accommodations were implemented for other cases, as this sets a precedent for what is considered reasonable.

School accommodations for students with the non-24 disorder

Sleep is an essential need for all humans, and is especially crucial for kids, as sleep loss can significantly impair not only their health but also their grades and hence their future. For them to have a fair, equal chance to education and to future work, they are elligible to reasonable accommodations. Reasonable accommodations are accommodations that can be reasonably expected to be implemented by the school, without much cost nor impact on their organization, which is arguably a significant restriction on disabilities rights but nevertheless allows for at least some partial accommodations.

Here are some suggestions of accommodations specifically for students with non-24 that was written by the Sleep Foundation, so you can use that as an official resource to present to the school:

> Students With Non-24-Hour Sleep-Wake Disorder
> As outlined under Section 504 of the 2008 Disabilities Act Amendment Act9, students with disabilities also have the right to an education that meets their needs, whether in elementary, secondary, or post-secondary school. Examples of reasonable accommodation for students might include taking classes online, allowing students to miss some classes and make up the work at another time, or taking a lighter course load.
Source: https://www.sleepfoundation.org/non-24-sleep-wake-disorder/living-managing

In the current document's author's opinion (based on his experience without accommodations), two reasonable accommodations that can significantly improve the fairness of academic training and evaluation of students with non-24 are:

  • Allowing the student to get access to the course content that they not be able to attend, for example by having other students share their course notes, or having handouts of the course by the professor, or online recordings accessible by internet.
  • Not sanctioning the student for their absenteeism, as it is unwillingly caused by their chronic illness. Attendance should not be a limiting factor, the students should be graded based on their academic merit, not their presence. This point is not for comfort, it is a crucial specific accommodation for non-24, since one characteristical effect of this disorder is a chaotic sleep-wake schedule and health status that cannot be planned. A child with non-24 who is sanctioned for missed classes will face the unfair dilemma of either damaging their health and grades by pulling all-nighters repeatedly, or they will face sanctions and potential school exclusion regardless of their academic merit just because of missed attendance. This would be as unacceptable as sanctioning and excluding motor disabled children because they can't participate in most physical exercise classes.

Both of these accommodations cost little to nothing in terms of effort or time (especially the avoiding of sanction of absenteeism) and hence can be considered reasonable accommodations.

The holy grail is asynchronous remote classes, that can be done at home, just as what was organized during the COVID-19 pandemic. But unless such a system is already in place at the school, it can be difficult to consider it a reasonable accommodation if it needs to be completely setup just for one or a few children.

Note that you can also come up with other suggestions, it's not limited to this list. The important thing is that you discuss with the school to find a common ground between your kid's needs and a reasonably implementable accommodation that the school can do without much cost.

See also the rights provided by the United Nations' Convention on the Rights of Persons with Disabilities (CRPD), especially the section "24. Education" in this easy read version.

More ideas of school accommodations: https://web.archive.org/web/20210927021722/https://old.reddit.com/r/N24/comments/ozzqkd/school_accommodations_with_non24/

Hopefully, with increased awareness about (sighted) non-24 in the future, next generation children with non24 will get proper accommodations and won't get unfairly penalized for their unavoidable and unwilling periodic absenteism.

Note for DSPD: the accommodations are very simple, allow for classes to start later in the day, preferably no earlier than noon. There are plenty of chronobiology researchers and clinicians in several papers already advocating for such a change with later school start times, as it was repeatedly shown to significantly increase the students academic performance.

Work accommodations with the non-24 disorder

Accomodating the non-24 circadian disorder and its variable and mostly unpredictable sleep-wake schedule with a stable work schedule is very challenging, with arguably most individuals with non-24 remaining unemployed most of their lives, regardless of their skillsets.

Although no definitive solution exist, here are some ideas for accomodations to optimize the chances of a stable employment and productivity with the non-24 disorder:

  • Get your disorder recognized medically (see the section on diagnosis), then as a disability. This will allow to get "access to employment" helps, including accommodations from your employer and financial help (eg, tax reductions) for your employer if needed.

  • In terms of practical work scheduling, foremost, seek an asynchronous workflow. Working remotely is not sufficient: because of the variable sleep-wake schedule, remote appointments at set times will also be as impossible to regularly achieve as in-person meetings. Likewise, flexible hours jobs aren't adequate either, since the variable sleep-wake schedule is unpredictable and makes planning "awake hours" impossible from one day to the next. Hence, the job needs to be achievable with no set hours, it's necessary to be able to accomplish work tasks at anytime of the day and night, whenever you are awake. Hence, prefer e-mails to chats (such as Slack) and (rare) videoconferences. If meetings are necessary, prefer videoconferences rather than in-person meetings, as these will allow you to get back to sleep just after in case they are scheduled in the middle of your circadian night (which is challenging to predict beforehand since the circadian rhythm is always moving with non-24, so usually it's impossible to predict exactly beyond a week before the scheduled date of the meeting). However, keep in mind that any event disrupting your circadian night will affect your sleep and work over the next days and hence your productivity, hence they should be avoided as much as possible when the circadian rhythm is not in phase with the day-night cycle. If possible, ask for recording all videoconferencing sessions so that you can watch them at anytime later at your convenience, and it can be useful for your team for archival purposes.

  • Seek a non-scheduled work position with minimal time-fixed events and planning, because: 1) due to non-24, it's often impossible to ascertain whether a time fixed event will happen during a sleep session, 2) it's also often impossible to determine how long and good a sleep session will be, hence it's necessary to take into account that several, if not most (depending on responsiveness to entrainment therapy), days will be spent exhausted, with very little productivity. These two points aren't exclusive, as interrupting a sleep session to meet a time fixed event such as an appointment will cause more exhaustion the next days due to the increased sleep deprivation that will take more time to clear up. The major source of time fixed events is business interpersonal relationships (ie, meetings), hence avoid any work that primarily involves client relationships or interactions with other humans, such as sales. Prefer works that can be done independently from other humans. Freelancing can be a partial solution but unfortunately incomplete as it still requires business client relationships, but it can be managed to your convenience as to reduce (but not eliminate) the impact on your sleep. Only non-scheduled jobs can fully accommodate non24, but flexible schedules are potentially partially possible with non24 although at the cost of some amount of chronic sleep deprivation, so the practical possibility depends on the exact terms of the flexible schedule position.

  • Adopt a task-based agenda instead of date-based or deadlines agenda. As with many chronic illnesses, energy levels can fluctuate a lot and imprevisibly from one day to the next with non-24. Hence, a usual date-based agenda (ie, "Do errands on Tuesday") is likely going to fail and lead to more self-shaming. Instead, adopt a task-based agenda, based on priorities: do first what matters you most, whenever you feel energized enough to do so. If you can't today, try tomorrow, and don't beat yourself meanwhile, allow yourself to rest whenever you need. It's necessary to regularly re-evaluate priorities as time passes. However, avoid a deadline approach, as any fixed date is likely going to be missed, even if it's "only" a personal deadline. Just plan tasks you want to achieve and rank their priorities according to what matters to you most. What matters is that you do what matters to you, not that you meet a specific deadline. It is unfortunately illusory to hope to meet deadlines when you have a chronic illness, especially a chronic illness such as non-24 that specifically impairs our temporal capacities.

  • Learn to rush/botch your work, especially if you are a perfectionnist. As the saying goes: done is better than perfect. With a chronic illness such as non-24, it's necessary to plan to have at least half as less time, and often much less, for any activity than non afflicted individuals. How much can you complete in half the time someone else has? This is what you need to aim for. If then you have time left, you can always further your work, but at least get the most important parts done, the crucial ones, and work on finition much later on if you have time left for that. This doesn't mean you should do work nor good quality work, but you need to significantly lower the bar and focus on fewer items, focus on the primary set of things that needs to be done for the thing to at least be functional/useful/interesting, the rest comes later.

  • The working memory (both verbal and visuospatial) are drastically impaired under sleep deprivation. Although sleep deprivation can be reduced with proper management of non-24, it's unlikely to be completely avoided and will still be a regular occurrence. It's necessary to take into account this impairment to reduce the potential for mistakes or accidents. A workaround is to prefer writing for communication and workflows, rather than oral communications, as the written supports will reduce the need to use your working memory.

  • It's crucial to account for a very prevalent cognitive bias: "out of sight, out of mind". This means that it's necessary to show up to meet your boss and colleagues from time to time to assert your presence and position in the team, otherwise you will be forgotten. Indeed, work quality and completion is not sufficient, humans forget what they do not see, and start acting regardless of the "missing" elements. This is not even specific to circadian rhythm disorders, as this phenomenon can also be observed with night shift workers, whether in the professional or private sphere. Since the workflow of a non-24 is necessarily asynchronous to be healthy and sustainable, this means there will be fewer opportunities to meet and assert one's own presence and position in the team. To optimize, the meetings can be selected: annual meetings, key projects deadline meetings and other key meetings should be attended, as long as it does not impact health too much (ie, these meetings need to be interspesed and rare, if they are weekly occurrences this is unsustainable, max is bimonthly). Any unnecessary meeting that can be done by an asynchronous mean such as e-mail should be done this way. Do not make the usual mistake of considering that work quality and productivity is sufficient: they are not. Even if you are an over-achiever and finish all tasks beyond expectations, you and your achievements will be quickly forgotten or not even accounted for if you do not show up from time to time.

  • Always take into account that you will always have far less opportunities than someone else with same or less abilities or qualifications, just because of the mismatch between your circadian rhythm and the rest of the world. This is a mechanical consequence of the non-24 disorder, as most opportunities are related to the actions of other humans and business networking relationships, so that if you are asleep when they are doing these actions, you miss most of the events, and hence the opportunities. There is no way around this "bad luck". The only thing that can be done is to be aware of this limitation so that to put safeguards in place for when you are asleep, and hence to maximally exploit the few opportunities you get access to.

  • Put your safety first. Do not drive if you are sleep deprived, you will have worse decisional capabilities and slower reaction time, just like as if you were drunk. In fact, sleepiness is the greatest cause of accidents in all modes of transport, far surpassing alcohol. Instead, prefer to plan ahead and use other means of transportation. If you are not sleep deprived but your circadian night will happen during the time you plan to drive, avoid driving as you are more likely to doze off on the wheel, especially for long driving sessions (eg, cross-country). Although not studied, circadian misalignment is very likely to contribute to dozing off while driving, whereas sleep deprivation is a well established factor.

  • Setup and furnish your work environment to allow for both working and sleeping, as sleep disorders makes wakefulness very fleeting and varying, which makes it necessary to work in an environment accomodating both wakefulness and sleep and everything in-between. For example, having a couch in addition to an ergonomic chair, and a mobile table to move the workstation to either. Such an environment will allow you to nap or to work in a laid down, more comfortable position when you are tired. Although it is usually disadvised to work in a laid down position, this recommendation is made by people who do not have energy issues due to a sleep disorder, for whom it is regularly impossible to work in a usual sitting position. Working in a laid down position allows to reduce physical energy expenditure and hence allow the body to allocate more ressources to cognitive functions. Ergonomic chairs make a real difference, especially when energy levels are low, as they reduce the tiredness from lombar support by transferring the weight onto the chair. Inexpensive ergonomic chairs are available from some manufacturers such as Sihoo or mFavour.

  • The only perennial workspace is at home. Due to non-24, the workspace needs to be accessible to work at any time of day and night, to be comfortable and safe for sleeping at any time of day and night, and to be accessible without driving to eliminate the very real risk of car accident due to drowsiness. Realistically, only a home workspace fits with all of these criteria. Dedicate a room for work, separate from the sleep space. Furbish it adequately for both work and impromptu naps/sleep, you can't expect to work to professional standards under an unprofessional environment and with no professional furniture.

  • Expect to work at any time of day and night. If you can't sleep after 30min of laying down, get out of bed and get back to activities, including work if you want. You can't force yourself to sleep, closing your eyes and wishes aren't going to make you sleep. But when you'll feel ready to sleep, go back to take another try, but expect this won't happen before several hours so you have time to work or do other activities meanwhile.

  • Work whenever you have enough energy on the most important/urgent tasks, as you never know when you will get enough energy again (it can be days or weeks from now), and do not wait for full energy level to work, as this will fluctuate a lot from day to day and during the day. Keep a set of tasks you can do with lower energy levels, and try to do what you can. Accept that you may not be able to achieve the tasks, aim to work and progress, not to complete. Far more will be accomplished by working on minor tasks at a slow pace and reduced capacity than not working at all. There are days when cognitive dysfunctions will be so great that you cannot achieve anything (ie, impossible to focus and think), accept these bad days as part of the illness.

  • Find smartphone apps that can be used for your work, so that you can work everywhere at anytime. The lack of a routine in non24 makes it hard to have a defined period at the desk, hence smartphone apps can circumvent partially this lack of physical routine. However be careful not to be overloaded, make sure to disable your smartphone's notifications when you need to sleep.

  • For appointments, use a chronobiological alarm clock (also called "smart alarm clock"), which monitors the user's sleep stages via actigraphy and vibrate when it detects the user is in a light sleep stage, such as Sleeptracker Pro (discontinued), Fitbit or Sleep as Android (but apps are much less effective than wearables worn on the wrist since it requires actigraphy). Make sure to select the model that offers both a smart alarm and vibration, it's much more effective and with vibration than an auditive signal.

Furthermore, the data on insomnia likely also applies to unmanaged non-24:
> With respect to vocational performance, several studies have found that sleep disturbance and/or chronic insomnia are associated with less job satisfaction, lower performance scores, less productivity, and higher rates of absenteeism.13,14 A study by Leger et al15 found that those with insomnia had more absenteeism compared to good sleepers (31% vs 19%) and made more errors at work in the previous month (15% vs 6%) and that 18% of those with insomnia, versus 8% of good sleepers, reported poor work efficiency in the past month. [...] Individuals with a variety of sleep disorders are thought to be at increased risk for motor vehicle accidents.18 Patients with insomnia in particular have been found to be 2½ times more likely to report car crashes because of feeling tired as compared to those who do not report insomnia.

A 2020 systematic review on sleep disturbances and risk of sick leave found the following:
> Sleep disturbances are risk factors for sick leave. Sleep problems can lead to various health problems that affect the amount of sick leave. Improving sleep quality can have a decisive impact on job performance. Sleep disturbances are risk factors for increased sick leave.

Additional information:

  • Expect to often be late if you have appointments. The non-24 makes it difficult to plan ahead of time at what time you will be awake, and so any planning becomes more difficult and productive time during office hours becomes compressed, so that you often end up trying to frantically complete as many tasks as possible under a very tight schedule, which is often impossible. Lower your expectations accordingly, and try to avoid appointments as much as possible, flexible schedules are necessary, so prefer deadline and task based schedules which do not require a completion at a specific time during the day.
  • Sleep deprivation impairs temporal preparation, so this also participates in the higher likelihood of being late as it makes it difficult to adequately prepare on time, every act becomes delayed and rely on automaticity.
  • Since the non-24 disorder makes it hard to maintain a stable employment status, it's necessary to plan to invest part of the earned money during the employed periods to build a safety fund, as is common practice for independent contractors. The first step is to learn how to be more financially literate. The videos of Mark Tilbury are a great start point.
  • Regular physical exercise is necessary for optimal cognitive performance. But it can be challenging with circadian rhythm disorders, especially non-24, to go to the gym because of the mismatch with the opening hours or exercise outside at night. An at-home inexpensive but effective alternative is to use resistance bands. Indeed, resistance bands were shown by a systematic review to be as effective as conventional resistance training including free weights for muscular and strength gain. Resistance bands allow to do all exercises achievable using free weights (see James Grage tutorials including this beginners tutorial). They can also be used to train cardio in combination with a HIIT or TABATA routine. These can be bought for 30 euros to 100 euros for the top quality (Undersun Fitness). Prefer to use loop type resistance bands rather than cord-like bands, as the former allow for a broader set of exercises and are more robust over time.
  • When sleep deprived, impairments in thoughts inhibition (ie, running thoughts) can be expected, hence on those days avoid interruptions especially social, as they will be much more disruptive to the workflow than on days with less sleep deprivation.
  • The home environment is also important for work, especially since with non-24 you will live and work mostly at home. It's necessary to choose a home environment that is well exposed to sunlight, especially in the morning, which will reduce the need or duration for bright light therapy, but also can be equipped with blackout opaque curtains to allow you to fully control your exposure to bright light (and avoid it when necessary). Thus, avoid living at the ground/first floor of a building, the higher is better.
  • At school, ask to favor mid term and end of term exams for kids with a circadian rhythm disorder, avoid "continuous exams" (ie, frequent exams done during classes) as these require the students to always be present in class, which is fine and can fit better for some kids, but certainly not for those with circadian rhythm disorders such as DSPD or especially non-24.
  • There are a few initiatives to help signal hidden disabilities and get discreet help or accommodations, such as the Hidden Disabilities Sunflower which is implemented since 2016 by several traveling entities in UK such as airports, railway, supermarkets, etc.
  • Here is a list of complaints and tips by individuals suffering from circadian rhythm disorders, demonstrating these issues are common for them, and these resources can provide additional practical advices and ideas for accommodations:

TODO: Add infos about chronic diseases and unemployment:

Home accommodations

Living in an adapted environment is crucial for any individual with a chronic illness, even more for those living in couples or with their family.

Here are some ideas for a home environment adapted to non-24 and other circadian rhythm disorders:

  • Move/choose a home with a separated livingroom, and where each room (including kitchen and sanitary) can be accessed without passing through or close to the bedroom. This is the most important tip, as this allows to make the livingroom the literal living room, where you or your partner/family can wake up and go to to do their activities without bothering those who are asleep. The idea is not to make big noises, but to be able to do the necessary activities without bothering others, such as cooking (carefully to lower noise), going to sanitary, and doing any kind of activity in the livingroom as long as it's not too noisy. For example, talking at a reasonable sound level should be possible at any time of day and night in the livingroom. Anyone should be able to go to the bedroom to sleep at any time, whether day or night, without impacting the activities of others in other rooms. Hence, the best are homes where each room is connected through a corridor, not through other rooms. This tip works for both non-24 and DSPD and is the single biggest improvement that can be made, see for example this New York Times story that was adapted in the Amazon Prime's Modern Love S2.2 episode. This reduces the "walking on eggshells" issue but does not eliminate it, especially not for the individual with the circadian rhythm disorder since they will still have to mind neighbors when they are awake at night (ie, nightwalking).
  • Reduce noise when you sleep, and take it into account as a primary factor when moving to another home. This is crucially important, as noise during sleep, even if heard only unconsciously (ie, no memories of interruptions due to noise at wake-up), it will still greatly impair sleep quality, to the point of feeling permanently exhausted. For example: building works that are common in cities especially in September-November ("back to work" season) and which usually start everyday at 8am and hence can overlap pretty much with a delayed circadian night (DSPD or non-24), relatives or neighbors in a too small flat, etc. Hence, living in cities is likely not a good idea, especially around the arteries or big roads.
  • Given the two points above, the ideal home environment for someone with a circadian rhythm disorder is hence an independent house. Otherwise, there is no other way than to permanently live on eggshells, which is very strenuous and limiting. But this is unfortunately a catch-22, as it is difficult to acquire the financial stability necessary to access the housing market when hindered by a disability.
  • Buy bluetooth bone conduction headphones. This will allow to use TV and computer at night, without bothering anyone. Usually, multiple headphones can be paired to the same device, so that for example if you have non24 and your kids have too, they can wake up at night, go to the livingroom (see the previous point), and watch TV or use a computer to watch films and anime, and you can even watch with them if you both have headphones! The advantage with bone conduction headphones is that they are very silent to others and also that they do not make the ears become itchy, so they are very comfortable and they do not damage the ear canals. This allows to freeroam and do activities just as if it was day and the speakers were used, but it's a wireless transmission instead that is silent to the environment. You can share some piece of musics and movies with your kids this way, just like you would in the day.

Coping and accepting a chronic illness

Certainly, one of the greatest challenges of acquiring, or discovering, a chronic illness such as non-24 and other circadian rhythm disorders is the necessity to learn how to cope and accept the disease and its chronicity (ie, that the disease is not curable and can only be partially managed with great efforts). Disease acceptance is a lengthy and grueling process spanning years if not decades. Acceptance is more formally called "normalizing" in the academic litterature.

The denial phase is very common and arguably the longest phase. Ignoring the limitations that are inherent to a disability is very different from acknowledging and working around the disability. The former, which is denial, is a sure way to crash into the wall at some point, whereas the latter, acceptance and understanding of the limitations, is the only viable long term solution that can allow to recover a better quality of life to some degree. One very important step to go out of the denial phase is to suppress wishful thinking, which is to believe that the illness can be overcome by willpower, which is a hard fallacy that bit everyone during the COVID-19 pandemic, and is a necessary step to pass through for all individuals with a chronic illness.

It is important to note that acceptance is here not meant in the usual, idealized form of accepting means that the individual is not affected by the disease anymore and everything gets better and positive. This is unfortunately a widespread ableist view of what acceptance is. Because the disease stays there, it is chronic, it likely does not ever get better for most. There is nothing that can make this soul crushing experience positive. Instead, realistic acceptance consists in accounting for the chronic illness, to acknowledge it really exists and that the individual has it, will likely keep it the rest of their lives, and to plan around it, instead of wishfully thinking it can be powered through via will, as the latter is a sure fire way to head straight into the wall. Acceptance really means to learn how to live with the chronic illness, not despite it, not via its strengths (as usually they provide none), but simply with it. It does not mean to be happy about it, just like accepting the death of a cherished one does not mean it will ever become a positive experience.

Rather than paraphrasing, we will extensively cite extracts from this impressively accurate and fairly exhaustive academic work: The Handbook of Social Studies in Health and Medicine, 2003, chapter Experiencing Chronic Illness, pp 277-292, ISBN: 0761942726, 9780761942726 :

> Chronically ill people seldom want to be invalids; they wish to be accepted as valid adults. Their self-doubts rise if other people imply that they wanted to get sick or harbor questionable motives for seeking care and claiming special needs: 'Are my symptoms real or all in my head?'. Their symptoms may be intermittent or gradually increase until they interfere with everyday life. The person cannot meet obligations, keep up with coworkers, maintain their households, or handle daily child care. Esoteric and invisible illnesses often prove elusive. Then, symptoms may become pronounced before they are recognized as such. Yet, ill people do delay seeking help if it poses risk of further loss. Social purposes rather than health needs take priority. People delay seeking help when they risk losing valued roles, responsibilities, and images of self. For example, a parent who resists relinquishing child-care duties may defer seeking help.
> Recognition of diminished function or inexplicable symptoms spurs a diagnostic search. Stewart and Sullivan (1982) found that patients with multiple sclerosis began their diagnostic search when they could no longer explain their symptoms. However, physicians and relatives typically did not affirm their symptoms as real until after diagnosis more than 2 years later. During this time, ill people live in 'diagnostic limbo' suspended in time. These patients often seek multiple physicians when their complains are discounted and dismissed. Discounting and dismissal also may occur after a problem has been defined as chronic but practitioners cannot ameliorate it, such as chronic back pain.
> Diagnostic shock follows an announcement of serious illness that shows up in testing -- cancer, multiple sclerosis, and diabetes -- before patients either note symptoms or grant them any significance. From the patient's viewpoint, diagnostic shock occurs without warning, such as during a routine physical. Part of the shock means having reality discomfirmed. Not only are the person's suppositions about his body shaken, but also to the extent that a diagnosis has foreboding meaning, prior reality is disconfirmed as this diagnosis is confirmed. Subsequently, prior identities are also disconfirmed. When people do not anticipate bad news, have little knowledge and few symptoms of their confirmed diagnosis, the disparity between diagnosis and self-concept is greatest. Then the person needs time, bodily experiences, social encounters, and self-definitions to redefine self and identity. Meanwhile, the diagnosis confirms being catapulted into a patient role. A new label, a new identity has been applied and given. Yet even the most dreaded and seemingly known diseases such as AIDS, leprosy, and cancer require learning what being ill means.
>
> Learning what Illness means
> In order to be ill, someone has to feel sick. Merely being informed that one has a disease seldom suffices. Until a person defines changes in bodily feeling or function, she may postpone dealing with a diagnosis, even a serious one, and subsequently ignore medical advice and regimen. Illness does not seem real. Then the person may cleam that the diagnosis is wrong, secondary, or inconsequential, and relations with practitioners suffer accordingly.
> People learn what illness is through their experience of it. Lessons in chronicity come in small everyday experiences such as difficulty in opening a can, bending over to pick up a newspaper, folding bedsheets, and weeding the garden. Comparisons with past effortless performance can be shocking. Such jolts later become measures explicitly sought and then assessed. A man with heart disease who used to stride across a golf course now shuffles half way across the company parking lot. A present reality jolt can be reinvoked as a future measure. Measures include time -- the person can only get through part of the work day, rest requirements become apparent to coworkers, fulfilling work standards takes hours or days longer. Indicators become measures when they are impossible to gloss over or to have someone else camouflage. A person may invoke measures, or other people may supply them. These measures can multiply and form a general standard against which to judge self.
> Historical, cultural, social, and situational contexts influence meanings of illness. Waxler (1981) argues that in every society, the sick person learns to take a role that society expects. [...]

Aparté: this progressive learning through experience of what a chronic illness is like is perfectly illustrated by the "spoon theory" by Christine Miserandino (although this is not a theory at all). This can also be used to explain chronic illnesses to external observers and relatives.

> Normalizing Illness and Regimen
> Normalizing illness and regimen means making them routine, and treating whatever changes and improvisations are created as ordinary. For some people, normalizing means letting past plans and projects go and scaling life down. For others, it means struggling with illness and regimen to make life manageable so a valued future is possible. In both cases, normalizing means adapting to the situation at hand. It also means proceeding with activities 'as if normal'. Normalizing means finding ways to minimize the impact of illness, disability, and regimen on daily life, including their visibility. It constitutes an attempt to contain illness to personal experience and not intrude upon interaction. Thus, chronically ill people cover up limitations and keep up normal appearances and activities. They normalize a certain amount of discomfort when they can still function in ordinary ways. Such strategies become hazardous if a person overextends his capacities and perhabs harms an already compromised body.
> However, when ill people normalize symptom control and regimen, they may increase their capacities and maintain their health. This kind of normalizing means making new routines the norm and the normal. What earlier seemed bizarre becomes customary and comfortable. [...] As innovations and changes become routine and accepted, they feel normal and allow the ill person to view the self as normal and they way of living now as natural.
> Normalization reduces disruption. It softens the impact of frailty and disability. Through normalizing, ill people take their way of being and the changes they have endured for granted. As their lives become more restricted, their world shrivels, frame of reference shrinks, and self contracts.
>
> Illness Management Strategies
> Chronically ill people learn ways to handle their physical symptoms through various strategies ranging from withdrawal to innovation. Strategies for managing illness also require strategies for effective negotiations. People in lengthy marriages make managing illness a coupled affair. Visible disability drives other adult relatives away. What people need to manage depends on their illness, its progression, and its meaning to them, as well as their situation and their responsibilities.
> [...] Younger and middle-aged people often make concerted efforts to manage their illness. They maintain hopes and plans, reasons, and responsibilities. They have not given up or given in. They become innovators. To do so they listen to their bodies and stay in tune with them in ways that they had not and in ways that Western culture discourages. They make use of indigenous support groups, newsletters, and computer networks independent of professionals. The groups and methods provide collective information and shared community. They may constitute the only community for people who have become isolated in their homes. Members compare stories, gain information, learn about treatment successes and failures, and offer encouragement to continue to struggle with illness and not to sink into invalidism. They may keep daily logs to refine and extend data for working with their professionals.
> Shared comparison give support group members measures of where and who they are now. Certain chronic conditions such as kidney failure and treatment programs such as cardiac rehabilitation bring people into sustained contact with others with similar problems. A collective spirit may develop in these situations that either supports patients remaining involved in prior pursuits, or confirms that the world of illness now dominates their lives.
> Some chronically ill people become so adept at monitoring and managing their illness that they break through textbook definitions, create individualized regimens, and construct new ways of living with their illness; but medical professionals may not welcome their innovations. Alonzo Plough (1986) argues that patients who know too much use medical terms and request specific treatments that anger their practitioners. Practitioners sometimes push these patients back into the sick role when challenged by their growing expertise. Chronically ill patients sometimes find that their practitioners hold an ambivalent stance toward them. Their practitioners want them to take responsibility for themselves but on professionals' terms, not on their own. When these ill people step outside or beyond medical authority, their practitioners resort to medical paternalism and authoritarian demands. Consequently, ill people's strategies for managing illness can require strategies for effective negotiations with professionals to minimize conflict. [...]
>
> Stigma and Stigma Control
> Experiencing stigma is a common consequence of chronic illness and a constant threat in some ill individuals' view. If so, stigma makes a person vulnerable to negative social identifications and self-definitions. Stigma results from being identified as flowed, discredited, or spoiled. A defined difference from ordinary peers separates a person and confers an actual or potentially devalued identity. That difference often becomes a master status, such as 'disabled person,' 'leper', or 'AIDS victim,' that floods all statuses and identities. The stigmatizing label defines the person and every other defining characteristic she possesses. Thus, a woman who uses a wheelchair because of multiple sclerosis becomes a disabled mother, handicapped driver, disabled worker, and wheelchair dancer. [...] Often other people dissociate the 'understandable' reason for an ill person's difference from his behavior eliciting the stigmatized response. Then blame is turned back upon this person, who is made morally culpable for the stigmatized response itself. In essence, the individual is blamed for the behavior and blamed again for being stigmatized for it. [...]
> Any illness that sets a person apart as different and diminished has stigma potential and thus can affect interaction. The following characteristics increase stigma potential: a high incidence within disparaged groups, compromised adult status, loss of bodily control, sexual transmission, possible pollution, odor, and uncleanliness. [...]
> Davis (1963) argues that efforts toward prior identity preservation fail in direct proportion to the degree and extent of visible disability. Both enacted and felt stigma contribute to difficulties in preserving prior identity. The disability rights movement has made significant recent changes in the lives of its proponents. However, many ill people still find themselves responsible for preserving or reconstructing their identity after losses -- whether their disability is visible or invisible. Concealment of an invisible but potentially stigmatizing mark of difference allows the person to preserve prior identities for a time and under specific conditions. Many disabilities do not remain completely invisible to a discerning observer. Partners or parents may perceive cues more readily than a professional who does not have steady contact. Fatigue, flare-ups, or distress may render symptoms visible. [...]
> When invisible disability undermines fundamental ways of defining self, the person is isolated, and social comparisons are not possible. Then coherence and stability of self-concept is at risk.
>
> Self and Social Identity
> Stigma can wreak havoc upon the self for it forces unwelcome new ways of conceiving self and situation. Still, serious chronic illness alone can render social identity and self problematic. For months and years, people may try to forestall illness from touching the self. Valued roles and pursuits preserve continuity and coherence of self. People may acknowledge that illness affects their lives but resist its effects upon the self. They conceptualize it as a 'condition, not an illness,' 'just aging,' or 'a spell' and therefore maintain a sense of continuity and coherence of self. They put it into the past by saying they 'had cancer' or 'had lupus' and decree that it will remain in the past. [...]
> People with serious chronic illnesses must repeatedly rethink how they live and who they are becoming. Self and social identities are intertwined in daily actions and endeavors. Chronically ill people seek to reestablish their legitimacy after disruption and devaluation makes them vulnerable. However, they may not go about it in ways of which their practitioners and families approve. As life narrows, the ingredients shrivel for constructing a valued self and legitimate social identity. Their quality of life becomes problematic. Social, economic and psychological resources expand possibilities and options rapidly contract. Using available resources may be fraught with risks and increase vulnerability. Taking sick leave can result in increased scrutiny of an employee's performance. Filing an insurance claim might contribute to raising the business's group insurance rates. Sociale resources mean that commitments, assistance, and back-up are available -- as long as caregivers do not wear out. Concrete assistance smoothes problems and reduces anxieties. Commitments keep the ill person within a web of relationships -- from commitments that permit returning to work to commitments to visit or to run errands. Economic resources allow an individual to purchase objects and services that make life easier -- a car with an automatic shift, a one-story home, household help. The more resources available, the more latitude the person has to take time-outs for illness and then return to earlier pursuits. Identity questions and change of self are muted or occur over long periods of time. As resources dwindle, identity questions and changes of self may be forced much earlier.

Aparté: According to studies, disabled americans need to spend on average 30% more than their non disabled counterparts. This represents about $17K/year.

> Experiencing chronic illness can mean embarking on an odyssey apart from the busyness of other adults' lives. Chronic illness separates the person from the social body, but also gives rise to a story that brings this individual back to reintegrate self on a different level. Someone may leave old identities behind but gain deeper meanings. Long stretches of time allow the person to reflect upon jarring images of self and to make sense of loss. Loss of self and social identity do comprise a fundamental form of suffering among chronically ill people. Still, they may come to believe that facing such losses moves them toward trascending loss. Earlier vulnerability becomes a source of strength as they redefine illness as a time for reflection, reassessment, and redirection.

The reading of the rest of this chapter is highly recommended.

A few additional practical tips by the present document's author:

  • Learn to recognize the effects of sleep deprivation and circadian misalignment, and discriminate what is caused by them (and hence by the non24 disorder) from the rest. By recognizing these effects on your health, it's possible to 1) better manage them (either by waiting out or by doing tasks that do not require high functioning and avoid affecting others with one's mood dysregulations — but it's not always possible to manage), 2) not feel guilty or shame for simply being ill, which can significantly decrease the risks of depression, as the illness's "episodes" just become a hassle rather than a pit of despair. If you don't know what are the symptoms, look up jetlag which is the most accurate model, or alcohol hang over since sleep deprivation is similar to alcohol intoxication.
  • Accept that it's likely not possible to fully control the effect of non24 on one's health. Even with the most effective therapies currently available, unproductive days with low mood due to sleep loss for various reasons will still happen regularly. They are part of the disease. Therapies can reduce their frequency, but they will still be relatively frequent (more for non24ers with an extremely long circadian period).
  • Accept that non24, just like any other disability, requires accommodations and prevents from doing some types of jobs. For example, it's unrealistic with non24 to pursue a commercial work position with clients contact, as a strict 9-5 work schedule is required. There are only very few jobs that are adequate for non24, but there are jobs that are sure ways to fail and damage health.
  • Although you may improve your condition a lot with adequate treatments and tools, you must understand and accept that there is no way back to your idealized future. It is impossible to be permanently cured from this chronic illness, and you will have to learn with it, and prioritize what matters to you and what you can do versus what you wished you could do.

Addendum: at some point, you may have a period when you identify yourself with your illness, that it defines you. Although such a chronic illness can certainly explain a lot of previously misunderstood "habits" that were mere consequences of the illness, it does not define you. Your abilities, your passions, your goals do not revolve around the illness, although it is certainly a limiting factor.

Addendum2: it's ludicrous to claim that acceptance of the non24 disorder and follow the natural sleep-wake pattern is acceptable. It drastically impairs quality of life, it is a very invasive disease that disables from doing everuday activies and essential life stages such as raising kids. Of course, without an effective entrainment therapy, there is no acceptable alternative to just following it, and acceptance involves accepting that the disabilities created by the non24 disorder. But chronic disorders induced disabilities do not get any better by acceptance. Hence, "accepting your disorder" is a fallacious mantra. Accepting the limitations and accommodations necessary around the disability is a necessary step, but the idea that accepting the disability will make everything work somehow is ludicrous. Without a stable entrainment, at least either social life, family care or your health will have to be compromised, often all will be in an attempt to juggle between them, and that's considering the best case scenario where your work position is not impacted. But since robustly stable entrainment is not currently achievable, only imperfect solutions are currently available, and hence sleeping in circadian alignment remains a much healthier and viable solution to working and sleeping in circadian misalignment and chronic sleep deprivation.

Additional reading materials on this topic of normalizing are available here, here, here, here and here.

For relatives and loved ones of people with a chronic illness such as non-24, here are some helpful resources:

Zeitgebers


Introduction to zeitgebers


What is the circadian rhythm(s)?

The circadian rhythm is an essential biological process that not only regulates sleep but also wakefulness, its purpose is to be in phase with the environment to improve the chances of survival. It appears very early in the life, with fetuses developing their circadian rhythm based on their mother's rythmic secretion of hormones and the stabilization of the circadian rhythm happening at 3 months after birth in most babies to synchronize with the parent's rhythm, transitioning from a pre-existing ultradian cycle, with hormones such as melatonin and cortisol appearing later around the 8th month of life (see also here) and the pineal gland size and melatonin secretion level stabilizing around 1 year of age. The circadian rhythm is a universal biological process observed in all living organisms, from mammals to plants and even bacteria, mitochondria and unicellular organisms.


Sleep graph from a sleep diary of a baby from 3 months old to 17 months, collected by u/jitney86. This shows how the baby's sleep transitions from an irregular sleep pattern into a biphasic or triphasic sleep pattern.


Another sleep graph for an even younger infant from 3 days old to 3 months old, showing a completely irregular sleep pattern. By u/AtmosChemist.

Although in the literature, the circadian rhythm is employed in the singular form, there are in fact multiple clocks throughout the body and down to every cells, with each organ having its own clock and time of peak performance, including different brain regions (see also this talk by the same author).

The body has 2 major biological processes to regulate sleep, according to the now well demonstrated empirically Borbély's model:

  • the homeostatic sleep pressure process S that relies on adenosine. The homeostatic process S is more like a countdown timer, which tracks how long the individual stayed awake and continues to build up without any limit as long as they stay awake. When this timer reaches beyond a threshold, which means the individual stayed awake for a long period of time, it ensures that individual will feel sleepy enough to get necessary sleep to avoid the risk of dying by prolonged sleep deprivation. In other words, the homeostatic process S is like a failsafe mechanism in case the individual didn't sleep during their circadian night. The more sleep pressure, the more slow wave deep sleep during the sleep session after, without affecting the core body temperature. The process S was discovered in 1984 by Borbély's team.
  • the circadian rhythm process C, most correlated with melatonin although it is more tightly coupled with core body temperature which seems to be the core method circadian rhythm phase changes are propagated throughout all cells in the body. The circadian rhythm (process C) is periodic, it doesn't account if the individual stayed awake for way too long, it's like a 24h clock defining different periods: one of activity (circadian day), one of sleep and rest (circadian night) and transition periods in-between, and it always repeats itself periodically no matter if the individual stayed awake or was asleep. This is the reason why if the individual stay awake beyond the circadian night, they will paradoxically feel less fatigued than during the circadian night, as although the sleep pressure of homeostatic process S will still build up, the pressure of the circadian rhythm will lift off. The circadian rhythm is what maintains all living organisms asleep for long periods of time. For example, if the individual wakes up only after sleeping a short period of time, it means they were sleeping in circadian misalignment, outside of their circadian night, so that their body didn't have the support of the circadian rhythm to maintain them asleep, and so they essentially napped.

Although these are two different systems, they do interact with each other (see also here and here and here and here and here). So using a treatment that affects one will also often affect the other (eg, both light therapy and melatonin have been shown to affect both processes). See this video by Thoughty2 for a nice introduction. However, keep in mind the effect of each system is minimal on the other, with a lab-controlled study demonstrating that the sleep homeostat S does not alter core body temperature and hence nor the circadian rhythm.

Neurologically, although research is still ongoing in this area, it appears that the association cortices, especially in the frontoparietal attention network, are particularly sensitive to sleep pressure, whereas the subcortical thalamic and basal ganglia brain regions are more affected by the circadian rhythm.

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TODO: add figure and rewrite section below to be more intelligible:

There are rules I derived for how much we can sleep in and out of circadian alignment and per 24h. I am still refining them but essentially, we usually can't sleep more than your ideal amount of sleep. For example, on average adult humans need to sleep 7-9h per night, let's say 8h to simplify. This means, if you fit in this average, that you need ideally to sleep 8h per night to feel fully restored and be healthy.

Now, if you sleep twice per day, eg during your circadian night and during the siesta, you will only be able to sleep a cumulative sum of 8h, for example 5h during your circadian night and 2-3h during the siesta. This is called a biphasic sleep pattern. This can even be a triphasic pattern for young children. This is in line with previous studies finding that children who take daytime naps actually have the same total sleep duration as children who don't.

So if you want to sleep a full night at once, you need to avoid the siesta in the 24h preceding the circadian night. But this only works if you can avoid using an alarm clock, and if you know when is your circadian night. Otherwise, it's much healthier to sleep the siesta (biphasic sleep), it's not for nothing that the body devised this failsafe mechanism.

Another rule is that it's only possible to sleep a full night of sleep during the circadian night. The siesta is limited to 1-2 ultradian cycles shorter than the circadian night. For example, if your ideal sleep duration is 8h, 1-2 ultradian cycle less represent 1.5 to 3h less, in other words 5h is the maximum duration of the siesta (ie, the longest nap that you can do). You will never be able to sleep more outside of the circadian night, unless you have a huge sleep pressure buildup (ie, you didn't sleep for 30h+) or acquired an illness that modifies your core body temperature.

Example of how the interplay between the circadian rhythm C and homeostatic process S can produce different sleep-wake patterns:

6 possible scenarios:

  • Monophasic in phase and woke up more than 10h before. Will sleep at maximum the optimal duration (eg, 8h on average for adults) and wake up at the natural wake up time or before when optimal duration is reached. Can only sleep 1 or 2 ultradian cycles earlier than optimal fall asleep time. Can sleep less if slept too late and natural wake up time happens before optimal duration (eg, 6h of sleep = 1 ultradian cycle less).
  • Monophasic out of phase woke up 10h before (will sleep max 5h).
  • Monophasic in phase woke up less than 10h before. Low homeostatic sleep pressure will make it difficult to fall asleep, but if it happens then the circadian rhythm will maintain the body asleep and it should be possible to sleep a full night if in alignment with the circadian night.
  • Biphasic idem 3 item. Then will sleep optimal duration - amount of time slept in the last 10h (eg, if napped for 2h, then can only sleep 6h during the circadian night).


In phase 8h max. Out of phase, 5h30 max incl nap in biphasic, it's the sum over 24h (or freerunning period eg 25h for non-24). We assume no prior sleep deprivation, which could result in increased homeostatic sleep pressure and chaotic circadian rhythm which could make sleep significantly longer or paradoxically shorter.

If we assume the current circadian night is from 2am to 10am:
- if woke up at 3pm, can sleep in phase at 2am, 8h. Wake up around 10am.
- can sleep out of phase 5.5h.
- can sleep partially out of phase between 6am and 8am, resulting in at least one ultradian cycle in phase and hence between 2 and 4h of optimal in phase sleep + 4 or 2h of out of phase sleep respectively totaling about 6 to 7h of sleep. Wake up around 1pm (if slept at 6am) to 2pm (if slept at 8am, we sleep less if sleeping later because more out of phase).
- can sleep biphasic, 2h to 4h before 10pm, then 4h anytime between 2am and 10am, totaling close to 8h (sometimes more up to 9.5h).
- can sleep completely out of phase, 2h before 2am and 3.5h after 10am, totalling 5h30 of sleep.

If woke up at 6am:
- can only sleep 6h from 4am to 10am.

What are zeitgebers?

Zeitgeber literally means "time giver" in german. A zeitgeber is any periodic signal of about 24h (ie, a cycling signal, such as light-dark), which the body can pick up and use to get entrained to (ie, synchronize like a clock to a 24h schedule). Since the circadian rhythm regulates crucial biological processes for health and survival, the periodic signal needs to be reliable (ie, not random) to be a zeitgeber and entrain the circadian rhythm.

Indeed, humans, and all biological systems, have no way to determine exactly the absolute time. Hence, we have biological, chemical and hormonal systems that approximate what can be called a biological clock. But since it's an approximation, it is imperfect: on average, humans follow a 24.2h schedule naturally according to the NIH. The remainder, 0.2h, serves as a margin of error, which is eliminated thanks to external time cues: the zeitgebers. When this margin of error is correctly eliminated, we say that the individual is entrained on a 24h schedule.

Why is it an approximation? This is because of synchronization theory. There is no way to design two independent clocks (eg, such as the human biological clock and day-night cycle) that will forever stay synchronized together. The only way for two clocks to become and stay synchronized is to link them, to make them dependent with the other in some way. For example, if you place two metronomes on the same physical support, they will at some point become synchronized with one another. Zeitgebers are the link, the physical support that links our biological clock with the external world. Without zeitgebers, it would be impossible to be synchronized with the day-night cycle, our clock would just be running on its own time, which is exactly what individuals with non-24 do.

Hence, zeitgebers are the essential tool we have to modify the circadian rhythm of humans, and hence potentially treat circadian rhythm disorders. When something alters the circadian rhythm, it is a zeitgeber (ie, a time cue that alters the biological clock) by definition.

Humans are biologically predetermined to respond more or less intensely to some zeitgebers, which includes the influence on their circadian rhythms. According to the current scientific literature, here is a rough outline of the order of power of zeitgebers on the circadian rhythm:

Light (strongest) > melatonin (strong) ~ food (likely strong) >> exercise (weak) ~ social interactions (weak) ~ sleep behavior (weak)

Light is the strongest zeitgeber by far. Indeed, we have specific photoreceptors, the ipRGC cells, in the eyes which are tailored to react to light to both dilate or contract the pupils and to shift the circadian rhythm. Light is undoubtedly the most potent zeitgeber both for the central clock (SCN in the brain) but also for all peripheral clocks of all the organs throughout the body, and hence bright light is the most potent therapeutic tool for circadian rhythm disorders. Light directly alters core body temperature. Note however that it's not just bright light that resets the circadian rhythm phase, but the alternance between high phases and low phases, here the alternance between bright light and darkness, as studies using the constant routine protocol demonstrated that individuals under constant bright light exposure lose entrainment and freerun just like individuals under constant darkness. The alternance between light color (blue versus yellow) also serves as a failsafe mechanism to entrain when light intensity doesn't vary.

Melatonin comes second, as its purpose is to both consolidate sleep and the circadian rhythm (ie, ensure you don't wake up in the second half of your night so you can sleep a full night), and phase advance.

Food is still under research but since the digestive tract produces most melatonin in the body by far, 2 orders of magnitude more than the brain, and also consumes it, food is thus arguably an also very strong zeitgeber. Food is thus an additional source of variation in circadian rhythm.

Other potential zeitgebers such as physical exercise or social interactions are very weak zeitgebers and named zeitnehmer ("time taker" in german) by some authors. Zeitnehmers are weaker than zeitgebers as although they can send rhythmical signals that can help with entrainment, they are also majorly affected by other oscillators through feedback loops. Hence, including them in an entrainment therapy leads to issues as they are often tricky to time appropriately (eg, exercise is more in phase with the circadian rhythm when done in the evening than the morning) and don't provide much circadian shifting or entrainment effects.

Physical exercise produces slight circadian rhythm shifts thanks to muscle contraction which modulates the BMAL1 clock gene in the muscle. The more muscle contraction, the more phase advance is obtained. Although exercise can slightly shift the circadian rhythm (see also here), it does not affect melatonin levels. Furthermore, a systematic review of 23 studies has shown that evening exercise does not affect sleep if done at least 1h before sleep, it instead helps people fall asleep and spend more time in deep sleep, the only exception being high-intensity exercise done under 1h of bedtime, which then caused people to take more time to fall asleep. Hence if you are night-walking (awake during the night and sleeping during the day), it's perfectly fine and actually healthy to do sports during the night, as long as your exercise session is at least 1h before your biological night. The precise effect of physical exercise on the circadian rhythm depends on the minimal core body temperature (CBTmin - can be approximated with wrist skin temperature too):

> When exercise was performed in the period between 4 h before and 1 h after the temperature minimum, there was a phase delay of 1.03 +/- 0.78 h (mean +/- s; n = 6); when performed between 3 and 8 h after the temperature minimum, there was a phase advance of 1.07 +/- 1.23 h (n = 9). [...] Performed at other times, exercise had no significant effect on the phase of the temperature rhythm.

Accordingly, a 2019 systematic review of physical exercise as a therapy for insomnia found only weak objective improvements in sleep parameters, mostly in reduced sleep latency (time to fall asleep). However, the effect of physical exercise on the circadian appears to be additive with other zeitgebers such as bright light therapy, so they can be combined. Furthermore, an analysis of the PRC curve of physical exercise relatively to the DLMO suggests that exercising in the circadian morning phase advances the phase, whereas exercising in the circadian evening or night delays the phase, which explains why individuals with DSPD who forcefully wake up early to exercise may in fact be delaying their circadian rhythm by exercising during their circadian night.

Social interactions were previously considered to the primary zeitgeber for humans since a 1971 study by Aschoff. However, these results were debated, and it was finally found that this study and others were confounded with uncontrolled light exposure amounts and patterns and furthermore later studies controlling for these factors could not reproduce the effect, so that the current consensus is that social interactions are not zeitgebers, the previously observed effects being due to uncontrolled light therapy:

> Early human entrainment studies led to the belief that the primary entraining agent for humans was not light, but rather social interaction (Wever, 1979; Aschoff & Wever, 1981). However, due to concerns about the design of these experiments (primarily the use of self‐selected lighting schedules) and the subsequent demonstration that light cycles indeed can entrain human circadian rhythms (Czeisler et al. 1981; Wever et al. 1983; Honma et al. 1987a), this belief is now considered unwarranted (Czeisler, 1995).

Nowadays, the well established high prevalence of the non-24 disorder in blind individuals, "in spite of living with strong social cues (e.g., employment, families, alarm clocks and guide dogs) [...] strongly supports the primary role of light in human entrainment" and is another empirical evidence in humans that social cues are not zeitgebers.
It should be noted that social factors can nevertheless affect sleep-wake patterns as demonstrated by the well established social jet lag phenomenon, which is important to distinguish from the inexistent effect on the circadian rhythm, since modifying the sleep-wake pattern does not affect the circadian rhythm.

What about sleep itself (ie, the sleep-wake schedule, which is to schedule a rigorous sleep and wake time)? Past studies found that the sleep-wake schedule may feed back to the circadian rhythm but weakly, and hence more likely qualifiable as a zeitnehmer. However, this and other past studies were biased by uncontrolled factors such as posture, as the participants are usually told to lay down to sleep at the same time as lights are switched off, with posture decreasing core body temperature for at least 2h and lights off also increasing melatonin levels and hence decreasing core body temperature. Indeed, later more stringently controlled studies found no effect: a an excellently designed lab-controlled study showed no effect of sleep (naps) and sleep pressure (complete sleep deprivation) on the core body temperature and hence the circadian rhythm of humans. On the other hand, they confirmed that the core body temperature and distal skin temperature showed great coupling with circadian factors such as the lighting pattern. Likewise, sleep deprivation did not demonstrate any incidence on core body temperature whether in a comfortable ambient temperature nor after cold air exposure (see also here and here). Note however that sleep deprivation does mask proximal skin temperature, but not core body temperature.. In other words, the sleep schedule does not affect at all the circadian rhythm, hence why chronotherapies and cognitive behavioral therapies (CBT) have shown low to no efficacy so far. In fact, it was already observed since 1987 that locomotor activity nor sleep had any effect on the circadian rhythm.

Relatively recently, it was discovered that the lunar cycle influences humans' sleep and melatonin rhythms, with a reduction of 30% of deep sleep during full moon, according to a well designed in-lab controlled human study.

Since we have multiple clocks throughout the body and down to every cells, we likely need to entrain them all, or at least most of them, for successful robust entrainment. The VLiDACMel protocol attempts to do that with a combination of light/dark therapy, melatonin and food (composition and timing) control.

To achieve greater circadian phase shifting, it is possible to combine multiple zeitgebers, which makes their effects additive, which means that a combination therapy produces more phase shift than any of the components alone. For example, light therapy's effect is additive with melatonin (see also here and here and here and here) and with physical exercise.

Can changing timezone help?

No it wouldn't work. But if you live in a latitude where there's not long enough sunlight such as closer to the arctica, then moving south can help.

What matters in different world regions is light exposure, not the timezone.

If light therapy doesn't work for you, it won't work better in another timezone of similar latitude or with a similar light exposure. And if light therapy does work for you, you don't need to move to a new latitude, you can just buy a lightbox or light therapy glasses.

As to why it wouldn't work, there is no absolute time, time is always relative (as demonstrated by Einstein's relativity theory). To know when it's day time or night time (and hence sleep time), our bodies use external time cues, formally called "zeitgebers". These include various things such as light, temperature, etc. These are more intense in the day, and lower in the evening and night, and is what hints our body to know the difference between day and night. So our body's rhythm always works relatively to these external cues.

To make an analogy, it's like navigation, when you're lost, you use points of interests to know where you are such as recognizable buildings in the distance and then you can deduce where you should head to to reach your destination, or you can use a compass to indicate the north. Without external tools, you have no way to know where to go, you will randomly walk and just get more lost.

Zeitgebers are the external compass that our body naturally uses to synchronize the circadian rhythm with the day night cycle. When you move to another timezone, the timing of these zeitgebers change, and so your body adapts. But it will adapt the same wherever you go. So after some time you will sleep and wake up at the same times as in your old timezone, but just shifted to the new timezone. The issue with DSPD, non-24 and other circadian rhythm disorders is likely not that they do not adapt to zeitgebers, it's that they adapt incorrectly, it's like having a miscalibrated compass that indicates an offset north pole.

The relative effect of zeitgebers

Every zeitgeber can be good (phase advance) or bad (phase delay) depending on the timing. Phase advance means that the circadian rhythm period is shortened, whereas phase delay lengthen it. This time-dependent effect, which is on top of the dose-dependent effect (eg, intensity of light or dosage of melatonin), is summarized in the Phase Response Curve (PRC) of the target treatment.

Zeitgebers are double-edged swords: since PRC is an intrinsic and universal property of all zeitgebers, present in all animals and even unicellular organisms, this means that when a factor can phase delay, it can also phase advance if exposure happens at another time. For example, if you suspect getting exposed to screens light in the evening phase delays your circadian rhythm, then the same screens light can be used at wake-up to phase advance.

All PRC curves have a tipping point, where the zeitgeber's effect on the circadian rhythm will completely reverse, from maximal phase delay to maximal phase advance or the opposite. Hence, the exact appropriate timing for phase advance or phase delaying depends on the zeitgeber, it's not necessarily at wake up for phase advance or at evening for phase delay (eg, for melatonin the PRC is inversed with the light PRC). For light therapy, this tipping point is the minimal core body temperature CBTmin (with more phase advance after), whereas for melatonin it's the DLMO (with more phase advance before DLMO or more delay after). The CBTmin matters for light therapy but not for melatonin, for which only DLMO matters. For physical exercise, the CBTmin is also the tipping point. Thus, adequate timing of zeitgebers is critical to get phase advance effects, otherwise a mistimed zeitgeber can not only be ineffective but even further worsen the delay and hence the circadian rhythm disorder condition.

Here are the simplified PRC curves for light and melatonin effect on humans (image from Wikipedia):

Citing Lewy (1985) explanation on bright light zeitgeber:

> In both diurnal and nocturnal species, certain features of PRCs appear to be universal. When the pulse of light occurs during the animal’s subjective day (based on the activity-rest cycle), hardly any effect is noted. When the pulse of light occurs during the beginning of the animal’s subjective night, the animal will delay the phase position of its subsequent activity-rest cycles. When the pulse of light occurs during the end of the animal’s subjective night, the animal will advance the phase position of its subsequent activity-rest cycles.

The relative effect of zeitgebers on the circadian rhythm can be confusing. We can make the following analogy: it's a bit like a boat, naturally you will float with the river (your natural circadian rhythm), but you can use paddles (light therapy) to row against the river (waking up earlier and earlier when used in the biological morning) or faster along the river (being exposed to bright light in the biological evening because you don't do dark therapy). But you can't just stick the paddles in the water to precisely stay where you are in the river, it doesn't work like that, you have to row in one direction or the other, even if just to stay in place (maintaining a stable wake up time), and where you will end up (your wake up time) won't be super exact and will change with the flow, but you can ensure what direction you go (against or with the river's flow = natural phase of the circadian rhythm). How much earlier you wake up is defined by how strong you row (light intensity), how aerodynamic your boat and paddles are (blue light color and ergonomic form factor to optimize delivery such as light therapy glasses instead of lamps), and how long you row (how long you do light therapy).

There are in theory two types of zeitgebers: the type-0 resetters, which theoretically can reset at the time you target regardless of your current circadian rhythm, versus type-1 resetters, which effect is dependent on the intake/exposure time relatively to your current circadian rhythm. In practice, all currently known zeitgebers (and hence treatments) are type-1 resetters. Hence, it's crucial to time all treatments relatively to your current sleep and wake up times, not the target/wished ones. This is true not only for melatonin (see also here), but also light therapy and food. It's not specific to treatments for circadian rhythm disorders, in fact there are now chronobiotics, an emerging field of scientific and medical study which is finding that virtually all drugs have a time-dependent effect relative to the circadian rhythm, such as antibiotics, so in fact all drugs are most efficient when taken relatively to the circadian rhythm. This makes sense, as it was discovered that nearly half of protein-coding genes are rhythmically expressed in at least one part (tissue) of the human body. This time-dependent effect of zeitgebers is also what makes research about them difficult, as it is easy for scientists, working at usual office hours, to miss time-dependent effects.

So far, we have mentioned only the temporal aspect of zeitgebers (ie, shifting the circadian rhythm). But zeitgebers also modulate the amplitude/magnitude of the circadian rhythm. In fact, both the amplitude and synchronization are simultaneously modulated in a non-linear and non-trivial way as shown experimentally, which can explain the asymmetrical response to bright light, with dimmer lights sufficient to shift the circadian rhythm at (circadian) night but brighter light necessary in the (circadian) day for the same effect.

Is it necessary to use multiple zeitgebers, even if we only have a slightly bigger circadian rhythm than the average, let's say 24.5h? Yes, because not only having multiple zeitgebers allows to have a failsafe in case you miss one of the zeitgebers (eg, forget to take the melatonin pill one day, then at least the light therapy will still help), and also because the body has multiple circadian clocks: the most famous one is the "master clock" in the brain, more formally known as the photoneuroendocrine system, which consists of the suprachiasmatic nucleus (SCN) in the hypothalamus, which is photoreceptive (respond to the photic signal from the ipRGC cells in the eyes) and communicates bidirectionally with the pineal gland which regulates melatonin (side-note: only in mammals did the pineal gland lose its photoreceptive capacity) , but there are also lots of peripheral clocks in other organs (liver, intestines, muscles) down to every cells (mitochondria produce and metabolize melatonin, see the Melatonin section). If a zeitgeber entrains one but not the others (such light not entraining the digestive clock), then the body may still continue to freerun because of the mismatch between the various body clocks and hence prevent whole body entrainment.

Since the industrial era, most zeitgebers are weakened in our daily lives, foremost light due to officies deprived from direct exposure to sunlight and artificial lighting in the evening, which led and is still leading to a widening and delaying of the chronotype distribution except for the very early morning larks, ultimately causing social jet lag for nearly everyone.

A few studies indicate that likely all zeitgebers work by ultimately modulate body temperature: body temperature modulation is the universal signal to reset the biological clocks throughout the body (see also here for a more easy to read article). This is further demonstrated by the fact that light therapy does not need the suprachiasmatic nucleus (SCN) to affect the circadian rhythm, only the ipRGC cells. Since light therapy modulates melatonin levels, and that one of the core melatonin activities is to modulate the body temperature, and given the widespread availability of melatonin receptors throughout the body, it appears likely that light therapy shifts the circadian rhythm by modulating melatonin levels which itself modulates the circadian rhythm clocks over both the central and peripheral systems.

(TODO: add the proposition of an evolutionarily derived algorithm for circadian rhythm entrainment to zeitgebers: https://archive.is/AvoPl )

Bedtime and wake up time are independent (seasonal variation and dual-oscillator model)

A common assumption is that human sleep schedule is flexible and can be manipulated by varying - or maintaining stable - the bedtime: an earlier bedtime will lead to an earlier wake up time, and a later bedtime to a later wake up time. This is however contradicted by the evidence.

Although this is commonly studied in seasonal animals such as migrating birds, a lesser known fact is that the circadian rhythm of humans also has seasonal variations, although artificial lighting can eliminate these variations. What is interesting with these seasonal variations is that they allow to observe how the human's circadian rhythm naturally fluctuates in typical sleepers with varying zeitgebers exposure: later, shorter and weaker zeitgebers such as sunlight during winter, versus stronger, longer and earlier sunlight during summer.

This figure (from this review on seasonal variations of the circadian rhythm and melatonin in humans) shows the changes in melatonin secretion start time (onset-time, left graph) and stop time (offset-time, right graph) relatively to the duration of melatonin secretion and season.

What this figure shows is that the start time of melatonin secretion (associated with the fall asleep time), on the left, doesn't change much with the season, despite the melatonin secretion duration (associated with the sleep duration) increasing in general during winter. But on the right, it's shown that the melatonin secretion stop time (associated with the wake up time) changes linearly with the melatonin secretion duration across seasons! So it's the melatonin secretion that stops later during winter, likely due to progressively later sunrise time and hence later start of exposure to bright light, resulting in a longer melatonin secretion. In other words, during the winter, humans sleep longer on average, and we have a longer melatonin secretion that goes well into the morning as the melatonin secretion stop time and wake up time get delayed later according to sunrise time, but not the fall asleep time which remains constant. This is the same phenomenon that underlies the relative coordination phenomenon (see the dedicated section below).

This is a crucial observation, as this is a very compelling evidence that the wake up time is decoupled/independent from sleep onset (fall asleep) time. Indeed, since sunlight is both rising later and setting earlier during winter compared to summer, we could assume that to sleep longer, humans would both sleep earlier and wake up later, with their circadian rhythm being recalibrated to fit the sunlight exposure. But this is not the case, since only the wake up time varies with season and sunlight exposure (onset and duration) but not the falling asleep time. This shows that sunlight (and hence light therapy) primary modulates the wake up time, but not the fall asleep time.

There is a model of the circadian rhythm that is founded on this sleep offset-onset decoupling: the Dual-Oscillator Model of Regulation of Human Melatonin Secretion : "the nocturnal period of melatonin secretion are governed by the mutual phase relationship of two circadian oscillators: one (E) that is entrained to sunset and controls the evening onset of activity and melatonin secretion, and another (M) that is entrained to sunrise and controls the morning offset of activity and melatonin secretion. In this way, when the interval between sunset and sunrise becomes longer, the duration of the nocturnal period of activity and melatonin secretion becomes longer. Results of our research suggest that this model can be extended to humans."

This model is quite old, and is based on findings on animals: "Studies examining the profile of melatonin secretion in rodents following phase shifts to light stimuli have indicated that the onset and offset of melatonin secretion do not always phase shift in a parallel manner. Accordingly, the hypothesis has been suggested that there may be two coupled oscillators, an evening or E oscillator associated with melatonin onset, and a morning or M oscillator associated with melatonin offset (Pittendrigh & Daan, 1976; Illnerová & Vanecek, 1982; Elliott & Tamarkin, 1994; Illnerová & Sumová, 1997). [...] In contrast to the pattern of light-induced phase delays noted in rats above, Elliott & Tamarkin (1994) have reported a tendency for the melatonin offset in hamsters to shift before that of the melatonin onset following phase-delaying light pulses. However, their results following phase-advancing light stimuli concurred with those of Illnerova & Sumová (1997), with the shift in melatonin offset occurring immediately, whereas the shift in melatonin onset advances only after several days of transient adjustment."

Altthough this model is based on animals findings, the above results on humans seasonal variations show this is applicable to humans too.

This is especially interesting as this indicates, by transitivity, that both the wake up time, bright light exposure, minimal core body temperature and melatonin offset (stop of endogenous melatonin secretion) are coupled, whereas the onset of melatonin secretion (DLMOn) seems to be decoupled and may be affected or play a role in photic history, and potentially be more controllable via other means such as with exogenous melatonin pills. Hence, it's no wonder the wake up time is a more reliable estimator of the circadian rhythm than the bedtime or the fall asleep time! Indeed, it was found that the wake-up time is a reliable predictor of the DLMO and the circadian rhythm similarly to the sleep midpoint, whereas the bedtime is not.

Interestingly, this means that the melatonin levels are independent (decoupled) from circadian phase shifting, and indeed that's the case as was later demonstrated (see also here and here and here). In fact, this was first discovered in 1985 by Lewy et al, as they found in humans that there is indeed a delayed effect of bright light on melatonin onset, concluding that bright light both entrained and suppressed melatonin, which prompted them to conceive the clock-gate model integrating this dual effect of bright light on melatonin. The dim light melatonin onset (DLMO) sampling method of the circadian rhythm phase was also orginally devised for this study (see also here). Combined with the fact that the melatonin onset is always delayed of several days after the circadian phase shift, this shows that the start of melatonin secretion (aka melatonin onset or DLMO or DLMOn) is a very unreliable proxy of the circadian rhythm, studies should prefer to measure the core body temperature or at least the wake up time instead.

However, this model assumed that melatonin is the underlying circadian rhythm signalling hormone, whereas recent evidence demonstrated that it's only a relay to modulate core body temperature, the latter being the core signalling pathway for circadian clocks throughout the body. Hence, this model is still valid if we simply replace the assumptions about melatonin secretion by the core body temperature pathway.

This hypothesis that the sleep offset (wake up time) is governed by the circadian rhythm with the sleep offset being delayed, dependent adjustment variable was already advanced by Krauchi et al in 1998:

> Does the SCN regulate heat production, heat loss, or both together? There are only few data available at present to answer this question. Czeisler (1978) has shown that the daily rhythm of heat loss from the extremities (as indicated by wrist skin temperature) is mainly coupled to sleep onset, and can be dissociated from the CBT rhythm when subjects internally desynchronize under free-running conditions. Thus, the heat loss rhythm cannot be the major circadian input of the CBT rhythm, but is rather the dominant contributor to the sleep-evoked component. One preliminary conclusion is that heat production seems to be driven by the SCN, and heat loss is rather the dependent variable which adjusts for heat balance.

This also suggest that any therapy aiming at controlling the bedtime, such as sleep hygiene and chronotherapy, is inappropriate to shift the circadian rhythm, as effective therapies should target the wake up time, such as light therapy.

In summary, the age old assumption that humans can control when they fall asleep is a core idea we got wrong before about sleep. Instead, we cannot control when we sleep, but we can indirectly control when we wake up via zeitgebers (such as bright light therapy), which in turns will drag the fall asleep time along with some delay.

(TODO: Distinct Components of Photoperiodic Light Are Differentially Encoded by the Mammalian Circadian Clock, 2020 https://doi.org/10.1177%2F0748730420929217 )

Melatonin


The many biological functions of melatonin

Melatonin has a ton of different biological functions, hence why it is qualified as a "pleiotropic agent" (meaning "many"). These functions can be classified under two broad families: 1- the receptor-dependent actions, where melatonin plays an indole hormonal role of circadian rhythm and wakefulness-sleep regulation by activating the melatonin receptors, 2- the receptor-independent (extracellular) actions, where melatonin does not need any receptor and will directly act on the cells to protect them from oxydative and inflammatory stress. Let's focus first on the circadian rhythm and sleep effects.

Although melatonin is often dubbed the "hormone of sleep", this is a misconception, as melatonin is rather a "hormone of darkness". Indeed, in all species, whether diurnal or nocturnal, melatonin is always secreted when it's dark (usually night time), which in humans triggers sleep related processes, whereas in nocturnal animals such as nocturnal rodents, melatonin does the opposite by increasing wakefulness. In other words, melatonin is a marker for darkness and hence is always secreted when its dark, but diurnal and nocturnal animals are wired oppositely to produce opposite effects on the sleep-wake schedule. Indeed, melatonin and bright light are wired inversely to the noradrenergic vasoconstrictor system in nocturnal animals compared to diurnal animals, so that melatonin signals wakefulness periods and bright light exposure induces sleep, but the circadian rhythm and its linear coupling with core body temperature remain the same as in diurnal animals, with high phases associated with wakefulness periods and low phases with sleep periods.

Melatonin can both phase advance the circadian rhythm by binding to the melatonin type 2 (MT2) receptors, and consolidate sleep and the circadian rhythm (ie, avoids fragmentation and waking up too early by ensuring the body stays asleep during the 2nd half of the biological night). It can also induce drowsiness by binding to melatonin type 1 (MT1) receptors, in other words it helps with feeling sleepiness (see also here). There is also a type 3 (MT3) receptor that melatonin (but not other drugs like ramelteon) stimulate.

According to the latest findings, it is currently theorized that one of the main biological purpose of melatonin is to be a circadian rhythm stabilizer, and not a zeitgeber, potentially through a feedback loop regulating the suprachiasmatic nucleus firing rate. This holds true for exogenous melatonin too, although it likely depends on the formulation: instant-release melatonin for circadian rhythm shifting, prolonged-release melatonin for primary insomnia (ie, sleep consolidation). Hence, it may not be biologically meant to shift the circadian rhythm, although it can be used for this purpose as shown by PRC curve studies.

Melatonin modulates, and is modulated by, the circadian rhythm by decreasing the core body temperature via vasodilatation at distal skin sites such as the hands (see also here). Body temperature changes are the primary way the body signals circadian clock changes throughout all cells, notably in response to bright light exposure through the SCN (although it was shown that the SCN is unnecessary as ipRGC cells are sufficient to induce acute temperature changes), and indeed melatonin works the same. Since at least 1992 it's known that endogenous melatonin levels are inversely coupled with peripheral (limbs) temperature (heat transfer to limbs is a way to reduce core body temperature, so increasing limbs temperature actually decreases core body temperature), and later that core body temperature reduction caused by melatonin is dose-dependent, with supraphysiological doses of melatonin being especially hypothermic. A 2001 study on elders found that 3mg of exogenous melatonin produced hypothermic effects whereas 0.3mg did not. Later, another study shown that only doses higher than 1mg of exogenous melatonin could produce hypothermia. Body temperature modulation was already suspected since at least 2007 to be the primary signalling pathway of circadian clock changes and synchronization, especially from melatonin, since supraphysiological melatonin doses were known to cause hypothermia, and it was even earlier hypothesized in 2000 that temperature may be a 3rd signalling pathway and potential treatment approach after light therapy and melatonin, which is further strenghtened by later empirical evidence and warm bath therapies being investigated (water-based passive body heating). Since then, experiments with daytime administration of melatonin clearly demonstrated that melatonin magnifies circadian rhythm induced thermoregulation and this is what underlies the soporific and circadian rhythm shifting actions of melatonin (see also here). Melatonin starts rapidly increasing, simultaneously to distal skin temperature rapidly decreasing and subjective sleepiness increasing, about 110min before core body temperature starts decreasing.

Melatonin is mostly secreted (2 orders of magnitude more) by the digestive tract, and to a lower extent by the pineal gland regulated by the suprachiasmatic nucleus in the brain, and to an even lesser extent by various structures such as the eyes themselves (including in the retina, lens and ciliary body), where melatonin "acts directly on ocular structures to mediate a variety of diurnal rhythms and physiological processes within the eye". The pineal gland can be considered a "vestigial eye". The melatonin secretion controlled by the retinohypothalamic-pineal (RHP) axis's responses to light is highly conserved throughout evolution in mammals, but melatonin secretion is present in almost all living organisms, "including bacteria, unicellular eukaryotes, algae, plants invertebrates and vertebrates" where it may also be the key player regulating the plants circadian rhythm despite the lack of a pineal gland. Virtually all biological structures in the body can produce melatonin thanks to the mitochondria (including skin - the largest human organ - but also the "brain, retina, Harderian gland, ciliary body, lens, thymus, airway epithelium, bone marrow, immune cells, gonads, placenta, gastrointestinal tract"), and they are themselves a primary target of the melatonin indole, as melatonin can be degraded via indolic and kynuric pathways with melatonin receptors widely distributed throughout the body, although melatonin has a wide spectrum of activities such as antioxydative and cytoprotective which are receptor-independent. Hence melatoninergic systems should be seen as decentralized, with a multitude of local melatoninergic systems at organs level and some global melatoninergic systems such as the chronobiotic regulation. Melatonin blood profile is primarily influenced by light exposure, and to a lesser extent by body position, physical activity, sleep, caffeine and drugs like beta-blockers such as atenolol, as these drugs increase core body temperature and hence affect the circadian rhythm and increase alertness. Melatonin is efficiently absorbed by the digestive tract, although its bioavailability remains low at around 15%.

Since melatonin is strongly associated with the circadian rhythm, and the DLMO marking the time of the beginning of an individual's biological night, melatonin profile is often used as a biomarker to measure the circadian rhythm, through salivary samples in a dim lit environment (dim-light melatonin onset). It was demonstrated that both non-24 (25h or 24.8h to 25.8h) and DSPD (between 24.5h and 25h) have a delayed and longer melatonin profile, confirming one of Czeisler CA et al's hypotheses. Although some studies suggested that a longer melatonin profile and hence a longer circadian period (tau) may be a hallmark of non-24 compared to other circadian rhythm disorders such as DSPD, the low sample size (less than 10 subjects in each studies, sometimes as low as 2 non-24) and the negligible difference particularly between studies does not allow to confirm this hypothesis.

About the receptor-independent extracellular actions of melatonin, a recent landmark 2020 study (and its awesome video abstract) have shed light on its likely major purpose. Indeed, this study is the first to investigate why sleep is necessary and how exactly it can cause death. Contrary to what was assumed before, it's not the brain, but the accumulation of reactive oxidative species (ROS) in the guts that cause death. By supplementing orally with melatonin to flies and rats who were prevented from sleeping, they could live a full life with no behavioral sign of brain injuries. Hence, this shows that melatonin, in addition to its receptor-dependent effect of inducing and consolidating sleep, is also used biologically to clean up oxidative stress and avoid death by cellular stress.

Due to these extracellular capabilities, melatonin is also be beneficial for a wealth of other health issues beside sleep, and melatonin deficiency can have life-threatening consequences. As an anecdote: everybody knows about the famous longevity experiment where mice that are restricted from eating, so that they eat a lot less, live a lot longer than mice who can feed anytime and as much as they want. This reproducible result is often interpreted in various ways: effect of fasting, calorie restriction, autophagy, etc. But in fact, it's known since at least the 90s that if melatonin is injected into the mice who can eat anytime they want, they will live longer, as long as the ones who are restricted (see this review for an explanation). Furthermore, if a pinealectomy (ie, remove the pineal gland which regulates melatonin secretion) is done on the mice who are restricted, they will die a lot younger, hence losing all the benefits of calorie restriction (TODO: check ref). In summary: instead of restricting eating, supplying melatonin was sufficient to extend the lifespan of the mice, and removing the organs regulating melatonin also removed all benefits from calorie restriction.

Melatonin was further shown in humans to substantially reduce risks of dying due to cancer according to a systematic review (see also this review, here and here) and from sepsis/severe inflammations, including in neonates (who do not produce melatonin yet), and even liver damage (potentially can help with the consequences of metabolic disorders such as NAFLD/NASH?). Melatonin is also hypothesized as being the reason why blind individuals have a much lower rate of cancers, as their melatonin levels are ever inhibited by light. Low melatonin levels are associated with endometrial cancer and breast cancer and is suggested to be used as a screening indicator of these cancers. A statistics study found that participants with higher melatonin levels had a lower likelihood of being diagnosed with COVID-19 and made an online calculator to predict those more at risk, and hence melatonin is part of the Marik's cocktail protocol for COVID-19 critical care. Melatonin supplementation may reduce delirium and symptoms of dementia such as sundowning and potentially increases brown adipose tissue which may help with diabetes. A review found that melatonin deficiency is associated with a "plethora of effects".
But melatonin activities go beyond the circadian rhythm regulation and antioxydative activity, it also regulates inflammation and melatonin supplementation has anti-inflammatory effects according to a 2021 systematic review of clinical trials, hence with applications for wound healing and tumor necrosis, and it also regulates a lot of other processes (such as hair growth and skin damage protection against sun's UVs), hence why melatonin is qualified as having pleiotropic actions (pleiotropic meaning "many") (see also this PhD thesis), including on the brain which makes it a candidate for the treatment of diverse neuropsychiatric disorders including epilepsy, schizophrenia, depression and anxiety disorders:

> A gathering body of evidence has shown that besides strong antioxidant activities, melatonin is a pleiotropic regulator molecule which orchestrates multiple functions through all the three melatonin receptors, i.e. MT1, MT2, and MT3. For example, MT2 receptor agonistic activity is attributed to neuroprotective, hypnotic and anxiolytic properties while MT1 and MT2 agonistic activity is associated with the clinical efficacy of agomelatine. The third melatonin receptor has been identified as quinone reductase (QR) 2, an enzyme involved in detoxification. MT3 agonist has been linked to strong hypotensive effects in preclinical study.
Ref: from this review.

Note however that to obtain these extracellular protective effects of melatonin, the dosage required is much beyond what is provided in melatonin pills for circadian rhythm disorders (more details in the dosage section below).

Melatonin's circadian rhythm phase shifting effect is at least are additive (see also here and here) with light therapy and maybe even more

Endogenous melatonin secretion has a seasonal cycle in humans, with longer secretions during winter and less during summer, unless artificial lights inhibit these seasonal variations.

Overview of the factors for optimal therapeutic effectiveness of melatonin pills

Therapeutic effectiveness of melatonin is influenced by several factors, including the following:

1- Immediate release formulation vs prolonged release: instant release form likely works better than prolonged release to treat circadian rhythm disorders. Instant release melatonin does not cause morning/wake-up drowsiness/brainfog whereas prolonged melatonin does. If unsure, just crush the pills into a powder, this will make it into an instant release form in any case because it's only the coating that can make melatonin into a prolonged release form. To crush tiny melatonin tablets, buy a mini-grater with tiny holes, such as those used to grate spices, such as this one (if the link is dead, see this picture for what it looks like).

2- Timing: intake should be before DLMO (ie, before the body starts producing melatonin), hence about 3-7h before your natural sleep onset (ie, when falling asleep), not the target one. However, the exact DLMO timing is highly variable between individuals, hence this requires some trial-and-error.

3- Dosage and overlap: bloodstream melatonin circulation from exogenous melatonin pills need to overlap with the endogenous melatonin secretion. Since higher dosages (1-3mg) remain longer in the bloodstream, they are easier for beginners. Furthermore, since melatonin's hypothermic effect and hence circadian rhythm shifting and sleep inducing effects, higher dosages should in theory produce more effect.

4- Bright light exposure (either by sunlight or bright room light) after taking melatonin will inhibit melatonin. Even a computer screen at medium or full brightness can inhibit melatonin (because the effect is stronger when you stare at the light source and humans are more sensitive to light at night than at day). Hence, it's crucial to avoid any bright light exposure and to remain in dim lighting conditions for melatonin to be effective. This was demonstrated in a study on using melatonin for typical sleepers to manage their jetlag, and which shown that indeed exogenous melatonin can shift the circadian rhythm faster but only in dim light conditions, demonstrating that light remains the strongest zeitgeber superceding any other, melatonin included. Indeed, it was demonstrated that a late evening administration of melatonin does not prevent the phase delay induced by concurrent bright light exposure. See the next section about light therapy for more details.

5- High variability in the quality control of over-the-counter melatonin pills, sometimes with a dosage 5x higher or smaller than what is labelled on the package, even for the same brand and product but between lots. This variability may be the root cause for why some people report too much effect, while others report no effect at all for the same dosage. It may simply be that under the hood they didn't have the same dosage at all. If you experienced too much effect with melatonin, at least this is a good hint this works, so you may try another brand with the same or different dosage to adjust and maybe find a brand with a good enough quality control, or ask a pharmacy to make a preparation in a lab for you. Personally, after trying lots of melatonin formulations including from pharmacies and labs, I found the Valdispert 1.9mg instant release melatonin works well and stably, but I can't guarantee the stability nor purity. Also, a tip as the authors note: "the least variable products were those that contained the simplest mix of ingredients, generally oral or sublingual tablets with melatonin added to a filler of silica or cellulose derivatives and were the most reproducible", which is the case of Valdispert 1.9mg instant release melatonin, where melatonin is the sole active component (no camomille or other "sleeping inducing natural herbs" stuff).

6- Optionally: Reduce/avoid food and sweet drinks after taking melatonin. Some people have a genetic mutation of the melatonin type 2 (MT2) receptor that does weird things when both glucose and melatonin are present in the blood stream.

Anecdotally, the author used melatonin for more than 10 years without any significant entrainment success, before finding the adequate parameters to increase the effectiveness of melatoninergic therapies.

Optimal timing of exogenous melatonin pills

To shift the circadian rhythm, exogenous melatonin needs to be taken before the body starts to produce endogenous melatonin, which is called the dim-light melatonin onset (DLMO). Technically, the DLMO is the tipping point of the melatonin PRC curve. If taken before the DLMO, exogenous melatonin advances the circadian rhythm phase by advancing the start of the endogenous melatonin secretion (DLMO). If taken more than 1h later than the DLMO, the phase is delayed according to some authors (see also here), whereas others state that melatonin's dead zone (where there is no effect) is during the biological night when endogenous melatonin levels are high in the blood, and the delays only start when residual melatonin is found after the endogenous melatonin offset:

> The dead zone of the PRC to light is during the day. The dead zone of the melatonin PRC, however, occurs during the “biological night,” that is, the time when endogenous levels of melatonin are usually high. Responses to melatonin are greatest when it is given exogenously at times when endogenous levels are not normally present, that is, during the day; when given in the morning, melatonin causes phase delays (shifts to a later time), and when given in the afternoon/evening it causes phase advances (shifts to an earlier time). Bright light causes phase shifts opposite to those caused by melatonin; that is, light exposure in the morning causes phase advances, and in the evening causes phase delays (responses are greatest during the night).
Ref: this letter.

Although it is now known that melatonin is most effective several hours : 3-5h before natural bedtime (not target bedtime), by assuming that on average DLMO happens 2-3h before the natural bedtime as in Lewy's PRC (see also here). This is in contrast with previous medical misconceptions, which often prescribed melatonin 1h before target bedtime which is ineffective:

> Although pharmacopoeias and the European food safety authority (EFSA) recommend administering melatonin 1–2 h before desired bedtime, several studies have shown that melatonin is not always effective if administered according to that recommendation. Crucial for optimal treatment of CRSD, melatonin and other treatments should be administered at a time related to individual circadian timing (typically assessed using the dim light melatonin onset (DLMO)). If not administered according to the individual patient's circadian timing, melatonin and other treatments may not only be ineffective, they may even result in contrary effects. Endogenous melatonin levels can be measured reliably in saliva collected at the patient's home. A clinically reliably DLMO can be calculated using a fixed threshold. Diary and polysomnographic sleep-onset time do not reliably predict DLMO or circadian timing in patients with CRSD. Knowing the patient's individual circadian timing by assessing DLMO can improve diagnosis and treatment of CRSD with melatonin as well as other therapies such as light or chronotherapy, and optimizing treatment timing will shorten the time required to achieve results.
Ref: this review. See also the figure 3 of this review for the appropriate timing for DSPD and non-24.

This usual recommendation is ineffective because of two points: the too late administration (1-2h before bedtime), and the uncoordination with the patient's circadian rhythm (by prescribing melatonin pills intake relative to the desired bedtime instead of the patient's current or natural bedtime).

This is because exogenous melatonin phase advances the circadian rhythm when taken before the body starts producing endogenous melatonin, which is called the DLMO point. In other words, exogenous melatonin is more effective when the body's endogenous melatonin level is low (ie, daytime levels): "phase shifts diminish around the time that endogenous melatonin appears in the circulation and remain minimal until melatonin levels start to decrease" (quote from this PRC study). Indeed, the DLMO point is the tipping point of the melatonin's PRC curve. By taking melatonin pills before the DLMO, the body is "tricked" into starting melatonin secretion earlier. However, if melatonin pills are taken after DLMO (1-2h before bedtime) as is usually advised, this will maximally delay the circadian rhythm, hence worsening non-24.

Due to inter-individual variability in DLMO (DLMO-to-bedtime is highly variable between individuals, 60% have a DLMO bigger or smaller than 2-3h before bedtime (range: -0.3h to 5.8h)) and variable sensitivity to melatonin, there is no way to tell apriori what time and dosage of melatonin will be ideal for everyone. Hence, it's why prior assessment of the current circadian rhythm phase is crucial, as otherwise there will be less or no benefit or even unwanted phase delays, which is in line with a 2006 study by Lewy et al, leaders in chronobiotic research for depression, which found that the same circadian phase based timing of administration for melatonin also improved depression, and depression symptoms were improved in proportion with the degree of circadian realignment.

This means that the best and only way to find the optimal timing and dosage of melatonin is by sampling melatonin throuhout the day, usually by saliva. Although this works to define the DLMO point at one point in time, since by definition the DLMO is constantly moving for individuals with non-24, this would require repeated salivary melatonin sampling everyday, which is unrealistic in practice as it must be done in the clinical setting and is costly. Urine melatonin sampling may provide a solution at home, but is currently unavailable on the consumer's market.

Hence, in practice as of 2021, since methods of assessment of the circadian rhythm are lacking for at-home settings, the currently only available method to optimally time melatonin for individuals with non-24 is unfortunately by trial-and-error, using the time windows given above as a reference (ie, 3-5h before natural bedtime).

The hypnotic, sedative effect of melatonin kicks in 1h after intake of instant release sublingual melatonin. Hence, that's why melatonin is often taken close to bedtime as a sedative (and sleep consolidator for elders who lack endogenous melatonin), but with no circadian rhythm shifting effect.

Adequate timing of melatonin intake relative to the current circadian phase is also required when used by children and teenagers with DSPD.

Optimal dosage of exogenous melatonin pills

Summary: What dosage is optimal for melatonin? Opinions currently diverge. But evidence suggests that higher doses (>1mg) are more effective in shifting the circadian rhythm as they induce more hypothermia, but the optimal dose balancing optimal circadian rhythm shifting and reduced next-morning drowsiness can vary by at least 10x between individuals so that trial and error is necessary and lower doses (<1mg or even <0.1mg) can be sufficient for some individuals. But testing such low doses should be done from starting from a higher dose showing efficacy and then reducing progressively down until finding the lowest dose to maintain the circadian rhythm shifting effects.

As explained earlier, melatonin modulates the circadian clock by modulating the temperature, more precisely by decreasing core body temperature and increasing limbs temperature. However, although higher dosage proportionally increases the hypothermic effect of melatonin and hence its circadian rhythm shifting effect, the melatoninergic receptors are exquisitively sensitive, as very low doses ("nanomolar or lower concentrations") of melatonin are sufficient to activate the receptors and hence their circadian rhythm shifting and sleep induction effects. This is probably what contributed to the confusion around the effect of low to very low melatonin doses, with some authors suggesting that very low melatonin doses of 0.3mg per pill could be sufficient, which is likely correct, but this does not preclude that higher dosages cannot be more beneficial. A study on the PRC curve of melatonin in humans observed bigger phase advances with bigger melatonin doses (5mg versus 0.5mg), and that lower doses of melatonin (0.5mg) produce a delayed PRC of slightly decreased magnitude compared to higher dosages (3mg). So indeed, very low doses can produce a circadian rhythm shifting effect, but higher doses can produce bigger shifts according to the current knowledge.

Another factor is that the exact optimal timing for melatonin pills intake may depend on the dosage. A PRC study on melatonin in humans found (see also this figure from this report) that lower dosages of melatonin were optimally taken later (ie, closer to DLMO) for maximal phase advance compared to higher dosages. This can be explained by Lewy's theory of overlapping, which proposed that the largest phase shifts in humans occur when exogenous melatonin in the bloodstream overlaps with the start of endogenous melatonin secretion (DLMO), so as to simulate an early dusk, and hence lower dosages such as 0.5mg need to be taken closer to DLMO to remain in blood circulation at DLMO compared to higher dosages such as 3mg. For an estimation, instant-release melatonin is eliminated within 3-4h of intake, although the blood levels may remain high up to the next morning when using supraphysiological doses. This hence suggests that higher dosages provide more leeway to get the therapeutic effects from melatonin, and hence higher doses of melatonin may be easier to time optimally for beginners. However, another study found an "inverse relationship between the timing of melatonin administration (irrespective of dose) and the magnitude of DLMO phase advance, such that earlier timing of the former (in relation to DLMO) resulted in greater phase advances", which suggests that the influence of timing is mostly independent from dosage, so that dosage does not need to be accounted for systematically when timing melatonin intake.

Furthermore, there is a high variability of melatonin sensitivity between individuals, partly due to different melatonin receptors density, and hence some individuals are insensitive with the common dosages. Other studies have estimated a 10-fold inter-individual variability in melatonin bioavailability or even up to 35-fold, in other words, some individuals require 10x to 35x the dosage that others use to get the same effect.

Although higher dosages of exogenous melatonin may ease the proper timing and overlapping with the endogenous melatonin profile, the longer bioavailability increases the risk of exogenous melatonin profile overlasting endogenous melatonin and hence spilling onto the phase delay portion of the melatonin PRC curve, in other words to keep residual exogenous melatonin the next morning, not only causing the dreaded morning drowsiness typical of a too high melatonin dosage but also phase delaying the circadian rhythm. As such, "care must be taken to avoid unnecessarily high doses that would cause trailing levels that spill over onto the wrong zone of the melatonin PRC". The risk of "phase spilling" is not present in light therapy and this may be one of the factors explaining the more robust phase shifting effects of light therapy.

Finally, melatonin levels varies with age, as melatonin levels are the highest for children (except neonates under the first 3 months of life), and then they decrease over time with age, with elders often having a deficiency of melatonin leading to age-caused insomnia. The progressive increase in melatonin in neonates can be explained by the pineal gland maturation as evidenced by the fact that its size stabilizes at around 1 year of age which coincides with a stabilization in melatonin levels, whereas the pituitary gland continues to grow afterward, explaining the progressive decrease with age. Hence, melatoning is more effective with age, with older adults needing lower dosages of melatonin to get the same effect as younger adults. See this figure from this review and this figure about "normal melatonin peaks" by age.


Variations in endogenous melatonin secretion by age. Figure from this review and licensed under CC-BY 2.0 Generic.

Accordingly, a year-long RCT study found that children with insomnia and autism needed between 2mg to 10mg melatonin for efficacy. Indeed, "children require a relative-to-bodyweight higher dose to induce sleep than adults". This shows that the dosage of melatonin need to be at least equal or higher than what the body naturally secretes to be effective.

To find the optimal (ie, minimal but effective) dosage of melatonin for children, a 2020 review on children with DSPD provide the following algorithm:

> We would advise starting melatonin treatment 3–5 h before bedtime. Try to find the lowest effective melatonin dose, starting with 1 mg in children between 6 and 18 years. If after one week no change occurs, increase the dose by 1 mg weekly until an effect occurs. When a 1 mg melatonin dose is already effective, try to lower the dose until a minimal effective dose is reached. If there is no effect using a 3–6 mg dose, stop melatonin treatment and try to measure DLMO, or reconsider the diagnosis [48] (clinical experience, MS).

Given all these information, why is there a common belief that very low doses of melatonin are better than higher doses? Very low doses of melatonin such as 0.05mg were indeed experimented, such as In this study, however only one blind non-24 entrained with 0.05mg, all the others had to use 0.5mg. Keep in mind they are blind, hence have lower melatonin levels than sighted individuals. Although these subjects could be entrained, the article makes no claim that this dosage is better than higher doses, simply that they may be sufficient, but by following a precise protocol of starting with a higher dose to first get an effect, and then progressively reduce until the subject reaches the lowest dosage they can use while still having the effect of melatonin.
To trace back where the belief that low dose melatonin is better than high dose comes from, we may find the following study, a follow-up study by the same authors as the above cited study stems from this single-case study, titled: "Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period". This result was hence only on one subject, and who was blind, hence with lower endogenous melatonin levels again... This is hence a preliminary result that cannot be generalized yet, and given there is at least a 10-fold inter-individual variability in melatonin bioavailability in typical sleepers, with this estimated variability not even accounting for extreme cases where the melatonin profile is modified as with circadian rhythm disorders such as non-24, it's unlikely to hold in the general case. Hence, it's safe to assume that low doses do indeed work for non-24, but not necessarily very low doses and some individuals may very well need dosages of up to 10mg/day depending on their sensitivity (melatonin bioavailability and receptors density). See also this interesting informal review about low dose vs high dose melatonin in 2001 and with a sales review showing that consumers preferred higher dosages (up to 10mg!).
Another study that certainly participated to the confusion as it is often cited to back up the claim of low doses being more effective is a 2001 study by the MIT of elders who commonly suffer from age-related insomnia due to reduced endogenous melatonin production with inxreasing age. The study found that low dose melatonin 0.3mg was as effective as 3mg but with reduced next morning drowsiness and hypothermia. The very low dose of 0.1mg was not as effective. This study is often used as evidence that low dose melatonin is always preferable for circadian rhythm disorders, which is misleading: first because the study was on elders who have very low engodenous melatonin production and hecne require lower doses of exogenous melatonin, so this result does not apply to younger adults and certainly not on kids, 2) this was a treatment on age-related insomnia, which is fundamentally different from circadian rhythm circadian rhythm disorders, as the aim of the former is to improve sleep consolidation as is the major metric used to claim efficacy in this study, whereas for circadian rhythm disorders the goal is to shift the circadian rhythm disorder, which was not studied here. Nevertheless, the study notes that only the 3mg dose induced a hypothermic effect, which suggests that 3mg was more effective at shifting the circadian rhythm, since core body temperature modulation is how the SCN in the brain synchronizes cells clocks throughout the body. As a side-note, the authors indeed patented low dose melatonin in USA but as of 2018 this patent expired so that other producers can manufacture low dose melatonin.

There is however some cases where low to very low doses of melatonin are always better indicated, such as restless legs syndrome (RLS) or periodic limbs movement disorder (PLMD). Indeed, the acute triggering of RLS symptoms shows a circadian pattern. This was also demonstrated for Periodic Limb Movements in Sleep (PLMS/PLMD). This is because melatonin can trigger the symptoms of RLS through an interaction with the dopaminergic system. Hence, low doses of melatonin should be preferred for people with RLS or PLMD, or alternatives not involving melatonin such as light therapy should be explored as a therapeutic option. There are also reports that bright light therapy may indirectly through photic history increase melatonin levels during subsequent nights, with a similar risk of increased triggering frequency of PLMD/RLS symptoms. Of note, sleep deprivation through adenosine buildup can downregulate dopamine receptors:

> Increased adenosine load associated with sleep deprivation triggers downregulation of dopamine (DA) D2 and D3 receptors (D2/3Rs), resulting in decreased receptor membrane expression within the striatum (internalized receptors; grey). Consequently, there is a greater ratio of D1R to D2/3R availability, and the relative increase in striatal D1R activation by DA.

Inversely to receptor-dependent effects which can be activated with very very low doses, receptor-independent cellular protective actions of melatonin, such as antioxydative effects, only appear with much higher doses of melatonin : "These receptor-independent protective actions of melatonin and its metabolites would require high intracellular levels of the molecules, which can only be met by melatonin in situ production in the relevant tissue, since cellular melatonin uptake is very limited because only 0.1% of extracellular melatonin can enter the cell (Fischer et al., 2006a)." This is not surprising, since the digestive system, which is by far the largest producer of melatonin, produces 2 orders of magnitude more than the brain, with the melatonin secreted by the digestive system likely for its antioxydative properties to repair oxydative damage following food consumption, whereas for the brain much smaller doses are sufficient to activate the melatoninergic receptors and induce the sleep-related actions of melatonin. In practice, as shown by the usage of melatonin on septic patients, the dosage necessary to produce the cellular protective actions would be about 8mg/kg/day in humans. Until more optimal delivery methods of huge doses of melatonin are found, dark therapy is the only way to preserve the bulk of endogenous melatonin secretions and its antioxydative action.

To test lower dosages of melatonin, below 1mg, which are usually very hard to find in both pharmaceutical products or over-the-counter dietary supplement products, it's possible to either ask for a magistrale preparation at the pharmacy (extemporaneous preparation) who can dose very precisely for you but will be more expensive, or get melatonin in liquid form, although note that in the latter case the degradation of melatonin is much faster, so once the liquid bottle is opened, expect the contained melatonin to be inactivated after a few days. It's also possible to try to cut solid tablets, although this leads to a great variability in the dosage between 50% and 150% even with specialized cutters, and it will break the coating and hence make the melatonin instant release (which can be an issue if you seek prolonged release melatonin, this is in fact contraindicated for any "slow or modified release" drug). For more details including a thorough evaluation of the efficacy of the various types of extemporaneous preparations (ie, methods of pharmacologists to prepare individually tailored drugs, and also various at-home transformations of drugs such as cutting tablets or grinding and dispersing in water the powder to drink), read here, here and here. Magistral preparations can only be done under some specific circumstances as regulated in the European Union (see also here). Extemporaneous preparations have fallen out of favor in some countries such as United Kingdom in favor of specials instead, which are manufactured by industrials specifically for a set of patients. If OTC products are chosen, always ensure to choose products that only contain pure synthetic melatonin, not any other compounds such as valerian as combined products usually have much lesser quality controls and hence more variable dosage, up to 10x less or more than what is claimed on the label.

Side-note: this blog post is often cited online to justify the use of very low melatonin dosage. However, the inference drawn by this source is incorrect, as it draws on studies on age-related insomnia, which is fundamentally different as the goal was not to treat a circadian misalignment but sleep fragmentation, and furthermore elders are a different population with very low endogenous melatonin secretion. A better resource is this one instead, from a medical doctor who did a more comprehensive and accurate literature review, with a clear distinction between the indication to treat insomnia and sleep fragmentation (lower dosage) versus circadian rhythm disorders (higher dosage may be preferable), or this set of recommendations by the Circadian Sleep Disorders Network.

Split-dosed melatonin

There is also an experimental "melatonin split-dosing" scheme, where a low dose of melatonin is taken before the DLMO (pill taken 3-7h before natural bedtime) to maximally shift the circadian rhythm, and a higher dose 1-2h before natural bedtime to maximally induce sleepiness (similarly to a sleeping pill). This approach is not yet validated and was only used for one published sighted non-24 case. The idea with split-dosed melatonin is to target both types of melatonin receptors with an optimally timed and dosed melatonin for each separately, instead of trying to target both with a single pill. In addition, this also doubles the likelihood of getting at least one timing right, and hence reduce the risk of disentrainment. However, given that exogenous melatonin needs to overlap with endogenous melatonin for maximal circadian rhythm shifting, it may be more effective to also use a high melatonin dose before DLMO (and hence high dose for both intakes). Thus, the author would recommend to test 1-3mg before DLMO (3-7h before bedtime), and 2-3mg 1-4h before bedtime. An individual with DSPD tried this scheme and reported great results, greater than with any other method they tried, although the dosage require some experimentation.

See also this discussion for some practical feedbacks: https://archive.is/FrkFN

Long-release versus instant-release melatonin

Unfortunately, there is a lack of clinical trials comparing instant-release melatonin versus long-release melatonin. Historically, long-release melatonin was devised for age-related insomnia, for which there is a biologically plausible reason, as the issue of age-related insomnia is a characteristic sleep fragmentation potentially caused by an irregular or too low endogenous secretion of melatonin. Hence, supplementing with melatonin during the whole sleep period makes sense to consolidate sleep.

In the case of circadian rhythm disorders, "most clinical studies in children with DSPD have been performed with immediate-release melatonin preparations".

It's worth noting that although some authors suggested cutting or crushing long-release melatonin tablets to transform them into an instant-release form, as it's only the special coating that makes melatonin in a long release form, recommending this is considered illegal:

> A paper by Chua et al. published in 2016 in the journal Pharmaceutics recommended the use of divided or crushed Circadin tablets (as a licensed product) where an immediate release melatonin was required, in preference to a manufactured immediate release tablet (unlicensed in the UK) [76]. However what the authors had not stated was that this represents off-license use of a licensed medicine, promotion of which is illegal [77]. Clinical studies to compare the efficacy of immediate- and controlled-release melatonin preparations have not yet been published [78].

Safety and contra-indications of exogenous melatonin

Is melatonin safe for kids? Melatonin should be safe for kids, as it was used in multiple trials for autistic children, including a long-term one (> 1 year) with doses up to 10mg/day, and is even commercially available as a medically regulated drug under the name of Circadin or PedPRM. There was a concern about the potential adverse effect of melatonin on growth hormone regulation and on reproductive function and development, but studies found no difference in adolescents using melatonin and a placebo, and melatonin was shown to be a reproductive organs protector and a potential candidate to treat diseases of male reproduction and also female reproduction (see also here, here and here with not only melatonin but circadian cycle impact on fetal and placenta physiology). The AASM guidelines issued a WEAK FOR in favor of melatonin treatment for children with DSPD. Melatonin is even considered safe for use in hospitalized neonates, to treat sleep issues and severe inflammations and tumor necrosis including in neonates.

Melatonin has very few side effects and no serious (dangerous) ones. It is non genotoxic, non mutagenic, non carcinogenic and there is no withdrawal nor dependency and hence not addictive. Both the EFSA (european commission for food safety) and the ANSES (french commission for drugs safety) considered melatonin effective for circadian rhythm adjustements if one day dose contains at least 0.5mg and generally safe except for individuals with neurological comorbidities and pregnant women. Apparently, the FDA also considered melatonin safe and decided not to regulate it as a drug. It's impossible in practice to overdose on melatonin, as the toxic threshold of >400mg/kg is only reached when taking tens of thousands more than what is provided in 3-6mg formulations. Even this figure is subject to debate, with some studies stating that no maximal safe dose (lethal dose) could be established yet, as "even enormous doses such as 800 mg/kg are not lethal" in animals, and furthermore "in a study of 11 patients, doses up to a massive 6600 mg/day for 35 days were given with no severe toxicities occurring". What about the long-term use of melatonin? According to the AASM 2015 guidelines, current evidence shows that melatonin is safe for long-term use, as was assessed on children with DSPD and ADHD for a mean follow-up time of 4 years with doses up to 10 mg with no serious adverse event, and an open-label follow-up study of adult patients with DSPD and neurodevelopmental disabilities who received prolonged-release melatonin up to 15 mg for up to 3.8 years found no adverse effects. A 2020 review of clinicial trials also found melatonin safe and effective for use in children and adolescents with DSPD from age 2 years and more, including long-term studies involving the use of melatonin in children and adolescents for 1 to 10 years, with "no substantial deviation of the development of children with respect to sleep quality, puberty development and mental health scores [...] provided that it is administered at the correct time (3–5 h before endogenous melatonin starts to rise in dim light (DLMO)), and in the correct (minimal effective) dose". Since the circadian rhythm may change with age, especially during adolescence, potentially making DSPD only a temporary issue, the authors further recommend in practice to "to stop melatonin treatment at least once a year (preferably during the summer holidays)".

There is a common minor side-effect at the root of most complaints, and is that melatonin can produce more vivid dreams. More vivid dreams are not necessarily nightmares, but they often are. Hence, melatonin increases the likelihood of experiencing nightmares. Are nightmares bad for the circadian rhythm or sleep? According to a study (the only one on this question, there is surprisingly very few scientists who investigated this question), nightmares affect subjective feelings of sleep quality but not sleep quality per se, as there is no objective change in the sleep structure whether or not the dream is good or bad. This finding can also be put into perspective with the slightly more extensive research about lucid dreams, which shows that being conscious during dreams does not impact the sleep structure or quality either. So this indicates that the dreams content is irrelevant to the sleep structure or quality. This matches what I observed experimentally, that nightmares do not impact the circadian rhythm nor mood nor energy levels during wakefulness periods, it's rather the sleep duration and timing (relative to the circadian rhythm) that matters.

Another potential minor side-effect is that melatonin may have a temporarily negative effect on mood, since melatonin is an antagonist to serotonin.

Another common complaint is the next morning drowsiness/brainfog, which is likely due to using a too high dosage (>2mg) of prolonged release melatonin, with a lower dosage or using instant release melatonin often fixing the issue, but this is only a temporary side effect that will disappear after reducing the dosage since there is no tolerance:

> In full agreement with numerous findings on immediate-release melatonin, all studies on the prolonged-release formulation unanimously show that the recommended dose does not cause next-day hangover, but rather favors morning alertness – although some exceptions have been described in other investigations using different doses. It does not lead to dependence, early or late withdrawal effects after discontinuation.51,77–79 The development of tolerance is usually absent with melatonin, although a few exceptions have been reported, especially in some children with neurological disorders.91–94 Should the development of tolerance turn out to be a consequence of altered metabolism, which remains to be demonstrated, other melatoninergic agonists might be tested. A recent randomized, double-blind, placebo-controlled crossover study on prolonged-release melatonin confirmed the absence of next-day impairments of psychomotor functions, driving skills and memory recall, in contrast to 10 mg zolpidem.109 Controlled-release melatonin (2 mg) was successfully used even for facilitating benzodiazepine discontinuation.110 Like melatonin, ramelteon did not cause next-day hangover (as revealed by subjective feeling, psychomotor and cognitive tests, and ability to concentrate),105 rebound insomnia or other withdrawal effects, or development of tolerance or addiction.20–22,105 Under these conditions, both prolonged-release melatonin and ramelteon appear safe in short-term treatment, as may be assumed for other exclusively melatoninergic drugs in general.

Melatonin can interact with the dopaminergic system as shown by its detrimental interaction with restless legs syndrome (RLS) (see also here and here), while sometimes producing a positive side-effect on mood and motivation (a user reported both effects simultaneously), but this effect of melatonin on the dopaminergic system is not well studied at the moment. Hence unfortunately for people with both RLS and a circadian rhythm disorder, melatonin is contra-indicated unless in very small doses if the individual tolerates it, but this should be done under a medical doctor's supervision.

Interestingly, in a mice study, dopamine was shown to cause phase delays (lengthening the freerunning circadian rhythm period).

Melatonin was found to be "remarkably effective" to treat jet lag by a 2002 Cochrane systematic review.

Although all the currently published research tend to demonstrate a lack of addiction and tolerance to melatonin, some reddit members anecdotally (but after extensive self-experimentation) reported a fast build up of addiction and tolerance to melatonin, with a withdrawal period of 2 months after 6 months of use.

There are anecdotal reports on peer communities (see here and here) of a potential paradoxical effect in some users, for whom melatonin does indeed help in inducing sleep earlier, but cause a sleep fragmentation with a premature wake up after just a few hours of sleep. This detrimental side effect is for the moment undocumented in the academic and medical literature. It may involve the interaction between the melatoninergic system and the dopaminergic system, as observed with RLS and PLMD patients, by causing a sort of forbidden sleep zone / second wind effect during sleep, especially in individuals with (potentially undiagnosed) RLS/PLMD or another disorder caused or triggered by an impaired dopaminergic system. Here is how an individual with non24 described this paradoxical effect, which interestingly mentions that this effect appeared after stopping bright light therapy while continuing melatonin supplementation (source: private communication):

> When I go to bed, I feel the “melatonin” coming out and I start to doze off, then I enter this state where I am 50% conscious 50% unconscious. I have “thoughts” that are very logical, and related to my every day activity. Not entirely dreams but close to dreams and close to reality at the same time. And this keeps going on for about 1 sleep cycle (~1h30?). I do NOT feel rested from this “weird state”, and then when I finally do sleep, I sleep for 4 sleep cycles directly (5.5-6h), and wake up not being able to go back to sleep. Usually, I never sleep 4 cycles without interruption, and I can go back to sleep. Usually I get 5-6 sleep cycles per night which is great. But with this thing happening, I am always getting 4 cycles and now I’m so tired. It has been happening all week this week and it started the day I stopped doing light therapy to free-run…

Some clinicians with 25 years of experience with DSPD in children report additional rare side effects, such as melatonin-induced diarrhoea, headache and enuresis. In case they appear, the authors recommend to discontinue melatonin and instead try other therapies such as bright light therapy, as in their experience there is no other treatment that can relieve these symptoms except melatonin discontinuation.

Difference between melatonin and hypnotics sleeping pills (benzodiazepines and Z drugs)

Melatonin is not a sleeping pill, it's different, because it does not affect GABA receptors, and hence does not affect REM sleep nor the distribution of sleep stages. Hence, melatonin is much safer than sleeping pills such as benzodiazepines. Furthermore, "melatoninergic agonists do not cause next-day hangover and withdrawal effects, or dependence [and] do not induce behavioral changes, as sometimes observed with z-drugs [ndlr: benzodiazepines sleeping pills]." Sleep researchers disadvised against the use of sleeping pills to treat sleeping disorders since at least the 1975s, and particularly for circadian rhythm disorders such as non24. Benzodiazepines analogs such as zolpidem or zopiclone can produce paradoxical insomnia (ie, long but unreparative sleep, in other words a superficial sleep) and in clinical trials worsened sleep parameters compared to age-matched insomniac but untreated patients, and interestingly most of them were also diagnosed with untreated sleep apnea. An observational study also found they increase the risk of developing dementia. Melatonin can be used to facilitate benzodiazepine discontinuation.

As several sources state, melatoninergic agonists are not addictive (see here, here and here). Although the melatonin receptors type 2 can be desensitized at the molecular level, just like all G-protein-coupled receptors, this desensitization is quickly reversible and hence there is no observed addiction nor tolerance in practice. Another piece of evidence is that the melatonin receptors density varies over the day but mostly in parallel with the circadian rhythm, so that there is a parallel increase in both melatonin receptors density and melatonin concentration (which should be the opposite if there was a desensitization), allowing receptor sensitivity to be sustained since it was demonstrated that "long-term melatonin exposure produces microtubule rearrangements that enhances protein kinase C activation (which modulates melatonin receptor function through its action on G-proteins)". Hence, it's not surprising that longitudinal studies shown that melatonin could be used with no loss of efficacy over a whole year in children at dosages from 2mg to 10mg/day.

Actually, melatoninergic agents, including melatonin, are nowadays under active investigation to reduce or eliminate the addiction to other substances: alcohol, cocaine and even benzodiazepines and non-benzodiazepine Z drugs. Indeed, in some countries such as France, sleeping pills are used over the indicated maximum 4 weeks, which prompted authorities to implement health strategies to reduce their use. Between 2008 and 2013, the launch of prolonged release melatonin in the market led to a huge decrease of the BZD/Z drugs consumption, with 4x less BZD/Z drug consumption for each single unit of melatonin consumed, also showing that the dosage of melatonin required by the patients is less than what they needed with BZD/Z drug, likely because the latter build up a tolerance and hence require higher and higher doses to maintain their effect, whereas melatonin does not and the same dose will elicit the same response for most users. Several scientists decry the "abusive" prescription of sleeping pills and support this call for switch from benzodiazepines and BZD/Z drugs to melatonin for all insomniac patients (see here and here), with a successful switch being associated with a reduction of co-morbid major depression disorder, whereas the type of antidepressant was not.

Indeed, hypnotics aka sleeping pills should not be prescribed for more than a few weeks at most because of the rapid development of tolerance, which progressively makes sleep issues reappear despite continued use of sleeping pills. But then, since the patient's neural networks have "habituated" to the sleeping pill, are because of changes to the GABA receptors (see also here) which are known to underlie addiction and tolerance buildups, they will experience a withdrawal syndrome when discontinuing use of hypnotics (since they would have no benefit anymore due to tolerance), insomnia will get drastically much worse. And it may take years without the drug to be able to just get to lessened insomnia symptoms as they were before starting the use of hypnotics. Hence, hypnotics tolerance not only guarantees the disappearance of the benefit after just a few weeks of use, tolerance also then worsen the patient's insomnia, and is thus the reason why hypnotics are now considered to have little if any benefit for treating insomnia. And the withdrawal side effects can remain for a very long time after discontinuation, for example up to 8.4 weeks after discontinuation of Alprazolam (Xanax). There is even a peer support group on Reddit focused on recovery from benzodiazepines withdrawal with quite a lot of horror stories about how fast the tolerance and addiction build up: r/benzorecovery. Consult this subreddit if you have doubts about whether a specific molecule is addictive or not (but you will likely find that all benzodiazepines and z-pills are).

In line with these observations, despite benzodiazepines and Z drugs are still widely prescribed for insomnia, a meta-analysis found that hypnotics capacity to induce sleep is so small compared to placebo that it may not even be clinically significant according to regulatory bodies, which, given the tolerance issue, prompted these bodies to disadvise prescription unless for a short term period, and instead explore alternative medications such as melatonin, as the UK NICE states (updated in 2019):

> As long ago as 1988, in the January issue of Current Problems in Pharmacovigilance, the committee on safety of medicines advised that benzodiazepine hypnotics should be used only if insomnia is severe, disabling or causing the person extreme distress. The lowest dose that controls symptoms should be used, for a maximum of 4 weeks and intermittently if possible.
> NICE's technology appraisal guidance on zolpidem and zopiclone recommends that when, after due consideration of the use of non-pharmacological measures, hypnotic drug therapy is considered appropriate for the management of severe insomnia interfering with normal daily life, hypnotics should be prescribed for short periods of time only, in strict accordance with their licensed indications. A meta-analysis discussed in NICE's eyes on evidence commentary on small benefits of Z drugs over placebo for insomnia found that 'Z drugs' reduce the time taken to fall asleep by 22 minutes compared with placebo but this may not be clinically significant. NICE's technology appraisal guidance states that there is no compelling evidence of a clinically useful difference between the 'Z drugs' and shorter-acting benzodiazepine hypnotics from the point of view of their effectiveness, adverse effects, or potential for dependence or abuse. There is no evidence to suggest that if people do not respond to one of these hypnotic drugs, they are likely to respond to another.

Interestingly, the meta-analysis notes that it was "found that both Z drugs and placebo statistically significantly reduced sleep latency", demonstrating that an intervention reduces sleep latency is not sufficient to prove efficacy if not properly controlled against a placebo.

However, despite current medical guidelines clearly disrecommending their prescription, benzodiazepines remain among the most prescribed drugs.

Note how the NICE states in the above excerpt that the common practice of switching a hypnotic class for another is not supported by evidence: if a patient does not see an improvement to their sleep issues using one class of hypnotics, it's unlikely to improve with another class. This does not apply to melatonin since it is not a hypnotic.

A 2017 American Family Physician guidelines statement goes further, by recommending melatonin as a first-line treatment for insomnia:

> Controlled-release melatonin and doxepin are recommended as first-line agents in older adults; the so-called z-drugs (zolpidem, eszopiclone, and zaleplon) should be reserved for use if the first-line agents are ineffective. For the general population with difficulty falling asleep, controlled-release melatonin and the z-drugs can be considered. For those who have difficulty staying asleep, low-dose doxepin and the z-drugs should be considered. Benzodiazepines are not recommended because of their high abuse potential and the availability of better alternatives. Although the orexin receptor antagonist suvorexant appears to be relatively effective, it is no more effective than the z-drugs and much more expensive. Sedating antihistamines, antiepileptics, and atypical antipsychotics are not recommended unless they are used primarily to treat another condition. Persons with sleep apnea or chronic lung disease with nocturnal hypoxia should be evaluated by a sleep specialist before sedating medications are prescribed.

A study on children with sleep-onset insomnia found that the combination of melatonin and bright light therapy was effective to improve their sleep parameters, with melatonin having the most important effect.

A common claim in defence of benzodiazepines use, even in the long-term, is that anything that can help sleeping is valuable to treat insomnia, especially in suicidal individuals, since insomnia can cause suicidal thoughts. There are however two issues to this claim: firstly, as explained above, the long-term use of benzodiazepines causes addiction and tolerance, which means that continuous use will cause the beneficial sleep-inducing effects to progressively wear off despite continued use of medication, and any withdrawal attempt will face a withdrawal syndrome that in this instance consists in experiencing an even poorer sleep than the individual had before starting benzodiazepines medication, and this can last for weeks to years. Secondly, there is no basis to assert that benzodiazepines use for insomniacs can reduce suicide risk. On the contrary, there is ample evidence from a majority of studies on humans and animals that benzodiazepines increase the risk of suicide, especially "for nonantidepressant users, for the young, and for males" (see also here, here, here and here). Even when the suicide attempt failed, there are lasting neurological changes in the density of benzodiazepine receptors (see also here) and anterograde amnesia. What insomniac individuals with suicidal ideation need is an antidepressive treatment, in addition to an appropriate treatment for their insomnia such as melatonin.

To help withdrawal from hypnotics, in addition to melatonin, antihistaminics such as doxylamine can be used, although the AASM 2008 guidelines on the clinical management of insomnia could not recommend antihistaminics due to the lack of trials on their safety and efficacy to treat insomnia.

See also these anecdotal experiences from individuals with DSPD, among which are medical interns and hence know perfectly well how to use drugs like lorazepam/ativan.

TODO: "Benzodiazepines (eg, valium) increase Stage 2 sleep, while decreasing the other Stages, including Slow Wave Sleep and REM sleep [JOURNAL OF SLEEP RESEARCH; Perlis,L; 6(3):179-188 (1997)]. Unlike sleep induced by benzodiazepine drugs, melatonin-induced sleep does not suppress Rapid Eye Movement (REM) sleep and slow-wave sleep — and does not result in "hangover" feelings the next day [CLINICAL PHARMACOLOGY AND THERAPEUTICS; Zhdanova,IV; 57(5):552-558 (1995)]. Nonsteroidal anti-inflammatory drugs such as aspirin (which disturbs sleep), decrease plasma melatonin levels [PHYSIOLOGY & BEHAVIOR; Murphy,PJ; 55(6):1063-1066 (1994)]." https://benbest.com/nutrceut/melatonin.html

Interactions between melatonin and other compounds

Over supplementation in vitamin D may inhibit melatonin which is hypothesized to result from a cross side effect of vitamin D production, which is triggered by skin exposure to UV, so the eyes are often also concurrently exposed to bright light, so a inhibiting pathway between vitamin D and the circadian rhythm may have hence developed as a byproduct of light exposure, although other individuals with non-24 and DSPD reported that treating their vitamin D deficiency significantly improved their sleep and circadian rhythm stability, so it seems there needs to be not too little but not too much vitamin D to avoid impairing sleep.

Light and dark therapy

Circadian rhythm disorder management involves maximal control of the pattern of exposure to light, which for diurnal animals such as humans includes being exposed to bright light during the circadian morning and day, and avoiding bright light exposure during the circadian evening and night. Furthermore, all zeitgebers work only when they have a periodic component, which is an alternance between high and low phases, for light it's composed of bright blue light phases versus dimly lit/dark reddish phases, as without such alternance, participants lose entrainment (ie, constant routine protocol). Hence, bright light therapy should always be complemented with dark therapy, and both therapies should really be considered a single therapy, a light exposure control therapy or, more prosaically, light and dark therapy.

The next subsections will cover the various parameters and findings about bright light therapy and dark therapy on the circadian rhythm.

Brief history of bright light therapy

Heliotherapy, which is bright light therapy using sunlight (or sunlight therapy nowadays), can be traced back to 15 centuries BC. Renewed interest by pre-modern medicine emerged with the discovery of the importance of UV light for the human body to produce the essential vitamin D during the mid nineteenth century, which led to the UV therapy craze and its excesses. Modern light therapy seems to have emerged around in the late 1970s to 1980s, with research on insomnia and on depression uncovering the previously unknown effects of bright light therapy on the human circadian rhythm and on mood. Indeed, until the early 1980s, it was assumed by chronobiologists that social cues were the main zeitgebers for the human circadian rhythm, with bright light having little importance, despite being the main zeitgeber for animals, until this assumption was disproven first by a review in 1981 by Czeisler et al and then by empirical data in 1986 and in 1989 demonstrating the vast underestimation of the magnitude of bright light circadian resetting effect. The existence of the ipRGC cells in the eyes, the cells that allow circadian rhythm shifting from bright light ocular exposure, was discovered in frogs and mice in 2000 and later in humans, in 2003 by Panda et al.

Norman E. Rosenthal is often credited as the first scientist to have coined the term Seasonal Affective Disorder (SAD) for seasonally-dependent depression, and the use of bright light therapy to treat it, in 1984, from a case study on a depressive patient admitted in 1980. However, Rosenthal is actually not the first to have used bright light therapy to treat depression. Indeed, there is another study published 1979 by Wehr which used bright light therapy to treat depression in a group of human patients. Wehr went on to become a principal investigator and led the study that Rosenthal worked on and which defined the SAD disorder.

The effect of bright light on the circadian rhythm is known since at least before 1966, thanks to the groundbreaking works of Kleitman in 1949 and later by the invention of the free-running protocol of Aschoff and Wever in 1962 inspired by the De Candolle experiments in 1832 successfully making the Mimosa Pudica (nicknamed the "Sensitive plant") free-run under constant dark conditions, which experiment was itself inspired from de Mairan precursory discovery of the existence of the circadian rhythm using the same plant. Hence, the knowledge that bright light influenced not only the circadian rhythm of animals and plants but also humans was well established much before 1979 when the effect of bright light on mood was discovered with Wehr's work. A review published in 1983 concludes that there was sufficient evidence of an effect of bright light on humans circadian rhythm similar to animals that this warranted further investigations into the use of bright light as a therapy for circadian rhythm disorders. Another review in 1983 specifically focuses on DSPD as a primary target of bright light therapy intervention. A group study was conducted in 1985 on healthy volunteers. Hence, light therapy was investigated for circadian rhythm shifting and potentially sleep disorders treatment directly subsequently to its use for depression.

In conclusion, the effect of bright light on the circadian rhythm was first discovered before its effect on mood. The first case studies investigating the use of bright light as a therapy were done first for mood disorders (depression, SAD), and then for circadian rhythm shifting on healthy volunteers, before starting trials for sleep disorders the next decade. However, it's important to note that the rationale for using bright light therapy for depression always involved the hypothesis of a circadian dysregulations underlying depression (the critical photosensitive period hypothesis, see also here, later renamed to circadian phase shift hypothesis) and that properly timed bright light could be an effective treatment to affect both the circadian and mood systems.

Hence, the circadian shifting effects of bright light exposure were amusingly enough discovered more than 40 years before the biological pathway was found, since the ipRGC cells existence was discovered only in the 2010s.

It's worth noting psychiatry (eg, Lewy, Krauchi) significantly contributed to the early research on circadian rhythm science, core body temperature, and bright light therapy to treat depression and sleep disorders, with both disorders being at the time considered to be of nonorganic cause and hence belonging to these specialties. These pioneers nevertheless did not restrict themselves to their field but also versed in a variety of other fields such as biology, physics and mathematics.

Artificial light is also intimately related to the modern society's economical and labour organization. The essay "The Biopolitics of Melanopic Illuminance, Magnus Eriksson and Geraldine Juárez, Scapegoat (10), 2017" describes how labour laws are a direct consequence of the invention of artificial lighting, how the 24/7 consumerist society is a byproduct of earlier military experimentations to create sleepless soldiers inspired from migratory birds and hence how not surprising it is that the "sleep is for losers" mindset is systematically implemented in the military up to this day, and how artificial lighting is still used as a torture tool in Guantanamo. Note that "biopolitics" is a term coined by Michel Foucault, a philosopher who studied the history of modern medicine and its sociopolitical use as a tool of power to control populations.

Nowadays, artificial bright light therapy is not only investigated for the treatment of circadian rhythm disorders and insomnia, but also for major depression, Alzheimer, delirium and ADHD.

Bright light therapy parameters, Luminette and photic history

Light therapy, or phototherapy, is a therapy that consists in being exposed to bright light on a precise timing relative to the user's circadian rhythm. The therapy is usually repeated everyday in practice, although studies demonstrated effects with a single exposure.

Light is without a doubt the most powerful tool we have to manipulate the circadian rhythm. Indeed, in case of conflicting inputs between clocks, light always has precedence over other clocks according to Aschoff, and it entrains all central and peripheral clocks throughout the body. Light is the main modulator of circadian rhythms, sleep and mood. Hence, light is the number 1 tool anyone with a (sighted) circadian rhythm disorder needs to try. All other currently available treatments (including melatonin) provide much less circadian shifts than light can (but they can be combined for greater effect).

The medical use of light therapy started in the 1900s with UV therapies which awarded its author a Nobel prize. However, modern bright light therapy only came up later, after the 1950s. The effect of bright light on the human circadian rhythm and its interaction with other vital signs such as core body temperature and heart rate was pioneered by the extensive works of Kleitman before 1966. The discovery of the biological pathway for the circadian shifting effects of bright light came even later, first named the "pre-optic area of the anterior hypothalamus" as it was assumed to be a yet to be discovered neurological structure, until the discovery of the ipRGC cells in the eyes in the 2010s.

Luminettes aren't really necessary, anything that stimulate your nasal hemiretina should work, but Luminette are more effective, because it is enriched in blue light and has a comfortable form factor (glasses) which guarantee an adequate and invariant and reproducible distance and angle of the LEDs relatively to the eyes as to optimally stimulate the ipRGC cells. This is why there are anecdotal reports of individuals achieving entrainment with a simple light from a computer screen, a make-up mirror with bright light, and also classical light therapy lamps for Seasonal Affective Disorder such as the Beurer TL30 lamp, but often short lived as it's difficult and cumbersome to optimally use light therapy lamps, whereas results are much more reproducible with light therapy glasses.

Light therapy affects the circadian rhythm by stimulating the intrinsically photoreceptive retinal ganglion cells (ipRGC) receptor cells (that can be connected to S-Cone cells) mostly present in the parafovea of the macula and nasal regions of the retina in humans (see also here), but according to an animal study, each ipRGC cells in fact axonally innervates bilaterally the suprachiasmatic nucleus (SCN), with ipRGC cells located in the dorsal-temporal region of the retina primarily targeting the dorsal part of the SCN, and those located in the ventral-nasal region targeting the ventro-medial parts of the SCN, although studies on humans so far found no evidence of a dorsal-ventral gradient in ipRGC cells placement in humans, contrary to other animals. The ipRGC (also called mRGC cells or melanopsin OPN4 cells) represent about 1% of all RGC cells on average in a middle-aged human. The ipRGC cells' effect on the circadian rhythm is due to the melanopsin photopigment these cells possess and which make them intrinsically photosensitive contrary to other retinal ganglion cells (RGCs), as discovered in 2003 by Satchidananda Panda et al, in addition to the MW-opsin pigment. The more these cells are stimulated, the more phase advance and melatonin inhibition will happen (as well as a few other hormonal chances such as cortisol secretion). Although the ipRGC cells relay the light signals directly to the SCN with equal contributions from both eyes, contrary to a previous widespread assumption, the SCN is not necessary for the phase advance effect of light therapy, likely through other unidentified retinorecipient regions, since the destruction of the SCN does not impair phase advance by light therapy and a subsequent study shown that the ipRGC cells are sufficient to cause circadian rhythm and body temperature shifts without the need for the SCN to be preserved, which shows that the non-visual effect of light on the circadian rhythm is independent from the SCN. Furthermore, although ipRGC cells stimulation exquisitively inhibits melatonin in a dose-dependent manner (brighter light inhibiting melatonin more), the phase shift induced by light therapy is decoupled from melatonin: it's possible to produce a big phase advance without any significant melatonin inhibition, and inversely (see also here and here and here and here and here). In other words, melatonin suppression is not necessary for entrainment and bright light does not always suppress melatonin, contrary to what was assumed before. Hence, the goal of an effective light therapy is to optimize the stimulation of a maximum of ipRGC cells and to result in a behavioral phase advance, or a phase advanced core body temperature profile if a more objective proxy is preferred.


Overview of the retina photoreceptors. The ipRGC cells are mostly located in the parafoveal area of the macula and in the nasal regions of both eyes retinas, and can be connected to S cones which are cone cells optimized to detect blue colored light (although melanopsin cells are distinct from S cones). The peak sensitivity of ipRGC cells (Melanopsin curve) is around ~480nm , more precisely between 479nm and 482nm. From the figure 3 of this review under CC-BY 4.0.

Several studies confirmed that rods and cones are unnecessary for circadian rhythm shifting, only the ipRGC cells are necessary, as demonstrated by experiments on rods- and cones-free animals and humans, although rods can contribute a bit to circadian rhythm shifting, and S cones can modulate the response of ipRGC cells depending on the light's color. Indeed, cones can suppress melatonin upon bright light short exposures of green light, but the effect decays exponentially with the duration of exposure, whereas the phase resetting effect is sustained with over long exposures of blue light via the mediation of ipRGC cells, which shows that both cones and ipRGC cells contribute to circadian resetting, but with different and non redundant purposes and mechanisms.

Furthermore, in addition to entraining the central clock (SCN) through the ipRGC cells, bright light exposure also entrains the peripheral (ie, body's organs) clocks. Indeed, although the adrenal gland, cornea, lung, liver, pituitary and spleen still exhibited robust circadian rhythms, it was out of synchronization with the environmental day-night cycle, which shows that peripheral clocks persist without needing the SCN, but the SCN plays a major role of synchronizing these clocks together. In other words, bright light entrains all clocks throughout the body.

Blue light stimulates the eyes' ipRGCs receptors more and produces the most phase advance compared to other colors, but amber light was also shown to affect the circadian rhythm (see also here) since the body can also use variations in the light's color as a zeitgeber, in addition (or replacement) to light intensity (eg, to continue to be entrained under cloudy sunlight, by detecting if it's blue - daytime - or amber/dark - night time). However, amber light has much less sustainable effect on the circadian rhythm than blue light. Also, blue light constantly suppresses melatonin during the whole exposure, whereas green light does only so temporarily for about 90 min. Blue light inhibits melatonin faster than natural endogenous synthesis cessation, which means that blue light can be used at wake-up to more quickly eliminate sleep inertia due to melatonin left-overs, whereas amber light does not. Blue light alone is sufficient to constantly suppress melatonin as long as the subject is exposed. Blue light not only phase advances the wake-up time but also the sleep timing (ie, falling asleep earlier) as observed by several studies. In other words, light therapy also allows to sleep earlier (ie, sleep onset), likely because of the photic history effect increasing next-morning melatonin concentrations (see below), and hence complementing exogenous melatonin pills, although the effect on sleep onset is not always present as light therapy is more effective to entrain the sleep offset (ie, wake up time), but this may be due to the experimental design as it's necessary to be repeatedly exposed over almost about a week to get this melatonin increase effect because of melatonin secretion phase advance lagging behind by a few days after circadian rhythm phase advance. Sunlight is rich in blue light. Blue light also increases serotonin levels and hence vigilance, particularly at wake-up when sleep inertia is at its highest, and hence bright light is a well-known tool to clear brain fog due to melatonin left overs in the morning as well as having an antidepressant effect likely due to the increase in serotonin levels. Compared to green light, blue light improved the activity of brain areas associated with emotion processing, which demonstrates that blue light is likely more effective to treat depression (eg, SAD) than other colors. A well designed study controlling for equal illuminance and color temperature found that blue-light enriched polychromatic white light resulted in a 50% melatonin suppression for a 175 lux light source, whereas no melatonin suppression occurred with a blue-light deprived white light.

Light intensity also matters, but with a limited range: the sensitivity bandwidth of the eyes is not the same for visual signals and non-visual signals (ie, circadian rhythm shift): 9 to 10 orders of magnitude for visual, whereas it's limited to 2 orders of magnitude for non-visual, hence the saturation point of light intensity is quite low, with a study showing that 2000lux light therapy already produces maximum phase shift with no additional phase shift with 8000 lux, and another study modelling the phototransduction by the human circadian rhythm by Rea et al suggesting that 1000 lux is already close the saturation point.
This saturation point is different for everyone since we all have different sensitivity to light (up to 50x fold difference!), so that some people saw a circadian rhythm shift and melatonin suppression achieved with light with an intensity as low as 5-10 lux with eyes closed (and even lower lux with eyes open). Also, with only 100 lux light therapy, this produces half of the circadian shifting effects of a 10K lux light therapy, "including melatonin suppression, circadian phase resetting and the alerting responses" (ie, vigilance boost). All these findings mean that humans are sensitive to light of virtually any intensity and color, and the maximum phase shift is reached with maximum 2,000 lux, and potentially even below for some people especially those with circadian rhythm disorders if they are hypersensitive to light as some studies found, so no need to burn your eyes with more intense lights. On the other hand, this also means that any effort to reduce artificial light exposure (ALAN) in the evening is of primary importance (see the section on dark therapy below).
Of critical importance, humans in industrialized countries are exposed to very little bright light. A study (see also the related PhD Thesis for more details), where the participants wore a light sensor pendant during 1 week, has shown that humans in modern society are exposed for the major part of their 24h cycle to low light (<500 lux for 21 h:27 min ± 23 min) even during daytime! Furthermore, they were exposed to long durations of very dim light during daytime (<10lux for 2h46min) and bright light during nighttime (>1000lux for 26min). Even through sunlight is available during daytime, the participants were only briefly exposed to bright light (>1000lux for 1h18min). This is in line with what previous studies observed: "these values are in the range of light exposure values for young adults in industrialized countries, most of whom typically receive only 20-120 mins of daily light exposure >1000 lux (Espiritu et al., 1994; Hebert et al., 1998; Mishima et al., 2001; Savides et al., 1986)." Hence, humans in modern society are mostly exposed to dim light during both daytime and nighttime, with only brief exposure to bright light both during daytime and to a lesser extent during nighttime, and even long bouts of very dim light exposure during daytime. This likely explains the major reason why light therapy can be so effective, even with low light intensity settings, as well as why dark therapy can be helpful, since humans in industrialized countries can be regularly exposed to >1000lux bright light during nighttime.
This low exposure to bright light can be experienced by anyone with a modern smartphone, as there are "lux meter apps" which use the phone's ambien light sensor on the screen to display how much light intensity the screen is exposed to. This is a very entertaining way to develop a first hand intuition of the real bright light exposure we get in our daily lives, which changes depending on the environment, head orientation, season, weather and time of the day. Anecdotally, the author of the present document measured exposure just in front of a very wide glass window with direct sun exposure over the course of two seasons in Belgium. Results: during autumn, >5K lux was common and >50K lux happened on cloudless bright days, but during winter with raining weather, daytime lux could be < 100lux for the whole day! Which shows that it's not just an issue with industrialization (although it worsen the issue), as virtually direct daylight exposure can still be lower than what is required for entrainment. Hence, daylight is inherently extremely variable on a logarithmic scale (ie, it can jump between several orders of magnitude). With less than 100 lux, this low amount of daylight would likely cause freerunning for any non24 individual. In fact, a theoretical study could indeed accurately estimate the circadian rhythm phase of humans using a mathematical model with logarithmic calculations, and found that more intense light ("larger amount of daylight") was associated with an earlier DLMO.

However, although all light colors and intensities can shift the circadian rhythm and hence help with entrainment, blue light alone is about 185 times more efficient for circadian rhythm shifting than polychromatic white light, in terms of the amount of photons, and hence energy, required to produce the same amount of melatonin suppression . This is because of circadian light subadditivity, which makes colors opposite on the spectrum such as blue and yellow or green and red to reduce the effect of each other when exposed to both simultaneously. Note however that this work on circadian light subadditivity used melatonin sampling as a proxy for circadian rhythm shifting.

For stable entrainment, the goal is to oppose the natural daily phase delay of an individual's non-24 circadian rhythm with an equal or greater amount of phase advance, such as by using bright light therapy. Hence, we want to maximize the phase advance to set all chances on our side. To maximize, the goal is to stimulate the ipRGC receptors in the eyes the most, and hence "all studied characteristics of light pattern (timing, intensity, rate of change, duration, and spectrum) influence the circadian system". In practice in the context of optimizing entrainment therapies, these parameters can be classified in 3 broad categories with subparameters (not unlike a previous categorization by Lewy in 1987):

  1. Maximizing ipRGC cells stimulation:
a- an adequate nasal angle or parafoveal angle to stimulate most ipRGC cells (see also here). Hence, light must be either looked at or be seen from on the lateral outer sides of the eyes (peripheral view) to have maximal efficacy. There is no evidence that light must have an incidence from the top of the eyes.
b- the light intensity, with a linear proportionality between light intensity (in lux) and the ipRGC cells stimulation (ie, how much they will phase advance) as also shown in humans. However, the ipRGC cells are saturated quite fast with a relatively low light intensity, so past this saturation point, there is no benefit from more intense light as demonstrated by a study showing no difference in phase shift between 2K and 8K light therapy.
c- light color modulates the light stimulation on ipRGC cells as well as S-Cones, with blue light stimulating the most and red light the least and green light stimulating cones instead of ipRGC cells and hence losing efficacy over long durations of bright light exposure. Blue light alone appears to be much more effective than blue-enriched white/polychromatic light due to circadian light subadditivity.
  1. Light exposure timing relatively to the individual's circadian rhythm (ie, the Phase-Response Curve - PRC). This manifests as two practical effects:
a- light exposure in one's circadian morning (after CBTmin) phase advances the most. More precisely, "the CBTmin (minimal core body temperature) serves as the “inflection point” between delaying and advancing effects for light" (second ref), hence light therapy should always be done relative to one's circadian rhythm (ie, after natural wake-up), never on an absolute time point (eg, 8am everyday), just like for melatonin. This means that alarm clocks should never be used for light therapy, as using light therapy too early (before the CBTmin) will delay instead of advancing the circadian phase, and mistimed light exposure was further shown to increase sleep fragmentation and hence worsen general sleep quality. In addition, alarm clocks will cause sleep deprivation, and sleep deprivation reduces light therapy effectiveness by reducing the magnitude of the light PRC, which shows that it is crucial to be well rested (eg, by freerunning) before starting the light therapy and is another reason to avoid the use of alarm clocks for light therapy administration.
b- a longer duration of exposure leads to a proportionally bigger phase advance: a study shown that using a relatively low light intensity of 500 lux but over 6.5h produced a 3h phase advance, whereas 1h of the same light therapy only produced a 1.15h phase advance. A previous 2011 study demonstrated a similar result, with 4h light therapy being more effective than shorter light therapy. Hence, as specifically demonstrated by a 2011 study, a longer duration of light therapy is more effective than increasing light intensity. Furthermore, there is no dead zone in the PRC curve (see also here), which means that there is no virtually no limit to the phase advance obtainable with light therapy, and that light therapy started later (even hours) than the wake up will still be effective (ie, during the circadian morning and circadian day), as long as it's before the circadian evening and circadian night.
  1. Optimize photic history: prior light exposure changes melatonin levels and response to future light therapy, "such that a history of less light exposure leads to a greater response to light" and inversely a history of greater light exposure will protect against unwanted phase delays due to light exposure during the biological evening (see also this review). Hence, repeated light therapy over multiple days will provide more effect than a single session, because a resistance to unwanted phase delays due to uncontrolled light exposure (eg, artificial evening light) will build up over repeated light therapy sessions. Consistent with this study finding elevated next-morning melatonin concentration after at least 5-7 days of bright light exposure, but not with less than 5 days, the author found that repeated exposure during about 10 days is necessary for the light therapy effect to converge to its maximum. This is likely, at least in part, due to the fact that melatonin onset (DLMO) has a delay of several days to catch up with circadian phase shifts, whereas the melatonin offset (stop of melatonin secretion) is instantaneous. In other words, entrainment of the wake up time is instantaneous, but the bedtime will continue to freerun for a few days until it finally gets entrained according to the new wake up time.

Point 1 should be taken care of by the light therapy device (especially if it's a blue light therapy glasses such as Luminette). Points 2 and 3 are reliant on user's handling of the device, and how compliant with the therapy they are (ie, to use light therapy daily for the required amount of time).

Photic history (or light history) is a crucial, but complex, phenomenon that remains poorly understood, as the temporal aspect of the circadian rhythm has been historically understudied. Photic history is the phenomenon characterized by how prior light exposure affects how the circadian rhythm will react to future light exposure, as well as other indirect changes such as increased next-morning melatonin levels, by previous days exposure to bright light. It may be through this melatonin regulating pathway that exposure to bright light can produce or eliminate biphasic sleep, which can be naturally induced by a too short exposure (10h) to bright light during the awake period, and eliminated by a longer bright light exposure (16h). In other words, the circadian system possess a memory of prior light exposures. Photic history can be both beneficial or detrimental depending on the timing: light therapy in the morning is less effective if an individual is exposed to light in the previous evening or night, whereas if the participant is exposed to blue light only during the biological morning and use dark therapy in the evening, this increases melatonin levels more than other colors while simultaneously phase advancing more than other colors. Furthermore, prior exposure to bright light during the biological day reduces sensitivity to light in the biological evening, and inversely prior exposure to less light (eg, only dim light) during the day increases the sensitivity to night-time light, which will more easily cause unwanted phase delays. Indeed, the ipRGC cells that are responsible for the circadian rhythm shifting after light exposure were demonstrated to have "larger responses to light stimuli after dim light exposure, and reduced responsiveness to light stimuli after bright background light exposure". Indeed, another study demonstrated that bright light inhibits melatonin more after being exposed to dim light at 0.5 lux compared to 200 lux, which confirms that being exposed to bright light during the circadian day reduces the effect of evening bright light exposure. Aberrant light exposure can cause major cognitive, learning and mood impairment directly through the ipRGC cells, and the opposite is true, with light exposure having an antidepressant effect, and indeed a 2019 systematic review and meta-analysis found that light therapy is as effective as antidepressants for the treatment of both seasonal and non-seasonal (major) depression, with the combination of both being even more effective (see also this other systematic review). A more fragmented light-exposure rhythm is associated with a more fragmented sleep. A more stable inter-days exposure to light is associated with a more stable sleep pattern in typical sleepers, although it's unclear how this would apply to people with circadian rhythm disorders.
Photic history may stem from the GABAergic signalling that ipRGC cells can do in addition to the better known excitatory signalling, as GABAergic signalling involves chemical processes that can modify structure and hence memorize at the synaptic level. It was also established that light therapy controls both the DLMOff (stop of melatonin secretion - around wake up) instantly, but also the DLMOn (start of melatonin secretion) with several days of delay, the latter may partially contribute to photic history and explain the delay before the full effects of light therapy are observed. This melatoninergic pathway for photic history seems to not be activated by intermittent light exposure since intermittent light therapy inhibits melatonin much less than continuous bright light therapy despite producing almost as much phase advance. The effect of photic history may span days or weeks.
To summarize, photic history shows that light therapy in the biological morning not only phase advances, but also 1- makes the participant more robust to insomnia by increasing endogenous melatonin levels and hence indirectly consolidating sleep, 2- reduces the sensitivity to phase delaying lights in the biological evening and hence may reduce the need for dark therapy.

Photic history explains why the effect of light therapy snowballs until it reaches its max effect at about the 10th day, because light therapy not only phase advances instantly the circadian rhythm, but also reduces evening light phase delays, so over time the phase advance becomes bigger and bigger. The author is convinced photic history plays a major role in the special effects I have observed with very long light therapy, and that this is a critical parameter to control for optimal therapeutic yields. Indeed, photic history explains the following practical observations:

  • why it takes a few days to work: 2 days for the first effects, 10 days to reach maximum phase advance without changing anything during the 10 days, because light therapy is self reinforcing ;
  • why the first effects observed are a stabilization of the wake up time, and only later of the bed time.
  • why feeling sleepier at the correct time after light therapy because melatonin levels are increased the biological nights after ;
  • why a longer exposure increases non linearly the phase advance, because not only the phase advance is linearly increased, but prior light therapy protects against evening light exposure so that sleepiness and melatonin levels will stay at high levels even when exposed to light. This point also explains why non-24 can be reinforced through a vicious cycle of dim lighting in the awake period (which can be inversed with the day-night cycle), which will only reinforce the hypersensitivity to light and hence the circadian misalignment problems. But the opposite is also true, as it can be used to create a virtuous cycle: through photic history, light therapy can make the user less hypersensitive to light (ie, more robust to unwanted phase delays due to bio evening lights).

Although photic history seems to have been mostly forgotten nowadays, it was already known since at least the studies by Rosenthal et al on bright light therapy for SAD in the 1980s (they are the original authors), stating that "patients generally respond to bright light therapy within four days of starting treatment and relapse within four days of discontinuing treatment" and note elsewhere that SAD patients usually respond within "2 to 4 days of initiating treatment", emphasizing the initial delay when starting treatment.

The suprachiasmatic nucleus (SCN) also modulates feeding behaviors, and can promote the consumption of dense food (ie, weight gain and obesity). Hence, light therapy may modulate feeding behaviors (ie, hunger) through the SCN.

Is more light intensity always better? Not necessarily, because there is a physiological limit beyond which light intensity doesn't matter because we already reached ipRGC cells max stimulation. This maximum stimulation limit was quantified and is limited to 2 orders of magnitude (eg, 100-10000 lux or 10-1000 lux, the exact boundaries of light sensitivity are not known and can vary from one person to the next). Since blue light is about 185 times more efficient to stimulate ipRGC cells, it's much easier with blue light to reach the max stimulation of ipRGC cells and hence maximize the phase advance than with white light or other colors. That's why most blue light therapy glasses only use a low lux setting such as 500 lux or max 1500 lux, whereas white light therapy lamps use 10K lux (the reduction in lux also serves as battery saving strategy since 10K lux is too much to run on a battery). Although more light intensity is not always necessary, sufficient light intensity is necessary to stimulate the ipRGC cells sufficiently to get enough phase advance to be entrained. It remains to be seen how little is sufficient for non24 entrainment, but 100 lux light therapy was found to be sufficient to produce half of the circadian shifting effects of 10K lux light therapy. Furthermore consistent entrainment was achieved during the self-experiment with 500 lux. The second subject could stay entrained for months at the time of this writing with only computer screens (but during spring-summer, so might be confounded with sunlight complementary effect). For comparison, computer screens at maximum brightness usually emit about 250 lux.

In addition to light intensity, the duration of light exposure also proportionally increases the amount of phase advance (see also here and here), and there is virtually no maximum limit since there is no dead zone in the light's PRC curve (see also here), contrary to what was thought before (that light would advance only during a limited timeframe around wake-up, we now know that it works for much longer than that and light therapy can be started much later than wake-up and still works) and contrary to light intensity which has a limit due to the relatively low saturation point between 1000 to 2000 lux. This is why increasing the duration of light therapy is much more effective than increasing the light intensity (see also this commentary), as we have much more leeway to increase the phase advance, whereas light intensity saturation is reached with pretty low lux levels. This lack of dead zone in light's PRC curve (see also here) also explains the result found in this study about 10h vs 16h of light therapy producing a biphasic or monophasic sleep, this result shouldn't be possible if there was a dead zone in the light's PRC curve. This disproves the 1960's critical photosensitivity period hypothesis, which posited that bright light could affect the human circadian rhythm but only in a specific time window. The temporal aspect of the circadian rhythm, including the duration of bright light exposure, is hence a crucial factor, despite being historically overlooked by researchers as they focused on the spectral sensitivity of the circadian system. The previously held assumption of a dead zone in the light PRC curve may also have played a role.


Phase advance is proportional to the duration of bright light therapy's exposure, with an almost linear increase up to 6.5h past wake-up, hence showing there is seemingly no limit to the amount of phase advance that can be obtained with longer durations of light exposure. Reinterpretation of the results from the Figure 2 of this study.

In fact, although not well known, Czeisler's team conducted a study in 2012 on 14 healthy men with a very long bright light therapy regimen of 5-8h of bright light exposure everyday for 5 days, which allowed them to achieve 8h of phase advance on average. The light therapy setup involved 10K lux lamps on the ceiling, walls and floor, with the subjects being restricted to this room for 5 days. During the evenings, light was dimmed to 5-15 lux. Initially, the astronauts subjects slept from 00h-08h, and at the end of experiment they slept from 16h-00h (target was 14-22h). To ensure light therapy would happen during the phase advance portion of the PRC curve, they used a mathematical model to predict the CBTmin point and planned light therapy to start 1h after the scheduled wake up time, in order to ensure some margin despite the progressive phase advance and hence moving CBTmin. This study further found that moderate lighting of 90-150 lux suppressed melatonin as much as 10K lux, further emphasizing the importance of dark therapy in the circadian evening. Of course, the results were obtained in a strictly controlled lab setting, with perfectly scheduled dark therapy and light therapy, with no interference from sunlight. In a realistic, at-home setting, a reduced magnitude should be expected (eg, maybe 3-4h of phase advance instead of 8h in the lab). This groundbreaking study demonstrates the viability of very long bright light therapy to produce significant phase advances in a short time span on the human circadian rhythm, in line with the current document's author's experiments results. Keep however in mind that this study only spanned one to two weeks, hence it didn't assess the long-term stability of the acquired phase shift, but since they could assess core body temperature (with a rectal probe) objectively confirms the circadian shifting effect and magnitude. One thing to note is that they found much better core body temperature shifting with high lux (10K) than with moderate lighting (90-150) lux, since for the high lux group they found that the core body temperature matched with the scheduled sleep-wake pattern, whereas the moderate light group still had a CBTmin delayed 5.5h compared to the scheduled wake up time:

Another study provided some figures of how much phase delay (not phase advance, which is more difficult to obtain) can be expected for different light therapy durations:

> one hour of bright light exposure (minus the delay under control conditions) resulted in a mean phase delay of 10 min, 2 h of light exposure resulted in a phase delay of 53 min, while 3 h of light during the night delayed the melatonin onset by about 1.5 h (averaged across different intensities).

Interestingly, seasonal affective disorder also requires 30 to 90 min of exposure at 10K lux for most people, although some may need more or less, contrary to the commonly prescribed too short duration of 20 min of exposure which stems from one of the earliest papers on using 10K lux bright light therapy which found that 20 min at 10K lux was equivalent to 1 or 2h at 2500 lux, the intensity used in the original paper on bright light therapy for SAD treatment, but this paper never demonstrated that 20 min was sufficient to treat most SAD patients, and hence this number remains to this day a clinical lore. In fact, it also did not study the circadian rhythm shifting effect of short very bright light therapy neither, but this 1990 study is unfortunately the source that initiated and spread the misconception that bright light therapy need to be highly intense but short, which was later contradicted by Dewan et al's study demonstrating that increasing the duration of light therapy was much more effective than the intensity, especially since the circadian system saturation point can be reached with a light intensity as low as about 1000 lux and that there is no dead zone in the light PRC curve. Another study further strengthen the inadequacy of the current focus on bright light intensity, as it was shown that low intensity light therapy (100 mLux) is sufficient to reduce objective daytime sleepiness as monitored with EEG, with fewer differences with higher illuminance, suggesting once again that duration and timing are likely higher yielding modifiable parameters. A systematic review on the use of light therapy to augment the effect of antidepressants for major depression and bipolar depression found that an illuminance greater than 5000 lux for periods longer than 30min were required to observe a significant effect.

Informally but interestingly, a member of the N24 Discord server, owner of a Beurer TL30, contacted Beurer in 2020 to ask what they would advise to treat circadian rhythm disorders, to which they replied to use the lamp for 4 hours at 1250 lux distance, suggesting they also are aware that long light therapy leads to more phase advance that can help with circadian rhythm disorders, maybe due to this 2011 study.

During the current document's author's self-experiment, it was found that lengthening the duration of light therapy was more effective to get additional phase advance in comparison to increasing light intensity, the latter showing no significant benefits but produced minor but uncomfortable side-effects such as dizziness and headaches due to sudden exposure to bright light. This is in line with the results of a previous study.

The effect of light on the circadian rhythm is not solely due to its inhibition of melatonin, because it was shown that intermittent light can phase advance the circadian rhythm without reducing melatonin secretion, and that a longer light exposure causes more phase advance irrespective of any effect on melatonin. Hence, melatonin is decoupled from the circadian rhythm as shown by several studies .

Blue light therapy's effects (both on the circadian rhythm and the potential phototoxicity) may be dependent on the user's age: the eyes lens (cristallin) obscures with age to a yellowish tint which is acting as a blue light filter and filters more with age, with 60 years olds having an average 2 times blue light filtering as 20 years old, and newborns having no blue light filter. Furthermore, the number of ipRGC cells is reduced with ageing beyond 80 years. The sleep of older individuals is also more fragmented and the circadian rhythm is phase advanced, has a lower amplitude and a shorter period. Hence, older individuals may need longer exposure to brighter light than when they were younger. A 2017 study found that younger adolescents see more inhibition from bright light than older adolescents. Another study in elders found no evidence that age affected the direction nor the magnitude of the circadian rhythm shifting effects of light therapy. However, another study found that melatonin inhibition by bright light varies with age, and interestingly the maximal suppression is achieved at different light colors depending on age, with younger individuals being more sensitive to shorter wavelength (ie, blue light), in line with the observation that the eyes lens obscure with age to a yellowish tint. A 2019 systematic review found that age impairs melatonin endogenous secretion and inhibition by light, but has no effect on the phase advance induced by light therapy. Hence, the light therapy duration or intensity can be adjusted accordingly to the user's age to adjust for the reduced efficiency on melatonin inhibition (ie, brain fog), with younger individuals being more sensitive to blue light, but the circadian phase advance produced by bright light therapy does not change with age. This also explain why children and adolescents are more affected by night-time exposure to non filtered blue light emitting screens such as phones and computers.

Although the phase advance effect of either light and melatonin is limited, combined their effects are additive (see also here and here and here and here), so that you can for example get 1h phase advance from melatonin and separately 1h from light therapy, and combining both would give you 2h in theory (in practice it will be less because there is some natural biological variability from day-to-day, but at least by combining multiple therapies you get more leeway to stay entrained despite uncontrollable disturbances).

So it is possible to try to use only light therapy alone, it was shown in lots of studies and in systematic reviews to work without needing melatonin, but of course you will get less effect. Expect about 1-2h of phase advance with each treatment alone (see here and here for light), and combined the effect is additive (melatonin + light therapy can help you to achieve 2-4h in total).

Can the light therapy glasses work even with eyes closed? Yes:

> The eyelid acts as a red-pass filter (Zeitzer et al. 2014) and transmits only approximately 3%–14% of light (Robinson et al. 1991) in a wavelength-dependent manner. Thus, the retinal exposure of light depends on the status of the eyes (open, closed).
> [...] Similarly, Figueiro and Rea (2012) showed how light delivered through eyelids during one hour suppressed melatonin and phase shift DLMO. Both studies suggested that phototherapy may also be given with closed eyes, and even while asleep (Zeitzer et al. 2014).
Source: Systematic Review of Light Exposure Impact on Human Circadian Rhythm, 2019, Chronobiology International

So yes it works, and even with light as low as 5-10 lux while the eyes are closed, but has of course much less effect on the circadian rhythm than with the eyes open. This is exploited by a new kind experimental light therapy device called a "light mask", a light-emitting device in the shape of an eye mask to be worn during sleeping and emitting light during the last 4 hours of sleep before wake-up, hence with the eyes closed, which shown some efficacy in phase advancing individuals with DSPD. It's likely that much longer exposures than usual (as they did with exposing for 4h to the light mask) are necessary to get any benefit from light therapy with the eyes closed.

But eyes closing can nevertheless be useful. If the light is blinding you when you switch on the Luminette, close your eyes at first for a few seconds and then open them, your eyes will have accomodated by then and the light won't blind you anymore. This should also avoid the dizziness and headaches that can happen when being suddenly exposed to bright light due to sudden increases in cortisol. It may also avoid the changes in the macula induced by sudden bright light exposure in a dim lit environment, by gently allowing for pupil contraction, the pupil area being correlated with melatonin suppression (TODO: and phototoxicity?). Then, when the eyes are contracted, it's better to open the eyes as soon as possible to get the full circadian shifting effect.

The bottom-line about the safety of ocular blue light phototherapy for circadian rhythm disorders and SAD: ocular blue light phototherapy is safe for the eyes, except if you have a photosensitivity disease such as a retinal disease or epilepsy or another disease that requires you to protect from natural sunlight by wearing sunglasses or similar protective eyewear.

What if light therapy does not work for you? Well, in the future definitely researchers and clinicians should try to devise test of circadian photosensitivity, to check if an individual is likely responsive to light therapy before they acquire such a device. One way, that the individuals can already do by themselves, is to maintain a sleep diary, and observe if a pattern of relative coordination can be observed (ie, faster freerunning when out of phase with the day-night cycle, and slower when in phase). Since relative coordination is due to sunlight exposure, this is strongly suggestive of responsiveness to light therapy. Other potential avenues are occular tests, by checking the pupils area or the pupil's contraction reflex to sudden bright light exposure, since it's the same ipRGC cells and their melanopsin photopigment that control both pupil's contraction reflex and circadian rhythm shifting in response to light exposure (see also here). Indeed, genetically muting the melanopsin pigment severely impairs both the pupillary light reflex and circadian alignment. In practice, pupillometry can be done with measuring either or both the amplitude and speed of contraction post light exposure as they are strongly correlated, with the light intensity, starting size of the pupils before the test and the age of the participant being irrelevant. A study on DSPD found that the pupil light reflex could diagnose circadian DSPD, as they had a faster pupil contraction speed than those without a circadian misalignment, and with brighter light being more effective to diagnose. This strongly suggest that individuals with DSPD are hyper photosensitive, and it's safe to assume the same for non-24. Interestingly, individuals with autism were also found to display a pupillary light reflex with more amplitude and correlated with their sensitivity to stimuli (sensory processing disorder), which is even more intriguing considering circadian rhythm disorders are very common for people with autism to the point some scientists suggest that circadian rhythm disorders underlie autism. Smartphone-based camera and LED flash apps have been demonstrated to provide an objective and equivalent assessment as infrared-based pupillometry, with reduced cost and increased versatility (see here and here). In fact, there is already a test to quantify the sensitivity of ipRGC cells in the eyes by ophthalmologists or optometrists: the maximum post-illumination pupil response (PIPR) after blue light exposure of variable light intensity or via a chemically induced test.

Interestingly, although apriori it is assumed that blind individuals with non-24 would not be responsive to light therapy, a study of 21 participants with blind non-24 found that 2/3rd were responsive to bright light, since their circadian rhythm demonstrated a relative entrainment. This may be explained by the fact that the visual and non-visual (circadian rhythm shifting) pathways are distinct, and hence that blind individuals may very well have their visual pathway damaged but their non-visual pathway intact. But then why are these individuals free-running (non-24) if they can still be entrained by light? Because since they lack their visual pathway, they are prone to stay in darker environment (ie, to position themselves less in places and in an orientation that is more illuminated). Hence, light therapy may represent a worthwhile intervention for blind individuals with non-24 too, and future clinical trials should investigate that.

A clinical trial found that bright, blue light therapy was found to increase effective connectivity within the DMN (awareness network) in patients with a mild traumatic brain injury (mTBI), who often suffer from post concussive symptoms including mood impairments which can improve with bright light therapy. Indeed, "mood dysregulation, including lower self-reported happiness and associated positive emotions, appears to be closely intertwined with the brain’s default-model network (DMN)." It remains to be seen whether patients with disorders of consciousness could also benefit from bright blue light therapy.

There is an emerging body of evidence, pioneered by Van Someren's team, that bright light therapy can reduce the cognitive impairments and may reduce the disease progression of Alzheimer’s disease and related dementias (ADRD) by consolidating sleep and the circadian rhythm. This neuroprotective effect is arguably not directly due to light therapy but by the reduction of sleep deprivation and circadian misalignment, as well as the increased melatonin secretions via photic history, which is a strong body-wide antioxydant.

To conclude, we will cite Figueiro et al, on the importance and challenges of bright light exposure control:

> The challenge for lighting researchers and professionals is that they have been so closely tied to thinking about a particular building – i.e. a single place where one needs to see tasks and perceive ambience instantaneously. Circadian hygiene is not instantaneous, but cumulative. Today, because people have luminous displays and active lives that change their 24-hour pattern of light and dark, they do not have a single lighting entity that is responsible for total 24-hour light exposure patterns, and therefore cannot address 24-hour light exposure issues. As shown by Rea et al.,68 however, it is the temporal relationship between the total circadian light–dark and activity–rest patterns that needs to be measured and controlled to reduce circadian disruption.

Indoor room lighting is not sufficient. For example, a study on undegrad students found that blue light enriched light therapy relieved post-lunch dip impairments in mood, subjective sleepiness and performance, contrary to normal indoor lighting.

Is exposure to sunlight through a glass window sufficient for light therapy? A study shown that glass windows do not filter all UVA, up to 75% pass through, although the glass color matters as green or a sunlight filter blocked all UVA, laminated glasses reduced UVA, and UVB is totally blocked by all glasses. Since UVA is close to the blue wavelength which is maximally stimulating the ipRGC cells, there is a possibility that some of this blue spectrum light is filtered too, reducing the effectiveness of sunlight therapy via glass windows. However, light intensity is still far more than enough usually to stimulate the ipRGC cells. The light intensity can easily be checked by using a smartphone lux meter app (see the next section), to ensure that there is enough light intensity (lux) to saturate the ipRGC cells.

Lastly, there is room for future discoveries on light therapy and circadian rhythm shifting, as studies on mice identified at least 6 different subtypes of ipRGC cells. Whether the subtypes have different functions and stimulation thresholds and conditions remain to be explored.

Other effects of non-UV bright light therapy

In mice, ocular stimulation with blue light (463 ± 50 nm, 20 kJ/m2) for at least 10 days also promotes hair growth, but not green light (522 ± 50 nm) nor when the optic nerve was destroyed:

> Fan and colleagues elegantly showed that daily blue light (463 ± 50 nm, 20 kJ/m2) for 10 days stimulated hair follicle anagen, leading to a significant hair growth compared to unexposed animals. Green light stimulation (522 ± 50 nm), at the same dose, also stimulated hair growth but less effectively. Blue light-induced hair growth was lost when the optic nerve was crushed and reduced in animals with rod and cone degeneration. Interestingly, in Opn4−/− mice, blue light stimulation did not affect hair growth compared to wild type animals. Mechanistically, blue light stimulation to the eyes increased systemic sympathetic activity and norepinephrine levels in the skin, and activated hedgehog pathways in wild type animals. All these effects were lost in Opn4−/− animals [194].

It is well established that vitamin D is secreted by the human body in response to skin exposure to UV light. But in addition to UV photosensitivity, it was recently discovered that human skin also expresses neuropsin pigments OPN5, which makes skin also photosensitive to non-UV bright light, and that the human circadian system may also integrate inputs from extraocular opsin photopigments similarly to other mammals, birds, fishes and amphibians. Skin photosensitivity to non-UV bright light was shown to be dependent on OPN5, not OPN4 (melanopsin, as in the eyes ipRGC cells).

> Circadian clocks within mammalian skin control the response to UV light [42, 43], as well as cell cycle progression in hair follicles [36] and keratinocytes [44, 45], and response to physical injury [46, 47]. The current results would suggest that light modulation of these clocks through OPN5 function may significantly influence these physiologies. Further, these results suggest that mammals, like fish [48], amphibians [49], and birds [17, 50], utilize extraocular opsin photopigments for direct, light-dependent regulation of circadian clock function in some peripheral tissues. This challenges the widely held dogma that peripheral circadian rhythms within mammals are synchronized exclusively by the master SCN circadian pacemaker via ocular photoreception [51, 52] and suggests that mammals also use local light sensing in peripheral tissues for this purpose."

This can help us answer the question of whether skin exposure to bright light, without exposing the eyes, can shift the circadian rhythm? Apart from the production of vitamin D via exposure of the skin to sunlight's UVs, which are mostly filtered by glass windows, but which has nothing to do with circadian rhythm shifting except for the indirect effect of a vitamin D deficiency on sleep processes, recent studies and reviews demonstrated that the human skin cells express neuropsin pigments OPN5 (ie, extraocular opsin photopigments) which can directly affect the circadian clock of peripheral tissues, such as hair growth, without inputs from the suprachiasmatic nucleus. The authors note that skin exposure to short-wavelength light also triggers some hormonal secretions such as β-endorphin and urocanic acid production. However, as the authors note, the maximal stimulation was for these skin photopigments were reached for UVA wavelength, and did not observe "significant phase shifting activity with light of 475 nm or 525 nm, a wavelength range encompassing maximal sensitivity for melanopsin (Opn4) and rhodopsin (Opn2)". This means that dark therapy does not require avoiding skin exposure to bright light or UVA light apriori, as such light only affect the exposed skin tissues local clock, not the main circadian rhythm clock (SCN) and does not inhibit melatonin. Furthermore, exposing skin to the artificial light therapy's light such as from Luminette will not shift the skin local clock, since the OPN5 pigment is not sensitive to this wavelength but to shorter ones. Nevertheless, the authors of the mice study found that the mice could entrain to a 24h schedule with only their skin being exposed to UVA light, which suggests that, in the absence of all other timecues, the skin may feedback into the central clock in some way. It's also conceivable that the skin tissues local clocks may get in circadian misalignment with the master clock and other peripheral clocks under specific conditions (eg, differently timed UVA and blue light exposures).

Tips for Luminette usage

Photos of the Luminette 3, which has a longer battery and 3 different light intensity between 500 and 1500 lux (on earlier versions only the maximum was available):

Luminette can be put on top of prescription glasses (personally tested with huge aviator-style glasses), and they use a battery that lasts for 5 days with 1 to 2 uses per day (= 1 to 2h with the 500 lux light intensity setting). Re-timer are also made to fit over prescription glasses (but did not test myself). However, make sure the prescription glasses do not have a blue light filtering coating, otherwise they will reduce the effectiveness of bright light therapy.

Before use, it's necessary to remove the blue filtering film on the hologram, some people don't notice it. The hologram should be silvery without the filter. Follow the quickstart instructions here: https://www.myluminette.com/en-us/instruction-manual

How to properly place the Luminette (picture from here and property of Luminette):

The FAQ further describes: "How can I tell if the Luminette is correctly positioned? Luminette is correctly positioned if the blue light reaches the lower half of your eyes when you look in a mirror. If this is not the case, adjust the Luminette by placing the nose rest into the slot."

Interestingly, the Luminette also says the following, which in the author's experience seems quite accurate: "How long will it be before I notice the effects ? The “boosting” effect of the Luminette® is almost immediate. After a few sessions, you’ll feel your energy returning and your mood improving. If you are using Luminette to rectify a sleep phase disorder the results will become noticeable between 4 to 5 days."

The Luminette already includes rubber (in blue) on the edges so that it can firmly stay fitted on the head:

However, for users who have an active lifestyle, this may not be sufficient. Inexpensive rubbery accessories to fixate glasses are available online, and most are compatible with the Luminette. Here is a selection tested by the current document's author:


The black rubber band should increase friction on the ears and reduce slippage, but this does not work better than the already rubbery blue bands designed into the Luminette v3.


The concept of a white disc is a simple yet effective one, it effectively prevents slippage in upstraight head orientations and it is very comfortable, almost unnoticeable both visually and sensorily (the disc is not felt on the ears). This is highly recommended if the goal is to just prevent slippage in upstraight, work positions. But if the goal is to wear the glasses while doing physical activities that involve sudden high amplitude movements or more extreme orientations such as facing the ground, then other solutions will be preferrable.


This L-shaped accessory prevents slippage in most orientations, even when facing down. However, it is highly uncomfortable, and makes fitting glasses on the nose much more difficult and unnatural.


An alternative to the disc-shaped accessory, this 9-shaped accessory does not reduce slippage more than the disc-shaped one, but it is significantly more uncomfortable due to the little spike at the bottom of the 9.


Finally, there are holder straps, which are the most reliable accessories to ensure glasses won't slip and fall on the ground. However, they may not fit perfectly to the head, and they make fitting glasses a bit more cumbersome and uncomfortable, although much less than the L-shaped accessory. This is the solution that the current document's author preferred and settled for. To further improve the fit and reduce slippage, the disc-shaped accessory was also added. This allows for the glasses to mostly stay in place just by the disc-shaped accessory, and the holder strap remains a last resort safety net in case the glasses may fall during sudden orientation changes.

Note that these accessories are not necessary, they are convenience items that significantly improve usage comfort for intensive users (the author started using them after more than 1 year from starting the daily use of Luminette).

The nose rest piece needs to be replaced about every 6 months. These can be ordered for 10 euros apiece from myluminette.com official website (direct link here for US, here for UK, here for France). Make sure to select the appropriate model of your Luminette, as by default it selects V2 but V3 is also available. It's possible to order several pieces at once, in case you plan on using Luminette over the long term.


On the left a nose rest piece for Luminette v3 after more than 1 year of use, versus a brand new piece on the right.

When the Luminette breaks, no LED lights up even during charging, they just become fully inert. Nothing happened, the day before i used them only 1h, then went to an appointment so i left them on a table. So there is still lots of battery left and there was no mechanical damage. Hence, it's an electronics components failure for sure.

In case the Luminette fails to light up, the producer Lucimed offers two aftersale options:

  • For 2 years, the Luminette is under warranty and can be repaired by Lucimed for free, if a purchase receipt can be provided and the use is not considered "abnormal" (ie, very long bright light therapy would likely be considered outside of warranty but I'm not a lawyer).
  • Beyond the 2 years of warranty or in case of "abnormal" use, Lucimed offers to repair the Luminette for 35 euros if possible, or if not they will offer a discount to buy a new pair.

There is a third possibility: self repair or a repair shop. The author of the present document successfully conducted a simple self repair, see below.

For an idea of how long the Luminette can last, my Luminette v3 broke after 1 year and 2 months of extensive daily use (1-3h the first 3 months, 3-6h the next 3 months, 5-9h the rest). The symptoms showing it was broken was that no light lit up, neither when clicking on the button nor the recharging LEDs when plugging to an electrical outlet. For those using the Luminette as long as i currently do (5-9h daily), i expect the Luminette breaks under about a year. For those using it less eg 1-3h daily, it should last longer.

To fix it, I tried a self-repair approach. I opened the Luminette using a torx screwdriver (I have a 10 euros multi pieces screwdriver for electronics). This is enough to remove the case and to see the upper part of the electronics board with the batteries, it's possible to unscrew further to remove the electronics board and access the down side but it only includes the LED components so that's mostly unnecessary, especially since no LED was lighting up which meant it wasn't an issue with the LEDs but with something else on the board that made the whole system dysfunction, not just one specific LED bursting.

Then, I simply used an electrical contact cleaner spray with a straw, both on the upper part of the board and on the down side of the board (there is a thin slit that allows to use the spray if you plug the straw in on the spray for more precision). I heard this is a common technique used to "repair" or at least extend the life of electronics boards, as often it's simply a problem of a short circuit appearing somewhere for some reason. I then let the board dry up for 20 min with the case still open, and finally I saw the charging LEDs light up cyclically about every 5-10 seconds (the glasses weren't plugged to the electrical outlet so that's the first time I see these LEDs light up like that on their own). These LEDs lit up without clicking on the device, I guess they are a debug code to signal that the case is open or that there is some issue with the Luminette, there is no information about it in the user manual unfortunately. I closed down the case, screwed back the torx screws on the glasses corners (attaching with the legs), and the glasses were fully functional again. I am not sure how long they will remain operational, but I'll let you guys know if it happens again. The board seem pretty simple, so I'm pretty sure this can be relatively easily fixed by repair shops and engineers. UPDATE: a few days only after, the issue reappeared and the Luminette broke down again.

If someone from Lucimed (Luminette producer), or someone who would like to make an even better light therapy glasses, is reading this document, here are my suggestions to improve:

  1. allow usb passthrough use while recharching (currently it switches off automatically when plugged in to a charger) - this would allow for very long light therapy session without worrying about whether the light glasses were charged the day before.
  2. more optimal led placement (eye level on the eyes sides, ie on the glasses legs) to stimulate the ipRGC cells in the nasal part of the retina but not the macula at all (reduce potential blue light phototoxicity since it only affects the macula). There are ipRGC cells in the parafovea, but why try to stimulate them when there are also lots of them in the nasal area and it's much further from the macula that is more sensitive to light damage? Another advantage would be ergonomics, since the LEDs would be placed in the horizontal sides of peripheral vision, instead of vertically, so the main body frame could be much more outside of view (although it will still need to be somewhat bulky to include the electronics board and battery). An issue would be robustness, as glasses legs are less robust than the body.
  3. more optimal blue light peaks at 479nm, the theoretically optimal wavelength for ipRGC cells stimulation, while reducing risks of blue light phototoxicity that ranges at least from 400 to 480nm (more towards 400nm and much less towards 480nm).
  4. stick with allowing 3 light intensities, from 500lux to 1500lux, as 500 lux is sufficient for most circadian rhythm disorders, but higher intensities and longer exposure may be necessary for older individuals to pass through the cristallin more obscured with age. More is likely useless for most individuals as it will produce too much side effects, and lower is no better than computer screens (which often emit 100-250lux at max brightness).
  5. At least maintain the battery capacity of Luminette 3. The long battery is necessary to sustain long light therapy sessions. The long battery is an overlooked feature but is critical for the efficacy of a light therapy device.
  6. If possible and if it doesn't reduce the comfort too much, increase the battery capacity of Luminette 3, as to allow very long light therapy sessions using the 1000 lux (medium) intensity setting. Currently, only the low light intensity (500 lux) allows for up to 11h of light therapy daily, the medium intensity setting cut that in half down to 5.5h max daily. There are however physical limitations, as cold light that emit more blue light and stimulate the ipRGC cells more also consume more energy.

Safety of blue light therapy

Is light therapy dangerous for the eyes, more precisely the macula?

To answer this question, we must understand how light can affect the eyes.

An excellent review by Christophe Martinsons outlines the 2 types of known risks: thermal and photochemical. Only the 2nd type, photochemical — which underlies blue light phototoxicity —, is confirmed and is well studied, and was described as follows:

> Type 2: the damage is a photoretinopathy caused by phototoxic reactions in the RPE, following an acute exposure to blue light. Blue light excites lipofuscin by producing reactive oxygen species and free radicals, causing an oxidative stress to the RPE cells.

This and another similar review and guidelines document allow to understand that light therapy safety is a factor of intensity (and hence eye-to-light-source distance) and color and duration of exposure, with some colors requiring less intensity and shorter exposure duration for the same phototoxicity. All light colors can be phototoxic with high enough intensity or long enough exposure duration. And when a light emitting device is certified safe for the eyes, it's only in the bounds of a specific duration according to a regulatory grid.

According to the same review, blue light phototoxicity spans the wide wavelength range from 380nm to 580nm, with a maximum around 437nm (see Figure 1 in the review). However, phototoxicity is not only a function of light wavelength (color), but also of dose of administration, which itself is a function of the light source's intensity, distance to the receiver's eyes and surface exposed. As shown in Figure 5, for light sources emitting above the 460nm range, the dose required for phototoxicity is high (100 to 1000 J/cm²).

The photobiological safety of blue light is hence defined according to the radiance (brightness of a light source) and duration of exposure, as defined by the ICNIRP standard:

This figure shows that the lowest the blue light source's radiance, the longer the user can be safely exposed to it. More specifically from the same review:

  • Risk Group 0 aka Exempt Group: no photobiological hazard under foreseeable conditions. Exposure limit is not exceeded within 10,000 s.
  • Risk Group 1: Low-risk group: products safe for most use applications, except for very prolonged exposures where direct ocular exposures may be expected. Exposure limit is not exceeded within 100 s.
  • Risk Group 2: Moderate-risk group: products generally do not pose a realistic optical hazard if the aversion response limits the exposure duration or when lengthy exposures are unrealistic. Exposure limit is not exceeded within 0.25 s (aversion time).
  • Risk Group 3: High-risk group: products pose a potential hazard even for momentary exposures. Exposure limit is exceeded within less than 0.25 s.

More precisely according to the IEC/EN 62471 regulation, the Risk Group 0 aka Exempt Group need to show the absence of the following risks:

  • an actinic ultraviolet hazard (Es) within 8-hours exposure (30000 s), nor
  • a near-UV hazard (EUVA) within 1000 s, (about 16 min) nor
  • a retinal blue-light hazard (LB) within 10000 s (about 2,8 h), nor
  • a retinal thermal hazard (LR) within 10 s, nor
  • an infrared radiation hazard for the eye (EIR) within 1000 s.
Additionally, infrared lamps at less than 10 candelas per square meter are exempt if they don't pose a near-infrared retinal hazard (LIR) within 1000 s.
(All those E and L acronyms should have the other letters subscripted.)

Notice how the lowest risk group, the risk group 0, states that the exposure limit to blue light needs to not be exceeded within 10,000s, which equals to 2h47min. This means that even beyond 10,000s of continuous exposure, exposure to light sources of this category may be perfectly safe, but it depends on the radiance. But we know with a certified device following this regulation that under 10,000s, the blue-light hazard should not be an issue. At radiance 100 or below, the risk stays in group 0 up to 100,000s, where this figure ends. This is why this category is also called "exempt group" as it presents no photobiological risk even with very long exposures. Note that radiance is not the same as luminance (lux), although luminance can be calculated from radiance. The point is that, from the point of view of a consumer, to assess the safety of a light source, it's necessary to assess both the luminance and the duration of exposure, as the safe duration of exposure will change depending on the luminance setting for light sources where it can be varied. Indeed, LEDs phototoxicity is dose-dependent on luminance (ie, light intensity). Ideally, light therapy devices such as light therapy glasses need to be classified in the risk group 0, which is the case for Luminette. But note that the whole device is classified, not just one parameter, hence we can assume that the worst parameter was tested. In other words, in the case of Luminette for example, we can assume that the device was deemed safe for use at the highest luminance (1500 lux) for at least 2h47min, which means logically that lower luminance settings (500 lux or 1000 lux) can be used safely for much longer. In a mice study, it was found that even just 24h of continuous exposure of pigmented non dilated rats to blue light emitting LEDs (455-465nm) already produced some retinal damage, however, cyclical exposure (ie, with a light-dark pattern) over 1 month only caused visible damage on albino mice with dilated pupils. On the other hand, white LED light caused less phototoxicity than blue-only LED, although it's unclear whether the study maintained the same melanopic illuminance, hence maybe the difference in phototoxicity lies in a difference in blue light emission.

According to European Union and FDA regulations, and also systematic reviews by scholars (see also here), if the device is filtering UV light and the intensity is not too much, and the user does not have a macular disease, then light therapy should be safe. The goal of this document is not to list all devices, but at least Luminette is validated under the all these regulations. However, the french ANSES considers that blue light phototoxicity starts is between 450-470nm (they include the effects on the circadian rhythm), and Luminette has a peak of blue light at 468nm according to the manufacturer Lucimed. A study on mice has shown that <440nm blue light is highly phototoxic with cell damage observed, but with 480nm minor cell damages are still observed (albeit much less than with <=440nm). Other studies on primates also observed macula phototoxicity with wavelength of 460nm and 465nm respectively, but a subsequent study demonstrated that even a 7000 lux exposure of primates' retina to LED contact lenses only caused temporary toxicity which was completely restored 14 days after the experiment. Phototoxicity is difficult to assess, as phototoxicity is a combination of factors that do not linearly add up so it's not possible currently to give any threshold. Knowing that blue light therapy is optimal ~480nm (more precisely between 479nm and 482nm), and that preliminary data on mice suggests that the 480nm does not produce any meaningful eye damage unless genetically modified, then it should be possible to design a theoretically safer blue light therapy glasses enriched at ~480nm. Nevertheless, keep in mind that the light therapy devices emit lower light intensity (up to 10K lux) than the sun (up to > 100K lux) by an order of magnitude, and sunlight is rich in blue light, so there is no doubt that light therapy has a lower impact than sunlight on eyes health. But phototoxicity should be assessed on a case-by-case basis, as some apriori unsuspected light emitting devices such as some frontal led lamps are in fact phototoxic according to the ANSES.

In addition, bright light exposure may be contra-indicated for some individuals, especially those with increased photosensitivity or an already present eye disease. A lot of drugs can induce photosensitivity or even drug-induced ocular disorders, making such treatments incompatible with bright light therapy, see this review for a list of such drugs. Individuals with dry eyes may be more at risk. Another review states that "people born without crystalline lens (aphakic) or having received intraocular lens implants (pseudophakic) are exposed to a greater amount of retinal blue and UV light compared to phakic subjects exposed to the same light source", and hence aphakic and pseudoaphakic people should avoid light therapy. Albinos individuals, who lack pigmentation, should likely also avoid bright light therapy, especially with blue LEDs, as well as individuals with often dilated pupils (eg, because of other medications or a genetic mutation).

Although blue light therapy with a european or FDA safety certification should be safe for use under the stated exposure duration, a recent study found that (green) light therapy devices (more precisely the Re-Timer) modified significantly the macula under 7 days of usage, with only 30 min of bright light exposure per day at wake up. However, the experiment design needs to be considered: the participants were maintained in a room constantly lit under 10 Lux, which is very low (1 lux = light emitted by 1 candle). Hence, this study did not just test the effect of bright light therapy, but more precisely the effect of sudden bright light therapy in a constantly dim environment. This is known to increase the effect of the bright light on the circadian rhythm through photic history, so increases in eye damages would not be surprising. Furthermore, this design forced the participants to have dilated pupils, which is known to multiply the effects of light. Hence, there needs to be more research to elucidate whether 1- the significant changes that were found are clinically significant (ie, can they lead to diseases or they are just natural body adaptations that are not indicative of any disease), and 2- whether these observed effects are due to pupil dilation, in other words if the user takes some time to adapt their eyes beforehand (eg, by being exposed to a more lit environment or by closing the eyes the first few minutes while under the bright light, to let their pupils contract) these effects would disappear.

Another study further explored what parameters could make blue light a photohazard. It was found that only the blue-only emitting LEDs induced eye damages in mice and maybe also the blue component of white light emitting LEDs, but not white light emitting fluorocompact lights (FLC). There is however evidence that blue only light therapy is much more effective than white light enriched with blue light therapy due to circadian light subadditivity, this suggests that blue only light therapy devices like Ayo may be more effective than blue-enriched white light therapy devices such as the Luminette, although there is at the moment clinical trials published only for Luminette.

All that said, light therapy using certified devices by current health regulations is considered a safe therapy by the AASM, and with their 2015 guidelines mentioning a study finding no adverse effect in season affective disorder patients who used light therapy for 6 years, hence suggesting long-term safety too. Indeed, light therapy with safety certified devices is no more dangerous than being outside on a sunny day.

But the safety is only guaranteed under the bounds of the duration of exposure that was tested and certified. Since treating circadian rhythm disorders require a (much) longer exposure than expected by the fabricant and regulators, extended continuous use of light therapy with very long exposure sessions may present a eye hazard. Hence, for very long light therapy sessions, it is important to stick to the lowest effective intensity, 500 lux or maximum 1000 lux, in order to reduce the risk of eye hazards, since this review (and this guideline document) shows that such an intensity and with the blue light spectrum are very unlikely to cause eye hazard even for very long exposures.

So, where is coming from the common misconception that blue light is toxic to the eyes? This may stem from blue light phototherapy devices used in dermatology. Indeed, these devices are much more powerful than their ocular counterparts originally designed for seasonal affective disorder (SAD), so that the dermatologic phototherapy devices, called photodynamic therapy (PDT), emit a much stronger light that is designed to cause skin damage to force it to regenerate. Hence, obviously protective eyewears are necessary to use dermatologic phototherapy. But ocular blue light phototherapy is designed to be projected into the eyes, and hence they are much weaker in intensity and filter UVs, so much so that they can only emit a fraction of what human eyes are exposed to with indirect natural sunlight.

In summary, if you can withstand sunlight exposure, light therapy glasses are much much safer and so should not affect your eyes anymore and likely much less than (direct and indirect) sunlight. Some people have retinal diseases or weaknesses, but these people are usually aware of their photosensitivity and also avoid sunlight. If you don't avoid sunlight, then there is no safety issue preventing you from trying light therapy.

In practice, check if the light therapy glasses is certified CE 0459 in Europe, which determines light therapy products, and IEC 62471 internationally or EN62471, for eyes safety. For example, Luminette was certified CE0459 in Europe and as a group 0 aka exempt group under IEC62471 "without photobiological risk".

In the past, it was suspected that light therapy may cause mental distress in prone individuals. However, a historical review found that current evidence suggest that light therapy does not increase the frequency of hypermanic nor hypomanic episodes in people with bipolar disorder, so it is doubtful that light therapy would cause any mental distress in other less susceptible individuals.

Sensory processing disorder involves extreme subjective stimulation from sensory inputs, such as bright light. It is more common among children and commonly comorbid with autism and ADHD and other disorders that are often associated with circadian rhythm disorders. First, it's important to note that there is some debate about whether this is really a disorder or simple child behavior. However, there is a growing suspicion that people with circadian rhythm disorders are hyper photosensitive (ie, more sensitive to bright light), which would fit with the idea of a sensory processing dysregulation, or more prosaically an individual specificity in photosensitivity. Indeed, studies have shown that there can be a 50-fold difference in photosensitivity between individuals, and this study was done on healthy volunteers, not on people with circadian rhythm disorders who may display even more extreme differences. Furthermore, it was demonstrated that children with autism are hyper photosensitive. Another clue is that sensory processing disorder seems to be strongly associated with seasonal affective disorder (SAD), the latter being known to be associated or even caused by the lack of bright light, and other studies showing that extreme sensory processing disorder symptoms are associated with a major depression disorder. (Aside: sensory therapy was rejected as ineffective by a systematic review, suggesting that sensory processing disorder is not just a subjective disorder but caused by an objective dysregulation, such as hyper photosensitivity maybe, that is not modifiable with psychological tools) Given than light therapy is effective not only for people with a circadian rhythm disorder but also with children with autism and ADHD, who frequently also have a sensory processing disorder, unless the patient complaints, the use of light therapy does not appear to be contra-indicated for people with a sensory processing disorder. Furthermore, modern light therapy using light therapy glasses emit a much less intense light between 500 and 1500 lux, which is roughly equivalent to a sunlit dusk (an overcast cloudy day is 1K-5K, a cloudless day is 30K up to >100K), which is unlikely to cause any uncomfortable effect if the patient can sustain exposure to cloudy daylight. It's however safer to approach light therapy for these patients by first using only the lowest light intensity, if necessary for a longer duration to compensate. It's also easy for the patient to check beforehand if they can sustain such an intensity of light by using a Lux Meter app on their smartphone, and measuring if they are already exposed to such light intensities.

There are very few studies on photohazard in children, for obviously difficult ethical issues. According to Lucimed in private communications, light therapy glasses such as Luminette can be used from 12 years old onward.

Interactions between drugs and light therapy

Some drugs can affect the responsiveness to light therapy.

Vitamin A is necessary to synthesize all opsins in the eyes, including the melanopsin pigment necessary for ipRGC cells and entrainment to bright light to work, hence it is necessary to ensure adequate levels of vitamin A, via supplementation if needed. Vitamin A also increases the photosensitivity to UV light which can be harmful, hence caution is required with direct sunlight exposure when supplementing with vitamin A. Throughout the animal kingdom, there are thousands of different variants of both visual and non-visual opsins (see also here), each with their own specificities.

Several ADHD and antidepressant drugs cause an increase in photosensitivity, which increases the risk of negative side effects when exposed to bright light (see the section on Hyper-photosensitization pharmacological therapies).

Anti-histaminics block entrainment of the circadian rhythm to bright light, and hence cause anyone to freerun (ie, wake up later and later, and likely sleep longer but not because of tiredness as is commonly assumed but because of the circadian rhythm progressively shifting):

> In phase shift studies, histamine given centrally seems to entrain the activity rhythm in the same way as light impulses and inhibition of histamine synthesis seems to block the entrainment by light.

Anti-histaminics are hence contra-indicated for individuals with a circadian rhythm disorder. Histamines have a bidirectional relationship with the circadian rhythm, the histamine levels being regulated by the circadian rhythm as they are high during the active period (day) and low during the sleep period, and the circadian rhythm being modified by histamines production potentiating the excitability of the neurons responsible for the entrainment to bright light (and more as recently discovered). This explains why "the intensity of symptoms and disease severity show a 24 h pattern in many immunological and allergic diseases" (see also here). Hence, comorbid diseases that produce histamines such as allergies and inflammations such as for example dyshydrosis due to a fungal infection may deplete histamines and worsen the circadian rhythm disorder. Other drugs that can block histamine H1 receptors such as Trazadone should also be contra-indicated.
Beyond the effects on circadian rhythm, anti-histaminics also modify sleep and wakefulness architectures, by increasing slow wave (deep and reparative) sleep and REM (dream) sleep stages durations, and also decreasing vigilance when awake. This contributes to the often reported effect of anti-histaminics making the subject feel more tired and sleepy. This is in fact a known side effect of some antihistaminics and is why the FDA disadvises the use of antihistaminics when driving.
However, the author suspects that antihistaminics may not necessarily completely block entrainment to bright light but partially: it may depend on the dosage of the antihistaminics drug and intensity and duration of bright light therapy. With a longer exposure to a brighter light, it may be possible that entrainment to bright light may still be achieved even under use of antihistaminics. Also different classes of antihistaminics may produce different results, although the studies mentioned above suggest that any histamines inhibitor will partially or completely block entrainment to light.
The role of histamines in the entrainment to bright light may explain why low doses of aripiprazole (see also here) was found to be an effective treatment to entrain individuals with DSPD, as aripiprazole activates the H1 histamines receptors, and thus increasing the responsiveness to light therapy. Hence, H1 histamine activating drugs may be a potential class of drug to complement light therapy.

Interestingly, it seems Vitamin D inhibits melatonin, maybe because the body does not expect to get exposed to Vitamin D unless there is sunlight with UVs, so we can hypothesize that a feedback loop was created between Vitamin D and UV exposure, which can make Vitamin D activates some of the pathways that bright light exposure can. What is surprising is that Vitamin D is secreted from skin exposure to UV light, not the eyes and not from non-UV bright light, so the interaction is quite complex. Given this finding, vitamin D supplementation should be avoided in the evening, as intake in the circadian morning should be favored.

Do-it-yourself, a cheaper alternative for light therapy?

First off, if you can afford light therapy glasses but are just wary that they may not work and hence to spend money for nothing, take note that most light therapy glasses manufacturers offer a money back guarantee of 30 days (such as Lucimed's Luminette), and since light therapy should show efficacy after 10 days max, this means that if you have plenty of time to test for free if it doesn't work out. The rest of this subsection describes cheaper, but less effective, alternatives.

Nevertheless, Luminette can be expensive especially in non occidental countries. But keep in mind that therapies and management devices for chronic illnesses usually cost magnitudes of order more, we are lucky that for non24 the two most effective treatments, melatonin and bright light, are non patentable and hence still reasonably affordable.

If you are really low on money and can't afford light therapy glasses, I strongly disadvise buying a light therapy lamp. Sure, there are inexpensive ones available, but there are three major downsides:

  1. the cheapest light therapy lamps are not very powerful, they say they emit 10K lux but it's only at point-blank with no range, and with lux approximately decreasing quadratically with the distance, it means that if you are just a few centimeters away from the ideal distance, you will get very low lux (low light intensity).
  2. they can't realistically be used to treat circadian rhythm disorders, since circadian rhythm disorders need long bright light therapy of several hours. With lamps, you need to stay just inches in front of them, and it's hard to do anything in front given how close you need to stay to the lamp and the angle you need for your eyes to get properly exposed.
  3. a major drawback is that it's only one lamp, whereas both of our eyes have ipRGC cells (the photoreceptive cells that shift the circadian rhythm depending on their exposure to light). The more ipRGC cells that are stimulated, the bigger circadian shift that happens. Unfortunately, with only one lamp, if it's set on the side of your peripheral vision, it will only stimulate one eye's ipRGC cells (since they are located in the parafovea of the macula and the nasal part of the retina, see also here). In other words, a lamp can only produce half of the results of light therapy glasses. Ideally, you would need 2 such lamps and adequately placed, but at this point light therapy glasses are as expensive and much more comfortable to use and they stimulate both eyes cells, while also having a more optimized spectral composition (ie, light color enriched in blue).


Ideal placement of 2 light therapy lamps, on the sides of both eyes so that the light can reach the nasal region of both eyes' retinas. Image from this study.

Although there is one review claiming that optimal light therapy should be angled downward at 15°, there is no reference and apparently no proof, since there is no evidence of a dorsal-ventral gradient in ipRGC cells placement in humans (although there is for mice's ipRGC cells - see also here -, as well as for their S-cones). The author of the present document could not trace the claim to any experimental observation nor solid theory, the commonly assumed hypothesis being the intuition that natural sunlight enters the eyes from a top-down fashion, and hence that light therapy should aim to do the same, although this ignores the mechanistic of light rays that in fact bounce up on surfaces and hence enter the eyes from all angles (otherwise we wouldn't be able to perceive objects in the environment), so this intuition is certainly not reliable. Since we know for sure that it's the ipRGC cells stimulation that is responsible for circadian phase shifting, and we know these cells are more concentrated in the nasal and parafoveal regions of the retina in humans, it's best to assume as did the study from which the above figure was extracted that light therapy lamps should optimally be placed at eyes level, and in the peripheral vision as to allow for the light beams to optimally reach the ipRGC cells in the nasal-macula area in the retina, with no influence of the vertical angle until more solid evidence appears.

An inexpensive and potentially more effective strategy than light therapy lamps is to use computer screens at their maximal intensity directly at natural wake-up for 1h to 3h, but longer is better. Indeed, it is easy to stare at screens for long periods of time (contrary to light therapy lamps), and the longer duration can compensate partially for the lack of light intensity. Not only the distance to the user is similar to a light therapy device (contrary to TV screens which may be too far to get enough lux), but also the user can stare directly at the screen, which light will stimulate directly a maximum of ipRGC cells in the macula of both eyes. Hence, the ergonomy of screens, which allows for staring directly at the light source and for long duration of time, makes them a quite good candidate for inexpensive bright light therapy but with limited efficacy compared to light therapy glasses. Then, the rest of the day, the user can get exposed to natural sunlight to increase the duration of light exposure without any device. In the evening, dark therapy is crucially necessary as otherwise the benefits will be erased by the evening phase delay produced by screen exposure, so the screens must be dimmed and blue light filtered to avoid the circadian phase delay effect opposing the circadian phase advance obtained in the morning. This "computer screen blue light therapy" can also be combined with melatonin in the circadian evening to increase efficacy. Anecdotally, this specific combination therapy allowed the author's father to stably entrain during the autumn, spring and summer. Note however that screens may not be sufficient in low sunlight seasons such as winter, due to the reduced intensity of natural sunlight, so light therapy glasses are certainly more reliable.

To ensure your computer screen is useable as a light therapy device, use a lux meter app on your smartphone, this will use the smartphone's light sensor to measure light intensity. Direct your phone towards your screen set at maximum brightness, and position it at about the same height and distance from the screen as your eyes would be when you use it. This measure will reflect what your eyes will perceive. A screen emitting at least 100 lux should be sufficient to get half of the circadian rhythm shifting obtainable with a 10K lux light therapy device.

Are computer screens safe as light therapy devices? They are made to be stared at, and furthermore they emit relatively low bright light (~250 lux at max brightness on the screens the author could measure), and since they are widely used worldwide, if this was unsafe there would be epidemiological data on diseases caused by screens. Nevertheless, the french ANSES stated that data was lacking on chronic exposure to cold light emitted from screens, so that it could not conclude about its safety or dangerosity.

Although DIY light therapy devices can certainly shift the circadian rhythm, they are certainly much less efficient and so the amount of phase shift obtained will be drastically smaller compared to the optimized light therapy glasses such as Luminette, as experienced by this reddit poster.

Is the sunlight sufficient or even better than light therapy lamps as some practicians suggest? Generally, no, but sometimes, sunlight an acceptable light therapy, if we keep in mind these limitations of sunlight therapy:

  • Sunlight is highly variable: not only on a day-to-day basis depending on if there are clouds or not (refer to this table, showing that cloudless sunlight is indeed more intense (~100K lux) than a light therapy lamp (~10K lux), but if the sun is cloudy or if you stay inside your flat then it can actually emit less light (<1K lux) and with poor blue light content (as shown in figure 2 of this review)), but also on a seasonal basis, with winter sunlight being of course usually lower in intensity than spring or summer sunlight. Hence, although light therapy can be done for free using sunlight during the summer and spring, it is much more advisable to use an artificial light therapy lamp during autumn and winter to ensure a robust and consistent duration and quantity of exposure to bright light every day. The fact that sunlight produces variable lux intensities depending on the weather and presence of clouds makes it a very bad tool for consistent therapies because the resulting effect on the circadian rhythm will vary uncontrollably from day to day and from seasons to seasons, it's like using a drug with a varying dosage everyday, no sane practician would ever suggest to do that. You don't need to trust the table linked above, you can test for yourself by using a lux meter app on your smartphone, this will display the lux you are exposed to (these sensors are linear, hence they should be reliable enough for lux in the range 100-10K).
  • Sunlight is inconvenient: a proper exposure to sunlight requires to go outdoors, as indoor sunlight filtered by windows is much less intense and can easily and frequently be lower than artificial lamps. An optimal bright light therapy is done as soon as one's wake up, as more circadian rhythm shifting effect is obtained when exposed to bright light close to the minimal core body temperature (CBTmin) which happens 1-2h before natural wake up. Getting sunlight directly at wake-up is inconvenient, as you need to jump out of bed and go outside as soon as possible, which may not always be possible depending on your other commitments, and also is subject to be exposed to unfavorable weather conditions such as rain and snow.
  • Sunlight is overkill: Sunlight is indeed the strongest light therapy, especially when cloudless as it can emit up to 120K lux, no artificial light therapy device can come even close. But having that much lux (light intensity) is unnecessary: the eye's ipRGC cells' sensitivity range spans only 2 orders of magnitude, it's nowhere close to the 9-10 orders of magnitude of the visual pathway. Since it was shown that most people's non-visual (ipRGC) sensitivity to light starts from a 5-10 lux (and sometimes even lower), this means that the saturation point for maximal ipRGC cells stimulation must be around 1000 to 10k lux depending on the individual. And indeed, a study found no additional phase shift using 8K lux compared to 2K lux, whereas increasing the duration of light therapy from 1h to 3h led to significantly increased phase shifts, which demonstrates that the light intensity saturation point is low. On the other hand, a study found that 100 lux causes 50% of the max stimulation of ipRGC cells in their participants, suggesting that the saturation point may be even much lower for some individuals. Hence, a light therapy device of 1000 to 10K lux is plenty sufficient to maximally stimulate the ipRGC cells and shift the circadian rhythm, as the sunlight won't provide any meaningfully bigger circadian rhythm shifting effect compared to an artificial light therapy.
  • Regularity and duration of bright light therapy are crucial: Since the saturation point is easily reached with artificial light therapy lamps, it's important to focus on regularity and duration of the light therapy sessions. Indeed, a longer session of 1-2h of artificial light therapy will always shift more the circadian rhythm than a shorter 20-30min of sunlight: "a longer period of moderate intensity light may be more effective than a shorter exposure period of high intensity light". Since regularity of exposure to a sufficient amount and duration of bright light is crucial, during the winter season (relatively to the geographical location of the user) an artificial light therapy device will certainly provide much greater benefits than the highly variable sunlight.
  • Just like food needs, all humans have "spectral diet" needs that are similar but different for each people, with some people needing more light intensity (lux) just like some people need more vitamins or proteins in their diet.
  • Note: do NOT directly look at the sun because it can damage the eyes otherwise! Even looking at reflections of sunlight in the snow can cause eyes damage!

If you still want to use sunlight as your first bright light therapy, at least make sure to use a Lux Meter app on your smartphone and direct your phone's screen towards where you are facing, to check if you get enough sunlight exposure to be effective. A lux value of 500 is the minimum, but at least 1K to 1500 lux or more should be preferred, since sunlight does not have the optimal spectral composition all the time (ie, it lacks blue light after the morning and on cloudy days).

Here is an objective protocol to assess whether sitting outside on a cloudy day is effective enough for you:

  • Download a lux meter app on your smartphone (such as this one for Android).
  • Go to sit outside during a usual cloudy day
  • Launch the app and turn the phone's screen towards the direction you would face if you would stay sitted here (taking into account of what activity you would be doing usually: for example if you would most likely be scrolling on your smartphone then direct the phone's screen towards the ground, not the sky). It's important to direct the phone where you would be looking so that the light sensor embedded in your phone's screen captures the light in the direction you would be facing.
  • Read the measurements. If it's at least 500 lux, then it's likely effective for your circadian rhythm. If it's below, then you can go home. If it's lower than 250 lux, you can get 250 lux by looking at your computer screen at full brightness, so no need to stay outside for that. Between 250lux and 500 lux can usually be achieved with bright indoor light fixtures.

Ambient lighting may also be used, and several companies are starting to offer "circadian lighting design" services. The color temperature (CCT) of a light, in kelvin, needs to be higher to emit more blue light, and this excellent paper provides a mathematical equation to precisely quantify how much melanopic illuminance can be obtained for different color temperatures. This means that the colder the light color is, the more blue light will be emitted, and the more circadian effect they will produce. However, there are three major issues with ambient lightings. First is the distance and orientation to the user's eyes, and this can hardly be controlled robustly with a fixture to the ceiling or to the wall. Secondly, colder light (higher MELR) consume much more energy than warmer colors for the same photopic utility (ie, how much it lights up a room). Thirdly and finally, ambient light fixtures are often not designed to reduce the lower part of the blue light band, which can be a photohazard (ie, harmful to the eyes). Finally, note that a study on albino mice found that a cold-white 6300K LED already produced some retinal damages under specific conditions.


Spectral power distributions of common light sources in our environment, illustrating how little blue light (400-490nm) can be emitted by some light sources including clouded daylight, but especially artificial lights. Figure from this review under CC-BY 4.0.

If you want a cheaper alternative, there are the Re-Timer glasses (cost: ~$120), which I did not try. Re-timer 's green light is sufficient to phase advance, but since it's using green light it doesn't increase vigilance so it doesn't change the feeling of subjective sleepiness in the morning, contrary to blue light which directly reduces sleep inertia and increases vigilance. It was also shown that although green initially suppresses melatonin, the effect is not sustained and melatonin levels recover after 90min even if still exposed to green light, contrary to blue light. Indeed, the study found that the phase shifting response to green light (555nm) is mediated by cones and is only temporary as it decayed exponentially with duration of exposure to bright green light, whereas blue light produced phase shifting over long duration light therapy with no such decay mediated by melanopsin ipRGC cells which are more responsive to long durations of blue light, which means that only blue light therapy can be used for long and very long bright light therapy. Using green light is a strange choice because green light is more effective at pain reduction and about 75% less at shifting the circadian rhythm compared to blue light (TODO: find the source), whereas blue light is optimal for vigilance and circadian rhythm shifting. Currently, only Luminette, Psio and Ayo make light therapy glasses with completely blue light and hence are the most effective light therapy glasses on the consumer market currently. Also both have several independent studies demonstrating significant phase advance (see their respective websites or google scholar), whereas Re-timer only has one as of 2020.

Another light therapy glasses alternative is Psio (cost: non disclosed publicly). It uses blue light similarly to Luminette (although it's pure blue LEDs, no white light, whereas Luminette uses white light enriched with blue light), but with the difference that the light is pulsed (aka intermittent light therapy). Although intermittent light therapy should be as efficient to induce phase advance than bright light therapy, it may produce less melatonin reduction, hence you would not get the vigilance boost that blue light provides, nor potentially the advantages in increased melatonin levels due to photic history.

Can you make your own light therapy device? I would strongly disadvise against. For two reasons: it's difficult to tweak exactly how much lux you will get and you won't get blue light, or if you do, you risk eye damage. Indeed, blue light therapy glasses project light in the range that is partially phototoxic, as it's also the same range (450-490nm, with an optimal peak at ~480nm , more precisely between 479nm and 482nm) that is necessary for optimal stimulation of melanopsin receptors. To reduce the risk of exposure to very phototoxic blue light wavelengths, the method found by light therapy device manufacturers is to add filters to bandpass filter the lower ranges of the blue light wavelengths with UV and near UV lights filters (UV = UV-B and UV-C, near-UV = UV-A, which is up to 400nm). For example, the Luminette enriches white light with blue light with a 468nm wavelength. Also, reducing the light intensity helps, so it's not surprising that blue light enriched lamps and glasses are calibrated to project lower lux (usually 500 to 1500 lux, compared to 10K white light therapy lamps). The phototoxicity is mostly an issue if the light source is directly looked at (ie, when the blue light beams hit the macula, which is what allows central vision), hence another solution is to avoid looking directly at the lamp and placing it in the peripheral vision, as shown in the figure above.

Let's say you can make a blue light boosted DIY lamp with the right amount of lux (that you can somewhat measure with smartphone apps). Then you cannot assess as easily if the color spectrum (ie, blue and green light emission) is correct and safe, because light spectrometers cost thousands of dollars, which defeats the purpose of DIY for cost effectiveness. Finally, you would also need to add a UV and near-UV light filter and also a complex blue light filter to let only the 479nm wavelength pass through (which would likely be a quite expensive filter to buy), and hope you're doing it right so that it's not harmful to your eyes. At this point, if you're worried about safety, it's just much easier and better to buy a certified light therapy device.

If you really do want to try to make a DIY light therapy lamp or glasses, then it's necessary to use a spectrometer to ensure that the light produced by your device is not emitting in the blue light phototoxic range. See for example this study and this review on the current regulations and equation to calculate phototoxicity of solid-state lighting (LEDs).

Finally, to optimally stimulate the ipRGC cells in both eyes, you would need at least 2 lamps. As written here, one DIY lamp of adequate lux would cost $50 (not including the necessary UV and blue light pass-band filters), for 2 it would be $100. At this point, there's not much advantage in terms of cost to buying a light therapy glasses such as Luminette 3 (229€ brand new, 150€ in second hand but very rare since Luminette 3 came out only recently in December 2019 - note it used to cost 380€ when it first came out in 2006) or a Re-Timer Gen1 (120€), and those devices are already designed to provide the right amount of lux and blue/green colored light to optimally stimulate the cells in both eyes, and their safety is certified. If the added cost is still too much, the Beurer TL30 lamp costs ~35€, for 2 then it costs 70€, which is a cheaper option to DIY. And I know of some people who got effective phase advance and entrainment using a Beurer TL30 daily for several hours so it's effective, you can even mail Beurer to tell you how to optimally use their lamp for circadian rhythm disorders.

So in the end, I think DIY is just too easy to mess up, and we already have devices that work and are affordable. If you just want something cheap to try light therapy asap, just either use a computer screen at max brightness, because they are made to be directly looked at so you know it's safe, or buy a Beurer TL30, which is less efficient than light therapy glasses in particular Luminette 3, but it's better than nothing.

For the mathematically inclined engineers who would like to conceive their own optimal DIY light therapy device, this review provides an excellent outline and references to the major models to modelize and optimize circadian rhythm phase shifting using bright light therapy. Especially look into melanopic illuminance.

However, there are some online tutorials for very interesting now kinds of do-it-yourself light therapy devices, such as a DIY square lamp mimicking sunlight through a window (with parallel light rays!), and which could be a very promising piece of furniture to equip rooms without a window and make them more hospital for humans, as humans biology requires daily sunlight exposure and hence cannot stay in a room without a window, but this solution could serve as an artificial replacement. Note however the author of the present document could not test the device and so cannot vouch for it, and furthermore given the technical documentation, the LEDs used in this furniture are too powerful and likely phototoxic since the range of wavelength covers the 380-780nm range with a peak at 452nm!

Camping can be an alternative but it's not a free lunch. Camping can indeed help if the circadian rhythm is not too out of phase with the external day night cycle (see also here and here) by getting exposed to sunlight and hence reaping the phase advancing effects of sunlight therapy. However, if the circadian rhythm is too delayed (eg, sleeping around dawn) then the light exposure can actually fall on the phase delay part of one's light PRC curve, which would only worsen the phase delay. Interestingly, it was found that modern occupations since the industrial era (ie, working in offices) leads to a reduced light exposure during the awake time (see also here), which was previously shown to cause biphasic sleep. Strategically, camping may be used in complement with artificial bright light therapy, by first starting artificial bright light therapy to obtain some phase advance, until it is sufficient to be reasonably aligned with the day-night cycle so that exposure to sunlight would happen during the phase advance section of the light PRC curve (ie, after the middle of the circadian night = minimal core body temperature point). Anecdotally, a reddit member with DSPD reported this strategy and its results: after a few months of artificial bright light therapy with Luminette (source: private communications) and melatonin which already produced an impressive 7h phase advance (wake up from 5pm to 10am) but with no improvement beyond this point, the phase advance could be pushed 2h further (to 8am) after just a weekend camping trip.

Dark therapy and blue blocker glasses

Definition and overview of dark therapy
Dark therapy is the strategic avoidance of light exposure, usually in the biological evening and night. Why is this necessary and how important is it? As explained in the Zeitgeber section above, zeitgebers are double-edged swords, anything that can phase advance your circadian rhythm can also phase delay it. Furthermore, bright light has a special property of lacking a PRC dead zone, so that it always affect the circadian rhythm, whatever the time of administration, which means that control of bright light exposure at all time is a necessity. This is the purpose of dark therapy as an adjunct to bright light therapy.

To quote a 2019 systematic review on light therapy giving a succinct definition of dark therapy: "To avoid unwanted changes in the circadian phase or night-time sleep, light exposure in the evening and at night as well as in the morning needs to be controlled, as even the longest wavelengths (631 nm) or intermittent light exposures do induce circadian resetting responses." Furthermore, beyond the mitigation of phase delay, the alternance of light and dark phases is what signals the periodic component of the zeitgeber, in other words, it's necessary to have dark periods for entrainment to bright light to work, as demonstrated by "constant routine" protocol studies where typical sleepers lose entrainment under either constantly dark or constantly brightly lit environments.

Since light therapy is the strongest zeitgeber and hence most helpful treatment, due to its dual effect on circadian shifting and melatonin suppression (which will hide subjective feelings of sleepiness and also increase sleep fragmentation), it can also be the most detrimental factor if your eyes are exposed to light in your biological evening. Hence, "just as light exposure can shift circadian timing, so too can the strategic avoidance or reduction of light". Indeed, for typical sleepers, as soon as the lights are switched off, both melatonin and body temperature start a fast change towards their high and low phases respectively in preparation for sleep, demonstrating how dark therapy directly affects the circadian rhythm.

Hence, dark therapy serves two purposes:

  1. to allow for melatonin to get secreted without inhibition from bright light,
  2. to avoid unwanted phase delays by bright light exposure during the circadian evening and night, an effect of bright light that is independent from melatonin suppression.

There are two broad categories of tools to do dark therapy:

  1. either by using wearables such as blue blocker glasses, which are glasses that filter out blue-green light, and can also dim down light intensity if VLT filter (same kind of filter used in sunglasses) is included.
  2. either by changing environmental light such as by using of blue filtering and brightness dimming apps in combination with switching off ambient lights.

The first approach is preferable if the user has no control on ambient light (such as when it's necessary to start dark therapy away from home), the second approach is more convenient but needs more preparation to buy adequate ambient lights and hence can be more expensive.

Due to photic history, dark therapy is also important to increase the effectiveness of light therapy in the morning.

Dark therapy is also the only currently available method to preserve the non-receptor dependent antioxydative action of melatonin, since this requires huge doses of melatonin (about 8mg/kg/day in humans) that are currently undeliverable to humans. Indeed, the digestive system produces 100x more melatonin than the brain, hence the dosage of melatonin pills, albeit sufficient to activate the brain receptors and induce sleep, is not nearly sufficient to have antioxydative properties. The only solution is to preserve the endogenous melatonin secretion of the digestive system.

Theory for effective dark therapy
Light exposure and timing relatively to the circadian rhythm accounts for 71% of the variability in circadian rhythm shifting, hence the importance of controlling light exposure to control the circadian rhythm.

Since blue light shifts the circadian rhythm the most and constantly suppresses melatonin during exposure, it is especially important to filter blue and green lights, using blue color filters or blue blocker glasses. Indeed, a well designed study controlling for equal illuminance and color temperature found that blue-light enriched polychromatic white light resulted in a 50% melatonin suppression for a 175 lux light source, whereas no melatonin suppression occurred with a blue-light deprived white light of the same illuminance and color temperature. Furthermore, since green light can also phase advance, albeit with a limited range as duration is capped since the effect is mediated by cones rather than ipRGC cells, and temporarily suppresses melatonin secretion for ~90 min, green light filtering is also preferable. Amber and red filters and glasses are generally effective to filter out blue and green light and avoid melatonin suppression due to ipRGC cells unwanted evening stimulation.

Light intensity is also crucial, and any effective dark therapy includes the dimming of light sources. By how much do lights need to be dimmed to avoid affecting the circadian rhythm? 100 lux was already sufficient to cause 50% of the max stimulation of ipRGC cells in a study, while in another <30 lux was sufficient for 50% melatonin suppression, and another found that 100 mLux (melanopic lux) significantly reduced objective sleepiness, with higher illuminance having little more benefits. In another study, most participant's non-visual (ipRGC) sensitivity to light started as low as 5-10 lux (and even lower in another study), even with the eyes closed! More precisely, another study found that human melatonin suppression occurs at ~10 log photons cm(-2) s(-1) at 460 nm. Given the high sensitivity of the human eye to low intensity non-photic inputs, it is likely that most people are exposed to bright light at inadequate timings in their circadian phase, which calls for the design of circadian lighting in home and work environments. This was tested in a naturalistic setting, which allowed to observe that half of the studied homes had bright enough ambient lighting to cause a 50% melatonin suppression at night, but, interestingly, not with other individuals under similar lighting conditions. This shows that not only is the lighting environment an issue that can be improved, but there is also differences between individuals' natural photosensitivity that make them more or less prone to the detrimental circadian shifting effects of ambient lighting. Furthermore, it was demonstrated that a late evening administration of melatonin does not prevent the phase delay induced by concurrent bright light exposure, so that the delay induced by an inadequate bright light environment cannot be solely compensated with melatonin intake, the lighting environment needs to be redesigned according to the human circadian physiology. In summary, this means that any light intensity will likely affect the circadian rhythm, although less with more dimmed lights, and some individuals are less photosensitive than others at equal light intensities, which means that the design of ambient lighting where humans live or do their activities crucially needs to be done with the human circadian physiology in mind, even at low light intensities, and there are indeed several companies providing such services.

Nevertheless, the difference between individuals' photosensitivities is an issue to implement dark therapy in practice, Indeed, how much dimming of light sources is necessary for effective dark therapy is highly variable between individuals depending on their photosensitivities. It was shown that people have different sensitivities to light, with some being hypersensitive to light while others are hyposensitive, as some individuals see their melatonin levels suppressed by half with light exposure of an intensity as low as 6 lux for the most sensitive individual to 350 lux for the least sensitive, hence a ">50-fold difference in sensitivity to evening light across individuals"! And this was done with typical sleepers, there may be an even greater variability for individuals with a circadian rhythm disorder. Circadian light hypersensitivity is common for individuals with DSPD (see also here and here), with an estimated 47% of DSPDs being light hypersensitive, and non24 (see also here), which can compound with the mistimed intrinsic circadian rhythm with the day-night cycle which makes these individuals more prone to the sensitive parts of the PRC (ie, the timing when light has more shifting effect on the circadian rhythm). The photic history is also variable between individuals.

Light hypersensitivity is positively correlated with the pupil area, with larger pupils allowing more light to enter the retina and hence more melatonin suppression. Hence, having wider pupils may be a sign of increased sensitivity to evening light. A study shown that the pupil's contraction reflex speed in response to bright light could detect DSPD. And indeed, a novel ophtalmological or optometrist test was devised with this principle at its core: the maximum post-illumination pupil response (PIPR) after blue light exposure after variable light intensity or chemically induced test. The purpose of this test is precisely to quantify the individual's photosensitivity to blue light, which is often termed circadian light as it is the light spectrum that affect the most the circadian rhythm. However, due to the novelty of this procedure, it is rare to find a clinicial who can offer it.

The DSM-5 recognizes the possibility of light hypo/hypersensitivity as a predisposing factor of DSPD and non-24: "predisposing factors may include a longer than average circadian period, changes in light sensitivity, and impaired homeostatic sleep drive. Some individuals with delayed sleep phase type may be hypersensitive to evening light, which can serve as a delay signal to the circadian clock, or they may be hyposensitive to morning light such that its phase-advancing effects are reduced".

Although it is often assumed that hypersensitivity and hyposensitivity are symmetrical, in that if someone is hypersensitive to light, they are so for both advancing and delaying. But that is not necessarily the case as the PRC can be nonlinear, as Czeisler et al hypothesized in the 1980s drawing inspiration from the fact that all humans have naturally asymmetrical light PRC, making it easier to phase delay up several hours rather than phase advance. Indeed, the response to advancing or delaying cues is asymmetrical: on average, humans have been shown to have a range of entrainment (ROE) — which is the range of day time that one can maintain — to have been estimated between about 23h to 28h (ie, that's why it's easier even for typical sleepers to rather sleep several hours later than to wake up even just 1h earlier than usual). And indeed, we now know that low light intensity light in the evening is sufficient to phase delay, whereas brighter light and longer exposure are necessary in the morning to phase advance.

This nonlinear response to light may be due to photic history, which can be manipulated advantageously to modify light sensitivity. It was shown that exposure to only dim light in the biological day made the participants hypersensitive to light in their biological night, and oppositely that being exposed to bright light during the day reduces the phase shifts induced by night-time light. Hence daytime light therapy has a protective effect against evening light, and reducing evening light improves the response to daytime light therapy: "the more daylight, the weaker the impact of articial light in the evening/at night". In practice, this means that people who are more prone to circadian photosensitivity may reduce it by increasing the duration or intensity of their daytime light therapy. This may explain parts of the reasons why very long light therapy seems to be so effective, by giving some additional protection against phase delays (if true, future studies will find that the phase advance of different durations of light therapy will not be linearly proportional but slightly non-linear).

Furthermore, another important consequence of the photic history is that light exposure in the previous evening will impair the effectiveness of light therapy in the next morning, and also decreases melatonin levels on the next days, and not just the evening when the light exposure happened. Hence, dark therapy increases the efficacy of light therapy. This is another reason why dark therapy always go hand-in-hand with light therapy, as both therapies mutually strengthen their efficacies.

In summary, all parameters of light therapy and properties of the effects of light on the circadian rhythm are also crucial to consider and control for an effective dark therapy: light intensity, light color and photic history.

It's important to understand that likely every levels of light intensity and color will affect the circadian rhythm, there is no 0 lux condition apart from staying in isolation in a pitch black room. But this is unnecessary, what matters is that the evening delay is much less than the daytime phase advance. For example, as described above, it was shown that being exposed to bright light during the day reduces the phase shifts induced by night-time light, with the opposite being also true. So this is all a matter of balance: to phase advance the circadian rhythm, either reduce the night time lights intensities, or increase the daytime light intensity (and exposure duration), both can result in equal benefits. Or both can be done to get even more phase advance.

As a mind image, picture the following: daytime light drags the circadian rhythm phase to the left (earlier time = phase advance), whereas biological evening and night time light drags the rhythm to the right (later time = phase delay), they are opposing forces and it's possible to tip the equilibrium one way or another by changing one or both forces. In addition, you can picture some kind of inertia in their movements, to illustrate the concept of photic history: when the circadian rhythm is pushed onto one direction because of strengthening one force, the circadian rhythm will continue to drift a bit in this direction even after the force stopped (eg, after doing weeks of light therapy, missing one day will not affect the circadian rhythm much).

Dark therapy in practice
In practice, an effective dark therapy consists of avoiding: bright light, blue-green lights, and at least a few hours before the natural bedtime. Hence, dimmed red light is acceptable.

Since pupil adjustment to light/darkness and circadian rhythm shifting are causally linked, because both are mostly modulated by the ipRGC cells, pupil dilation is a sign that the dark therapy is done optimally. In practice, this is known since a long time by astronomers, who use red filtered light to avoid pupils contraction which hinders looking at dim light sources such as stars. In scientific studies, low level light therapy (LLLT) consists of providing light therapy but with red light instead of blue or white light, with the red LLLT light used as placebo control to measure the efficiency of blue light therapy. In other words, if you can't see in the dark, there's likely still a too bright light source in your environment that you need to dim down or replace by something else such as red filtered light. Eyes refractive errors such as myopy or emmetropy do not change how the ipRGC cells work.

Furthermore, red light therapy (LLLT) may even be a treatment to help mitochondria in the retina's photoreceptor cells to repair faster and hence improve declining eyesight in aged (>40 years old) individuals. Indeed, "mitochondrial density is greatest in the retina's photoreceptor cells, which have high energy demands, [...] as a result, the retina ages faster than other organs, with a 70% ATP reduction over life, causing a significant decline in photoreceptor function as they lack the energy to perform their normal role."

However, although red light indeed does not inhibit melatonin contrary to blue light, 40 lux of red light is sufficient to change cortisol and alpha amylase levels, which suggests that there may be other non-visual pathways mediating these physiological changes induced by light beside the well-known one mediating melatonin inhibition through the suprachiasmatic nucleus and the pineal gland (but take this result with a grain of salt as it was published by one study in Hindawi, a predatory journal, this needs confirmation). Another study also finds that even polychromatic white light at 175 lux but with reduced blue wavelength light does not inhibit melatonin. Hence, environmental red or amber lighting is likely acceptable during the circadian night, as red lighting guarantees limited blue wavelength light, although polychromatic white light with reduced blue light may be acceptable too.

To do dark therapy without blue blocker glasses, it's possible to install f.lux or another blue light filter app. These apps are effective, but not sufficient, as it's also necessary to dim the screen brightness to the minimum and also of course dim environmental light sources (lamps). Indeed, both light intensity and color matters, it's not enough to just filter blue light, or to dim down the light intensity, it's necessary to do both.

Here are the effect of blue light filtering apps and screen brightness dimming, as indicated by this excellent review:

> Smartphone use may delay sleep onset. One factor is the light emitted by their screens, but another may also be its entertaining character or related psychological effects, or both. Using the “night shift” mode of modern smartphones, the colour balance of the screen can be shifted to “warmer” and orangeish colours depleted in short-wavelength light. On a recent iPhone 7, this amounts to a reduction of melanopsin activation by 67% at full display brightness. This might seem like a large reduction at first, though by simply dimming the smartphone to its minimum level, the melanopsin activation can be reduced to less than 1% of the activation at maximum display brightness.

And this quote is for smartphones, which have a much lower minimal brightness than computer screens because they need to save power for extended battery duration, and so they try to save on hardware backlight power. In my experience, using a smartphone with the Twilight app for blue filtering and dimming light to the minimum on the phone and a bit more using the Twilight app allows to use the smartphone with little impact on the circadian rhythm or feelings of tiredness, without needing to wear blue blocker glasses. Configured like that, a smartphone is probably safer to use for reading than a book, because the bed lamp you need to light your book can also shift your circadian rhythm.

Furthermore, using a blue light filter software changes the content color, which can be troublesome. Escofet and Bara shown that dimming light sources and screens is more effective than filtering blue light, although arguably the combination of both is more effective.

On computers, unfortunately most computer screens do not dim much the backlight or even at all, as they rather use a variable flickering scheme - called Pulse-Width Modulation, so it's preferable to rather use a smartphone or wear blue blocker sunglasses. Indeed, if the screen uses PMW, then it is always backlighted at the maximum intensity it can, but it is simply intermittent so it visually looks like it's dimmed, but your eyes still receive as many photons and hence a PMW screen acts just like a pulsed light therapy device. Thus, if your screen uses PMW, it cannot be used in your biological evening without risking unwanted circadian phase delays and melatonin inhibition (ie, not feeling sleepy). Prefer to use your smartphone, which usually don't use PMW, since it's less effective at reducing battery consumption than really dimming the backlighting. If you plan on buying a new computer, you can check whether it uses PWM by reading notebookcheck reviews.

If your screen is not using PMW but cannot dim as much as you would like, some apps such as Nelson Pires' Dimmer can be used to add a transparent black window that will mimic a brightness reduction, but it won't actually reduce the backlighting, so the reduction of lux won't be optimal but it will be better than without dimming.

Although screens are often incriminated, and indeed need to be adjusted for evening use, ambient lighting by lamps plays a major, likely greater, role in unwanted circadian rhythm shifting. Indeed, a study found that half of the studied homes had bright enough lamps to suppress melatonin by 50%, although the exact suppression varied a lot for each user (0% to 87%), and greater exposure to evening light was associated with increased wakefulness later bedtime. Of note, energy-efficient lights produced nearly double the light intensity and melatonin suppression than incandescent lighting. Hence, home lighting can certainly affect the circadian rhythm, but not of everyone, some are more sensitive than others, and hence it's unpredictable how much lighting affect a specific individual. This further supports the importance of wearing blue blocker glasses evening indoors, in case the user can't fully control (and dim or switch off) ambient lighting.

Indeed, a very convenient alternative, instead of installing all these softwares and modifying all ambient light lamps, is to wear blue blocker glasses or even better blue blocker SUNglasses.

Blue blocker glasses are just a wearable device that allows to do dark therapy while being independent from environmental conditions. Blue blocker glasses are amber/orange glasses filtering blue and green light, without dimming the light. You can use them when you are out at a friend's house for example, or if someone is at your house for a dinner or something, you can still do your dark therapy while keeping the lights on for your guests, or simply to read a book without changing your light (else you need to use a red light bulb, which is inexpensive but makes it hard to read).

Prefer industrial-grade blue blocker glasses, as they provide complete filtration instead of partial as do the "comfort" glasses. A good and inexpensive (~$20) brand of blue-green blocker glasses is the UVEX line of glasses with the SCT Orange coating.

Here is a photo of the blue blocker glasses UVEX S0360X Ultra-Spec SCT Orange:

Blue blocker SUNglasses are just like blue blocker glasses, but in addition they have a transparent black shading layer to dim down light. Hence, they both filter blue light and dim any light source (which includes devices where you can't install a blue filtering app, such as alarm clocks, TV screens, etc).

Blue blocker glasses should be used 2-3h before habitual bedtime to allow for endogenous melatonin to build up.

Here is a DIY blue blocker sunglasses made out of a UVEX Skyper blue blocker glasses, with added 5% black shading/tinting filters for cars windows (one filter outside and one filter outside = 2 in total, 5% means that 95% of light is filtered), simply taped onto the frame:

And here is what it looks like to look through a blue blocker SUNglasses (so it's also dimming down the light - in practice it can dim down sunlight so much that it looks like it's night, which is perfect):

Without:

With the blue blocker SUNglasses (same ISO and photo parameters as the picture above - note how we can see the shape of the neon tube, just as if it was itself less intense, which also shows that obviously you should NOT drive when using the blue blocker SUNglasses):

If it's cumbersome to do your own blue blocker SUNglasses, it is possible to find laser safety glasses with a certified wavelength filtering range and red lenses. There are laser safety glasses for all ranges of light colors (wavelengths), for dark therapy what is needed is to block both blue and green lasers, hence the lenses should be red. The advantage with red tinted glasses is that they filter the whole blue and green wavelengths range, whereas orange tinted glasses such as UVEX only filter blue color and a bit of green, but the remaining green colored light can still affect the circadian rhythm, albeit less than blue light. Additionally, the laser safety glasses should also be described as having a reduced "visible light transmittance" or "Daylight Transmission (VLT)", which means that it will not only filter blue-green light but also dim down the intensity, just like sunglasses.

Here is a picture of a laser safety glasses filtering the 190nm-550nm range (ultraviolet, blue and green colors), optical density OD 4+ and Visible Light Transmittance: 30% (