new research on melatonin

What New Research Says About Melatonin and Sleep

Here is what you need to know about taking melatonin to help you sleep....

Posted February 13, 2020 | Reviewed by Chloe Williams

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Most people think of melatonin as primarily—or even exclusively—a sleep remedy. Melatonin, of course, is critical for healthy sleep. The body’s own melatonin production is essential to circadian rhythm regulation and the maintenance of daily sleep-wake cycles.

As a supplement, melatonin has grown tremendously popular, largely on the basis of its reputation as a sleep promoter. Indeed, melatonin is among the most used in the United States, according to the National Institutes of Health. Between 2007 and 2012, use of melatonin doubled among adults in the US, rising to slightly more than three million.

Here’s what’s fascinating: Some of the most broad and potent benefits of melatonin may lay outside the sleep realm. As this interesting Medscape article explains, scientists are learning more and more about the role melatonin can play in treating and preventing disease. At the same time, the effectiveness of melatonin’s most well-known use—sleep—remains something of an open question in the scientific community, even as millions of people take melatonin regularly for sleep.

Read on to learn what the latest science is telling us about how melatonin’s therapeutic reach may extend way beyond sleep, and how I think melatonin can be deployed most effectively in treating sleep problems.

Potential health benefits of melatonin beyond sleep

It’s almost getting easier to ask: what chronic diseases don’t melatonin play a role in? Recent years have seen a flurry of studies showing the protective and therapeutic benefits of melatonin in the fight against the most significant chronic diseases of our time—heart disease, cancer, dementia , diabetes. It’s role as an antioxidant and anti-inflammatory, as an anti-tumor agent, and its importance in maintaining circadian clock timing are some of the critical ways melatonin appears to have a far-reaching impact on health and disease, especially as we age.

Melatonin protects cardiovascular health. Melatonin has powerful antioxidant capabilities. Antioxidants work to protect cells and genes from damage, which can lead to dysfunction and the onset of disease. Antioxidant action reduces harmful inflammation and limits cellular and DNA damage from a process known as “ oxidative stress ,” which occurs when volatile chemicals known as “free radicals” proliferate in the body. Substances that function as antioxidants can neutralize the damaging effects of free radicals to hurt the integrity and proper functioning of cells and genes.

Melatonin’s antioxidant abilities are one mechanism by which this hormone may prevent and treat the damage of chronic and age-related diseases, from cardiovascular disease to cancer and neurodegenerative diseases like Alzheimer’s. (More on the melatonin-cancer connection in a minute.)

Recent research continues to demonstrate that melatonin may protect against and treat a range of cardiovascular conditions , including heart attack , stroke, high blood pressure and atherosclerosis (the accumulation of fat and cholesterol in the arteries).

Melatonin affects diabetes risk. Melatonin has been shown to have an influence over both blood sugar and insulin, key markers for metabolic health and drivers of metabolic disease, particularly type 2 diabetes. The science of melatonin’s role in diabetes risk and treatment is complicated and not yet well enough understood. There’s a robust body of research that indicates melatonin has a protective effect over metabolic health and can lower diabetes risk. The body’s own natural nighttime levels of melatonin have been linked to risk for developing diabetes. According to research, maintaining healthy nocturnal melatonin levels may cut one’s risk for diabetes in half, compared to people with low nighttime melatonin production. And other recent research has shown that supplemental melatonin may help to regulate blood sugar, keeping it from rising too high.

Still, other recent research has shown melatonin may complicate risk for diabetes by interfering with insulin, a hormone that helps cells access glucose from the bloodstream, thereby regulating blood sugar levels. Elevating levels of melatonin, in some people, may reduce the ability of specialized cells to release insulin, leading to higher blood sugar levels. These insulin-limiting effects of melatonin were shown to be particularly strong in people with a specific genetic variation that affects melatonin receptor cells. That same genetic variation has also been linked to a higher risk for type 2 diabetes.

Melatonin protects against age-related brain disease, including Alzheimer’s. Melatonin levels have been associated with Alzheimer’s disease for decades. People with Alzheimer’s tend to show lower levels of melatonin compared to age peers without the disease . And melatonin loss continues to escalate as the neurodegenerative disease progresses. A growing body of research shows melatonin has significant neuroprotective capabilities and may help to prevent Alzheimer’s in part by slowing or stopping the accumulation of damaging amyloid plaque and other harmful proteins in the brain, which many scientists think are behind the onset of the disease. Other research suggests that supplemental melatonin may help to reverse cognitive decline when Alzheimer’s disease is already present.

As it does throughout the body, melatonin functions as a powerful antioxidant in the brain.

Oxidative stress that damages brain cells is believed to be one significant contributing cause for age-related cognitive problems, and a factor in the development of neurodegenerative diseases including Alzheimer’s disease and others. Another likely reason for melatonin’s ability to protect brain health , according to scientific study? Its role in keeping circadian rhythms in sync.

Melatonin is an anticancer agent. Exciting research over the past several years has demonstrated the many ways that melatonin halts the onset and progression of several types of cancer. Studies have shown that melatonin can:

Suppress cancer cell and tumor growth.
Inhibit cancer metastasis .
Help boost the effectiveness of cancer treatment, including for some treatment-resistant cancers .
Reduce the severity of side effects from radiation and chemotherapy.
Prevent cancer from developing in the first place.

Why is melatonin so effective in combating cancer at every phase of its development, from prevention to limiting progression and improving treatment? Scientists are still unpacking the complicated answer to that big question. Melatonin’s influence over circadian rhythms is one likely important factor. So is melatonin’s role in protecting cellular health, including limiting the effects of oxidative stress and promoting the orderly death of damaged and aged cells—a biological process known as “apoptosis.” When cells die in an orderly, systematic way, it eliminates damaged and dysfunctional cellular actors in the body, reducing the risk for cancerous cells to grow and replicate.

Next week we will discuss some more things to know about melatonin use.

Michael J. Breus, Ph.D. , is a clinical psychologist and a diplomate of the American Board of Sleep Medicine. He is the author of Beauty Sleep.

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The body naturally produces the hormone melatonin, but among older people levels of the hormone are on the decline.

Iryna Imago/iStock

Researchers find sleep benefit in higher dose of melatonin

BWH Communications

Supplements show promise in small study of older adults

In a small study of healthy adults aged 55 and older, 5 mg of melatonin increased total sleep time compared to a placebo.

Researchers from Brigham and Women’s Hospital conducted the study in 24 healthy, older adults to evaluate whether a high-dose or a low-dose melatonin supplement could improve sleep. The team found that the higher dose had a significant impact, increasing total sleep time compared to placebo by more than 15 minutes for nighttime sleep and by half an hour for daytime sleep. Results are published in The Journal of Pineal Research .

“Sleep deficiency becomes more common as people age, and, given the drawbacks to many prescription sleep aids, many older adults report taking melatonin,” said senior author Charles Czeisler, chief of the Brigham’s Division of Sleep and Circadian Disorders. “But we’ve had little evidence on the effects of melatonin on the sleep health of older adults. Our study provides new evidence and insight, and points to the importance of considering dosage and timing when it comes to the effects of supplements like melatonin, especially in older people.”

The body naturally produces the hormone melatonin, which helps regulate a person’s sleep-wake cycle with night and day. Melatonin levels peak at night. But among older people, levels of the hormone are often lower. Exogenous melatonin is sold over the counter and can be taken before bedtime as a dietary supplement, usually in the form of a pill or capsule.

To rigorously evaluate the effects of melatonin supplements, the study’s authors focused on healthy, older adults with no history of major sleep complaints. All potential participants were screened for sleep disorders. The study included 24 participants (13 women, 11 men) between the ages of 55 and 78.

During the monthlong study period, participants lived in individual study rooms with no windows, clocks, or other indications of time of day. Participants followed a forced desynchrony protocol — instead of experiencing 24-hour cycles of days and nights, they were on schedules of 20-hour cycles to disentangle the effects of rest-activity from the circadian clock. This allowed the sleep to be scheduled both at night and during the day, but with a similar duration of waking before each sleep. Participants were randomly assigned to receive two weeks of a placebo pill and two weeks of either a low (0.3 mg) or high (5 mg) dose of melatonin 30 minutes before bedtime. Researchers used polysomnography to record brain waves, eye movement, muscle tone, and other key sleep metrics.

The team found that the low dose of melatonin did not lead to a statistically significant change in overall sleep time and that the changes that were seen were when sleep was scheduled during the biological day. Participants taking the 5 mg dose had a significant increase in total sleep time and sleep efficiency regardless of whether sleep was scheduled during the day or night.

The authors note that their study will need to be replicated in larger trials and with other doses of melatonin to determine whether a dose between 0.3 and 5 mg may work as well. The study did not include participants who had a significant sleep disorder and the study’s findings may not be applicable to people who do. “It’s exciting to see evidence that melatonin may have an impact on sleep at night for older adults because we know that so many older people have trouble sleeping,” said lead author Jeanne Duffy of the Division of Sleep and Circadian Disorders. “But before taking a dietary supplement, it’s important for people to talk to their primary care physician and get a referral to a sleep specialist to rule out an undiagnosed sleep disorder.”

Disclosures: Czeisler is/was a paid consultant to Physician’s Seal, Tencent Holdings, and Teva Pharma, and is a paid consultant and holds an equity interest in With Deep and Vanda Pharmaceuticals Inc., is/was an expert witness in legal cases, including those involving Vanda Pharmaceuticals; serves as the incumbent of an endowed professorship provided to Harvard University by Cephalon, Inc., which was acquired by Teva Pharma; and receives royalties from Philips Respironics for the Actiwatch-2 and Actiwatch Spectrum devices.

This work was supported by the National Institutes of Health (grants P01 AG09975, AG06072 and AG044416), the Brigham and Women’s Hospital BRI Fund to Sustain Research Excellence, and were conducted in the Brigham and Women’s Hospital General Clinical Research Center (supported by M01 RR02635).

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More people are turning to melatonin to sleep. But experts say it's not a panacea for everyone

A u.s. study found melatonin use 'significantly increased' from 1999 to 2018.

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More adults are turning to melatonin supplements and taking larger amounts of the sleep aid to get a good night's rest, according to a new study from the United States.

The study, published in the Journal of the American Medical Association (JAMA) this month, found that melatonin use "significantly increased" from 1999 to 2018 across all demographic groups.

The research was carried out before the COVID-19 pandemic was declared, a time when sleep disruption has been on the rise .

Although considered to be relatively safe, Canadian sleep experts and pharmacists say the supplement may not be beneficial for everyone.

"The problem is that sleep is a very complicated issue, and it's sometimes correlated with other clinical factors," said Mina Tadrous, a drug safety expert and assistant professor in the University of Toronto's Leslie Dan faculty of pharmacy.

"So one of the concerns is that if people are just using melatonin as a Band-Aid, they might not be addressing an underlying issue."

What we know about melatonin use

Melatonin is a hormone produced naturally by the brain's pineal gland, mainly at nighttime, and it helps to synchronize our sleep-wake cycle with night and day.

It is also sold in many Canadian pharmacies as an over-the-counter sleep aid supplement.

A container of melatonin pills stands beside several spilled drops.

The supplement is gaining popularity in the U.S., according to the study published in JAMA, which found that overall melatonin use over the study period grew from 0.4 per cent of those surveyed in 1999-2000 to 2.1 per cent in 2017-2018.

Based on data from 55,021 Americans aged 20 and older, melatonin use really kicked off in 2009, the study found.

It didn't say why, but one Canadian psychiatrist says people may have started making the switch to melatonin that year.

Can't sleep? Here are some tips to tackle pandemic-induced insomnia
How to keep COVID-19 stress from ruining your sleep

"There might have been a decrease, for example, in the use of prescription sleeping pills, which would be a good reason to switch to more natural-sounding alternatives or to use non-prescription medications to try to get healthier sleep without pills at all," said Dr. Ramandeep Randhawa, an assistant professor and a psychiatrist in the University of British Columbia's sleep disorders program in Vancouver.

Canadian experts say that based on what they're hearing from patients and consumers, melatonin use is common.

"Although we don't have the same evaluation, many of my colleagues and myself have noticed the same thing where people are speaking about melatonin and using melatonin more often," Tadrous said.

There was also a slight uptick in the number of people relying on larger amounts of the sleep aid to fall asleep, according to the U.S. study.

The study's researchers found that the number of Americans using the sleeping aid in amounts greater than the recommended maximum of five milligrams per day grew from 0.08 per cent in 2005-06 to 0.28 per cent in 2017-18. Dosage amounts weren't tracked prior to 2005.

Melatonin is considered a dietary supplement in the U.S. , where it's regulated by the Food and Drug Administration but less strictly than a prescription or over-the-counter drug.

Higher doses can cause side-effects

Melatonin is considered to be relatively safe for most people, but it's important to know that the long-term effects of using it at higher doses are still unclear, Randhawa said.

"There's some evidence that the higher the doses, the less effective it might be," he said.

Dr. Brian Goldman’s top five tips for overcoming insomnia

Randhawa said higher doses could cause such side-effects as dizziness, nausea, headaches and muscle aches.

Experts also warned that all melatonin supplements are not the same and that the product on the pharmacy shelf could have higher-than-listed levels of melatonin.

A 2017 study by University of Guelph researchers in Ontario found that some supplements had nearly three to five times more melatonin than what was listed on the label.

Thousands 'suffering in silence' as sleep disorder clinic backlog balloons: Doctors Manitoba

The study, published in the Journal of Clinical Sleep Medicine , also found that some supplements contained up to 83 per cent less of the hormone than what was listed on the label.

Melatonin was first licensed in Canada in 2005 as a natural health product ingredient, and it is regulated under the Natural Health Products Regulations . Once a product is approved, Health Canada issues a product licence and Natural Product Number (NPN), which must appear on the label.

This number lets you know that the product has been reviewed and approved by Health Canada.

One sleep medicine specialist said there should be better regulation of melatonin levels in these products.

"There should be oversight to ensure that if people are buying melatonin that they're actually getting what they thought they're getting on the label," said Dr. Michael Mak, a psychiatrist at Toronto's Centre for Addiction and Mental Health and a sleep medicine specialist.

Is melatonin right for all adults?

Mak said melatonin can be beneficial for people who do shift work or are dealing with jet lag.

The supplement also works "very well" for people who struggle to fall asleep before 2 or 3 a.m. during the workweek, he said.

"But if you're a person with an insomnia disorder, a person who has problems falling asleep, staying asleep or waking up too early — and it's not related to internal body-clock issues — then melatonin doesn't seem to help very much at all," Mak said.

Randhawa said it's important for people to address why they're having trouble falling asleep because they could have underlying health issues.

"Those underlying issues can range from being overly stressed, having a lot of other pressures, trouble with anxiety or depression, or just bad sleep habits," he said. "Certainly taking a pill is no substitute for addressing those problems."

Mak said although melatonin can be good for some people, he recommends also using other ways to fall asleep, such as waking up every day at the same time.

THE DOSE 5 sleep tips from 'veteran insomniac' Dr. Brian Goldman

He also recommends looking at bright light first thing in the morning and avoiding bright lights — especially those from screens — closer to bedtime.

Randhawa said that if you are someone who struggles with sleep, don't despair because you're not alone.

"If you're having trouble with your sleep, you're in good company — and keep working at it and it will get better."

Corrections

A previous version of this story that stated that melatonin is currently not regulated in Canada. It is in fact regulated by Health Canada under the Natural Health Products Regulations. Feb 21, 2022 12:34 PM ET

ABOUT THE AUTHOR

Stephanie Dubois is a journalist with CBC News. Share your story ideas with her at [email protected]

With files from Christine Birak and Marcy Cuttler

Dream discovery: Melatonin's key role in REM sleep revealed

by McGill University

A significant breakthrough in the understanding of sleep mechanism opens new promise for treating sleep disorders and associated neuropsychiatric conditions: Scientists have pinpointed the melatonin receptor MT1 as a crucial regulator of REM (Rapid Eye Movement) sleep.

REM sleep is crucial for dreaming, memory consolidation, and emotional regulation. In the brain, the melatonin MT1 receptor affects a type of neuron that synthesizes the neurotransmitter and hormone noradrenaline, found in an area known as the Locus Coeruleus, or "blue spot" in Latin.

During REM sleep, these neurons quiet down and stop their activity. Serious conditions such as Parkinson's disease and Lewy body dementia—which currently lack effective treatments—are linked to disruptions in REM sleep.

"This discovery not only advances our understanding of sleep mechanisms but also holds significant clinical potential," said Gabriella Gobbi, principal investigator of a new study published in the Journal of Neuroscience . She is a Professor of Psychiatry at McGill University, clinician-scientist at the McGill University Health Center, and Canada Research Chair in Therapeutics for Mental Health.

The science of snoozing

Human sleep unfolds in a precise sequence of non-REM and REM stages, each serving distinct physiological functions. REM sleep plays a pivotal role in memory consolidation and emotional regulation. Non-REM sleep supports physical recovery and repair processes. Disruptions in this cycle can impair cognitive function and increase vulnerability to neuropsychiatric diseases.

Until now, the specific receptor triggering REM sleep had eluded scientists. The new study has identified the melatonin MT1 receptor as an important regulator of this sleep stage. Using a novel drug targeting MT1 receptors, researchers successfully enhanced REM sleep duration in experimental animals, while simultaneously reducing neuronal activity.

"Currently, there are no drugs specifically targeting REM sleep. Most hypnotic drugs on the market, while extending total sleep duration, tend to adversely affect REM sleep," said Dr. Stefano Comai, co-senior author of the study and Professor at the University of Padua and Adjunct Professor at McGill University.

Further research into the neurobiology and pharmacology of REM sleep is crucial for developing targeted treatments that could improve the quality of life for patients affected by these debilitating diseases, according to the researchers. As scientists continue to explore the complexities of sleep regulation, the hope for effective interventions in neurological disorders grow increasingly promising.

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Melatonin is an endocrine hormone with a monoamine alkaloid structure, produced from the amino acid tryptophan. Melatonin is generated by the pineal gland in mammals. Melatonin is involved in entrainment of plant and animal circadian clocks via its action on melatonin receptors, expressed abundantly in the central nervous system, and through its direct antioxidant activity.

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New Uses of Melatonin as a Drug; A Review

Affiliation.

1 Faculty of Military Health Sciences, University of Defense, Trebesska 1575, Hradec Kralove CZ-50001, Czech Republic.
PMID: 34986763
DOI: 10.2174/0929867329666220105115755

Melatonin is a simple compound called N-acetyl-5-methoxy tryptamine and is known as a hormone controlling the circadian rhythm. Melatonin is produced by the human body naturally. The production of melatonin increases in the evening, causing a state of sleep at night and wakefulness during the day. Melatonin interacts with melatonin receptors MT1 and MT2, but it was revealed that melatonin is a strong antioxidant and it also has a role in the regulation of the cell cycle. Melatonin is now used as a medicine to treat some types of sleep disorders. Moreover, recent research suggests that it can also be utilized for other purposes, such as prevention from chemical exposure and treatment of various diseases, including cancer, neurodegenerative disorders, etc. This review summarizes the basic facts and direction of the current research on melatonin. The existing literature was scrutinized for this review.

Keywords: Antioxidant; biomedicine; cancer; circadian rhythm; neurodegenerative disorder; oxidative stress; senescence; sleep.

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New Research Finds a Higher Dose of Melatonin Improved Sleep

By Brigham and Women's Hospital June 4, 2022

In a study published in The Journal of Pineal Research, 5 mg of melatonin increased total sleep time compared to placebo.

In a small study of healthy adults aged 55 and older, 5 mg of melatonin increased total sleep time compared to placebo.

Although recent research by the University of Cambridge and Fudan University found that seven hours is the ideal amount of sleep , many Americans get less than that. In fact, data from the CDC from 2014 found that 35.2% of adults in the U.S. get less than 7 hours of sleep. Clearly, many of us could use help to fall asleep faster and sleep better.

Melatonin is one of the most used supplements in the United States. Among older adults, its use has tripled in the last two decades. But there is no consensus on the right dosage of melatonin, and studies of its effects on sleep quality in older adults have had mixed results. Researchers from Brigham and Women’s Hospital conducted a study in 24 healthy, older adults to evaluate whether a high-dose or a low-dose melatonin supplement could improve sleep. The team found that the higher dose had a significant impact, increasing total sleep time compared to placebo by more than 15 minutes for nighttime sleep and by half an hour for daytime sleep. Results are published in The Journal of Pineal Research.

Melatonin is a hormone that the pineal gland in your brain produces in response to darkness. It helps with the timing of your circadian rhythms (24-hour internal clock) and with control of the sleep–wake cycle. Being exposed to light at night can block melatonin production.

“Sleep deficiency becomes more common as people age, and, given the drawbacks to many prescription sleep aids, many older adults report taking melatonin,” said senior author Charles Czeisler, PhD, MD, chief of the Brigham’s Division of Sleep and Circadian Disorders. “But we’ve had little evidence on the effects of melatonin on the sleep health of older adults. Our study provides new evidence and insight, and points to the importance of considering dosage and timing when it comes to the effects of supplements like melatonin, especially in older people.”

During the month-long study period, participants lived in individual study rooms with no windows, clocks, or other indications of time of day. Participants followed a forced desynchrony protocol — instead of experiencing 24-hour cycles of days and nights, they were on schedules of 20-hour cycles to disentangle the effects of rest-activity from the circadian clock. This allowed the sleep to be scheduled both at night and during the day, but with a similar duration of waking before each sleep.

Polysomnography , a type of sleep study, records your brain waves, the oxygen level in your blood, heart rate and breathing, as well as eye and leg movements.

Participants were randomly assigned to receive two weeks of a placebo pill and two weeks of either a low (0.3 mg) or high (5 mg) dose of melatonin 30 minutes before bedtime. Researchers used polysomnography to record brain waves, eye movement, muscle tone, and other key sleep metrics.

“It’s exciting to see evidence that melatonin may have an impact on sleep at night for older adults because we know that so many older people have trouble sleeping,” said lead author Jeanne Duffy, MBA, PhD, of the Division of Sleep and Circadian Disorders. “But before taking a dietary supplement, it’s important for people to talk to their primary care physician and get a referral to a sleep specialist to rule out an undiagnosed sleep disorder.”

Reference: “High dose melatonin increases sleep duration during nighttime and daytime sleep episodes in older adults” by Jeanne F. Duffy, Wei Wang, Joseph M. Ronda and Charles A. Czeisler, 18 April 2022, The Journal of Pineal Research . DOI: 10.1111/jpi.12801

Funding: This work was supported by the National Institutes of Health (grants P01 AG09975, AG06072 and AG044416), the Brigham and Women’s Hospital BRI Fund to Sustain Research Excellence, and were conducted in the Brigham and Women’s Hospital General Clinical Research Center (supported by M01 RR02635).

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For getting better sleep, resistance exercise may be superior to aerobic exercise, 17 comments on "new research finds a higher dose of melatonin improved sleep".

they chose people who had no problems sleeping? Seriously?

I once looked into this with a sleep specialist. He showed me that the melatonin cycle started six hours before bed and the amounts were in micrograms. So I have been taking low doses 6 hours before bed and it is more effective than a big dose at the last minute (which puts me to sleep for a few hours, followed by insomnia for the rest. How much of the dose is absorbed is a big problem so I am using sublingual tabs (limits variability and absorbtion is higher).

Did somebody actually pay to do this study? Why would anyone pay to make a study about something already known?

OTC Melatonin has proven useless to me. Nothing prescribed has helped. When will this problem be addressed? People need sleep!!!!

Hello Admin, How I get my article published in your website. Waiting for your response.

I’ve always slept soundly through the night never a problem until last summer. Melatonin was suggested so I would take one at bed time with little success 2mg. Late fall of 2021 I found fast dissolving melatonin 5mg I place under my tongue about three hours before bedtime and I’ve been sleeping through the night with the exception of 2to 3 nights out of a month( nothings perfect)I also use guided meditation recordings while sleeping. I’m grateful for any studies regarding melatonin and those who participate 🙏🏻 I’m a healthy 77 year young and am thankful for melatonin. Thanks for the study and the article 🌈🌞

I take 10 mg nights I can’t sleep. Most times it helps but sometimes it don’t. U need to relaxed to let it work. Sometimes that’s a hard thing to do. But helps me most of the time

I have used it for it for well over 15 years and never leave home without it about 3 years ago. I went to 5mg from 3 and always get a wonderful nights sleep.

Perhaps, but that’s way more melatonin then is natural in the human body. And studies have shown that too much melatonin cause testicular and ovarian shrinking in lab animals. No thanks, I’ll pass on the melatonin and just drink more wine before bed.

My 83 year old father has trouble sleeping. The pills prescribed to him weren’t working so we tried 5mg of melatonin nightly, and now he usually sleeps about 9 hours a night.

Alt Title: “‘Science’ says ‘low’ dose (5mg) of melatonin helps you sleep 15 minutes longer, incase you live under a rock for 30 years”

Over the years I have been on every sleeping medication that is available. By chance, with a sound bath and 5 mg I sleep like a baby at 51 year’s.

Anybody in the military would have confirmed this without expensive surveys 😂

Does more melatonin make a person lazy too or just slow them down to sleep longer/better?

Pineal gland is also called 2nd eye and is very sensitive to light. It controls our ability to tolerate bright lights esp the ultra Violet rays and sunshine I don’t have any insomnia but have an abnormally extreme photosensitivity issue. I am from Pakistan and here we have intensive heat from 38 to 40-45 C for most of the months. It is since last 15-20 yrs that going in the sun even for 10 minutes takes away all of my strength. I feel excessively lithergic and feel unable to move from the bed for hours. Sometimes it is followed by nausea & vomiting and sometimes very very intensive lithergy which continues for 3-4 days Doctors in Pakistan conclude that it is due to calcification of my pineal gland

I know that Melatonin tabs are it’s cure but I fear taking it due to 2 reasons. 1. To my knowledge these are not FDA approved and can be risky then 2. Any globally leading pharmaceutical like Pfizer etc has never prepared it. Why? 3. I already sleep for 7-8 hours a day. If it is increased by these tabs how will I complete my every day jobs

Please help and guide me to solve this extra photosensitivity problem

Scientist is just a fancy word for “failures who like to do dumb research on meaningless things and waste money.”

BREAKING NEWS, NEW STUDY FINDS DRINKING ANOTHER BEER AFTER ALREADY BEING DRUNK COULD RESULT IN BEING MORE DRUNK

Children's Health

Research shows a big increase in children taking melatonin.

Maria Godoy

New research shows a big increase in children taking melatonin to help with sleep. Pediatricians warn the long-term effects of the hormone supplement aren't known.

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Use of melatonin supplements rising among adults

At a glance.

The use of melatonin supplements by adults in the United States more than quintupled between 1999 and 2018.
The findings highlight the need to better understand the long-term safety of melatonin use and its ability to help with certain sleep problems.

Woman sitting up in bed and looking at a pill bottle.

Many aspects of modern life, including screen use and shift work, can confuse the body’s natural sleep and wake cycle. Up to 19% of adults in the U.S. report not getting enough rest or sleep every day. Chronic lack of sleep can harm both your mental and physical health.

A range of chemicals and hormones circulate in the body to help control when and for how long people sleep. One such hormone, melatonin, is produced by a gland within the brain in response to darkness. It helps cue the body that it’s time to sleep.

Melatonin is sold as an over-the-counter dietary supplement in a range of doses. But studies to date have not consistently shown that taking melatonin supplements helps with insomnia, jet lag, or recovery from shift work. It may provide some benefits for people with less-common sleep disorders caused by problems with the body’s internal clock. But more research is needed to understand how and when it can be used effectively.

Short-term use of melatonin supplements appears to be safe for most people. However, information on the long-term safety of these supplements is lacking. It also hasn’t been clear how common the use of melatonin is in the U.S.

Researchers led by Dr. Naima Covassin from the Mayo Clinic examined data on melatonin use collected by the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. More than 55,000 adults aged 20 and older reported their dietary supplement use to the survey during those two decades. Supplement containers were verified during in-home interviews for 94% of the participants.

The research team was supported in part by NIH’s National Heart, Lung, and Blood Institute (NHLBI). Results were published on February 1, 2022, in JAMA .

Melatonin use increased from 0.4% of survey respondents in 1999 to 2000 to 2.1% in 2017 to 2018. This trend was similar between men and women, and across age groups.

Starting in 2005, respondents began reporting the use of doses greater than 5 milligrams per day. This use of high-dose melatonin supplementation more than tripled over the period studied, from 0.08% of study participants in 2005-2006 to 0.28% in 2017-2018.

Even with this rise, the use of high-dose melatonin remained very low overall. However, these estimates raise safety concerns, as the actual content of melatonin in commercial supplements may be many times higher than what’s listed on the label.

“Our findings highlight the importance of well-designed clinical studies to look at the long-term safety of melatonin use in different populations, as well as whether it can effectively help people with sleep problems,” Covassin says.

—by Sharon Reynolds

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Study: Scientists unravel the many physiological roles of melatonin

By ellen goldbaum, a new mouse model reveals the hormone directly affects several key physiological functions.

Release Date: July 14, 2021

BUFFALO, N.Y. — Mention melatonin and many people think of the over-the-counter sleep aid. But the hormone made in the brain’s pineal gland controls much more than just how sleepy we get, according to research published in the Journal of Pineal Research by a team of scientists from the University at Buffalo, RIKEN in Japan and other institutions.

The research reveals for the first time the multiple roles that the naturally occurring melatonin molecule plays in processes ranging from circadian rhythms to reproduction to “torpor,” an energy-conserving state similar to short-term hibernation.

“For the first time, we can say that endogenous melatonin is involved in the modulation of these physiological functions,” said Margarita Dubocovich, PhD, a senior and co-corresponding author on the paper and SUNY Distinguished Professor in the Department of Pharmacology and Toxicology in the Jacobs School of Medicine and Biomedical Sciences at UB. Takaoki Kasahara of RIKEN is co-corresponding author on the paper.

“All species that ever existed continue to synthesize melatonin in the pineal gland, retina and a number of peripheral tissues and organelles such as in mitochondria, where it signals through receptor-mediated pathways and often functions as a receptor-independent antioxidant,” Dubocovich said.

“It is well recognized that in both animals and humans, melatonin participates in regulating sleep, modulating circadian rhythms, enhancing immunity and acting as a multifunctional anti-cancer agent through actions on its G-protein coupled receptors while retaining the ability to act as a free radical scavenger, anti-oxidant and anti-inflammatory agent.”

Dubocovich has pioneered research that has led to a better understanding of the role of melatonin in mammals. Over the past several decades, she has made major contributions to the scientific understanding of how melatonin impacts circadian rhythms, sleep disorders, drug addiction and depression.

The new findings are the first to demonstrate unequivocally what endogenous melatonin does because the research was done on two genetically identical mice, except one mouse produced melatonin and the other did not.

“Previous studies on the role of endogenous, or naturally occurring, melatonin in physiological functions were conducted using rodents whose pineal gland had been removed. The drawback of that research is that this blocks the production not only of melatonin, but of many other molecules as well, so it wasn’t clear if it was the lack of melatonin or other molecules that was having the observed effect,” said Dubocovich.

“Now we have a mouse model where we can test the effect of endogenous melatonin on reproduction, torpor, body weight and other physiological functions,” she continued. “These results can be used to advance the understanding in how endogenous melatonin affects mice behavior and physiology, which could then provide insights into the role of endogenous melatonin in humans.”

The findings pave the way for further investigations into the role of endogenous melatonin on the immune system, bone formation, inflammation and actions on peripheral tissues involved in metabolic function, such as the pancreas and liver.

In particular, the researchers found that endogenous melatonin does the following:

· Facilitates and accelerates re-entrainment, the alignment of the body clock to the outside world; in other words, it allows the body to adjust more easily to abrupt changes in the light/dark cycle, like when flying from New York to Paris.

· Decreases body weight.

· Decreases reproductive performance.

· Induces daily torpor (an energy-conserving function in animals).

The finding that melatonin induces daily torpor is of particular interest, the researchers said. Torpor is a pre-hibernation state that allows mice to slow down their metabolism and survive when food is scarce, or temperatures are cold.

“The experiments conducted at RIKEN clearly demonstrated that in the mice that produced melatonin, there was a significant increase in daily torpor, which can last for hours, but only during periods of food scarcity,” said Dubocovich.

She noted that while daily torpor has not been clearly demonstrated in humans, there is interest in such a physiological state that could potentially be induced in astronauts to withstand long space journeys; it might also be relevant in treating critically ill or injured patients. Melatonin’s effects related to torpor will also be valuable in further study on treating people with sleep disorders, depression and seasonal affective disorder.

“Our research at UB showed that mice producing melatonin re-entrained faster after an abrupt six-hour advance of dark onset like in eastbound jet travel, facilitating clock alignment to destination time,” said co-first author Chongyang Zhang, who completed her master in science degree with the Dubocovich team at UB and is now a doctoral student at the School of Medicine and Dentistry at the University of Rochester.

According to Dubocovich, evidence suggests that at least in terms of modulation of circadian rhythms by melatonin and other phase-shifting agents, there is a direct translation from mice to humans.

“In other words, the amplitude and direction of phase shifts by melatonin and other drugs identified in mice are directly translatable to humans,” she said.

The new research confirms previous findings suggesting that melatonin is responsible for inhibiting reproductive function in rodents. Indeed, mice deficient in melatonin had higher success in mating, with larger litter sizes associated with enlarged gonads and larger overall body size. Dubocovich noted that this finding is known to be responsible for the artificial selection of domesticated melatonin-deficient mice, who exhibit higher reproductive performance.

The researchers also settled the question of whether naturally occurring melatonin, which has been proposed as a possible anti-aging agent, has any life-extending effects: The research showed it does not.

The work was funded by the Japan Society for the Promotion of Science, and by the Jacobs School.

In addition to Dubocovich and Zhang, other UB authors are co-first author Shannon J. Clough, and co-authors Ekue B. Adamah-Biassi, Michelle H. Sveinsson, Anthony J. Hutchinson and Randall L. Hudson.

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Melatonin is a hormone in your body that plays a role in sleep. The production and release of melatonin in the brain is connected to time of day, increasing when it's dark and decreasing when it's light. Melatonin production declines with age.

Melatonin is also available as a supplement, typically as an oral tablet or capsule. Most melatonin supplements are made in a lab.

People commonly use melatonin for sleep disorders, such as insomnia and jet lag.

What the research says

Research on melatonin use for specific conditions shows:

Circadian rhythm sleep disorders in the blind. Melatonin can help improve these disorders in adults and children.
Delayed sleep phase (delayed sleep-wake phase sleep disorder). In this disorder, your sleep pattern is delayed two hours or more from a conventional sleep pattern, causing you to go to sleep later and wake up later. Research shows that melatonin reduces the length of time needed to fall asleep and advances the start of sleep in adults and children with this condition. Talk to your child's doctor before giving melatonin to a child.
Insomnia. Research suggests that melatonin might slightly reduce the time it takes to fall asleep, but its effects on sleep quality and total sleep time aren't clear. Melatonin might be more beneficial for older adults who could be melatonin deficient.
Jet lag. Evidence shows that melatonin can improve jet lag symptoms, such as alertness and daytime sleepiness.
Shift work disorder. It's not clear whether melatonin can improve daytime sleep quality and duration in people whose jobs require them to work outside the traditional morning to evening schedule.
Sleep disorders in children. Small studies have suggested melatonin might help treat sleep disturbances in children with a number of disabilities. However, good bedtime habits are usually recommended as an initial treatment. Talk to your child's doctor before giving melatonin to a child.

Research suggests that melatonin might reduce evening confusion and restlessness in people with Alzheimer's disease, but it doesn't seem to improve cognition.

Generally safe

Your body likely produces enough melatonin for its general needs. However, evidence suggests that melatonin supplements promote sleep and are safe for short-term use. Melatonin can be used to treat delayed sleep phase and circadian rhythm sleep disorders in the blind and provide some insomnia relief. Treat melatonin as you would any sleeping pill and use it under your doctor's supervision.

Safety and side effects

Melatonin taken orally in appropriate amounts is generally safe. Melatonin can cause:

Less common melatonin side effects might include short-lasting feelings of depression, mild tremor, mild anxiety, abdominal cramps, irritability, reduced alertness, confusion or disorientation.

Because melatonin can cause daytime drowsiness, don't drive or use machinery within five hours of taking the supplement.

Don't use melatonin if you have an autoimmune disease.

Interactions

Possible drug interactions include:

Anticoagulants and anti-platelet drugs, herbs and supplements. These types of drugs, herbs and supplements reduce blood clotting. Combining use of melatonin with them might increase the risk of bleeding.
Anticonvulsants. Melatonin might inhibit the effects of anticonvulsants and increase the frequency of seizures particularly in children with neurological disabilities.
Blood pressure drugs. Melatonin might worsen blood pressure in people taking blood pressure medications.
Central nervous system (CNS) depressants. Melatonin use with these medications might cause an additive sedative effect.
Diabetes medications. Melatonin might affect sugar levels. If you take diabetes medications, talk to your doctor before using melatonin.
Contraceptive drugs. Use of contraceptive drugs with melatonin might cause an additive sedative effect and increase possible side effects of melatonin.
Cytochrome P450 1A2 (CYP1A2) and cytochrome P450 2C19 (CPY2C19) substrates. Use melatonin cautiously if you take drugs such as diazepam (Valium, Valtoco, others) and others that are affected by these enzymes.
Fluvoxamine (Luvox). This medication used to treat obsessive-compulsive disorder can increase melatonin levels, causing unwanted excessive drowsiness.
Immunosuppressants. Melatonin can stimulate immune function and interfere with immunosuppressive therapy.
Seizure threshold lowering drugs. Taking melatonin with these drugs might increase the risk of seizures.

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Melatonin: What you need to know. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know. Accessed Jan. 24, 2021.
Melatonin. Natural Medicines. https://naturalmedicines.therapeuticresearch.com. Accessed Jan. 24, 2021.
Melatonin. Facts & Comparisons eAnswers. https://www.wolterskluwercdi.com/facts-comparisons-online/. Accessed Jan. 24, 2021.
Melatonin. IBM Micromedex. https://www.microdemexsolutions.com. Accessed Jan. 24, 2021.
Pizzorono JE, et al., eds. Melatonin. In: Textbook of Natural Medicine. 5th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Jan. 24, 2021.
Kellerman RD, et al. Popular herbs and nutritional supplements. In: Conn's Current Therapy 2021. Elsevier; 2021. https://www.clinicalkey.com. Accessed Jan. 24, 2021.
Wurtman R. Physiology and available preparations of melatonin. https://www.uptodate.com/contents/search. Accessed Jan. 24, 2021.

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Melatonin may stave off age-related vision loss, study hints

A large new analysis has tied the use of supplemental melatonin to a lower risk of developing one of the most common age-related causes of vision loss.

Mature woman is shown having her eyes tested by an opthalomogist. A black device is in front of her eyes which is in focus. The rest of the image is blurred

Melatonin supplements may reduce the risk of developing age-related macular degeneration (AMD), the most common cause of severe vision loss in people over age 50.

Researchers uncovered this link after analyzing electronic medical records gathered between 2008 and 2023 from patients in the U.S.

The scientists examined records from more than 238,000 people over age 50 who had no history of AMD, about 121,000 of whom reported taking melatonin. From this data, the scientists estimated that the individuals taking melatonin were 58% less likely to go on to be diagnosed with AMD within the 15-year study period than those who were not.

The former group had to have reported to their doctor that they were taking melatonin at least four times within the 15-year window, with a minimum three-month gap between these reports. In the U.S., melatonin is considered to be a dietary supplement , so it can be purchased without a prescription.

Related: Kids' use of melatonin 'exceedingly common,' Colorado study finds

Although it revealed an interesting link, the study has some major caveats.

Notably, over-the-counter melatonin supplements can vary considerably in terms of their purity and the concentration of ingredients included. Studies have suggested that melatonin gummies sold in the U.S. often contain much higher doses than listed — or more rarely, they contain no melatonin at all. This means that the actual dose of melatonin that people were taking in this study is unknown.

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But even so, the research, published June 6 in the journal JAMA Ophthalmology , hints that melatonin could potentially help ward off a very common form of vision loss.

"I think the potential of this low cost, widely available supplement in reducing the risk AMD is potentially exciting," Dr. Glenn Yiu , a professor of ophthalmology at University of California, Davis Health who was not involved in the research, told Live Science in an email. With the current study's caveats in mind, "I will be interested to see if other more rigorous studies confirm these interesting findings," he added.

Melatonin tablets spilling from a green bottle. The tablets are white in color with tiny pink specks on them. They are like little discs.

Melatonin and vision loss

In the human eye, the retina contains light-sensitive cells that send messages to the brain. The macula, the central part of the retina , enables us to see objects that are directly in front of us. AMD affects eyesight because it progressively damages the macula. People with AMD can experience blurred or distorted vision in the center of their visual field, but the disease doesn't cause total blindness.

Two major types of AMD exist: dry AMD and wet AMD. Dry AMD is the milder form of the disease that occurs in 80% of cases, and it's caused by the gradual breakdown of light-sensitive cells in the macula. Wet AMD additionally involves the abnormal growth of blood vessels under the retina, and these blood vessels can begin to leak fluid , damaging cells and leading to severe vision loss. Between 10% and 15% of patients with dry AMD will go on to develop wet AMD.

In addition to looking at people without AMD who later developed the disease, the researchers wanted to see if taking melatonin could prevent the progression from dry to wet. So, in a second analysis, the team probed the medical records of about 128,000 patients who had been diagnosed with dry AMD, roughly 66,000 of whom were taking melatonin and 62,000 were not. They found that those who were taking melatonin were 56% less likely to go on to develop wet AMD in a 15-year time frame than those who weren't.

In both analyses, similar patterns were seen among patients in their 50s, 60s and 70s, the team found.

Because the study looked at only associations between melatonin and AMD, it cannot prove that melatonin directly counters the biological processes behind the condition. The authors also acknowledge that people's lifestyle habits and health care access may have influenced their risk of AMD, rather than melatonin, but they didn't consider these factors.

The findings do reaffirm earlier research in rodents and humans that suggest melatonin, which is often prescribed to treat sleep disorders such as insomnia, may be able to target some of the key biological processes that underlie AMD. This includes heightened inflammation and oxidative stress , or a build-up of free radicals in the body that can damage cells. This is important considering that there is currently no cure for AMD, and preventive interventions are often limited to lifestyle modifications , such as maintaining a healthy diet and quitting smoking.

"The potential benefits of new treatments to prevent AMD are enormous from a public health perspective," David Rein , a senior fellow in public health at the National Opinion Research Center (NORC) at the University of Chicago, who was not involved in the research, told Live Science in an email.

— Scientists may have found the missing link between heart disease and sleep problems

— Most melatonin gummies have higher doses than what's on the label

— Weighted-blanket use may boost sleep hormone melatonin, small study hints

Gold-standard clinical trials are still needed to determine whether melatonin actually prevents the development or progression of AMD. These trials would compare people who take melatonin to those who don't, and the doses and quality of the supplements would be carefully controlled.

It's important that these trials be completed before doctors make any recommendations about patients using melatonin for eye health, Dr. Rajendra Apte , a professor of opthalamology and visual sciences at Washington University in St. Louis, who was not involved in the research, told Live Science in an email.

This article is for informational purposes only and is not meant to offer medical advice.

Ever wonder why some people build muscle more easily than others or why freckles come out in the sun ? Send us your questions about how the human body works to [email protected] with the subject line "Health Desk Q," and you may see your question answered on the website!

Emily is a health news writer based in London, United Kingdom. She holds a bachelor's degree in biology from Durham University and a master's degree in clinical and therapeutic neuroscience from Oxford University. She has worked in science communication, medical writing and as a local news reporter while undertaking journalism training. In 2018, she was named one of MHP Communications' 30 journalists to watch under 30. ( [email protected] )

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Article Information

The unweighted numbers of participants using melatonin overall and using >5 mg/d of melatonin were 296 and 39, respectively. Shaded areas indicate 95% confidence intervals. P values for linear and quadratic trends were calculated using linear regression modeling survey cycle as a continuous variable. For overall use, linear P = .004 and quadratic P < .001; for use greater than 5 mg/d, linear P = .005 and quadratic P = .04. Prevalence trends for melatonin use greater than 5 mg/d were estimated from the 2005-2006 to 2017-2018 cycles.

Melatonin for Insomnia in Children JAMA From The Medical Letter on Drugs and Therapeutics October 20, 2020 This Medical Letter review summarizes evidence about the safety and efficacy of over-the-counter melatonin-containing products as sleep aids for insomnia in children, and their role relative to standard nonpharmacological treatments.
Young Children Increasingly Ingest Melatonin, With Serious Outcomes JAMA News From the Centers for Disease Control and Prevention July 12, 2022 Bridget M. Kuehn, MSJ
Climbing Melatonin Use for Insomnia Raises Safety Concerns JAMA Medical News & Perspectives August 16, 2022 This Medical News article describes recent increases in melatonin use and the potential harm associated with taking it for insomnia. Bridget M. Kuehn, MSJ
Association of Sleep Problems and Melatonin Use in School-aged Children JAMA Pediatrics Research Letter September 1, 2019 This cross-sectional study examines subjectively and objectively assessed sleep and melatonin use in children. M. Elisabeth Koopman-Verhoeff, MSc; Michiel A. van den Dries, MSc; Judith J. van Seters, BSc; Maartje P. C. M. Luijk, PhD; Henning Tiemeier, MD, PhD; Annemarie I. Luik, PhD

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Li J , Somers VK , Xu H , Lopez-Jimenez F , Covassin N. Trends in Use of Melatonin Supplements Among US Adults, 1999-2018. JAMA. 2022;327(5):483–485. doi:10.1001/jama.2021.23652

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1 Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
2 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
3 National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Beijing, China
From The Medical Letter on Drugs and Therapeutics Melatonin for Insomnia in Children JAMA
News From the Centers for Disease Control and Prevention Young Children Increasingly Ingest Melatonin, With Serious Outcomes Bridget M. Kuehn, MSJ JAMA
Medical News & Perspectives Climbing Melatonin Use for Insomnia Raises Safety Concerns Bridget M. Kuehn, MSJ JAMA
Research Letter Association of Sleep Problems and Melatonin Use in School-aged Children M. Elisabeth Koopman-Verhoeff, MSc; Michiel A. van den Dries, MSc; Judith J. van Seters, BSc; Maartje P. C. M. Luijk, PhD; Henning Tiemeier, MD, PhD; Annemarie I. Luik, PhD JAMA Pediatrics

Exogenous supplementation of melatonin, one of the key hormones governing circadian rhythm, is indicated for treatment of circadian rhythm sleep disorders 1 and, despite insufficient evidence, 2 is widely used as an over-the-counter sleep aid. Evidence of antioxidant and anti-inflammatory properties of melatonin 3 has prompted investigation of its therapeutic value in multiple diseases. 4 Although melatonin is generally regarded as safe, adverse effects have been reported, and data on long-term use and high-dose use are scarce. 5 The heterogeneity in over-the-counter formulations 6 further supports the need for a broader understanding of consumption of exogenous melatonin in the population.

We examined reported prevalence and trends in use of melatonin supplements among US adults from 1999 through 2018. Because the recommended dosage of melatonin typically does not exceed 5 mg/d, we additionally evaluated prevalence and trends in use of greater than 5 mg/d of melatonin.

We used data from the 1999-2000 through 2017-2018 cycles of the National Health and Nutrition Examination Survey (NHANES), a series of cross-sectional, stratified, multistage probability sample surveys of the noninstitutionalized US population, with response rates ranging from 51.9% (2017-2018) to 84.0% (2001-2002). Participants younger than 20 years (n = 46 235) or without available dietary supplement data (n = 58) were excluded. For the analysis on greater than 5 mg/d of melatonin use, we additionally excluded those reporting melatonin use but without daily dose information (n = 2). The National Center for Health Statistics Institutional Review Board approved the NHANES protocol and all participants provided written informed consent. Data on dietary supplement use during the past 30 days and daily dose used when taking the supplements were collected through in-home interview, and to aid reporting, participants were required to show supplement containers.

For each survey cycle, we computed weighted prevalences and 95% CIs of melatonin use in the overall sample and across sex and age categories. Prevalences and 95% CIs of greater than 5 mg/d of melatonin use was also estimated. P values for linear and quadratic trends were calculated using linear regression modeling with survey cycle as a continuous variable. To determine if trends varied by demographic characteristics, interaction effects were assessed using weighted logistic regression. R version 4.0.1 (R Foundation) and SPSS version 20.0 (IBM Corp) were used for analysis, and a 2-sided P < .05 was considered statistically significant.

Data from 55 021 adults (mean age, 47.5 [SD, 17.1] years; 52.0% women) from 10 NHANES cycles were included. The number of participants included in each cycle ranged from 4865 to 6214 ( Table ), and supplement containers were verified by interviewers for 93.9% of self-reported melatonin users. The overall reported weighted prevalence of melatonin use increased from 0.4% (95% CI, 0.2%-1.0%) in 1999-2000 to 2.1% (95% CI, 1.5%-2.9%) in 2017-2018 (linear P = .004) ( Figure ), with an increase beginning in 2009-2010 (quadratic P < .001). Trends were similar across sex and age groups (interaction P > .05 for all) ( Table ).

Melatonin use of greater than 5 mg/d was not reported before 2005-2006. The reported prevalence of melatonin use greater than 5 mg/d increased from 0.08% (95% CI, 0.02%-0.38%) in 2005-2006 to 0.28% (0.13%-0.60%) in 2017-2018 (linear P = .005) ( Figure ).

Among US adults, reported prevalence of melatonin supplement consumption significantly increased from 1999-2000 to 2017-2018 across all demographic groups. Although it remained very low, prevalence of self-reported use of greater than 5 mg/d of melatonin also increased over time. These estimates may raise safety concerns, especially given that the actual content of melatonin in marketed supplements may be up to 478% higher than the labeled content 6 and that evidence supporting melatonin use for sleep disturbances is weak. 2 The growing use of exogenous melatonin in the general population and its expanding therapeutic potential 4 provide impetus for the acquisition of robust evidence of long-term safety of melatonin supplementation. Limitations include self-reported use of melatonin, although supplement containers were verified in nearly all participants. Because of the small number of melatonin users in some subgroups, results of stratified analyses should be interpreted with caution. Reliable estimates of trends in melatonin use across racial/ethnic groups cannot be provided. Also, reasons for use were not available in all cycles.

Corresponding Author: Naima Covassin, PhD, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55902 ( [email protected] ).

Accepted for Publication: December 13, 2021.

Author Contributions: Drs Covassin and Li had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Li, Somers, Lopez-Jimenez, Covassin.

Acquisition, analysis, or interpretation of data: Li, Covassin.

Drafting of the manuscript: Li, Covassin.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Li.

Administrative, technical, or material support: Somers, Covassin.

Supervision: Covassin.

Conflict of Interest Disclosures: Dr Somers reported having served as a consultant for Respicardia, Baker Tilly, Bayer, and Jazz Pharmaceuticals and serving on the Sleep Number Research Advisory Board. No other disclosures were reported.

Funding/Support: Dr Li is supported by grant 82004301 from the National Natural Science Foundation of China. Dr Somers is supported in part by grants HL65176, HL134885, and HL134808 from the National Institutes of Health, grants from Sleep Number Corporation to Mayo Clinic, and the Alice Sheets Marriott Professorship. Dr Covassin is supported by grants HL134885 and HL134808 from the National Institutes of Health, a Mayo Clinic Marie Ingalls Research Career Development Award, and a grant from Sleep Number Corporation to Mayo Clinic.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Additional Information: This work was done when Dr Li was a visiting fellow at Mayo Clinic.

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U.S. Department of Health and Human Services
National Institutes of Health

Melatonin: What You Need To Know

Woman looking at computer screen at night

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} What is melatonin and how does it work?

Melatonin is a hormone that your brain produces in response to darkness. It helps with the timing of your circadian rhythms (24-hour internal clock) and with sleep. Being exposed to light at night can block melatonin production.

Research suggests that melatonin plays other important roles in the body beyond sleep. However, these effects are not fully understood.

Melatonin dietary supplements can be made from animals or microorganisms, but most often they’re made synthetically. The information below is about melatonin dietary supplements.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} What are the health benefits of taking melatonin?

Melatonin supplements may help with certain conditions, such as jet lag, delayed sleep-wake phase disorder, some sleep disorders in children, and anxiety before and after surgery.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Jet lag

Jet lag affects people when they travel by air across multiple time zones. With jet lag, you may not feel well overall and you may have disturbed sleep, daytime tiredness, impaired functioning, and digestive problems.

Research suggests that melatonin supplements may help with jet lag. This is based on medium-sized reviews from 2010 and 2014.

Four studies that included a total of 142 travelers showed that melatonin may be better than a placebo (an inactive substance) in reducing overall symptoms of jet lag after eastward flights. Another study of 234 travelers on eastward flights looked at only sleep quality and found low-quality evidence that melatonin may be better than placebo for improving sleep quality.
Two studies that included a total of 90 travelers showed that melatonin may be better than a placebo in reducing symptoms of jet lag after westward flights.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Delayed sleep-wake phase disorder (DSWPD)

People with DSWPD have trouble falling asleep at the usual times and waking up in the morning. They typically have difficulty getting to sleep before 2 to 6 a.m. and would prefer to wake up between 10 a.m. and 1 p.m.

Melatonin supplements appear to help with sleep in people with DSWPD, but it’s uncertain whether the benefits outweigh the possible harms. This is based on a clinical practice guideline, a small review, and a more recent study.

In 2015, the American Academy of Sleep Medicine recommended melatonin supplements given at specific times for DSWPD. The recommendation was a weak one, and it came with uncertainty about whether the benefits of melatonin outweigh its potential harms.
A 2016 review that looked at a small number of people (52) from two studies showed that melatonin supplements reduced the time it took for people with DSWPD to fall asleep when compared to placebo. On average, it took about 22 minutes less for them to fall asleep.
A 2018 randomized controlled trial that lasted 4 weeks and included 307 people with DSWPD found that taking melatonin 1 hour before the desired bedtime combined with going to bed at a set time led to several improvements. Those improvements included falling asleep an average of 34 minutes earlier, better sleep during the first third of the night, and better daytime functioning.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Some sleep disorders in children

Sleep problems in children can have undesirable effects on their behavior, daytime functioning, and quality of life. Children with certain conditions, such as atopic dermatitis, asthma, attention-deficit hyperactivity disorder (ADHD), or autism spectrum disorder (ASD), are more prone to sleep problems than other children.

There are no overall guidelines on the best approach to improving sleep in children. However, guidelines for specific conditions recommend behavioral treatments, such as good bedtime habits and parent education, as an initial treatment that may be supplemented with medicines.

The list below shows the review’s results on melatonin’s short-term effects for children with specific conditions.

Children with ASD fell asleep 37 minutes earlier and slept 48 minutes longer.
Children with ADHD fell asleep 20 minutes earlier and slept 33 minutes longer.
Children with atopic dermatitis fell asleep 6.8 minutes earlier and slept 35 minutes longer.
Children with chronic sleep-onset insomnia fell asleep 24 minutes earlier and slept 25 minutes longer.

Because there aren’t many studies on children and melatonin supplements, there is a lot we don’t know about the use of melatonin in children. For example, there are uncertainties about what dose to use and when to give it, the effects of melatonin use over long periods of time, and whether melatonin’s benefits outweigh its possible risks. Because melatonin is a hormone, it’s possible that melatonin supplements could affect hormonal development, including puberty, menstrual cycles, and overproduction of the hormone prolactin, but we don’t know for sure.

Because of these uncertainties, it’s best to work with a health care provider if you’re considering giving a child melatonin for sleep problems.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Anxiety before and after surgery

Anxiety before and after surgery happens in up to 80 percent of patients.

Melatonin supplements appear to be helpful in reducing anxiety before surgery, but it’s unclear if it helps to lower anxiety after surgery. This is a based on a 2015 review.

The 2015 review looked at 12 studies that involved 774 people and assessed melatonin supplements for treating anxiety before surgery, anxiety after surgery, or both. The review found strong evidence that melatonin is better than placebo at reducing anxiety before surgery. Melatonin supplements may be as effective as standard treatment (the antianxiety medicine midazolam). However, the results on melatonin’s benefits for reducing anxiety after surgery were mixed.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Is melatonin helpful for preventing or treating COVID-19?

Current research looking at the effects of melatonin on COVID-19 is only in the early stages. There are a few randomized controlled trials (studies evaluating melatonin in people) in progress. At this point, it is too soon to reach conclusions on whether melatonin is helpful for COVID-19.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Does melatonin help with cancer symptoms?

Studies of the effect of melatonin supplements on cancer symptoms or treatment-related side effects have been small and have had mixed results.

Keep in mind that unproven products should not be used to replace or delay conventional medical treatment for cancer. Also, some products can interfere with standard cancer treatments or have special risks for people who’ve been diagnosed with cancer. Before using any complementary health approach, including melatonin, people who’ve been diagnosed with cancer should talk with their health care providers to make sure that all aspects of their care work together.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Can melatonin help with insomnia?

People with insomnia have trouble falling asleep, staying asleep, or both. When symptoms last a month or longer, it’s called chronic insomnia.

According to practice guidelines from the American Academy of Sleep Medicine (2017) and the American College of Physicians (2016), there’s not enough strong evidence on the effectiveness or safety of melatonin supplementation for chronic insomnia to recommend its use. The American College of Physicians guidelines strongly recommend the use of cognitive behavioral therapy for insomnia (CBT-I) as an initial treatment for insomnia.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Does melatonin work for shift workers?

Shift work that involves night shifts may cause people to feel sleepy at work and make it difficult to sleep during the daytime after a shift ends.

According to two 2014 research reviews, studies on whether melatonin supplements help shift workers were generally small or inconclusive.

The first review looked at 7 studies that included a total of 263 participants. The results suggested that (1) people taking melatonin may sleep about 24 minutes longer during the daytime, but (2) other aspects of sleep, such as time needed to fall asleep, may not change. The evidence, however, was considered to be of low quality.
The other review looked at 8 studies (5 of which were also in the first review), with a total of 300 participants, to see whether melatonin helped promote sleep in shift workers. Six of the studies were high quality, and they had inconclusive results. The review did not make any recommendations for melatonin use in shift workers.

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For melatonin supplements, particularly at doses higher than what the body normally produces, there’s not enough information yet about possible side effects to have a clear picture of overall safety. Short-term use of melatonin supplements appears to be safe for most people, but information on the long-term safety of supplementing with melatonin is lacking.

Also keep in mind:

Interactions with medicines

As with all dietary supplements, people who are taking medicine should consult their health care providers before using melatonin. In particular, people with epilepsy and those taking blood thinner medications need to be under medical supervision when taking melatonin supplements.

Possible allergic reaction risk

There may be a risk of allergic reactions to melatonin supplements.

Safety concerns for pregnant and breastfeeding women

There’s been a lack of research on the safety of melatonin use in pregnant or breastfeeding women.

Safety concerns for older people

The 2015 guidelines by the American Academy of Sleep Medicine recommend against melatonin use by people with dementia.
Melatonin may stay active in older people longer than in younger people and cause daytime drowsiness.

Melatonin is regulated as a dietary supplement

In the United States, melatonin is considered a dietary supplement. This means that it’s regulated less strictly by the Food and Drug Administration (FDA) than a prescription or over-the-counter drug would be. In several other countries, melatonin is available only with a prescription and is considered a drug.

Products may not contain what’s listed on the label

Some melatonin supplements may not contain what’s listed on the product label. A 2017 study tested 31 different melatonin supplements bought from grocery stores and pharmacies. For most of the supplements, the amount of melatonin in the product didn’t match what was listed on the product label. Also, 26 percent of the supplements contained serotonin, a hormone that can have harmful effects even at relatively low levels.

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In addition to issues mentioned above, there are some things to consider regarding melatonin’s safety in children.

Parents considering giving their children melatonin should first speak with a health care provider about melatonin use in children.
A 2023 study found that 22 out of 25 over-the-counter melatonin gummy products were inaccurately labeled. One product did not contain detectable levels of melatonin. In the remaining products, the melatonin levels ranged from 74 to 347 percent of the labeled quantity (i.e., up to almost 3.5 times more melatonin than reported on the label). Most had more than the label said, with the majority containing between 1.2 to 1.7 times more melatonin than the amount listed.
Parents need to ensure safe storage and appropriate use of melatonin supplements. Based on case surveillance data, a 2024 report by the U.S. Centers for Disease Control and Prevention (CDC) estimated that from 2019 to 2022, 11,000 emergency department visits were for unsupervised melatonin ingestion by children 5 years and younger. The report noted that many of the incidents involved ingestion of flavored products such as gummies and emphasized the importance of keeping medications and supplements out of children’s reach and sight.
A 2022 study indicated that U.S. sales of melatonin—which is widely available in tablet, capsule, liquid, and gummy formulations—increased by about 150 percent between 2016 and 2020. The study authors said that the increase in sales, availability, and widespread use of melatonin in the United States has likely resulted in increased access to melatonin among children in the home.
The 2022 study also showed that the number of reports to U.S. poison control centers about people 19 years and younger who took melatonin increased from 8,337 in 2012 to 52,563 in 2021. Over the 10-year period, the number of reports increased each year. Hospitalizations and serious outcomes from melatonin ingestion by people 19 years and younger also increased over the 10 years. Most hospitalizations involved teenagers who had intentionally taken melatonin overdoses, and the largest increase in hospitalizations occurred in children 5 years and younger.

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Most of the calls to poison control centers—94.3 percent—were for children 5 years and younger who accidentally consumed melatonin products in their homes.
Data from the calls show that most of the people who had taken melatonin—82.8 percent—did not have any symptoms. Among those who did have symptoms, gastrointestinal, cardiovascular, or symptoms related to the central nervous system were the most common.
Of the 4,097 people who were hospitalized over the 10-year period, 287 needed intensive care.
Five individuals required mechanical ventilation, and two children younger than age 2 died, but the data from the poison control centers did not show whether the two deaths were caused by a melatonin overdose or another cause.

Melatonin supplements at normal doses appear to be safe for most children for short-term use, but there aren’t many studies on children and melatonin. Also, there’s little information on the long-term effects of melatonin use in children. Because melatonin is a hormone, it’s possible that melatonin supplements could affect hormonal development, including puberty, menstrual cycles, and overproduction of the hormone prolactin, but we don’t know for sure.

Possible melatonin supplement side effects reported in children have usually been mild and have included:

Increased bedwetting or urination in the evening

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} What are the side effects of melatonin?

A 2015 review on the safety of melatonin supplements indicated that only mild side effects were reported in various short-term studies that involved adults, surgical patients, and critically ill patients. Some of the mild side effects that were reported in the studies included:

The possible long-term side effects of melatonin use are unclear.

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Remember that even though the FDA regulates dietary supplements, such as melatonin, the regulations for dietary supplements are different and less strict than those for prescription or over-the-counter drugs.
Some dietary supplements may interact with medicines or pose risks if you have medical problems or are going to have surgery.
If you’re pregnant or nursing a child, it’s especially important to see your health care provider before taking any medicine or supplement, including melatonin.
If you use dietary supplements, such as melatonin, read and follow label instructions. “Natural” doesn’t always mean “safe.” For more information, see Using Dietary Supplements Wisely .
Take charge of your health—talk with your health care providers about any complementary health approaches you use. Together, you can make shared, well-informed decisions.

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Nccih clearinghouse.

The NCCIH Clearinghouse provides information on NCCIH and complementary and integrative health approaches, including publications and searches of Federal databases of scientific and medical literature. The Clearinghouse does not provide medical advice, treatment recommendations, or referrals to practitioners.

Toll-free in the U.S.: 1-888-644-6226

Telecommunications relay service (TRS): 7-1-1

Website: https://www.nccih.nih.gov

Email: [email protected] (link sends email)

Know the Science

NCCIH and the National Institutes of Health (NIH) provide tools to help you understand the basics and terminology of scientific research so you can make well-informed decisions about your health. Know the Science features a variety of materials, including interactive modules, quizzes, and videos, as well as links to informative content from Federal resources designed to help consumers make sense of health information.

Explaining How Research Works (NIH)

Know the Science: How To Make Sense of a Scientific Journal Article

Understanding Clinical Studies (NIH)

A service of the National Library of Medicine, PubMed® contains publication information and (in most cases) brief summaries of articles from scientific and medical journals. For guidance from NCCIH on using PubMed, see How To Find Information About Complementary Health Approaches on PubMed .

Website: https://pubmed.ncbi.nlm.nih.gov/

NIH Clinical Research Trials and You

The National Institutes of Health (NIH) has created a website, NIH Clinical Research Trials and You, to help people learn about clinical trials, why they matter, and how to participate. The site includes questions and answers about clinical trials, guidance on how to find clinical trials through ClinicalTrials.gov and other resources, and stories about the personal experiences of clinical trial participants. Clinical trials are necessary to find better ways to prevent, diagnose, and treat diseases.

Website: https://www.nih.gov/health-information/nih-clinical-research-trials-you

National Heart, Lung, and Blood Institute (NHLBI)

The NHLBI Health Information Center provides information to health professionals, patients, and the public about heart, lung, and blood diseases and sleep disorders and accepts orders for publications.

P.O. Box 30105 Bethesda, MD 20824-0105

Toll-free in the U.S.: 1-877-NHLBI4U (1-877-645-2448)

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Auger RR, Burgess HJ, Emens JS, et al. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An update for 2015. Journal of Clinical Sleep Medicine . 2015;11(10):1199-1236.
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Del Fabbro E, Dev R, Hui D, et al. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. Journal of Clinical Oncology . 2013;31(10):1271-1276.
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Masters A, Pandi-Perumal SR, Seixas A, et al. Melatonin, the hormone of darkness: from sleep promotion to Ebola treatment. Brain Disorders & Therapy . 2014;4(1):1000151.
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Sletten TL, Magee M, Murray JM, et al. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: a double-blind, randomised clinical trial. PLoS Medicine . 2018;15(6):e1002587.
Tordjman S, Chokron S, Delorme R, et al. Melatonin: pharmacology, functions and therapeutic benefits. Current Neuropharmacology . 2017;15(3):434-443.
Vural EMS, van Munster BC, de Rooij SE. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. Drugs & Aging . 2014;31(6):441-451.
Wilt TJ, MacDonald R, Brasure M, et al. Pharmacologic treatment of insomnia disorder: an evidence report for a clinical practice guideline by the American College of Physicians. Annals of Internal Medicine . 2016;165(2):103-113.

Acknowledgments

NCCIH thanks D. Craig Hopp, Ph.D., and David Shurtleff, Ph.D., NCCIH, for their review of this publication.

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Screen Time and Sleep—It’s Different for Adults

By Mary Grace and Sharon Brock, MEd, MS

Many of us have heard that looking at our phones late at night can keep us awake due to light exposure, however, research shows this may be true for children, but there is not sufficient evidence to support this claim for adults .

“Young children have a greater sensitivity to light because more light gets to the retina of a child than an adult,” says Jamie Zeitzer, PhD, Co-Director of the Stanford Center for Sleep and Circadian Sciences. “Since adults have more opacities in their eyes and smaller pupils than children, less light passes through adult eyes, so there’s less of an effect on melatonin production.”

Melatonin is a hormone that makes us feel sleepy and is released when the eyes perceive darkness. Conversely, when we see natural light in the morning, we feel more awake because light hitting our eyes stops the production of melatonin.

Given this logic, it would seem reasonable that looking at our screens (smart phones, computers, iPads, etc.) at night could delay melatonin production and inhibit our ability to fall asleep, but Dr. Zeitzer says this is not the case.

While darkness enables melatonin production, suppressing melatonin production works by the brain comparing the amount of light we receive during at night with how much we received during the day. It’s the shift from light to dark that cues the release of melatonin, which is why we start to feel sleepy after the sun goes down.

Since natural sunlight emits 10,000-100,000 lux of light and phone screens emit 25-50 luxunder usual conditions at night, Dr. Zeitzer says the light from our screens doesn’t have much of an impact on the melatonin cueing process.

“There just isn’t that much light coming from your phone,” says Dr. Zeitzer. “As long as you go outside during the day and get exposed to the intensity of natural light then the amount of light from a screen in the evening most likely won’t halt the production of melatonin.”

If it’s Not Light, What Keeps us Up at Night?

Rather than light exposure, Dr. Zeitzer believes that what is keeping us awake is what we are watching on our screens. Millions of Americans stay awake at night scrolling on social media looking at page after page of emotionally activating content and writing posts that lead to likes, comments, and followers. Others stay up to play games on their phones or computers, all of which stimulate the dopamine reward system in the brain, which is the basis of addictive behaviors .

“In the past, when a television show ended, you turned off the TV and went to sleep because there was nothing else to do,” says Dr. Zeitzer. “But now you could watch Netflix, look at apps or play computer games all night because this entertainment has been commodified to engaged with it for as long as possible; it’s optimized to never stop playing and this is causing sleep deprivation.”

When watching screens before bed, Dr. Zeitzer recommends that we not only avoid content that could be distressing, but also content that could stir excitement within us.

“In order to fall asleep, we need to reduce stimuli exposure and calm our mind and body,” says Dr. Zeitzer. “Even if you’re watching something positive, if it stirs excitement, the brain will release dopamine, and over time we can develop a dopamine addiction, making staying awake playing games or on social media much more fun that going to sleep.”

Lastly, Dr. Zeitzer says that he can’t make a general statement that nighttime screen use negatively affects everyone’s sleep. For some, their addiction to games or apps could make falling asleep a challenge, while others may watch soothing nature videos on their phones to help them relax and fall asleep. Therefore, Dr. Zeitzer suggests that you take note of how screens are impacting your sleep health by asking yourself these questions:

Is the content of your screen time making you feel distressed or excited? If yes, then you should not look at screens for about an hour before bedtime to calm the mind and body and prepare for sleep.
Also, do you engage with screens throughout the night when you could be sleeping? If so, you may have a dopamine addiction that is making screen time activities more enjoyable than sleep.

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These Melatonin Supplements Were Trending on TikTok. So, I Tried the Viral Lemme Sleep Gummies for Myself

The sleep supplement market is overwhelming, so choosing one brand can be tricky. I tested Lemme Sleep for a month to see if they are worth the hype.

I tested Lemme Sleep to see if it would improve my sleep quality.

It’s no secret that sleep is essential to our well-being. However, it's common to struggle with getting enough sleep. Long-term sleep deprivation can have severe consequences and health implications, such as high blood pressure , diabetes, obesity and depression .

Like others, I struggle with getting enough rest and always look for ways to improve my sleep quality. I'd seen a few TikTok videos about the Lemme Sleep brand and the effectiveness of its sleep gummies, but I remained skeptical. I’ve tried countless sleep hacks, remedies and supplements over the years -- would this one be any different? I decided to jump on the bandwagon and give it a shot.

What is Lemme?

Lemme (or Lemme Live) is a vitamin brand created by American media personality Kourtney Kardashian Barker. The line features a variety of wellness supplements for sleep and de-stressing, boosting energy, digestive health, vaginal probiotics, fat-burning gummies and more. Kourtney explains on Lemme’s website that her mission was to develop vitamins and supplements with clinically backed ingredients that are also tasty.

I have to hand it to them -- Lemme’s marketing is superior. Its email campaigns and social media posts are aesthetically pleasing, striking a balance of simple and informative. It stays on top of trends and strategically offers attractive solutions to common health issues or insecurities many people face: Do you desire radiant hair and skin? Try the Lemme Glow gummies. Are you struggling to lose weight? Consider the Lemme Burn and Lemme Curb duo to combat fat and manage unwanted cravings. Do you want to be more productive throughout your busy day? Try the Lemme Matcha gummies for sustained energy and focus. The list goes on.

Lemme offers a variety of health supplements, not just sleep aids.

Initial thoughts on Lemme

The sleep gummies were sold out when I initially tried purchasing them, so I signed up for their emails. I was notified that they were back in stock a few days later and immediately ordered a bottle. Since signing up for their email and text campaigns just a couple of months ago, I’ve noticed that the Lemme Sleep gummies have gone out of stock multiple times -- a sign that they remain trendy.

Right away, I was impressed by the container. I am a sucker for good packaging, and Lemme nailed it. The bottle is fun, and the materials feel high-quality. It is made of 100% post-consumer recycled plastic, so no new plastic is created to make these bottles and caps. The mailers and shipping boxes are also recyclable and biodegradable, which I appreciate (and expect, quite frankly).

The Lemme Sleep gummies are packaged in fun, recycled plastic bottles.

Olly vs. Lemme

My Lemme Sleep gummies arrived just as I ran out of the Olly Sleep gummies I had been taking for the past month. Olly is a comparable brand that offers a variety of vitamins and supplements. With Olly Sleep, I noticed that while they would make me almost immediately sleepy, it was not always enough for me to get solid, deep sleep and stay asleep throughout the night -- my two main issues. However, they were consistent and certainly never made my sleep any worse.

To compare the ingredients:

Olly Sleep has melatonin, L-theanine and botanicals
Lemme Sleep has melatonin, L-theanine, magnesium and botanicals
Olly has 3 mg of melatonin, whereas Lemme Sleep has 5 mg
Olly has 100 mg of L-theanine, and Lemme Sleep has 50 mg

I had just finished a bottle of Olly Sleep when my Lemme Sleep gummies arrived.

Given that a serving of the Olly Sleep gummies has less melatonin but more L-theanine than Lemme Sleep, I wasn’t sure how the two would compare as far as my sleep quality.

To me, the berry flavor of Lemme Sleep tasted slightly better than Olly Sleep’s blackberry flavor, but I wouldn’t necessarily want to eat either of them like candy. The Lemme gummies dissolved much faster than Olly's, which are, well, gummier.

A bottle of Lemme Sleep has 60 gummies (30 servings) and costs $30. A bottle of Olly Sleep has 50 gummies (25 servings) and is priced at only $14 -- less than half the price. $30 for a bottle of dietary sleep supplements like this is one of the higher price tags I've seen.

My first night taking Lemme Sleep

While preparing for bed, I took the recommended dosage of two gummies. Less than 30 minutes later, I felt myself drift off to sleep. I remember feeling incredibly relaxed as if peacefully floating on a cloud. According to my sleep tracker , I slept for 10 hours and 4 minutes -- a new high score. I’m not sure that I’ve ever slept that long.

As shown in my sleep data below, I woke up a few times throughout the night but fell back asleep quickly each time. I didn’t remember having any crazy or bizarre dreams , which is unusual for me. I did wake up feeling rather groggy and probably would have slept even longer if my dog hadn’t woken me up asking to go outside.

In those 10 hours, I spent less than 1 hour in deep sleep (53 minutes) and most of the time in core/light sleep (7 hours). The recommended amount of deep sleep for adults is around 1.5 to 2 hours , or 20 to 25% of the total time asleep. Ideally, I would have spent 2 to 2.5 hours in deep sleep, which may explain why I woke up still tired -- that, or I “ overslept ” for the first time in years. My sleep latency , or the time it takes to fall asleep, was also very short.

After taking two Lemme Sleep gummies, I slept for a shocking 10 hours.

Overall, I was impressed by my experience on the first night of taking Lemme Sleep. My average sleep time is usually around 6.5 to 7 hours, so this was a surprisingly drastic difference. Needless to say, I began the trial with high expectations.

Is it OK to take sleep supplements every night?

Throughout my years of testing and researching various sleep aids , I have grown hesitant to rely heavily on supplements with melatonin. Dr. Navya Mysore , primary care physician and media health expert, confirmed these hesitations. "Sleep supplements are OK from time to time. Generally, I don't recommend them for everyday long-term use. Up to two months is OK while you are trying to figure out the source of the sleep issue, but long-term use of melatonin may affect how you naturally produce melatonin."

To avoid overdoing it and to test the actual effectiveness of Lemme Sleep, I varied the number of gummies I took each night. The instructions on Lemme's website also say that you can start with a one-gummy dose if you are looking for lighter sleep or want to see the effect before taking a two-gummy dose. Throughout the 24 days of my experiment, there were eight nights when I took two gummies, eight nights when I took one gummy and eight nights when I took none.

My second night taking Lemme Sleep

Having slept for a deliciously long time after the first night of taking Lemme Sleep, I was looking forward to it the next night. I only took one gummy and was surprised by the results. Like the first night, I fell asleep quickly. Unlike the first night, I slept for a measly 5 hours, 15 minutes, and spent over 2 hours awake throughout the night.

Of course, other factors could influence sleep quality, such as bedroom environment, stress levels , extraneous noises , exercise , etc. On this particular night, nothing out of the ordinary would have been to blame otherwise. For hours, I was awake, frustrated and confused about why I couldn’t sleep when the previous night had been so successful. It was as if taking one gummy had the opposite effect.

I slept half as long the second night as I did the first night after taking Lemme Sleep.

Trial and error: testing various amounts

About a week later, I had another 10-hour night after taking two Lemme Sleep gummies. Like that first night, I didn’t get as much deep sleep as I would have liked (less than an hour). I spent nearly an hour awake, which is more than preferred. Regardless, I woke up feeling refreshed and rejuvenated -- not as groggy as I had the first time.

The second (and final) night of getting 10 hours of sleep during the testing period.

My sleep data results

On average, I slept the most (around 8 hours per night) after taking two Lemme Sleep gummies. Compare that to a lower average of 7 hours, 22 minutes after taking one Lemme Sleep gummy, and the lowest of 6 hours, 38 minutes on nights when I took zero gummies.

I slept the most after taking two Lemme Sleep gummies, around 8 hours.

Though I slept the most after taking two Lemme Sleep gummies, it was not consistent, and it wasn't necessarily better sleep, as shown below. Toward the end of the trial, taking one gummy resulted in the most consistent sleep and the least amount of time awake. I was impressed by the low awake times I experienced after taking only one gummy. For four nights, I was awake for 6 minutes or less, which is a significant improvement.

I got the least amount of sleep on the nights when I took no gummies.

As far as my sleep cycle , the biggest difference is that I spent more time in light/core sleep after taking two gummies. Interestingly, my deep sleep remained roughly the same (about an hour) regardless of how many gummies I took. I spent just about as much time awake on nights when I had no gummies and nights when I took two. On the nights when I took only one gummy, I spent the least amount of time awake.

I spent the least time awake on nights when I took only one gummy.

Lemme break down the ingredients

In one serving (or two gummies), Lemme Sleep has:

5 mg of melatonin
20 mg of magnesium
50 mg of L-theanine
25 mg of a botanical blend (chamomile, lavender and elderberry)

Lemme Sleep has melatonin, magnesium, L-theanine and a proprietary herbal blend.

I consulted with Dr. Navya Mysore about these ingredients. “The melatonin dose is a good average amount -- usually what I recommend to my patients to try. Magnesium citrate is very low and not what I would suggest for sleep. I like magnesium bisglycinate ; about 400 mg before bed is a good dose. They are still trying to figure out the dosage for L-theanine and what would help with sleep, but 50 mg seems on the lower end.”

In regard to the botanical blend within the Lemme Sleep gummies, Dr. Mysore explains, “There is little evidence that the other ingredients [in the botanical blend] support sleep. In general, I'm not a fan when they try to mix many things into one supplement. It's often better to take the individual supplement where you can have a higher dose of the supplement itself.” This is a notion that I encountered from other online reviews of Lemme Sleep.

It’s also important to note the disclaimer on Lemme’s website, which reads, “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease .”

What people are saying about Lemme

Lemme’s vitamins and supplements are also available on Amazon , with mixed customer reviews. The Lemme Sleep gummies currently have a 3.8/5 star rating out of 1,150 reviews – 20% of which are 1 star. Most users who left negative reviews said that while the gummies are undeniably tasty, they didn’t seem to improve their sleep quality, and some reviewers claimed that they slept worse or were awake longer than usual throughout the night after taking them.

Fifty-seven percent of customers have left glowing five-star reviews on Amazon. Many said taking Lemme Sleep fixed their out-of-whack sleep schedules by helping them fall asleep faster and stay asleep longer. It would appear that the contrasting reviews, similar to my own experience, remain somewhat divided -- after all, sleep patterns, behaviors and reactions to supplements are extremely personal, subjective and different for everyone.

The reviews on Lemme Glow’s website are much more positive: currently, 80% of the reviews are five stars, and many users claim they are the best sleep supplements they’ve ever taken.

Final thoughts on the Lemme Sleep gummies

The inconsistencies in my sleep when taking the Lemme Sleep gummies were not what I expected. Sometimes, I would wake up feeling groggy; other times, I was wide awake and ready to start the day. Sometimes I would sleep for 10 hours, sometimes 5. Overall, it improved my sleep latency (the time it takes to fall asleep) and helped me get more sleep, on average, though not necessarily better sleep.

Toward the end of the experiment, I found that taking one gummy seemed to be the most effective in terms of keeping me asleep throughout the night. Moving forward, I’ll likely take the Lemme Sleep gummies on nights when I’m feeling especially sleep-deprived and have the time to potentially sleep for 10 hours.

Be sure to consult your doctor before trying Lemme Sleep or other dietary supplements. Generally, it’s best not to rely on a nightly sleep supplement and to work on naturally enhancing your body’s ability to produce melatonin. For additional ways to improve your sleep habits , Dr. Mysore recommends getting enough exercise, stopping caffeine intake by noon and limiting the number of caffeinated drinks you have (no more than two to three), having a consistent sleep/wake schedule , keeping the bedroom cool and turning off screens at least 1 hour before bed.

You should try the Lemme Sleep gummies if:

You regularly struggle to fall asleep and stay asleep
You want a sleep supplement with melatonin
You’re searching for a temporary solution for getting into a regular sleep pattern

You should skip the Lemme Sleep gummies if:

You don’t want a sleep supplement with multiple ingredients
You are looking for a consistent, long-term solution for insomnia
You're looking for a budget sleep supplement

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Melatonin: Facts, Extrapolations and Clinical Trials

J. a. boutin.

1 Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, University of Normandy, INSERM U1239, 76000 Rouen, France

D. J. Kennaway

2 Robinson Research Institute and Adelaide School of Medicine, University of Adelaide, Adelaide Health and Medical Science Building, North Terrace, Adelaide, SA 5006, Australia; [email protected]

3 Institut Cochin, Université Paris Cité, INSERM, CNRS, 75014 Paris, France; [email protected]

Associated Data

Not applicable.

Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the (generally) positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated. Based on the assumption that melatonin is safe, high doses have been administered to patients, including the elderly and children, in clinical trials. In this review, we critically review the corresponding literature, including the hypotheses that melatonin acts as a scavenger molecule, in particular in mitochondria, by trying not only to contextualize these interests but also by attempting to separate the wheat from the chaff (or the wishful thinking from the facts). We conclude that most claims remain hypotheses and that the experimental evidence used to promote them is limited and sometimes flawed. Our review will hopefully encourage clinical researchers to reflect on what melatonin can and cannot do and help move the field forward on a solid basis.

1. Foreword

A review is a survey of the existing literature on a given subject and the analysis of it by the author(s). Even if the interpretation of the author(s) about the facts is important, it should be identified as such. The present review presents a critical assessment of the existing literature on melatonin effects, including the conclusions drawn by their authors. Such a critical assessment is, by nature, subjective and has to be further discussed by the community in order to reach a consensus on where the field stands in terms of its hypotheses and facts. The new consensual hypothesis and perspective should then guide future research, which will go through the usual cycle of data acquisition that will then be submitted for peer review.

2. Background, Facts

Melatonin is a natural compound synthesized in the pineal gland during the nighttime, discovered by Lerner et al. [ 1 ].

Melatonin is synthesized in the pineal gland under the control of the hypothalamic suprachiasmatic nucleus, such that it is high during the night and low during the day. In humans, circulating melatonin is lowest during the day, at <2 pg/mL (8 pM), and is at 30–70 pg/mL (130–300 pM) during the night [ 2 ]. Of course, absolute concentrations can be misleading, as they depend on the age, conditions and health status of the patients; however, these levels are generally accepted by the community and were also validated in post-mortem measures of melatonin in human pineal glands [ 3 , 4 ]. The biosynthesis of melatonin is well established [ 5 , 6 ]. This cycle commands the wake/sleep cycle of almost all animals [ 7 ]. As the day length varies during the year, melatonin also indirectly commands the circannual rhythm and thus the reproduction season [ 8 ].

The main targets of endogenous melatonin in mammals are its two G-protein coupled receptors, MT 1 and MT 2, which have high affinities for the hormone 1 nM and lower. The receptors are activated by circulating levels of melatonin at night and are believed to translate most of its physiological actions [ 9 ].

3. Background, History

The history of melatonin use can be divided into two periods:

The first period is characterized by the establishment of a wide consensus about the nature of melatonin’s role, its synthesis and its regulation with outstanding discoveries on those subjects, and was followed by progress on the molecular mechanisms by which melatonin exerts its effect on biological rhythms [ 9 ] and sleep initiation [ 10 , 11 ]. In the meantime, the pharmaceutical industry described analogs of melatonin that serve as drugs in disordered sleep conditions [ 11 , 12 ], such as delayed sleep-wake phase disorder and jetlag, but also in cases where disrupted melatonin rhythmicity was associated with neurological conditions such as depression and anxiety [ 13 ], where they have been promising results based on standard clinical trials [ 14 , 15 ]. The present essay does not address this aspect of melatonin or its analogs (e.g., agomelatine, tasimelteon or ramelteon).

The second period of melatonin research is still ongoing and addresses the possible role of melatonin as an antioxidant and scavenger molecule; however, this is characterized by the absence of a general consensus in the field [ 16 ]. Hundreds of publications have proposed that melatonin can act as an agent to treat almost all the main disease conditions, such as cancers, obesity, Alzheimer’s, Parkinson’s and various virological problems, such as AIDS, Ebola and COVID-19 (see Table 1 ). We have previously reviewed several of these conditions, raising doubts about some claims [ 17 , 18 ], questioning whether a natural molecule could be used to treat so many diseases without actually addressing the mechanism(s) of actions or suggesting mechanisms of action that were independent of the melatonin receptors. Table 1 is mostly restricted to the more recent or significant claims. In short, this table essentially regroups the reviews in which the activity of melatonin on a given pathology is indicated/extrapolated. A common trait of most of these studies is the use of supra-physiological concentrations of melatonin (sometimes by six orders of magnitude higher than physiological concentrations). As pointed out earlier, “In principle, the established role of melatonin in rhythmic function is not necessarily incompatible with the use of high doses for ‘protective’ effects.” [ 19 ]; however, researchers need to carefully distinguish between the role of endogenous melatonin and the effects observed at high doses of exogenous melatonin. In a clinical setting, the question of specificity and side effects have to be carefully addressed at these supra-physiological concentration levels (see below).

A non-exhaustive list of the many claimed wonders of melatonin.

Pathological Conditions	Title		Exp/Rev	Melatonin Concentration
Aging	Melatonin as an Anti-Aging Therapy	[ ]	Rev
Aging	Protective Role of Melatonin and Its Metabolites in Skin Aging	[ ]	Rev
Alzheimer’s Disease	Mechanisms of Melatonin in Alleviating Alzheimer’s Disease.	[ ]	Rev
Anxiety	Melatonin as a Potential Approach to Anxiety Treatment.	[ ]	Rev
Atherosclerosis	Melatonin-based therapeutics for atherosclerotic lesions and beyond:	[ ]	Rev
Bacteria infection	Melatonin inhibits Gram-negative pathogens	[ ]	Exp	1 to 4 mM *
Cancer	Melatonin and cancer suppression: …	[ ]	Rev
Cancer	Melatonin Reverses the Warburg-Type Metabolism	[ ]	Exp	3.2 mM
Cancer	Oncostatic activities of melatonin: …	[ ]	Rev
Cardiovascular diseases	Evidence for the Benefits of Melatonin in Cardiovascular Disease	[ ]	Rev
Coronavirus infection	Melatonin and other indoles show antiviral activities	[ ]	Exp	3 mM **
Diabetes	Coadministration of Melatonin and Insulin Improves Diabetes-Induced…	[ ]	Exp	~40 µM **
Dislipidemia	The Mechanism of Oral Melatonin Ameliorates Intestinal and Adipose Lipid Dysmetabolis	[ ]	Exp	0.4 mg/mL ***
Ischemy (cellular)	Melatonin Attenuates Ischemic-like Cell Injury	[ ]	Exp	50 µM
Neurodegeneration	…New insights into the role of melatonin in neuronal recovery	[ ]	Rev
Neurodegeneration	Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders	[ ]	Rev
Parkinson’s Disease	Melatonin and Parkinson Disease: Current Status…	[ ]	Rev
SARS infection	Melatonin use for SARS-CoV-2 infection: …	[ ]	Rev
SARS infection	Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection	[ ]	Rev

* Assuming 100% passage in 30 g mice with 4 mL of blood; ** melatonin is not the best inhibitor among the indoles tested; *** of drinking water.

4. Melatonin Goes to Clinic Why? For What?

In order to be entered into a clinical trial, a compound should have shown activity on the defined pathological model(s), exhibit low or no toxicity and be superior to the existing drugs (if there are any). Dietary “supplements”, as melatonin is defined in the USA, do not have the same legal constraints as pharmaceuticals, and their marketing information must not infer their use to treat diseases.

In general, such clinical trials are directed at a specific pathological condition and are based on a body of relevant preclinical studies. In the case of melatonin, it seems that almost all the pathological conditions one can think of have been reported in the literature to be ameliorated by melatonin! Thus, the conditions for which melatonin has been tested in clinical studies are extensive and are listed in Table 2 and Table 3 . It is difficult to find a category that is not listed, and the immense spectrum of conditions reported to be treatable by melatonin is the obvious weakness of those claims.

“Main” categories under which the melatonin trials have been conducted.

Abnormalities, Multiple	Colitis	Genetic Diseases, Inborn	Musculoskeletal Abnormalities	REM Sleep Parasomnias
Acute Graft versus Host Disease	Colitis, Ulcerative	Genetic Diseases, X-Linked	Musculoskeletal Diseases	Renal Insufficiency
Acute Kidney Injury	Collagen Diseases	Genital Neoplasms, Female	Musculoskeletal Pain	Renal Insufficiency, Chronic
Acute Lung Injury	Colonic Diseases	Glioma	Myalgia	Reperfusion Injury
Acute Respiratory Distress Syndrome	Colonic Diseases, Functional	Glucose Intolerance	Myocardial Infarction	Respiration Disorders
Adnexal Diseases	Communicable Diseases	Glucose Metabolism Disorders	Myocardial Ischemia	Respiratory Aspiration
Alcoholism	Confusion	Gonadal Disorders	Narcolepsy	Respiratory Distress Syndrome
Alcohol-Related Disorders	Congenital Abnormalities	Growth Disorders	Necrosis	Respiratory Distress Syndrome, Infant
Alzheimer’s Disease	Connective Tissue Diseases	Head and Neck Neoplasms	Necrotizing Enterocolitis	Respiratory Distress Syndrome, Newborn
Anaplastic Astrocytoma	Consciousness Disorders	Head Injuries, Closed	Neoplasm Metastasis	Respiratory Hypersensitivity
Anaplastic Ependymoma	Constriction, Pathologic	Headache	Neoplasms by Histologic Type	Respiratory Tract Diseases
Anaplastic Oligodendroglioma	Coronary Artery Disease	Headache Disorders	Neoplasms, Germ Cell and Embryonal	Respiratory Tract Infections
Aneurysm	Coronary Disease	Headache Disorders, Primary	Neoplasms, Glandular and Epithelial	Respiratory Tract Neoplasms
Angelman Syndrome	Coronaviridae Infections	Heart Diseases	Neoplasms, Nerve Tissue	Retinal Diseases
Anorexia	Coronavirus Infections	Heart Failure	Neoplastic Processes	Rheumatic Diseases
Anxiety Disorders	COVID-19	Hemorrhage	Nervous System Neoplasms	RNA Virus Infections
Apnea	Cranial Nerve Diseases	Heredodegenerative Disorders, Nervous System	Neurobehavioral Manifestations	Schizophrenia
Arrhythmias, Cardiac	Craniocerebral Trauma	Hot Flashes	Neurocognitive Disorders	Schizophrenia Spectrum and Other Psychotic Disorders
Arterial Occlusive Diseases	Craniofacial Abnormalities	Hyperglycemia	Neurodegenerative Diseases	Sclerosis
Arteriosclerosis	Critical Illness	Hyperinsulinism	Neurodevelopmental Disorders	Seasonal Affective Disorder
Arthritis	Cysts	Hyperkinesis	Neuroectodermal Tumors	Seizures
Asphyxia	Death	Hyperlipidemias	Neuroectodermal Tumors, Primitive	Sensation Disorders
Asphyxia Neonatorum	Deglutition Disorders	Hyperlipoproteinemias	Neuroendocrine Tumors	Sepsis
Asthma	Delirium	Hyperphagia	Neuroepithelioma	Shock
Astrocytoma	Dementia	Hyperplasia	Neurologic Manifestations	Shock, Septic
Atrophy	Demyelinating Autoimmune Diseases, CNS	Hypersensitivity	Neuromuscular Diseases	Signs and Symptoms, Digestive
Attention Deficit and Disruptive Behavior Disorders	Demyelinating Diseases	Hypersensitivity, Immediate	Neurotoxicity Syndromes	Signs and Symptoms, Respiratory
Attention Deficit Disorder with Hyperactivity	Depression	Hypertension	Nevi and Melanomas	Skin Diseases
Autism Spectrum Disorder	Depression, Postpartum	Hyperthermia	Nevus	Skin Diseases, Eczematous
Autistic Disorder	Depressive Disorder	Hypothermia	Nevus, Pigmented	Skin Diseases, Genetic
Autoimmune Diseases	Depressive Disorder, Major	Hypoxia	Nidovirales Infections	Skin Manifestations
Autoimmune, Diseases of the Nervous System	Dermatitis	Hypoxia, Brain	Non-24-Hour Sleep-Wake Disorder	Sleep Apnea Syndromes
Autonomic Nervous System Diseases	Dermatitis, Atopic	Hypoxia-Ischemia, Brain	Nutrition Disorders	Sleep Apnea, Obstructive
Basal Ganglia Diseases	Developmental Disabilities	Immune System Diseases	Obesity	Sleep Deprivation
Behavioral Symptoms	Diabetes Complications	Infant, Newborn Diseases	Obstetric Labor Complications	Sleep Disorders, Circadian Rhythm
Bipolar and Related Disorders	Diabetes Mellitus	Infant, Premature, Diseases	Obstetric Labor, Premature	Sleep Disorders, Intrinsic
Bipolar Disorder	Diabetes Mellitus, Type 1	Infarction	Occupational Diseases	Sleep Initiation and Maintenance Disorders
Blindness	Diabetes Mellitus, Type 2	Infections	Oculo-cerebral Syndrome With Hypopigmentation	Sleep-Wake Disorders
Body Temperature Changes	Diabetic Angiopathies	Infertility	Oligodendroglioma	Sleepiness
Body Weight	Diabetic Retinopathy	Infertility, Female	Orthostatic Intolerance	Smith-Magenis Syndrome
Body Weight Changes	Digestive System Diseases	Inflammation	Osteoporosis	Spinal Cord Diseases
Bone Diseases	Digestive System Neoplasms	Inflammatory Bowel Diseases	Ovarian Cysts	Spinal Cord Injuries
Bone Diseases, Metabolic	Disease Attributes	Insulin Resistance	Ovarian Diseases	ST Elevation
Brain Concussion	Disease Progression	Intellectual Disability	Overnutrition	Myocardial Infarction
Brain Diseases	Disorders of Excessive Somnolence	Intestinal Diseases	Overweight	Stomatitis
Brain Diseases, Metabolic	Dyskinesias	Intracranial Hemorrhages	Pain	Stomatognathic Diseases
Brain Infarction	Dyslipidemias	Irritable Bowel Syndrome	Pain, Post-operative	Stomatognathic System
Brain Injuries	Dyspepsia	Ischemia	Paralysis	Abnormalities
Brain Injuries, Traumatic	Dyssomnias	Ischemic Stroke	Parasomnias	Stress Disorders, Traumatic
Brain Ischemia	Eczema	Jet Lag Syndrome	Parkinson’s Disease	Stress, Psychological
Brain Neoplasms	Emergence Delirium	Joint Diseases	Parkinsonian Disorders	Stroke
Breast Diseases	Emergencies	Kidney Diseases	Pathological Conditions, Anatomical	Substance-Related Disorders
Breast Neoplasms	Encephalomyelitis	Kidney Failure, Chronic	Pediatric Obesity	Syndrome
Bronchial Diseases	Endocrine System Diseases	Lens Diseases	Periodontal Diseases	Synovial Cyst
Burning Mouth Syndrome	Endometriosis	Lipid Metabolism Disorders	Periodontitis	Synucleinopathies
Burns	Enterocolitis	Liver Cirrhosis	Personality Disorders	Systemic Inflammatory Response Syndrome
Cachexia	Enterocolitis, Necrotizing	Liver Diseases	Photophobia	Tauopathies
Calcinosis	Ependymoma	Lower Urinary Tract Symptoms	Pneumonia	Thoracic Neoplasms
Calcium Metabolism Disorders	Epilepsy	Lung Diseases	Pneumonia, Viral	Tooth Diseases
Carcinoma	Esophageal Diseases	Lung Diseases, Obstructive	Poisoning	Toxemia
Carcinoma, Non-Small-Cell Lung	Esophageal Motility Disorders	Lung Injury	Polycystic Ovary Syndrome	Trauma, Nervous System
Cardiomyopathies	Esophageal Spasm, Diffuse	Lung Neoplasms	Post-operative Complications	Travel-Related Illness
Carotid Artery Diseases	Essential Hypertension	Mania	Precancerous Conditions	Tuberous Sclerosis
Carotid Stenosis	Eye Diseases	Maxillofacial Abnormalities	Prediabetic State	Tuberous Sclerosis Complex
Cataract	Familial Alzheimer Disease	Melanoma	Pregnancy Complications	Ulcer
Central Nervous System Diseases	Fatigue	Menopause	Premature Birth	Urogenital Neoplasms
Central Nervous System Infections	Fatigue Syndrome, Chronic	Menstruation Disturbances	Primary Dysautonomias	Urologic Diseases
Central Nervous System Neoplasms	Feeding and Eating Disorders	Mental Disorders	Problem Behavior	Urological Manifestations
Cerebral Infarction	Fetal Diseases	Metabolic Diseases	Prostatic Diseases	Uterine Cervical Diseases
Cerebral Palsy	Fetal Growth Retardation	Metabolic Syndrome	Pruritus	Uterine Cervical Neoplasms
Cerebrovascular Disorders	Fever	Migraine Disorders	Psychomotor Agitation	Uterine Diseases
Chemically-Induced Disorders	Fibrosis	Mood Disorders	Psychomotor Disorders	Uterine Neoplasms
Child Development Disorders, Pervasive	Flaviviridae Infections	Mouth Diseases	Psychotic Disorders	Vascular Diseases
Chromosome Disorders	Fractures, Bone	Movement Disorders	Puerperal Disorders	Vascular System Injuries
Chronic Graft Versus Host Disease	Frailty	Mucinoses	Quadriplegia	Virus Diseases
Chronic Pain	Ganglion Cysts	Mucositis	Quality of Life	Vision Disorders
Chronic Periodontitis	Gastroenteritis	Multiple Sclerosis	Radiation Injuries	Wasting Syndrome
Chronobiology Disorders	Gastroesophageal Reflux	Multiple Sclerosis, Relapsing-Remitting	Radiodermatitis	Weight Gain
Cognition Disorders	Gastrointestinal Diseases	Muscular Atrophy	Recurrence	Weight Loss
Cognitive Dysfunction	Gastrointestinal Neoplasms	Muscular Diseases	REM Sleep Behavior Disorder

Each category corresponds to a single trial for melatonin effect(s).

Acanthosis Nigricans	Chromosome Deletion	Hepatitis	Marijuana Abuse	Prognathism
Acid-Base Imbalance	Chronic Disease	Hepatitis A	Melanosis	Prostatic Hyperplasia
Acidosis	Cluster Headache	Hepatitis C	MELAS Syndrome	Prostatic Neoplasms
Acquired Immunodeficiency Syndrome	Colic	Hepatitis C, Chronic	Memory Disorders	Psychophysiologic Disorders
ACTH-Secreting Pituitary Adenoma	Colonic Neoplasms	Hepatitis, Chronic	Mental Retardation, X-Linked	Rare Diseases
Acute Coronary Syndrome	Colorectal Neoplasms	Hepatitis, Viral, Human	Metabolism, Inborn Errors	Retinal Degeneration
Acute Mountain Sickness	Communication Disorders	Herpes Genitalis	Microvascular Angina	Retrognathia
Adamantinoma	Constipation	Herpes Simplex	Migraine with Aura	Rupture
Adrenal Gland Diseases	Contusions	Herpesviridae Infections	Migraine without Aura	Salivary Gland Diseases
Adrenal Insufficiency	Craniopharyngioma	Hip Fractures	Monosomy	Sarcopenia
Adrenocortical Hyperfunction	Crohn Disease	Hip Injuries	Mouth Neoplasms	Scoliosis
Aggression	Cushing Syndrome	HIV Infections	Mouth, Edentulous	Seizures, Febrile
Alcohol Drinking	Delayed Emergence from Anesthesia	Hodgkin Disease	Multiple Myeloma	Self-Injurious Behavior
Alternating Hemiplegia of Childhood	Dengue	Hodgkin Lymphoma	Multiple System Atrophy	Septo-Optic Dysplasia
Altitude Sickness	Dengue Fever	Huntington Disease	Myocardial Reperfusion Injury	Septo-optic Dysplasia Spectrum
Alveolar Bone Loss	Dentofacial Deformities	Hyperadrenalism	Myofascial Pain Syndromes	Severe Acute Respiratory Syndrome
Ameloblastoma	Depressive Disorder, Treatment-Resistant	Hyperandrogenism	Narcotic-Related Disorders	Sex Chromosome Disorders
Amino Acid Metabolism, Inborn Errors	Diabetes Insipidus	Hyperpigmentation	Neonatal Sepsis	Sexually Transmitted Diseases
Anaplastic Oligoastrocytoma	Diabetes Insipidus, Neurogenic	Hypertension, Portal	Neoplasms, Neuroepithelial	Sexually Transmitted Diseases, Viral
Aneuploidy	Diarrhea	Hypertension, Pregnancy-Induced	Neoplasms, Plasma Cell	Shy-Drager Syndrome
Anodontia	Diffuse Large B-Cell Lymphoma	Hypo-hidrotic Ectodermal Dysplasia	Neoplasms, Squamous Cell	Skin Abnormalities
Anorexia Nervosa	DNA Virus Infections	Hypokinesia	Nervous System Malformations	Skin Diseases, Infectious
Aortic Aneurysm	Drug-Resistant Epilepsy	Hypopituitarism	Neuromuscular Manifestations	Skin Diseases, Viral
Aortic Aneurysm, Abdominal	Drug-Related Side Effects and Adverse Reactions	Hypotension	Night Eating Syndrome	Somatoform Disorders
Aortic Diseases	Dysbiosis	Hypotension, Orthostatic	Nocturia	Speech Disorders
Aphasia	Dyskinesia, Drug-Induced	Hypothalamic Diseases	Nocturnal Enuresis	Spinal Curvatures
Arbovirus Infections	Dysmenorrhea	Hypothalamic Obesity	Obesity, Morbid	Spinal Diseases
Arthritis, Juvenile	Ear Diseases	Idiopathic Hypersomnia	Oligoastrocytoma	Squamous Cell Carcinoma of Head and Neck
Arthritis, Rheumatoid	Ectodermal Dysplasia	Immunoproliferative Disorders	Opioid-Related Disorders	Stillbirth
Atrial Fibrillation	Ectodermal Dysplasia 1, Anhidrotic	Inborn Amino Acid Metabolism Disorder	Optic Nerve Diseases	Stress Disorders, Traumatic, Acute
B-cell Lymphoma	Emaciation	Influenza, Human	Optic Nerve Hypoplasia	Substance Withdrawal Syndrome
Back Pain	Endotoxemia	Intestinal Neoplasms	Oral Cancer	Sunburn
Bacteremia	Enterovirus Infections	Intracranial Aneurysm	Oral Leukoplakia	Tachycardia
Barrett Esophagus	Enuresis	Intracranial Arterial Diseases	Oral Squamous Cell Carcinoma	Tachycardia, Sinus
Binge-Eating Disorder	Epilepsy, Generalized	Intracranial Hemorrhage, Traumatic	Osteoarthritis	Tardive Dyskinesia
Birth Weight	Epileptic Syndromes	Intraocular Melanoma	Osteoarthritis, Knee	Thoracic Injuries
Blood-Borne Infections	Erythema	Jaw Abnormalities	Osteoporosis, Postmenopausal	Tic Disorders
Bone Neoplasms	Eye Diseases, Hereditary	Jaw Diseases	Otorhinolaryngologic Diseases	Tics
Bone Resorption	Eye Neoplasms	Lacerations	Pancreatic Cancer	Tinnitus
Borderline Personality Disorder	Facies	Language Disorders	Pancreatic Neoplasms	Tobacco Use Disorder
Brain Damage, Chronic	Femoral Fractures	Leg Injuries	Pelvic Pain	Tooth Abnormalities
Brain Diseases, Metabolic, Inborn	Fetal Alcohol Spectrum Disorders	Lennox Gastaut Syndrome	Periodontal Atrophy	Tooth Loss
Bronchial Neoplasms	Fetal Death	Leukoencephalopathies	Phenylketonurias	Tooth, Impacted
Bronchitis	Fetal Membranes, Premature Rupture	Leukoplakia	Photosensitivity Disorders	Tourette Syndrome
Bulimia	Fibromyalgia	Leukoplakia, Oral	Picornaviridae Infections	Trauma and Stressor Related Disorders
Bulimia Nervosa	Flavivirus Infections	Lewy Body Disease	Pigmentation Disorders	Trigeminal Autonomic Cephalalgias
Burnout, Psychological	Flushing	Lightning Injuries	Pinealoma	Unconsciousness
Carcinogenesis	Fragile X Syndrome	Liver Failure	Pineocytoma	Urinary Incontinence
Carcinoma, Bronchogenic	Genital Neoplasms, Male	Low Back Pain	Pituitary ACTH Hypersecretion	Urination Disorders
Carcinoma, Squamous Cell	Headache Disorders, Secondary	Lymphatic Diseases	Pituitary Diseases	Uterine Hemorrhage
Cardiac Conduction System Disease	Hearing Disorders	Lymphoma	Post-Concussion Syndrome	Uveal Diseases
Caregiver Burden	Heat Stress Disorders	Lymphoma, B-Cell	Post-operative Cognitive Complications	Uveal Neoplasms
Central Diabetes Insipidus	Hematoma	Lymphoma, Large B-Cell, Diffuse	Postpartum Hemorrhage	Vector Borne Diseases
Cerebral Hemorrhage	Hematoma, Subdural	Lymphoma, Non-Hodgkin	Postural Orthostatic Tachycardia Syndrome	Viral Hemorrhagic Fever
Childhood Acute Lymphoblastic Leukemia	Hematoma, Subdural, Chronic	Lymphoproliferative Disorders	Prader-Willi Syndrome	Vision, Low
Chorea	Hemiplegia	Lymphosarcoma	Prehypertension	X-linked Hypo-hidrotic Ectodermal Dysplasia
Chorioamnionitis	Hemorrhagic Fevers, Viral	Macular Degeneration	Premenstrual Dysphoric Disorder	Xerostomia
Chromosome 17p Deletion	Hepatic Encephalopathy	Malocclusion, Angle Class III	Premenstrual Syndrome
Chromosome Aberrations	Hepatic Insufficiency	Mandibular Diseases	Primary Orthostatic Hypotension

In brief, whenever a clinical trial is launched, if declared on the official site ( www.ClinicalTrials.gov , accessed on 23 January 2023, see below), the declaration comprises a series of keywords/categories, according to which the compound tested would have an effect—presumably—on the disease discussed (See Table 2 and Table 3 for an exhaustive list of such keywords linked to actual clinical studies, past, present and future).

One should recall (i) all the studies on a compound are not necessarily declared on this site, and (ii), more surprisingly, the data obtained are not necessarily published or made public. They belong to the initiator of the study and remain its property, translating into an absence of published results in most cases.

One should also point out that some of these studies are purely observational, aimed at measuring the levels of melatonin in patients with particular pathological conditions.

5. Clinical Studies

Melatonin is sold over the counter in several Western countries, such as Western Europa and the USA, in doses ranging from 1 to 10 mg. In clinical trials, doses of up to 100 mg have been reported (see Table 4 ). Several studies on humans showed that 100 mg of melatonin would result in a plasma Cmax of 1,252,500 pg/mL [i.v., bolus [ 39 ]] or 101 163 pg/mL [oral [ 40 ]]. Incidentally, 100 mg can be considered a huge dosage—the maximal level recorded in the complete review of Harpsøe et al. [ 41 ]. This raises the question of the safety of such doses. Because melatonin is considered a natural agent and not a drug, it is accessible without prescription in the USA, Canada and some other Western countries. There have been no large, long-term, high-quality randomized clinical trials specifically addressing melatonin safety in adults or children, probably because no Phase I information is required prior to commencing a clinical trial. It is unlikely that manufacturers and suppliers of melatonin as a dietary supplement would ever sponsor such an expensive trial. Nevertheless, melatonin is said to have a benign safety profile [ 42 ], yet this flies in the face of the multitude of physiological systems that melatonin has been associated with that are unrelated to any role in sleep. In a recent review, interactions with the cardiovascular, reproductive, endocrine and metabolic systems in humans were discussed, along with prescription drug interactions [ 43 ]. These interactions were discovered in controlled experiments in healthy subjects; we do not know what the effects of melatonin might be for people with cardiovascular diseases, diabetes, cancer, etc. A drug can only be termed safe in relation to what has been investigated. Nevertheless, even in 2023, researchers are calling for studies on the long-term safety of melatonin [ 44 , 45 , 46 ]. In the meantime, we are left with a somewhat patchy data collection via poison centers receiving information on adverse events ( www.poison.org/ accessed on 4 February 2023). Indeed, the review by Vines et al. [ 47 ] indicated that no formal safety trials had been performed. All the available information in the public domain comes from poison and other centers, as briefly summarized here: “Health Information” given by the NIH on the side effects of melatonin mentions headaches, dizziness, nausea and sleepiness, with the possible long-term side effects remaining unclear [ 48 ]. Furthermore, a recent report by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) reached a similar conclusion based on 90 responses collected in a nutri-vigilance program between 2009 and 2017 [ 49 ], which was complemented by similar data available from other European countries and Canada [ 50 ]. Of note, the alert put forward a possible link between melatonin and infant sudden death syndrome [ 51 ]. While this study could not directly attribute these infant deaths to the use of melatonin, they concluded that “Melatonin is not known to be acutely toxic; however, it causes a multitude of systemic effects by way of mechanisms of action that are not entirely understood, especially in developing infants.” More guidance is critical for parents and pediatricians who use melatonin as a routine sleep aid for young children. This caution is also shared by another group in their recent communication [ 52 ] (see also Section 6 ).

Details of the currently recruiting trials on melatonin.

Conditions	Number Patients	Treatment	Duration (Days) (Years)	Observational
Smith-Magenis syndrome	8		1	Mel measure	NCT02180451
Autism	105		3	Mel measure	NCT02878499
Cushing disease	15		90	Mel measure	NCT03343470
Breast Neoplasms	27		270	Mel measure	NCT04364347
Alzheimer’s Disease	60		*	Mel measure	NCT04522960
Sleep deprivation	20		32	Mel measure	NCT04868539
Frail Elderly	300		3	Mel measure	NCT05107947
Hypo-hidrotic Ectodermal Dysplasia	80		10	Mel measure	NCT05378932
Bipolar disorder	80		2	Mel measure	NCT05413486
Alzheimer’s Disease	164		42	Mel measure	NCT05543681
Sleep Disturbance	60		3	Mel measure	NCT05647148
Hypoxic-ischemic Encephalopathy	70	0.5–5 mg	14		NCT02621944
Delirium	190	4 mg	28		NCT03438526
Multiple Progressive Primary Sclerosis	50	100 mg daily	2		NCT03540485
Alzheimer’s Disease	230	5 mg daily	231		NCT03954899
Osteopenia	40	5 mg daily	1		NCT04233112
Attention Deficit Hyperactivity Disorder	80	3 mg daily	0.5		NCT04318067
Postoperative delirium	790	4 mg daily	10		NCT04335968
Huntington’s Disease	20	5 mg daily	63		NCT04421339
COVID-19 infection	30	3 × 10 mg daily	28		NCT04474483
Diabetic Eye Problems	36	3 mg daily	14		NCT04547439
Post-operative pain	60	10 mg 3 days	21		NCT04791943
Osteoarthritis	252	5 mg daily	60		NCT04795336
Traumatic Brain Injury	110	3–5 mg daily	30		NCT04932096
Necrotizing Enterocolitis	100	6 mg daily	150		NCT05033639
Emergence Agitation	117	5 mg pre-op ***	1		NCT05223010
Ischemic Stroke	80	3 mg daily	14		NCT05247125
Hypertension	23	1 mg daily	1		NCT05257291
PD	50	5 mg daily	28		NCT05307770
Epilepsy	120	5 mg daily	28		NCT05439876
Post-menopause insomnia	14	2 mg daily	15		NCT05440734
Chronic Fatigue Syndrome	106	1 mg daily	28		NCT05454683
Uveal Melanoma	100	20 mg daily	5		NCT05502900
Severe Preterm Fetal Growth Restriction	336	3 × 10 mg daily **	126		NCT05651347

* From 2 days to 2 years. ** Treatment to the mother, not clearly stating for how many days.*** Pre-op means pre-operation.

Interrogating the www.ClinicalTrials.gov site (accessed on 23 January 2023), we found an impressive number (742) of clinical studies on melatonin on the conditions listed in Table 2 and Table 3 . The condition list can be divided into two parts: the “generic” ones; these 399 conditions regroup several trials ( Table 2 ), for example, “Mental disorders” containing 279 studies, such as “psychosis & sleep”, “Rapid Eye Movement, Sleep Behavior Disorder & Parkinson Disease” etc., and the “unique” ones (296), corresponding to a single study, such as “Digestive system diseases or Necrotizing Enterocolitis” or “Bacteremia or Human Endotoxaemia”, etc. ( Table 3 ). By tapping the conditions into the search query on the site, one can have access to the trials and their details.

This body of trials comprises all the declared trials in the past, present and future. As a basis for comparison, we did the same query for “resveratrol”, a natural product also reported having many beneficial actions in traditional medicine, and found 147 studies, or “vitamin C”, and found 453 trials (400 of which are completed). Melatonin has attracted a lot of attention, as the diversity of conditions (and thus of pathological conditions) covers most, if not all, human diseases.

From the trial list, we have removed 118 conditions where the status is “unknown”. Another 40 studies were reportedly withdrawn, without obvious reasons, but one might speculate that this was due to difficulties in recruiting patients or to the lack of results, particularly on delirium prophylaxis, Parkinson’s disease, coronary artery calcification, intensive care elderly population or “melatonin inhibition of NLRP3 inflammasome in COVID19 patients”, to name only but a few.

Looking at the 56 trials currently recruiting, one can separate them into two main categories: observational and interventional. The first section, “observational”, comprises all the studies in which the patient’s melatonin levels are measured as a function of (i) their pathological conditions and (ii) their daily circadian rhythms. Those studies are basically clinical biochemistry research trials and are extremely useful for our understanding of the dependence of circadian rhythms on pathological conditions. Among the pathological conditions that have been studied are Cushing’s syndrome, autism, hypo-hidrotic ectodermal dysplasia, bipolar disorder, frail elderly, etc. The data arising from those studies may be expected to have a major impact on our understanding of how melatonin synthesis and release are influenced by pathological conditions. In our view, those studies are quite important, hopefully leading to scientific paper(s) explaining the results, as those in the Harpsoe et al. review [ 41 ], including the negative results in which the melatonin rhythm remains completely “normal”.

The intervention group comprises all the studies in which melatonin is tested as a therapeutic agent. Table 4 lists 35 recruiting studies, which are both interventional and observational. It is clear that the conditions studied are numerous and diverse, including cognitive dysfunction, bone diseases, attention deficit and disruptive behavior disorders, bone fractures, chorea, coronavirus infections, diabetes complications, post-operative pain, arthritis and traumatic brain injuries.

Because cancer is one of the most documented and searched domains in pathology, we have selected the trials in which cancer patients were treated with melatonin. Sixty-five studies tested its effectiveness in various cancer-related parameters, such as a loss of appetite, sleep quality, etc. Those studies also comprised trials in which the effects of melatonin as an anti-cancer adjuvant or drug, with direct effects on the disease itself, were reported. Half of the trials are reported as completed (32 studies), yet only the following four had published their results. We have briefly summarized their results and their conclusions:

Trial {"type":"clinical-trial","attrs":{"text":"NCT00513357","term_id":"NCT00513357"}} NCT00513357 (USA): Conclusion: “In cachectic patients with advanced cancer, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo” [ 53 ].

Trial {"type":"clinical-trial","attrs":{"text":"NCT00668707","term_id":"NCT00668707"}} NCT00668707 (Canada): Conclusion: “Melatonin may benefit cancer patients who are also receiving chemotherapy, radiotherapy, supportive therapy or palliative therapy by improving survival and ameliorating the side effects of chemotherapy” [ 54 ].

Trial {"type":"clinical-trial","attrs":{"text":"NCT00925899","term_id":"NCT00925899"}} NCT00925899 (Denmark): Conclusion: “In the current study, oral melatonin at a dose of 20 mg was not found to improve fatigue or other symptoms in patients with advanced cancer” [ 55 ].

Trial {"type":"clinical-trial","attrs":{"text":"NCT04137627","term_id":"NCT04137627"}} NCT04137627 (Indonesia): Conclusion: “In patients with squamous cell carcinoma of the oral cavity, the addition of 20-mg melatonin to neoadjuvant chemotherapy reduced the expression of miR-210 and CD44 and decreased the percentage of tumor residue; however, no statistically significant result was observed”.

The survey of those trials currently recruiting is a good image of the other ongoing trials: from those using small to large dosages of melatonin, 50 to 100 patients, spanning a month to more than a year. We would argue that the spectrum of diseases and/or conditions cannot seriously be attributed to a single melatonin-related cause.

It is very often under-regarded that melatonin has poor bioavailability. Indeed, the vast majority (>80%) of melatonin is hydroxylated by cytochrome P450 [ 56 ], conjugated with sulphate or glucuronic acid and excreted as conjugates [ 57 ], which is a classical scheme in drug metabolism. Melatonin is also a substrate of the indoleamine 2,3-dioxygenase, leading to the opening of the indole cycle, leading to AFMK (N1-acetyl-N2-formyl-5-methoxykynurenamine), which is then rapidly metabolized further to AMK (N1-acetyl-5-methoxykynurenamine) [ 58 ].

The wide range of dosages for the patients undergoing these recruiting trials varies from 0.5 to 100 mg, with most of them in the low milligram range. Once again, one should recall that at low ‘physiological’ doses—those in the 1 to 3 mg range, the resulting C max is low (~10 nM), even if it is two orders of magnitude higher than the nocturnal produced level. If one is given 100 mg, the circulating concentration of the compound is in the 0.5 µM range [ 40 ], as reviewed by Harpsoe et al. [ 41 ], although both concentrations vary widely between the various studies. Furthermore, the first pass principle of drug metabolism [ 59 ] clearly states that roughly half of the dose in the blood is eliminated by the liver minutes after ingestion and even shorter if injected intravenously [ 60 ]. This principle translates into the fact that melatonin remains in the µM range concentrations in the blood for a few minutes.

In the preclinical studies upon which trials are usually based, melatonin was generally used at concentrations higher than 1 µM—and even 1 mM. Thus, those concentrations are not expected to be naturally reached in living animals or in humans, and certainly not for prolonged periods. Thus, the transposition to clinical trials of those data might be considered more an act of faith than an experimental reality.

The main issue to be considered here is that nearly 4000 patients have entered these trials and have been treated with 0.5 mg to 100 mg melatonin daily. Furthermore, some of those studies are designed to run for very long periods (for several years, in some cases). In one clinical trial on melatonin and autoimmune diseases (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03540485","term_id":"NCT03540485"}} NCT03540485 , accessed on 23 January 2023), it is planned that 50 patients recruited because of their neurological conditions will receive a daily administration of 100 mg of melatonin, or a placebo, orally between 10 pm and 11 pm for 24 months. Finally, several studies are using newborn children (from a few hours to a few days old) with quite desperate health conditions—a feature that is commented on below.

In a survey (meta-analysis) of melatonin used for cardio-protection, the authors stated that the data was difficult to generalize due to the numerous possible biases, the low number of patients and their high heterogeneity [ 61 ]. Note that the combined number of patients was 396, half of which were tested with a placebo across six studies. Three of these studies were labeled as ‘no or poor effect’ (of melatonin as cardio-protectors). The doses were from 12 to 50 mg orally plus 1 or 2 mg intracoronary. Finally, the only study where the myocardial IR injury site was assessed using resonance imaging was classified as ‘no effect’ [ 62 , 63 ]. Incidentally, one of those articles stated, “…treatment with melatonin was associated with a larger infarct size in the group of patients” [ 63 ].

In conclusion, many clinical studies appear to have been based on scientifically poor experimental (preclinical) studies or overenthusiastic interpretations of the preclinical experimental data, thus explaining the overall poor outcome of these studies. The use of small populations of patients—elderly people as well as infants and toddlers in desperate health conditions—may have ethical considerations.

6. Melatonin in Kids

The first reports of the administration of melatonin to children were conducted by Jan and colleagues more than 28 years ago [ 64 , 65 , 66 ] in attempts to modify their disordered sleep resulting from neurodevelopmental disorders or blindness. Since that time, there have been many studies published on the pediatric use of melatonin, generally in children with comorbidities, such as autism spectrum disorder or attention deficit/hyperactivity disorder [ 44 ], as opposed to typically developing children with sleep problems. The majority of studies conducted in both adults and children have been small and short-term, although there are reports of treatments continuing for many years outside of the trials. The melatonin used in trials has usually been an immediate release preparation from non-pharmaceutical companies (dietary supplement manufacturers or chemical suppliers), with the first pharmaceutical preparation, Circadin, being approved in Europe in 2007. Circadin, a prolonged-release formulation, is authorized for the short-term treatment of primary insomnia in adults aged 55 years and older. It was not until 2018 that a formulation, Slenyto, was approved in Europe for the treatment of insomnia in children from 2 years of age with autism spectrum disorder and Smith–Magenis syndrome. With respect to the efficacy of melatonin in improving sleep in children presenting with sleep disorders, there is evidence that melatonin can have a role in those with neurodevelopmental disorders [ 42 , 67 , 68 ]; however, the effects are modest [ 43 ].

Since melatonin in the USA is not considered a drug, there is no requirement to report adverse events. The latest such report, covering 2012–21, documented more than 250,000 pediatric ingestions, 45,000 symptomatic effects, 3211 serious outcomes and 2 deaths [ 69 ]. Further, unintentional melatonin ingestion and its related hospitalizations and serious outcomes are increasing in the USA [ 69 ]. A separate recent study reported seven undetermined deaths of infants and toddlers with high exogenous melatonin as a result of deliberate or incidental ingestion of melatonin [ 51 ]. Based on these observations, careful evaluation and caution might be wise before administering melatonin to young children.

It is true that one cannot be sure that melatonin played a significant role in the deaths of infants. It is, however, an indication that melatonin is being recklessly administered to children in the absence of any formal safety information. Even the pharmaceutical companies that sell melatonin say not to take melatonin during pregnancy or when breastfeeding.

The uncertainty about the use of (high dosages of) melatonin by mothers during pregnancy and lactation remains. Indeed, in their thorough review of the subject, Vine et al. [ 47 ] concluded, “clinical studies to date suggest that melatonin use during pregnancy and breastfeeding is probably safe in humans and emphasizes the need for clinical studies…, including exogenous melatonin, during pregnancy and lactation”. The key word, for us, is certainly “probably safe”. To the best of our knowledge, no actual trial results whose primary outcomes were the safety or efficacy of melatonin for insomnia or other sleep disorders during pregnancy and lactation have been issued. Furthermore, no trial comprising “lactation” has been declared on the trial site.

Overall, our feeling is that, while the study could not directly attribute the deaths to the use of melatonin, they concluded that “Melatonin is not known to be acutely toxic; however, it causes a multitude of systemic effects by way of mechanisms of action that are not entirely understood, especially in developing infants. More guidance is critical for parents and pediatricians who use melatonin as a routine sleep aid for young children” [ 51 ].

7. Some Proposed Mechanisms behind the Claimed Beneficial Effects of Melatonin

7.1. melatonin as an antioxidant, 7.1.1. melatonin as a scavenger.

In an initial influential paper, melatonin, as well as other indole-based molecules, was shown to be a good scavenger in an a-cellular system. Then, to render the experiment transposable to a “living” system, the tissue homogenate was added to the medium, and it was found that the trapping operation still occurred. Thus, melatonin was called a scavenger. As a direct consequence, more than 1727 (23 February 2023) articles have been published using the words “melatonin” and “scavenger”. The initial publications can be pinpointed to Poeggeler et al. [ 70 ] and. The influence of this statement can be seen through the evolution of the number of papers appearing in the literature over the years after this publication ( Figure 1 A). The possibility that melatonin could be an antioxidant molecule appeared early in 1958. Ever since this date, publications formulating hypotheses or reporting experiments started to appear in the literature. On 25 March 2023, a query of “melatonin” + “antioxidant” returned 24,271 results (see Figure 1 B).

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PubMed extraction of queries “melatonin + scavenger” ( A ); and “melatonin + antioxidant” ( B ).

The statement that melatonin and many other purported antioxidants are scavengers is common in the introduction of hundreds of publications. We consider the term “scavengers” to be misleading because, while these compounds can react with oxidants, they are generally no more reactive than the thousands of other compounds in cells [ 71 ]. Thus, to be 50% effective, they would need to be at a concentration approximately equal to all the other compounds in the cell that could react with the oxidant. In cell culture experiments, scavenging can seem effective; however, it is likely to be because the ratio of the compound to its putative targets is likely thousands of times higher than would occur in vivo [ 72 ].

Scavengers do not exist in complex media, living systems, etc. A true antioxidant defense is provided by enzymes that remove superoxide and hydrogen peroxide with rate constants that are hundreds of thousands to more than a million times greater than that of melatonin. For hydroxyl radical, no compound is an effective scavenger, and the antioxidant defense involves the prevention of its formation rather than its removal (see discussions in [ 73 , 74 , 75 ]).

Many of the compounds purported to have antioxidant activity can react with Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1), sparing Nrf2 from degradation and thereby activating transcription of the genes for antioxidant enzymes. Several compounds have been reported as such protectors for Keap1 degradation: TBE-31 [ 76 , 77 ], CDDO, a triterpenoid [ 78 ], or curcumin and caffeic acid [ 79 , 80 ], to name only but a few. However, many of those compounds also affect other signaling pathways that result in the protection of cells from injury [ 73 ].

7.1.2. If Not a Scavenger, Then What?

The toxicity of ROS and oxidative stress is controlled by several enzymes, the activity of which detoxifies ROS, such as the three superoxide dismutases (see discussion in Keller et al. [ 81 ]. These enzymes are under the control of oxidative response elements that, once activated, induce their expression. This process is dependent on a nuclear receptor, such as nrf2, and melatonin has been suggested to be able to induce the expression of cellular defenses against oxidative stress (see also discussion in Amoroso et al. [ 82 ]). Many years later, this nuclear receptor has still not been found. Nrf2 might be a candidate [ 83 , 84 ], as might be Hem oxidase 1 [ 85 ], or both [ 86 ]; however, their role is yet to be experimentally demonstrated (see also Section 7.2 ).

7.2. Melatonin Nuclear Receptor

The proposed potential role of the nuclear receptors, promoted by many authors, remains an example of the enthusiastic support of a study that has not been reproduced (and thus confirmed) anywhere. In 1994, it was reported that melatonin binds to the receptor RZRα and activates it [ 87 ]. Another paper from the same group was published at the same time, reporting the binding affinities of iodo-melatonin in nuclear homogenates from cells in which RZR was cloned and expressed [ 88 ], which has been cited ever since 314 times. After several years of unsuccessful attempts to confirm the results in several laboratories, the 1994 paper was withdrawn in 1997 [ 89 ]. It has been cited and was continued to be cited 546 times, including 271 times since it was retracted. One possible explanation for that might be the seductiveness of the idea of a nuclear melatonin receptor, knowing that melatonin easily penetrates cells and nuclei, and the number of reported transcriptional effects of melatonin. The goal of the community is to discover the nuclear factor that is activated by melatonin leading to the neo-synthesis of antioxidant proteins, possibly explaining the melatonin antioxidant properties. The possibility that melatonin could be an antioxidant molecule appeared early in the 1990s [ 90 ]. Ever since this date, experiments and hypotheses publications started to appear in the literature; as a query, “melatonin” + “antioxidant” returned 24,271 results on 25 March 2023 (see Figure 1 B).

7.3. Melatonin in Bacteria and Mitochondria

The idea that bacteria produce melatonin has been formulated in statements such as the following one: “Evolution’s best idea” is that melatonin is supposedly produced in bacteria. From there, because bacteria colonized cells several million years ago, eukaryotic cells became mitochondria; mitochondria are thus full of melatonin. Additionally, melatonin is there to protect mitochondria, cells and living organisms from oxidative stress [ 91 ].

7.3.1. Melatonin in Bacteria

This statement can be challenged as follows:

Melatonin synthesis in microorganisms has been reviewed by Que et al. [ 92 ]. Indeed, numerous yeast, protozoa and algae are reported as capable of synthesizing the hormone, as optimistically reportedly reviewed by Hardeland et al. [ 93 , 94 ]. Algae, protozoa and fungi are eukaryotic organisms. On the contrary, bacteria are prokaryotic organisms, and they might have the capacity to synthesize melatonin, as reported in just six publications, listed in Table 5 .

Bacteria that produce melatonin, as reported by Que et al. [ 92 ].

Bacteria Type	Reference	Comments (See Text)
	]
	, ]
	]
	]
	]
sp.	]
	]
	]
	]
sp.	]
,	]
,	]
	]
,	]
TH10,	]
,	]
,	]
,	]
	]
	]
	]
	]

Color code: green : melatonin synthesis proven; orange : melatonin synthesis claimed (by patents); red : absence of melatonin synthesis reported.

It is interesting to look closely at those articles cited to provide proof of bacterial melatonin synthesis.

In an article by Byeon and Back on the cloning of E. coli using the necessary enzymatic machinery for this bacterium to produce melatonin, the only mention of two bacterial melatonin productions is in the following sentence: “Melatonin is predicted to have evolved from the precursor bacteria of mitochondria and chloroplasts, such as Rhodospirillum rubrum and Cyanobacteria , respectively, via an endosymbiotic event with their ancestral eukaryotic host” [ 95 ]. This is not evidence of these bacteria producing melatonin.
Manchester et al. reported a melatonin immunoreactivity in this Rhodospirillum rubrum [ 96 ]; however, this observation has never been reported independently, nor has melatonin been directly measured in the bacterium. Given the capital importance of Rhodospirillum rubrum and other purple non-sulfur bacteria, predicted to be at the origin of mitochondria according to the endosymbiotic theory of mitochondria [ 100 ], it is surprising that no more effort has been spent to clarify this point.
Jiao et al. [ 97 ] reported a thorough study on eight strains of bacteria and found melatonin in only four: Agrobacterium tumefaciens , Bacillus amyloliquefaciens , Bacillus thuringiensis and barely in Pseudomonas sp.
A review by Tan et al., while not providing any experimental data on bacteria melatonin production [ 98 ], stated that a series of Lactobacillus had been patented for their production of melatonin. Furthermore, they wrote: “ If these speculations are valid , the beneficial effects in consumption of these products may, at least partially, be explained by the presence of melatonin and its isomers” [ 98 ]. This statement was later used as evidence that several Lactobacillus produce melatonin. For example, in a trial on abdominal pain in children, Lactobacillus and exogenous melatonin were used for the health of the patient [ 101 ], as if melatonin produced by Lactobacillus was not enough to obtain the desired effect. In another study, melatonin was shown to increase the amount of Lactobacillus previously decreased by sleep deprivation as if the production of melatonin by Lactobacillus was not enough to counterbalance the decrease in circulating melatonin [ 102 ]. Finally, in an earlier study on the possible relationship between several “antioxidant” molecules and their capacity to inhibit bacterial growth in the presence of mycotoxins, melatonin did not show any significant effect on the growth of Lactobacillus [ 103 ]; however, if this bacterium produces melatonin, those authors should have seen an effect of the addition of melatonin to the bacteria. In conclusion, the situation of Lactobacillus as a source of melatonin production remains, at the very least, unclear.
In Erythrobacter longus , Tilden et al. [ 99 ] reported the presence of melatonin by using a radioimmunoassay, although there is reason to be cautious when using immunoassay melatonin by radioimmunoassay in complex matrices [ 2 , 104 ].

Very recently, Chen et al. reported the discovery of the gene encoding for a serotonin N -acetyltransferase gene, xoSNAT3, in the bacteria Xanthomonas oryzae [ 105 ]. The synthetic melatonin capacity of this bacterium was not reported in this paper, nor was the presence of melatonin. This very large family of enzymes has been reported from many organisms [ 106 ], including by us [ 107 , 108 ]; however, its expression does not grant the capacity to synthesize melatonin.

We conclude that whether bacteria widely produce melatonin remains to be proven.

7.3.2. Melatonin in Mitochondria

Melatonin is claimed to be present/enriched in mitochondria [ 91 , 109 ].

However, robust and, in particular, quantitative data are not available. To our knowledge, massive amounts of melatonin have not been reported in mitochondria. Furthermore, if melatonin is a ROS scavenger, it would be expected to be transformed into hydroxy-melatonin or possibly into a kynurenamine, as shown by mass spectrometry analyses [ 110 , 111 ]. To the best of our knowledge, the generation of such metabolites was never directly correlated with the trapping of ROS by melatonin in mitochondria—or in other systems. However, 2-hydroxymelatonin, 4-hydroxymelatonin and 6-hydroxymelatonin have been reported in various other situations. Further examples are 2-hydroxymelatonin in the signaling pathways in Arabidopsis [ 112 ], the generation of 6- and 2-hydroxymelatonin upon the action of cytochrome P450 on melatonin [ 113 ] or the a-cellular system scavenging property of 4-hydroxymelatonin, which was described as superior to that of 2-hydroxymelatonin [ 114 ].

It is assumed that the mitochondria occupy a tenth to a twentieth of the total cellular volume [ 115 ]. Therefore, any concentration of melatonin in the mitochondria would translate as its tenth or twentieth volume in the whole cells. Assuming a high concentration of melatonin in mitochondria of 1 mM for its role in neutralizing ROS production, it would lead to cell homogenates in a melatonin concentration of ca. 50 to 100 µM (~12 to 23 µg/mL). A feature never measured in the literature is where, in blood, the melatonin concentration during the night is about 60 to 70 pg/mL [ 116 ], up to 300 pM. Similarly, in sheep brain tissue, melatonin concentrations of ~1 nM (i.e., 232 pg/mL) and 10 nM have been measured during the day and night, respectively [ 117 ]. This would translate into a concentration 10 times higher in mitochondria: 10 to 100 nM, which is far from any capacity to protect those organelles from ROS injuries. One can argue that melatonin concentrations are not in equilibrium between mitochondria and the rest of the cell because mitochondria have the capacity to either enrich melatonin or retain the melatonin synthesized in mitochondria. However, for the moment, there is no experimental evidence supporting these hypotheses. The well-characterized physical properties of melatonin show that exogenous melatonin equilibrates within seconds with the cytoplasm, confirming that melatonin crosses biological membranes rapidly [ 118 ].

The question of intra-mitochondrial melatonin synthesis has been recently reexamined by Suofo et al. [ 119 ]. The authors identified, using a Western blot, the two enzymes of the biosynthesis pathway, AANAT and ASMT, in preparations of purified mouse non-synaptosomal brain mitochondria. These bands were fully resistant to proteinase K digestion and digitonin treatment, indicating their localization in the mitochondrial matrix. In contrast to the pineal AANAT levels, these mitochondrial AANAT levels did not change along the circadian cycle. The authors demonstrated further that, in mouse neuroblastoma (N2a) cell knockout for AANAT, mitochondrial-generated superoxide production was increased. No alteration of the mitochondrial membrane potential was seen in these cells. In an attempt to address melatonin synthesis in mitochondria more directly, purified mitochondria were treated with deuterated (d4)-serotonin, the AANAT substrate. The generation of d4-n-acetylserotonin and d4-melatonin was observed by mass spectrometry, indicating that mitochondria can indeed synthesize melatonin if the serotonin precursor is available. These data represent, by far, the most convincing dataset in support of melatonin synthesis in mitochondria. However, several important questions still have to be solved. Furthermore, as whole-brain mitochondria were used, the question of whether melatonin synthesis can occur in the mitochondria of all brain cells or of a subset of cells is unknown. Whether this capacity of melatonin synthesis also exists in mitochondria from other tissues remains to be studied, as the quantity of mitochondria varies widely from cell type to cell type, and the repertoire of proteins imported into mitochondria largely depends on the cell type. Importantly, whether the generated quantities of melatonin are significant or anecdotal remains an open question, as no quantitative conclusion can be drawn from the data presented by Suofo et al. [ 119 ]. To show that melatonin is really synthesized by mitochondria in vivo, in other words, whether the precursor concentrations and enzyme levels are sufficient, remains an important goal for future studies.

7.3.3. Conclusions

In summary, evidence on melatonin synthesis in bacteria remains weak and warrants independent replications. Other bacterial strains should be investigated to determine how generalizable they are. Studies should focus on Rhodospirillum rubrum and related species to provide evidence for the assumption that mitochondria are producing melatonin because the bacteria engulfed millions of years ago already produced this molecule. Collectively, the experimental evidence for melatonin synthesis in mitochondria and, in particular, its quantitative aspects and generalization to all mitochondria-containing cells is still weak. This includes the presence of its main precursors, such as serotonin, as well as its main metabolites that could be expected, assuming the highly oxidative environment of the mitochondrial matrix.

7.4. Melatonin as a Co-Substrate of NQO2

Although not really related to the previous points but providing an example of how ideas may emerge, a third melatonin receptor was reported [ 120 ] and systematized later on, particularly with a specific ligand, MCA-NAT [ 121 , 122 ]. The identity between this third melatonin binding site and the enzyme NQO2 has been reported [ 123 , 124 ]. In the following years, a mini-review was published hypothesizing that melatonin is, in fact, a co-substrate of NQO2 [ 125 ]. That would explain how melatonin regulates the antioxidant capacity of the enzyme. This hypothesis was then experimentally tested by another group and proven to be wrong [ 126 ]. Despite the disapproval of the initial hypothesis, it still continued to be mentioned in the literature by citing the mini-review with some citations, even transforming the hypothesis into a fact. Unfortunately, this persistence of the wrong hypothesis may have retarded the field by redirecting future research in the wrong direction.

8. Melatonin Has Many Effects and Targets

The suspected beneficial effect of melatonin in such a large spectrum of diseases is often justified by the involvement of melatonin in a large spectrum of biological processes, as reported in preclinical (cellular and animal) studies. To illustrate this diversity in terms of the melatonin effects, the following 30 randomly selected examples were extracted from a PubMed interrogation with the words “melatonin” and “inhibit”, which retrieved 400 items in total between 2018 and the end of 2022.

In also the following publications, the effect of melatonin is associated with a molecular target (IGF1, CYP, Akt, etc.) in a way that might suggest to the reader that melatonin is indeed binding to those targets. This is not the case; in most of the publications, the authors suggest that melatonin does “something” that leads to a pathway acting through one of these proteins without convincingly demonstrating a molecular interaction between melatonin and a protein. Melatonin protects from experimental models of newborn hypoxic-ischemic brain injury via the MT 1 receptor [ 127 ]. Melatonin inhibits LH + insulin-like growth factor 1 (IGF1)-induced androstenedione and progesterone production as well as the expression of steroidogenic acute regulatory protein (StAR) mRNA (via real-time polymerase chain reaction) in Theca cells. Melatonin has no effect on cytochrome P450 11A1 (CYP11A1) and cytochrome P450 17A1 (CYP17A1) mRNA abundance [ 128 ]. Melatonin increases apoptosis, induced by cisplatin, by inhibiting the JNK/Parkin/mitophagy axis [ 129 ]. Melatonin elevates α-ketoglutarate and diverts adipose-derived exosomes to macrophages in mice [ 130 ]. Melatonin downregulates the expression of the dynamin-related protein 1 [ 131 ]. Melatonin restores mitochondrial normalcy after MPTP treatment in zebrafish [ 132 ]. Melatonin (3 mM), combined with 20 nM of rapamycin, suppresses the AKT/mTOR pathway activation, mitophagy and apoptosis via the regulation of mitochondrial function(s) in cultured cells [ 133 ]. Melatonin inhibits ERK phosphorylation [ 134 ]. Melatonin attenuates lung ischemia-reperfusion injury by inhibiting oxidative stress and inflammation [ 135 ]. Melatonin inhibits the HIF-1α-VEGF pathway in oxygen-induced retinopathy mice [ 136 ]. Melatonin activates Src and PKA in parallel and, thus, regulates CRE-dependent gene transcription [ 137 ]. Melatonin preserves insulin secretion and hepatic glycogen synthesis in rats [ 138 ]. Melatonin inhibits Cav3.2 T-type Ca 2+ channels (about 40% at 10 µM) [ 139 ]. Melatonin activates the ERK1/2 signaling pathway [ 140 ]. Melatonin preserves the YAP expression during doxorubicin-induced cardiotoxicity [ 141 ]. Melatonin induces apoptosis in VCR-resistant oral cancer cells [ 142 ]. Melatonin induces apoptosis in 3T3-L1 preadipocytes as well [ 143 ]. However, melatonin inhibits apoptosis through the upregulation of sestrin2 in vascular smooth muscle cells [ 144 ]. Melatonin attenuates Atg5-dependent autophagy and activates the Akt/mTOR pathway [ 145 ]. Melatonin inhibits excessive mitophagy through the MT2/SIRT3/FoxO3a signaling pathway in cells [ 146 ]. Melatonin blocks the ROS-mediated HIF-1α/miR210/ISCU axis activation [ 147 ]. Melatonin inhibits the mitochondrial permeability transition pore opening [ 148 ]. Melatonin partially inhibits the NE/AKT/β-catenin/SLUG axis [ 149 ]. Melatonin inhibits TRPV4 activity (about 80 % at 1 mM) [ 150 ]. Melatonin promotes endocytosis and the subsequent degradation of HER2 [ 151 ]. Melatonin (0.2 mM) suppresses O-GlcNAcylation of cyclin-dependent-like kinase 5 [ 152 ]. Melatonin activates the ATF6 and PERK signaling pathways [ 153 ]. Melatonin activates the Nrf2/HO-1 signaling pathway [ 154 ]. Of note, the interaction between melatonin and NF-κB has been reported in numerous pathological cases, such as osteoarthritis [ 155 ], breast cancer [ 156 ] or, more generally, in inflammatory pathways [ 157 ]; however, the nature of the interaction has not been convincingly demonstrated.

This snapshot of articles is not meant to be exhaustive, as the search using keywords will always return only a partial picture. Nevertheless, we found the exercise quite informative on two counts:

(i) The concentration of melatonin needed for most of the abovementioned effects is high, e.g., in the range of 1µM and up to several mMs. This leads to two remarks: (1) whether these effects are specific for melatonin or would they also be observed in structurally related molecules; (2) related to this first point is the question of the molecular target(s) or mechanism(s) behind it. Most studies lack the appropriate experimental conditions to—or at least start to—address these questions appropriately. For the first point, the most obvious structurally related candidate class of molecules is indoles (see below, Section 9 ); however, other classes of chemical compounds should also be considered, such as primary amines, etc. The second remark on molecular targets and mechanisms is a crucial step toward a better understanding of the observed effects [ 158 ]. The most obvious experiments, in this respect, are the establishment of concentration (dose)–response curves to determine an EC 50 value. Low EC 50 values generally hint at specific molecular targets, whereas a high EC 50 value hints at targets with lower specificity. The absence of EC 50 values (no saturation) may hint at a general property, such as membrane fluidity or intactness. Unfortunately, many of the articles describing the effects of melatonin use only a single (often high) melatonin concentration/dose.
(ii) The reported effects of melatonin tend to be over-interpreted. The effects are not only system-dependent but, on their own, do not necessarily allow for conclusions on the precise mechanism or targets involved. These ‘descriptive’ data should therefore be interpreted with caution, not only in terms of the molecular mechanism and specificity but also in terms of translatability into another cell type, tissue and its relevance for pathologies. Unfortunately, the often-used perspective phrase “… these findings open new avenues in therapeutics” should be used with more precaution, considering the high melatonin concentrations used and the fact that almost all experimental protocols use melatonin in a preventive paradigm instead of a treatment paradigm.

Another misleading habit is the transformation of the working hypotheses and ideas formulated in an article into a fact in the following article and then propagated from review to review. This is nicely illustrated by the literature associating melatonin with the recent COVID-19 pandemic. A PubMed search using the terms “melatonin” and “COVID” retrieved 217 publications (25 February 2023) in just a three-year period. Incidentally, most of the papers claim that melatonin is active because it is an antioxidant and scavenger and has anti-inflammatory properties [ 159 ], and thus it is unsurprising to reach the conclusion that melatonin would be the ideal anti-COVID-19 therapeutic agent, as proclaimed in many reviews. However, a closer look at the more than 200 publications on COVID-19 and melatonin shows that most of them are reviews or comments and that experimental pieces of evidence are actually only reported in a small number of original articles. Interestingly, the anticipated anti-inflammatory effect of melatonin was not observed in K18-hACE2 mice infected with SARS-CoV-2 [ 160 ]. Whether this lack of effect is specific to this mouse model and that of a rapid manifestation of severe COVID-19 symptoms occurred remains to be determined in further studies. The totally unexpected effect of melatonin in this mouse model was the protection of the brain from SARS-CoV-2 infection, as compared to the lungs at high doses of melatonin [ 161 ]. Even more unexpected, the mechanistic studies suggest that this effect is mediated by the binding of melatonin to an allosteric binding site at the human angiotensin-converting enzyme 2 (ACE2), thus interfering with the ACE2 function as an entry receptor for SARS-CoV-2.

Altogether, we conclude that the use of high melatonin doses can be problematic in terms of specificity and engagement of molecular targets, two aspects that are rarely addressed but need to be clarified based on experimental evidence (see also the discussion and recommendations in Cecon et al. [ 9 ]).

9. The Indole Hypothesis

As we detailed previously, particularly in the recommendations on melatonin-related publications [ 162 ], the necessity must be emphasized to use the control substances at concentrations similar to melatonin concentrations to evaluate the specificity of an observed effect. This includes the use of other indole-based compounds, including those that may not be oxidized in the same way as melatonin, to address and demonstrate the possible mechanism of action of melatonin for the particular outcome.

Concerning indole-based compounds, it is interesting to evaluate some of the examples that addressed the question of specificity: (a) serotonin was found to be the most effective compound for inhibiting amyloid-β peptide aggregation. Almost all the indole compounds tested in this study prevented amyloid-β peptide fibril formation and increased cell viability between 9 and 25%. Melatonin and serotonin were found to be the most active. Moreover, serotonin increased the expression of SIRT-1 and 2, heat shock protein 70, and heme oxygenase activity—as melatonin is reported to do as well—this being a possible mechanism underlying the observed neuroprotective effect [ 163 ]. This paragraph, adapted from the abstract of the paper, is a rare break from the melatonin-does-everything system, suggesting that either high concentrations of natural compounds may have beneficial effects on the disease models or that indole-based compounds have the propensity to interfere with proteins due to their chemical natures. (b) Zhai et al. demonstrated that a series of indole-based compounds (including tryptamine and tryptophane but not the unrelated histidine) were able, at the same concentrations (3 mM), to block the virus infectivity, probably via a virus/receptor interaction [ 30 ]; see also [ 161 ]. (c) Wölfler et al. showed that N -acetylserotonin is a better compound for antioxidant activity than melatonin, especially at 10 µM, at which the concentration of melatonin is almost inactive in this cellular model [ 164 ]. (d) When the neuroblastoma SK-N-MC cells were treated either by hydrogen peroxide (H 2 O 2 ) or following glutamate-induced cell death, N -acetyltryptamine, as well as melatonin, were reported to protect the cells against those injuries, although at concentrations from 10 to 500 µM. The authors suggested that the protection occurred via the induction of NF-κB [ 165 ]. The systematic inclusion of melatonin-related compounds and the determination of the EC 50 values are highly desirable in future studies to better understand the effects associated with melatonin, in particular, at high concentrations. From a therapeutic point of view, the putative interchangeability of indole-based compounds, such as melatonin, N -acetyltryptamine, etc., would increase the number of therapeutic choices to minimize the harmful effects, depending on the disease context.

10. What to do?

For several years now, a growing number of claims can be said to have distracted melatonin research and trivialized the role that endogenously produced melatonin has in maintaining circadian sleep patterns, metabolism and mental health.

Indeed, the disruption of light rhythms in our cities and the constant use of electronic devices with artificial light have led to questions about the way public health is affected by such changes. In the meantime, significant resources—intellectual, financial and societal—are potentially wasted by moving forward the working repetitive claims/hypotheses that are not, or only insufficiently, supported by experimental evidence with all the required scientific rigor. Clearly, only the clarification of the basics and not the extension of non-consensual theories will lead to a general consensus in the scientific community to eventually move on in a coordinated manner and on a solid scientific basis to address the most relevant questions and challenges.

Another way to reduce the impact of misleading claims is to discourage reviews of the literature that simply and uncritically repeat statements or discuss experiments.

Another point should be stressed: the use of melatonin at very high dosages in patients and infants should be restricted as a precautionary principle. Indeed, as pointed out on several occasions, melatonin toxicity, in vivo, remains unexplored territory at these dosages, even at moderate dosages. There have been no rigorous toxicity studies reported in humans, and the repeated claims that a compound being natural cannot be toxic, are potentially harmful.

Acknowledgments

The authors are indebted to H.J. Forman (University of Southern California at Los Angeles, CA, USA) for his help in Section 7.1.1 ’s writing. The work of R.J. was supported by the Agence Nationale de la Recherche (ANR-19-CE16-0025-01 « mitoGPCR », ANR-21-CE18-00XX « alloGLP1R », ANR-20-COV4-0001 « MELATOVID »), the Fondation de la Recherche Médicale (Equipe FRM DEQ20130326503), La Ligue Contre le Cancer N/Ref: RS19/75-127, Plan de Relance 2021 and the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS).

Funding Statement

The work of R.J. was supported by the Agence Nationale de la Recherche (ANR-19-CE16-0025-01 « mitoGPCR », ANR-21-CE18-00XX « alloGLP1R », ANR-20-COV4-0001 « MELATOVID »), the Fondation de la Recherche Médicale (Equipe FRM DEQ20130326503), La Ligue Contre le Cancer N/Ref: RS19/75-127, Plan de Relance 2021 and the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS).

Author Contributions

All the authors equally contributed to the writing and editing of the review. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

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Melatonin Overdose and Treatment

Side effects, drug interactions, when to see a healthcare provider.

Melatonin overdose is not common, but there are questions about how much melatonin is too much. With a significant rise in melatonin use in children (sometimes at higher doses of 10 milligrams), and concern about its safety and use in kids as well as adults, there's renewed attention to the risks and side effects.

Proper dosage varies from person to person, so it can be difficult to determine the optimal dose of this sleep cycle-regulating hormone. Because the supplements are not regulated in the U.S., there are extreme variations in how much melatonin you may actually be taking.

Dietary Supplements in the United States

In the United States, the Food and Drug Administration (FDA) does not regulate supplements the way it regulates prescription drugs. That means some supplement products may not contain what the label says. When choosing a supplement , look for third-party tested products and consult a healthcare provider, registered dietitian nutritionist (RD or RDN), or pharmacist.

AnnaStills / Getty Images

People take melatonin supplements to boost their own production levels. There is no specific recommended dose of melatonin. Some experts recommend keeping the adult level as close to 0.3 milligrams (mg) or less each day. A dose of 40 mg or 60 mg would be considered quite high.

Your body produces melatonin naturally, with the pineal gland releasing between 0.1 and 0.9 mg of melatonin per day. Children produce more melatonin than adults do and it declines with age.

Some studies demonstrate the optimal melatonin dose by age is as follows:

Infants : 1 mg
Children : 2.5 to 3 mg
Adolescents : 5 mg
Adults : Anywhere between 0.5 and 5 mg
Older adults : Starting dose between 0.3 and 2 mg

In addition to the pineal gland response to darkness, factors that affect melatonin production include:

Disruptions to sleep schedules, like jet lag or shift work
Artificial light exposure, including phones and computer screens
Diet and nutrition
Illness (including critical illnesses like stroke and sepsis )
Medication use

With insomnia, additional research suggests that 1 to 3 mg of an immediate-release melatonin product taken 30 minutes before bed is an effective treatment level.

Insomnia and Treatment Options

Melatonin is among the most-often used supplements in the United States; sales doubled between 2017 and 2021. However, the American Academy of Sleep Medicine recommends cognitive behavioral therapy for insomnia rather than first-line medication. Some studies suggest other medications are more helpful in treating insomnia in adults, with melatonin showing limited benefit.

Melatonin Overdose

Taking too much melatonin is not more effective and can have the opposite effect. This means that the sleep hormone may actually make it harder to fall asleep if too much is in your system.

Taking too much melatonin can lead to symptoms such as:

Changes in blood pressure
Heart rate changes
Nausea and vomiting

People who have naturally low levels of melatonin in the body, like older adults, may be more susceptible to symptoms and side effects. Melatonin supplements may stay active longer in older adults than they do in younger people.

In some cases, alcohol use can affect melatonin use. However, melatonin also may prove a helpful treatment in alcohol use disorder and related complications, including liver damage.

Is There a Lethal Dose of Melatonin?

Researchers have not yet identified a dose that would be lethal, although reports of overdose in children have increased by 530% between 2012 and 2021 and two fatalities in children are documented. Typically, too much melatonin leads to mild to moderate symptoms that correct themselves when the melatonin use is stopped.

Occasional, short-term use of melatonin is considered generally safe. But melatonin can lead to common side effects including:

Although adverse effects are rare, they can occur. Allergic reactions, fatigue , mood changes, and worsened cognitive performance can all be driven by melatonin use.

Using melatonin is typically only recommended on a short-term basis. Long-term use can build tolerance over time. Age may also play a role and your needs may change. Research has found that adolescents beginning melatonin use before the age of 12 who used the supplement for just over seven years had normal sleep quality a decade later.

When taking new supplements, it’s important to consider possible drug interactions that may occur with the medications you take regularly. People who take the following medications should talk to a healthcare provider before using melatonin:

Blood thinners
Benzodiazepines
Epilepsy medications
Blood pressure medications
Birth control medications

You should see your healthcare provider before you begin taking melatonin. A provider will determine how much you should be taking and which supplement to buy based on your optimal dose.

The most effective, first-line treatment option for melatonin overdose is eliminating the supplement from your routine. If the overdose symptoms are serious, you may have to see a healthcare provider. Seek immediate care if you:

Experience symptoms of an allergic reaction
Shortness of breath
A rise in blood pressure after taking melatonin

The FDA hasn’t evaluated or approved the use of melatonin in kids and there is a lack of evidence surrounding any side effects involved in using melatonin at a young age. Because of this, always speak to your healthcare provider before giving your child melatonin.

Melatonin is a naturally produced hormone that regulates your sleep-wake cycle, and can also be found in supplement form. When taken at low doses, melatonin is safe and effective. However, taking too much melatonin can lead to an overdose. When an overdose occurs, people may experience symptoms such as daytime sleepiness, vomiting, and high blood pressure.

In rare cases, serious health consequences can occur, but clinical research surrounding melatonin overdose is limited. To treat melatonin overdose, the first step is eliminating use so that it can be excreted from the body. This will result in symptom relief.

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By Angelica Bottaro Bottaro has a Bachelor of Science in Psychology and an Advanced Diploma in Journalism. She is based in Canada.

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How Could My Friend Give My Child Melatonin Without My Permission?

A reader was shocked and infuriated when she wasn’t consulted before her 10-year-old was given a melatonin supplement at a sleepover.

By Philip Galanes

My 10-year-old daughter attended a sleepover recently. It was hosted by a family we have known and trusted for eight years. I consider the mother a personal friend — not just the mom of my daughter’s friend. So, I was alarmed and, frankly, furious when my daughter told me that the mother had distributed melatonin gummies to every girl at the sleepover. I think it’s dangerous to give medication or supplements to other people’s children. I have already talked to my daughter about what she should do if she’s offered medicine when I’m not around. But how should I handle my friend’s major breach of trust? Should I confront her or just move on knowing that I can no longer trust her?

SHOCKED MOM

There is no question that your friend made an error in judgment when she gave your child melatonin without your permission. But the only way this story makes sense to me is if your trusted friend believed that the gummies — a version of the hormone our bodies produce naturally when it’s time to sleep — were harmless. They are sold over the counter, after all, and short-term use by children your daughter’s age is generally considered safe .

Now, that doesn’t erase your friend’s error, but it suggests a more benign explanation: misunderstanding, not betrayal. And it makes your sustained reaction — shock, alarm, fury — seem a little over-the-top. You don’t mention anyone suffering ill effects from the gummies. Yet calmly discussing the episode with your good friend and sharing your expectations for the future doesn’t appear on your menu of possible responses. (And no, a confrontation is not a discussion.) Talk to her nicely!

We all make mistakes, mothers included. It would also be wise to verify the account of a 10-year-old child. You are absolutely entitled to your honest feelings, even your strong ones. But now I urge you to put this episode in perspective before you damage a long friendship or decide to abandon it.

You Can Hold the ‘Milady’ and Still Hold the Door

I have a great boss, the best of my career. She reports to a woman I also respect and admire. The issue: As a man, how do I mind my manners with these women (opening doors for them, for instance, or helping with their luggage) without treating them like damsels in distress? It seems as if I’m damned if I do and damned if I don’t.

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IMAGES

New Developments in Melatonin Research
Vol 3 No 1 (2020): Melatonin Research
Vol 2 No 2 (2019): Melatonin research
Melatonin Research
Research weighs risks and benefits of melatonin use
Vol 6 No 3 (2023): Melatonin Research

COMMENTS

Is Melatonin the "Next Vitamin D"?: A Review of Emerging Science
Melatonin has become a popular dietary supplement, most known as a chronobiotic, and for establishing healthy sleep. Research over the last decade into cancer, Alzheimer's disease, multiple sclerosis, fertility, PCOS, and many other conditions, ...
Using melatonin for sleep is on the rise, study says, despite ...
More adults are taking over-the-counter melatonin to get to sleep, a study found, despite potential harm to health and little proof of efficacy.
What New Research Says About Melatonin and Sleep
Melatonin, of course, is critical for healthy sleep. The body's own melatonin production is essential to circadian rhythm regulation and the maintenance of daily sleep-wake cycles. As a ...
Higher dose of melatonin improved sleep in older adults
In a small study of healthy adults aged 55 and older, 5 mg of melatonin increased total sleep time compared to a placebo. Researchers from Brigham and Women's Hospital conducted the study in 24 healthy, older adults to evaluate whether a high-dose or a low-dose melatonin supplement could improve sleep. The team found that the higher dose had ...
More evidence suggests regular consumption of melatonin can reduce
In recent years, research teams have been finding that people taking melatonin supplements may be less likely to develop the condition. In 2020, one team found that the higher levels of melatonin ...
More people are turning to melatonin to sleep. But experts say it's not
Melatonin use has increased since 1999, according to a new study out of the United States. Canadian sleep and drug safety experts say more people are turning to the supplement to fall asleep.
Dream discovery: Melatonin's key role in REM sleep revealed
The new study has identified the melatonin MT1 receptor as an important regulator of this sleep stage. ... Daily science news on research developments and the latest scientific innovations.
New perspectives on the role of melatonin in human sleep, circadian
The role of melatonin in the regulation of the circadian clock and sleep has led to translational research into melatonin as a treatment of human disease, in particular circadian rhythm and sleep disorders, with further implications as a disease modifying agent in neurodegenerative and cardiovascular disease as described below. Go to:
Melatonin
Type 2 diabetes mellitus and obesity are major public health challenges; emerging evidence suggests that melatonin is involved in the development of these disorders, opening new avenues for research.
Melatonin for Sleep: How the Aid Works
How do doctors use melatonin? Sleep doctors may use melatonin to help patients with circadian rhythm disorders regulate their sleep-wake cycles.
Study finds melatonin use soaring among youth
Nearly one in five school-aged children and preteens now take melatonin for sleep, and some parents routinely give the hormone to preschoolers, according to new research.
New Uses of Melatonin as a Drug; A Review
Abstract. Melatonin is a simple compound called N-acetyl-5-methoxy tryptamine and is known as a hormone controlling the circadian rhythm. Melatonin is produced by the human body naturally. The production of melatonin increases in the evening, causing a state of sleep at night and wakefulness during the day. Melatonin interacts with melatonin ...
Current Insights into the Risks of Using Melatonin as a Treatment for
Melatonin is commonly perceived to be a safe alternative to other hypnotics and is available without prescription in some jurisdictions. New evidence suggests that endogenous melatonin has pleomorphic effects on multiple organ systems, many of which are poorly understood.
New Research Finds a Higher Dose of Melatonin Improved Sleep
New Research Finds a Higher Dose of Melatonin Improved Sleep. In a study published in The Journal of Pineal Research, 5 mg of melatonin increased total sleep time compared to placebo. In a small study of healthy adults aged 55 and older, 5 mg of melatonin increased total sleep time compared to placebo. Although recent research by the University ...
Research shows a big increase in children taking melatonin
New research shows a big increase in children taking melatonin to help with sleep. Pediatricians warn the long-term effects of the hormone supplement aren't known.
Use of melatonin supplements rising among adults
At a Glance The use of melatonin supplements by adults in the United States more than quintupled between 1999 and 2018. The findings highlight the need to better understand the long-term safety of melatonin use and its ability to help with certain sleep problems.
Study: Scientists unravel the many physiological roles of melatonin
The research reveals for the first time the multiple roles that the naturally occurring melatonin molecule plays in processes ranging from circadian rhythms to reproduction to "torpor," an energy-conserving state similar to short-term hibernation. "For the first time, we can say that endogenous melatonin is involved in the modulation of ...
Melatonin
Research shows that melatonin reduces the length of time needed to fall asleep and advances the start of sleep in adults and children with this condition. Talk to your child's doctor before giving melatonin to a child. Insomnia.
Melatonin may stave off age-related vision loss, study hints
A large new analysis has tied the use of supplemental melatonin to a lower risk of developing one of the most common age-related causes of vision loss.
Trends in Use of Melatonin Supplements Among US Adults, 1999-2018
This study examines reported prevalence and trends in use of melatonin supplements among US adults from 1999 through 2018.
Opinion: You might want to rethink taking melatonin as a sleep aid
We need to dispel the myth that melatonin is an effective sleep aid and instead spread awareness about a treatment that is proven to help with insomnia: cognitive behavioral therapy for insomnia ...
Melatonin: What You Need To Know
Melatonin is a hormone that your brain produces in response to darkness. It helps with the timing of your circadian rhythms (24-hour internal clock) and with sleep. Being exposed to light at night can block melatonin production. Research suggests that melatonin plays other important roles in the body beyond sleep.
Melatonin as a medication and supplement
Melatonin is a dietary supplement and medication as well as naturally occurring hormone. ... The New England Journal of Medicine editorialized in 2000: ... Some research supports an antidepressant effect of melatonin. Bipolar disorder
Screen Time and Sleep—It's Different for Adults
While darkness enables melatonin production, suppressing melatonin production works by the brain comparing the amount of light we receive during at night with how much we received during the day. It's the shift from light to dark that cues the release of melatonin, which is why we start to feel sleepy after the sun goes down.
These Melatonin Supplements Were Trending on TikTok. So, I Tried ...
The sleep supplement market is overwhelming, so choosing one brand can be tricky. I tested Lemme Sleep for a month to see if they are worth the hype.
Melatonin: Facts, Extrapolations and Clinical Trials
Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems ...
Melatonin
This podcast discusses the popular sleep hormone melatonin.We discuss its role in promoting sleep and our circadian rhythm, review the studies that explore the supplements role in treating sleep issues in pediatrics and typical dosage and timing and for administration.
Melatonin Overdose: How Much Is Too Much
Learn about melatonin overdose, how to recognize the signs, and why taking too much of this natural supplement may lead to adverse side effects.
David Blask, MD, PhD
Melatonin/Circadian Regulation and Light at Night Circadian Disruption of Cancer Growth; Tulane Cancer Center Program Member. For the past 35 years I have dedicated my research career to understanding the mechanisms by which the central circadian system of the brain regulates human breast cancer growth and metabolism via the nighttime circadian production of the pineal gland hormone melatonin.
How Could My Friend Give My Child Melatonin ...
A reader was shocked and infuriated when she wasn't consulted before her 10-year-old was given a melatonin supplement at a sleepover.