Low Dose Melatonin: Optimal for Circadian Rhythms?

What is low dose melatonin?

300 mcg (micrograms) or less – equivalent to 0.3 mg or less.

This is my answer – so let me explain how I came up with this number.

There’s no objective scientific/medical consensus for what is “low-dose” melatonin.

You might ask several friends what they consider to be low-dose melatonin – and you might get completely different responses.

“Does anybody know how much melatonin is typically produced by the human body?” (Read this posting for a barrage of complex, scientific responses). (R)

According to a medical doctor (u/herman_gill) discussing melatonin on Reddit, “natural production is on the order of 100-300 mcg/night” – which should trigger tiredness at night followed by subsequent sleep. (R)

After having read countless melatonin studies and opinions of researchers, I think most would objectively agree that a good consensus threshold for low-dose melatonin is 300 mcg (0.3 mg) or less.

Why? Because greater than this amount exceeds standard physiologic concentrations via endogenous production.

That said, bioavailability of oral melatonin supplements is ~15%.

Therefore, from a 300 mcg (0.3 mg) melatonin supplement – only 45 mcg (0.045 mg) becomes biologically active. (R)

Some might argue that 300 mcg is far too low to be considered the highest threshold to qualify as “low-dose” melatonin for multiple reasons: (A) bioavailability is poor AND (B) doses over 22000-fold this amount have been tested in human research.

Nonetheless, I think 300 mcg is a pretty good cutoff.

Doses higher than 1 mg (1000 mcg) would be the highest cutoff for “low-dose” melatonin that most would be willing to concede.

I’d personally argue that 1 mg is an average dose – not a low dose.

Richard Wurtman (MD) of MIT Department of Brain & Cognitive Sciences studies neuroendocrine regulation and melatonin – and thinks that doses above 300 mcg (0.3 mg) are excessive for humans. (R)

Perhaps from Richard Wurtman’s perspective, 300 mcg (0.3 mg) melatonin taken via supplementation might actually be more of a moderate or standard dose – rather than a low-dose, but I’m not sure.

Melatonin microdosing

A melatonin microdose is considered a dose of melatonin that is extremely low – such that it:

1. Does NOT induce significant whole-body effects.
2. Produces “subtherapeutic” effects.
3. Will produce effects that are subjectively unnoticeable or barely noticed.

Most people likely consider the term “low-dose” to be analogous the term “microdose.”

Why? “Micro” = small/tiny – hence: small dose.

For this reason, most would likely consider a good consensus threshold for a melatonin microdose to be 300 mcg (0.3 mg) or less.

However, others may interpret the term microdose as: a dose that’s orders of magnitude lower than “low doses” (akin to the degree to which “megadose” would exceed a “high-dose”).

Furthermore, not everyone necessarily considers 300 mcg (0.3 mg) to be a “low dose.”

Some might argue that 300 mcg should actually be a standard dose (such that most supplement companies are delivering abnormally high-doses of melatonin at commonly manufactured dosing increments).

If going by the interpretation that microdose should be considerably lower than even “low doses” – then one might argue microdoses should be something like 5-to-10-fold less potent.

In this scenario, melatonin microdoses should be 60 mcg (0.06 mg) to 30 mcg (0.03 mg) or less.

It’s really up to you to determine how you want to define microdose here.  What do I personally think should be considered a melatonin microdose?

I agree with most people that 300 mcg (0.3 mg) or less probably should be considered both a “low dose” and a “microdose” for a few key reasons:

Searching Amazon for “Low Dose” Melatonin…

Out of curiosity, I conducted a cursory search on Amazon to determine the specific dosages supplement manufacturers label as “low dose” for melatonin.

Included below are various brands and respective manufactured low dosages.

This suggests that a majority of supplement manufacturers consider dosages of: (A) 250 mcg (0.25 mg); (B) 300 mcg (0.3 mg); (C) 500 mcg (0.5 mg); and (D) 1000 mcg (1 mg) – to qualify as “low doses” for melatonin.

This is fairly consistent with the definition for “low dose” that I’ve established (300 mcg or less) – as well as the highest dose I’d be willing to concede as qualifying for low dose (1 mg).

Which do I think is the best “low dose” melatonin to use?

Ideally we’d have all melatonin supplements analyzed with chromatography & mass spectrometry to ensure that the dosages listed accurately reflect the melatonin contents.

However, because this hasn’t been done – it’s impossible to know which low-dose melatonin product is “best” – they might all be fine.

When I take low dose melatonin, I use Life Extension (300 mcg) XR (extended-release format). (This is an affiliate link).

Why? It (theoretically) should help more with sleep maintenance and doesn’t saturate melatonin receptors as significantly at any given time as immediate-release versions.

Note: The amount of actual melatonin in these supplements may not accurately reflect dosages listed on the label (i.e. advertised). Why? Supplements aren’t regulated and have poorer quality control standards (such that some might contain significantly higher/lower melatonin doses than what’s listed).

An analysis of 31 OTC melatonin supplements was conducted by Erland & Saxena (2017) (R)

• “Melatonin did NOT meet label within 10% of the margin of label claim in more than 71% of supplements and an additional 26% were found to contain serotonin.”
• “Melatonin content was found to range from -83% to +478% of the labelled content.”

This analysis was done on Canadian brands of melatonin.

It’s unclear as to whether the most popular (i.e. highest selling) supplements were analyzed – or if supplements were chosen at random (such as those made by less reputable supplement companies).

It’s also unknown as to whether melatonin supplements in the U.S. are less problematic.

Low-Dose Melatonin (1 mg or Less): Bioavailability at Specific Doses

Included below are brief notes regarding hypothesized “average” bioavailabilities of common dosing increments for low-dose melatonin supplements.

(Keep in mind that this assumes listed dosages accurately reflect supplement contents).

Assuming average bioavailability for oral melatonin supplements (~15%) – any supplements below 1 mg should generally provide less melatonin than the body endogenously secretes each night (100-300 mcg).

However, you should keep in mind that the exogenous melatonin is still “added” to the amount that is endogenously secreted.

In other words: If your body endogenously produces 200 mcg melatonin each night – and you supplement with 1 mg melatonin (providing ~150 mcg after adjusting for low bioavailability), the total amount of melatonin in circulation might be around 350 mcg.

Although 350 mcg is slightly above the normal range for most people, it’s probably not that big of a deal unless you’re a poor melatonin metabolizer.

Even then, if natural melatonin production is low – then even a 1 mg dose is unlikely to increase melatonin concentrations to a supraphysiologic level.

Why is there confusion about what constitutes a “low dose” of melatonin?

According to Dr. Richard Wurtman (MIT Department of Brain & Cognitive Sciences) – (among the first scientists to discover melatonin and research its role in the human body):

“MIT was so excited about our research team’s melatonin-sleep connection discovery that they decided to patent the use of reasonable doses of melatonin—up to 1 mg—for promoting sleep.

But they made a big mistake. They assumed that the FDA would want to regulate the hormone and its use as a sleep therapy. They also thought the FDA wouldn’t allow companies to sell melatonin in doses 3-times, 10-times, even 15-times more than what’s necessary to promote sound sleep.

Much to MIT’s surprise, however, the FDA took a pass on melatonin. At that time, the FDA was focusing on other issues, like nicotine addiction, and they may have felt they had bigger fish to fry.

Also, the FDA knew that the research on melatonin showed it to be non-toxic, even at extremely high doses, so they probably weren’t too worried about how consumers might use it. In the end, and as a way of getting melatonin on to the market, the FDA chose to label it a dietary supplement, which does not require FDA regulation. Clearly, this was wrong because melatonin is a hormone, not a dietary supplement.

Quickly, supplement manufacturers saw the huge potential in selling melatonin to promote good sleep. After all, millions of Americans struggled to get to sleep and stay asleep, and were desperate for safe alternatives to anti-anxiety medicines and sleeping pills that rarely worked well and came with plenty of side effects.

Also, manufacturers must have realized that they could avoid paying royalties to MIT for melatonin doses over the 1 mg measure. So, they produced doses of 3 mg, 5 mg, 10 mg and more! Their thinking–like so much else in our American society–was likely, “bigger is better!” But, they couldn’t be more wrong.”

Credit to SlateStarCodex for the following information: (R)

However, I don’t think most supplement companies were bothered by the fact that they couldn’t produce the endorsed-as-optimal-by-MIT dose (300 mcg) or below 1 mg (1000 mcg).

I also don’t think most people cared much about not being able to buy melatonin at the endorsed-as-optimal-by-MIT dose (300 mcg).  Why?  Several reasons, including:

• Supplement companies know that many people perceive “higher doses” of melatonin as being “better” or “more effective” than “lower doses.”
• Many people actually want higher doses – especially when the dosage doesn’t significantly affect supplement price (high dose melatonin is still extremely inexpensive).
• Many melatonin users have self-tested low doses, standard doses, and high doses – and prefer to take high doses (for various reasons such as greater perceived efficacy).
• High-dose melatonin may elicit physiological effects that are more therapeutically relevant than, or distinct from, low-dose melatonin.
• High-dose melatonin might be more effective (in some cases) for sleep maintenance – relative to low-dose melatonin.
• The scientific literature shows that doses far greater than 300 mcg (the dose recommended by MIT) provide clinical benefit in many populations without adverse events (e.g. circadian dysregulation) or tolerance – even when used for a long-term (i.e. years).

Had MIT not been granted a patent for melatonin dosages below 1 mg (1000 mcg) – it’s fair to suspect commonly manufactured melatonin dosing increments might differ.

Because melatonin research in the 1970s, 1980s, and 1990s utilized relatively high dosages (e.g. 10+ milligrams) – it’s possible that MIT’s “patent” of dosages below 1 mg for sleep had negligible impact on dosage increments chosen by supplement manufacturers.

Assuming the MIT melatonin patent did significantly influence melatonin dosing increments chosen by supplement manufacturers – it’s reasonable to suspect that average melatonin dosing increments were impacted significantly – such that they skew higher than what they would’ve been without the initial patent for doses under 1 mg.

I’d guess that: (1) most use high dose melatonin with good outcomes (i.e. therapeutic effect & limited side effects); (2) many people prefer high dose melatonin (relative to lower dose); (3) high-dose melatonin may sell better than low-dose melatonin; (4) pricing between low and higher doses doesn’t differ much (e.g. 300 mcg = $6.80 & 1 mg = $7) – and some might perceive the higher-dose as being a better “value” (melatonin per $).

I’m guessing since the MIT patent expired for doses like 300 mcg (0.3 mg) – supplement companies decided to manufacture this dose as a “niche” product for those who cannot tolerate higher doses (e.g. CYP1A2 poor metabolizers) and/or those who want the MIT-recommended or “scientifically optimal” amount.

Because melatonin is cheap to manufacture, profit margins may be greater for supplement companies if a reasonable number of consumers opt for lower-dosed melatonin products (e.g. 300 mcg) instead of higher-dosed ones.

For example: Life Extension sells 3 mg melatonin (60 capsules) for $7.50 ($0.12/capsule) – and 300 mcg (100 capsules) for $6.80 ($0.07/capsule).

It takes 10 of the 300 mcg capsules to equal the same melatonin content as a single 3 mg capsule.

This means that there’s around a ~5.83-fold price markup on the melatonin content in lower dose formats – relative to higher ones.

(Note: I compared immediate-release formats here as of December 2021 – not to be confused with extended-release versions, which tend to cost more).

Low Dose Melatonin (Scientific Research)

Included below are studies and/or reports specifically mentioning “low dose” melatonin – or evaluating various effects of “low dose” melatonin.

Low-Dose Melatonin for Sleep Disturbances in Early-Stage Cirrhosis (R)

• Date: 2020
• Authors: De Silva et al.
• Aim: Determine the safety & efficacy of low-dose melatonin for sleep disorders among patients with early-stage cirrhosis.
• Design: Randomized, placebo-controlled, crossover
• Methods: 60 patients (~61.7 years old) with early-stage cirrhosis were randomized to receive either placebo or melatonin (3 mg) for 2 weeks. After 2 weeks, there was a 1-week washout period and crossed over to receive the opposite of what each received in the first 2 weeks.
• Measures: Pittsburgh Sleep Quality Index (PSQI); Epworth Sleepiness Scale (ESS) – to determine sleep quality (PSQI) and daytime sleepiness (ESS)
• Results: Melatonin (3 mg) significantly improved sleep quality and reduced daytime sleepiness in the study cohort (60 patients with early-stage cirrhosis) – with good tolerability and few adverse events – relative to pre-treatment and placebo.

Note: “3 mg” isn’t universally regarded as being a “low dose” of melatonin.

Optimal Dosages of Melatonin Supplementation Therapy in Older Adults (R)

• Date: 2014
• Authors: Vural et al.
• Aim: Define the “optimal” dosage of melatonin in disorders related to altered melatonin levels in older adults (55+ years old).
• Methods: Systematic review of studies involving melatonin in older adults from 1980-2013. A total of 16 articles were found – 9 of which were RCTs.
• Analysis: Melatonin dosage varied in the studies from 0.1 mg to 50 mg/kg. Melatonin supplements dose-dependently increased melatonin concentrations in serum and urine. There was a relationship between age and the duration over which melatonin remained above certain thresholds. (Older age = elevated melatonin concentrations for a longer duration after supplementation).

Authors noted that the “best applicable dosage for melatonin” (in older adults) cannot be universally stated due to high intraindividual variability in pharmacokinetics & pharmacodynamics.

However, authors believe that excessive melatonin dosages cause prolonged elevations in melatonin concentrations throughout the body – which could induce adverse physiologic effects.

Furthermore, authors state that while controlled-release formats most closely mimic natural melatonin production, they cause prolongation of elevated melatonin levels in older adults and are not advisable.

Effect of Prolonged-Release Melatonin on Sleep Measures & Psychomotor Performance in Elderly Patients with Insomnia (R)

• Date: 2009
• Authors: Luthringer et al.
• Aim: Evaluate effects of prolonged-release melatonin (2 mg) on sleep and subsequent daytime psychomotor performance in adults over 55 with primary insomnia.
• Methods: 40 adults (55+) were treated nightly with a placebo (single-blind) for 2 weeks – then randomized double-blind to either: melatonin (2 mg) or placebo for 3 weeks – then underwent a withdrawal period of no treatment (3 weeks).
• Measures: Polysomnography; Leeds Psychomotor Test battery; EEG (all-night); questionnaires
• Results: Prolonged-release melatonin (2 mg) significantly decreased sleep onset latency and improved aspects of psychomotor performance – relative to the placebo. There was no significant change in sleep structure or architecture from melatonin. 50% reported substantial improvement in sleep quality with melatonin – versus just 15% with placebo.

Although this study reported significant benefit from prolonged-release melatonin, some might not consider “2 mg” to be “low dose.”

What is the dosing recommendation of melatonin (from this study)?

“In older adults, we advise the use of the lowest possible dose of immediate-release melatonin to best mimic the normal physiological circadian rhythm of melatonin and to avoid prolonged, supra-physiological blood levels.”

Dosage should vary from 0.3 mg to a maximum of 1 or 2 mg – taken ~1 hour before bedtime to best mimic the normal physiological circadian rhythm and to avoid prolonged supraphysiological blood levels.

The Effects of Low-Dose (0.5 mg) Melatonin on Free-Running Circadian Rhythms of Blind Subjects (R)

• Date: 2003
• Authors: Hack et al.
• Study type: Placebo-controlled, single-blind
• Participants: 10 blind individuals (ages 32-65) with “free running” circadian rhythms
• Methods: Participants received 0.5 mg melatonin or a placebo daily at 9:00 PM. Subjective sleep was assessed via daily sleep and nap diaries. Urinary cortisol and melatonin metabolite concentrations were documented 24-48 hours per week via radioimmunoassay.
• Results: 4 participants exhibited circadian entrainment with periods indistinguishable from 24 hours. 2 participants continued to free run up to 25 days before their cortisol rhythm became entrained. 1 participant showed a shorted cortisol period. 3 participants failed to entrain with initial melatonin treatment.

What are the takeaways from this study?

Low-dose (0.5 mg) melatonin is effective for entrainment of a 24-hour circadian rhythm in a subset of blind persons with “free running” circadian rhythms.

Some individuals will respond favorably to low-dose melatonin – such that they end up fully entrained to a 24-hour circadian rhythm within ~1 week of treatment, whereas others may require longer-term treatment.

Another subset of blind individuals with “free running” circadian rhythms do not respond to the 0.5 mg dose – and thus may require adjustment to the: (1) timing of melatonin administration and/or (2) melatonin dosage (e.g. an increase) – for greater therapeutic effect.

In this study, low-dose (0.5 mg) melatonin significantly: (1) increased nighttime sleep duration & (2) reduced the number and duration of daytime naps – both of which were favorable.

Low but not high doses of melatonin entrained a free-running blind person with a long circadian period (R)

• Date: 2002
• Authors: Lewy et al.
• Case: 46-year-old male (blind with circadian dysregulation)

Authors stated that in a previous study, they were unable to entrain 1 of 7 totally blind people with “free running” using high-dose melatonin (10 mg per night).

The remaining 6/7 blind people with “free running” benefitted significantly from 10 mg exogenous melatonin each night as evidenced by: normalization of circadian rhythms (which drifted later each day), improved nighttime sleep quality, and decreased daytime napping.

The one non-responder (failing circadian entrainment with 10 mg/nightly melatonin supplementation) was hypothesized to need a higher dose of melatonin (e.g. 20 mg/night).

Why? (1) He exhibited the longest circadian rhythm (24.9 hours) of the entire group & (2) animal research suggested that more significant differences between one’s circadian rhythms and a normal 24-hour cycle require proportionately stronger entraining agents.

In this case, high-dose melatonin (20 mg/night) was trialed without significant benefit.

Dose vs. Circadian effect

A low dose of just 0.5 mg (500 mcg) was highly effective for entraining this individual.

Why did this individual require a lower dose of melatonin?

According to authors, the larger the dose of melatonin, the more likely it will “spill over” onto the “wrong” zone of the melatonin phase-response curve (PRC).

Important notes from researchers…

• It should NOT be assumed that blind people with free-running rhythms who have long circadian periods will be (A) unentrainable OR (B) require high-doses of melatonin.
• Higher doses of melatonin may be unnecessary and even detrimental in some people.
• The 0.5 mg (500 mcg) melatonin dose was also effective as a de novo treatment (by researchers) in 3 individuals with circadian periods of 24.2-24.5 hours.
• Blind people with atypically long circadian periods and/or slow melatonin metabolizers (mediated by CYP1A2 enzymes in the liver) – should probably use low dose melatonin instead of high-dose.
• Research suggests that low-dose melatonin can be administered therapeutically over a long-term without any diminished effect – and should be physiologically safer than high doses.
• Low doses are less often associated with “sleepiness” (relative to high doses), however, it’s possible to increase evening sleepiness by administering low-dose melatonin earlier in the evening (e.g. ~2 hours before bed).

Double-Blind Randomized Placebo-Controlled Trial of Low Dose Melatonin for Sleep Disorders in Dementia (R)

• Date: 2002
• Authors: Serfaty et al.
• Aim: Determine whether melatonin supplementation (6 mg, slow-release) improves sleep in patients with dementia – relative to a placebo.
• Participants: 25 patients with Alzheimer’s-type dementia
• Results: Melatonin (6 mg, slow-release) had no significant effect on: total sleep time; number of awakenings; sleep efficiency.
• Conclusion: Melatonin does NOT appear to enhance sleep parameters in persons with Alzheimer’s-type dementia.

It was noted that this outcome differed from previous findings wherein melatonin significantly improved sleep parameters among patients with dementia.

Note: “6 mg” isn’t what most would consider low-dose melatonin.  However, I included the above study in this discussion because researchers involved in this study considered it “low dose” (see: the title).

Acute Effects of Low Doses of Melatonin on the Sleep of Young Healthy Subjects (R)

• Date: 2001
• Authors: Pires et al.
• Aim: Evaluate the acute effects of single, low-doses of melatonin (0.3 mg & 1 mg) vs. a placebo – in 6 healthy male volunteers (22-24 years old) at 3 fixed times (6:00 PM; 8:00 PM; 9:00 PM).
• Measures: Polysomnography; sleep quality questionnaire; Profile of Mood States; Stanford Sleepiness Scale; visual reaction test
• Results: Melatonin treatment at 6:00 PM and 8:00 PM significantly decreased sleep onset latency. Melatonin improved sleep efficiency and decreased intermittent wakefulness.

What can we extrapolate from this study?

It should be noted that the study is limited by its small sample size, however, comparing polysomnography post-melatonin vs. post-placebo should provide reasonably accurate data.

Low-dose melatonin (0.3 mg & 1 mg) is effective for expediting sleep onset, improving sleep efficiency, and reducing intermittent wakefulness – in healthy young adults when administered at 6:00 PM and 8:00 PM.

However, there’s evidence that melatonin needs to be administered at times that are synergistic with circadian-mediated physiology – or it may not work well:

• 3 mg melatonin at 9:00 PM increased sleep onset latency
• 1 mg melatonin at 9:00 PM had no effect on sleep variables

Melatonin given at different times (6:00 PM; 8:00 PM; 9:00 PM) had no effect on subjective sleepiness; mood; or reaction times – the following morning.

This study supports the idea that low-dose melatonin exerts sleep-inducing effects and enhances sleep quality – but only if administered at times that are compatible with circadian-mediated physiology.

Thermoregulatory and Soporific Effects of Very Low Dose Melatonin Injection (R)

• Date: 1999
• Authors: van den Heuvel et al.
• Aim: Determine the effect of melatonin level on body temperature and subjective sleepiness.
• Participants: 8 young adults (~23.9 years old; 4 male & 4 female)
• Methods: Participants were required to abstain from caffeine and alcohol during the experiment – and received injections of either saline (placebo) or melatonin (at various dosage increments) during the daytime.
• Measures: Plasma melatonin levels; body temperature; subjective sleepiness.
• Results: Plasma and salivary melatonin concentrations were significantly greater than the saline placebo following administration of 10 mcg and 30 mcg doses – but NOT after the 3 mcg dose.

What were the key findings in this study?

A melatonin microdose of 3 mcg (0.03 mg) did NOT significantly change plasma or salivary concentrations of melatonin.

Low-dose melatonin at 10 mcg (0.1 mg) and 30 mcg (0.3 mg) significantly increased plasma and salivary concentrations of melatonin – to levels consistent with endogenous physiologic concentrations of melatonin at night.

Low-dose melatonin (10 mcg & 30 mcg) significantly suppressed normative daytime increases in rectal and hand temperature (respectively) – and this temperature suppression was maintained for longer than the statistical elevation of melatonin in plasma and saliva.

Daytime intravenous (IV) injections of melatonin to achieve normal nocturnal levels in young adults may produce substantial thermoregulatory changes without soporific effects (i.e. without induction of sleepiness).

(A slight but nonsignificant trend for increased subjective sleepiness was observed at the highest dose of melatonin.)

What can we extrapolate from this study?

Melatonin microdosing at 3 mcg (0.03 mg) is unlikely to have any objectively significant or subjectively noticeable impact on physiology.

Administration of low-dose melatonin between 0.1-0.3 mg (10-30 mcg) is likely to significantly increase melatonin concentrations within a normal physiologic range.

Low-dose melatonin (0.1-0.3 mg) seems to significantly decrease body temperature – which may be one mechanism by which it enhances sleep quality.

Although this study failed to find any significant soporific (i.e. sleepiness-inducing) effect from melatonin, the lack of sleepiness may have been explained by one or more of the following:

• Daytime administration (such that it was a circadian mismatch – and was working against other alertness-promoting physiological actions)
• Insufficient dosage (a higher dosage may have been needed produced significant soporific effects, particularly during the daytime – such as to override alertness associated with daytime)
• Small sample size: Results might’ve been different with a larger sample (e.g. random variation within the small sample may have prevented researchers from noticing a soporific effect)

One might hypothesize (based on this study) that low-dose melatonin 0.1-0.3 mg might not actually induce sleepiness at night – particularly in young adults.

However, this study administered melatonin: (A) during the daytime (circadian mismatch) and (B) intravenously (which may have been uncomfortable or distracting) – which might’ve explained the lack of sleepiness.

Moreover, the study had many other limitations – and other research supports the idea that low-dose melatonin 0.1-0.3 mcg can decrease sleep onset latency (at night) via enhancement of circadian rhythms, induction of sleepiness, and reduction in core body temperature.

Note: It is important to note that melatonin was administered intravenously (IV) – which may exhibit a slightly or significantly different bioavailability relative to oral melatonin administration (which is ~15%).

Effects of Low Dose Melatonin on Sleep in Children with Angelman Syndrome (R)

• Date: 1999
• Authors: Zhdanova et al.
• Aim: Determine the effects of low-dose melatonin (0.3 mg) therapy on sleep – taken ~0.5-1 hour before bedtime – in 13 children (ages 2-10) with Angelman syndrome (AS) for 5 days.
• Measures: Blood samples (endogenous melatonin levels & levels from melatonin treatment); Actigraphy recordings (motor activity); Parents’ reports
• Results: Peak nocturnal melatonin levels post-supplementation ranged 128-2800 pg/mL (increasing from an endogenous range of 19-177 pg/mL). Actigraphy and parents’ reports revealed significant improvement in nocturnal sleep patterns as a result of melatonin supplementation.

What were the takeaways from this study?

Moderately increasing nocturnal melatonin concentrations via low-dose (0.3 mg) supplementation: (A) promotes sleep AND (B) significantly improves nocturnal sleep patterns (evidenced by decreased motor activity) – in pediatrics with Angelman syndrome.

Comparative Study to Determine the Optimal Melatonin Dosage form for the Alleviation of Jet Lag (R)

• Date: 1998
• Authors: Suhner et al.
• Participants: 320 volunteers who had flights over 6-8 time zones were recruited for a double-blind, randomized, placebo-controlled study.
• Methods: Volunteers received melatonin: 0.5 mg (fast-release); 5 mg (fast-release); 2 mg (controlled-release); or placebo. These were taken once daily at bedtime during 4 days after an eastward flight.
• Measures: Profile of Mood States (POMS); sleep log; symptom questionnaires (once daily)
• Results: Fast-release melatonin formats were more effective than controlled-release. The 5 mg fast-release formulation significantly: improved sleep quality, reduced sleep latency, and decreased fatigue & daytime sleepiness – after an intercontinental flight. The low dose of 0.5 mg was almost as effective as the 5 mg dose.

Pharmacological doses of melatonin (5 mg) induce larger advances of the endogenous melatonin rhythm and faster resynchronization of the sleep-wake cycle than physiological doses (0.5 mg).

Researchers stated that because melatonin’s bioavailability varies between 10% and 56% – low doses may not generate sufficient spikes in blood to have a strong effect.

Why was slow-release melatonin (2 mg) less effective than both 0.5 mg and 5 mg fast-release versions?

A rapid and significant increase in melatonin concentration appears necessary to synchronize the circadian rhythm and suprachiasmatic nucleus (SCN) to a new time zone – and induce sleep.

Slow-release melatonin fails to generate a supraphysiologic spike in melatonin that’s required to shift circadian rhythm significantly.

Low dose melatonin improves sleep in healthy middle-aged subjects (R)

• Date: 1996
• Authors: Attenburrow et al.
• Study design: Placebo-controlled, double-blind, cross-over
• Participants: 15 healthy adults (middle-aged = 41-67 years old)
• Methods: Compare single evening doses of orally-administered melatonin (0.3 mg & 1 mg) to a placebo.
• Measures: Polysomnography
• Results: Low dose melatonin (1 mg) significantly increased: (1) actual sleep time; (2) sleep efficiency; (3) non-REM sleep; (4) REM sleep latency – relative to the placebo.

Researchers noted that low-dose melatonin (1 mg) improved sleep parameters in healthy middle-aged adults sleeping at home.

It was noted that 3 of the 15 participants were excluded from the study because they slept or napped prior to nighttime sleep – which may have altered outcomes.

Researchers speculate that taking melatonin ~2 hours before sleep times may have caused the napping in 2 of the 3 excluded participants.

Why was melatonin administered 2 hours before sleeping? The rationale: Exogenous melatonin should “boost” the natural onset of pineal melatonin secretion which usually occurs around 9:00 PM.

Researchers admitted that it may have been better to administer the melatonin closer to actual sleep times (as levels peak ~60 minutes after ingestion).

Interestingly, sleep onset latency was low in the placebo condition and NOT significantly reduced by melatonin administration.

Melatonin doses of 1 mg typically yield plasma concentrations that are several times greater than the normative physiological peak.

This study is significantly limited by its small sample size (just 12 participants included in the final analysis).  Nonetheless, its result indicates that melatonin at a dose of 1 mg/night appears beneficial for sleep in middle-aged adults.

That said, there was no significant benefit from 0.3 mg melatonin (relative to the placebo) – indicating that too low of a dose might not significantly enhance sleep in healthy adults.

Effects of low oral doses of melatonin (2-4 hours before habitual bedtime) on sleep in normal young humans (R)

• Date: 1996
• Authors: Zhdanova et al.
• Aim: Determine effects of augmented circulating melatonin levels within the physiologic nocturnal range on polysomnographic parameters of overnight sleep in young healthy volunteers with normal sleep quality.
• Study design: 3 double-blind, placebo-controlled test sessions (5 days between each session)
• Participants: 12 male volunteers (~28.5 years old)
• Measures: Polysomnography; blood samples; self-report questionnaires (evening sleepiness, bedtime, sleep quality)
• Methods: Participants refrained from caffeine and alcohol during testing, and received meals (15% protein, 35% fat, 50% carbs) at 5:00 PMs (dinner) and 8:30 PM (small snack). On treatment nights, participants received melatonin (0.3 mg or 1 mg) at 9:00 PM and retired in darkness ~1 hour later (10:00 PM). Blood samples were collected at multiple intervals (6:30 PM, 7:00 PM, 10:50 PM) and assayed for melatonin. Polysomnography recorded each participant until 7:00 AM.

What were the findings?

Both doses of melatonin (0.3 mg & 1 mg) significantly decreased sleep onset latency (SoL) and increased sleep efficiency – relative to the placebo (as evidenced by polysomnography data).

Physiologically-dosed (0.3 mg) and low-dose (1 mg) melatonin did NOT significantly differ in respective effects on sleep onset latency and sleep efficiency.

No significant alterations in sleep architecture were detected as a result of melatonin treatment:

• Latency to REM sleep did not significantly change – but had a tendency to decline after administration of physiologically-dosed (0.3 mg) melatonin.
• Neither dose of melatonin significantly altered the lengths of sleep stages.
• There was a trend for a reduction in the duration of slow-wave sleep – but the reduction was insignificant.

Peak endogenous serum melatonin levels ranged from 72-287 pg/mL (mean = ~145.3 pg/mL) and varied significantly among participants.

There was a clear correlation between time of onset of nocturnal melatonin increase and time of onset of habitual evening sleepiness. That said, habitual bedtime did NOT correlate with melatonin onset.

Administration of 0.3 mg melatonin (at 9:00 PM): increased serum melatonin within the normal nocturnal range (~112.6 pg/mL) upon initiation of sleep testing.

Administration of 1 mg melatonin (at 9:00 PM): increased serum melatonin to supraphysiologic levels ~50 minutes post-administration (~521.4 pg/mL).

The data from this study indicate that increasing physiological concentrations of melatonin 2-4 hours before habitual bedtime exerts a sleep promoting effect in healthy young men.

Moreover, 6-8 hours after administration of a physiologic dose (0.3 mg) of melatonin – serum concentrations return to baseline (which is a good thing – as you don’t want high melatonin levels in the morning).

The outcome in this study supported previous findings from these researchers wherein low-dose melatonin administered at noon (12:00 PM) or later in the evening (6:00 PM, 8:00 PM, 9:00 PM) – promotes sleep onset.

Zhdanova et al. state:

“An increase in serum melatonin levels within the physiologic range, either during the daytime or late in the evening, is not an imperative signal for sleep, but a gentle promoter of general relaxation and sedation, the elements of sleepiness that, in favorable conditions, significantly facilitate sleep onset.”

I like this quote because it sums up my experience with melatonin.

It seems to subtly enhance my sleep in favorable conditions – but it doesn’t do much if I’m extremely stressed or neglecting some aspect of my health such as failing to get enough exercise, etc.

Sleep-Inducing Effects of Low Doses of Melatonin Ingested in the Evening (R)

• Date: 1995
• Authors: Zhdanova et al.
• Methods: 6 healthy male volunteers (~26.5 years old) received melatonin (0.3 & 1 mg) or placebo at 6 PM, 8 PM, & 9 PM.
• Measures: Polysomnography (sleep onset latency; time to “stage 2” sleep; REM)
• Results: Low-dose melatonin (both: 0.3 & 1 mg) significantly decreased sleep onset latency and latency to “stage 2” sleep (regardless administration timing: 6 PM, 8 PM, 9 PM)
  • Melatonin did NOT suppress REM (rapid-eye movement) or delay its onset.
  • Most volunteers could subjectively distinguish between the effects of melatonin or the placebo when administered at 6:00 & 8:00 PM.
  • None of the volunteers mistook the placebo for melatonin in self-reports.
  • Neither dose of melatonin had “hangover effects” (as confirmed by mood & performance tests in the morning).

Additional notes from the study

The effects of physiologically-dosed (0.3 mg) and low-dose (1 mg) melatonin did NOT significantly differ with regard to any parameters measured.

Therefore (according to the results) higher doses (above 0.3 mg) do NOT appear to enhance hypnotic effects.

There were NOT significant differences in latency to REM sleep after melatonin or placebo administration at 9 PM.  That said, latency to REM decreased in 3/6 participants with the lower dose (0.3 mg).

Time-specific effects & sleep onset latency reductions

• 6 PM: 57.3 minutes (placebo); 10.8 minutes (0.3 mg); 8.5 minutes (1 mg)
• 8 PM: 29.4 minutes (placebo); 6.4 minutes (0.3 mg); 7.2 minutes (1 mg)
• 9 PM: 54.8 minutes (placebo); 7.1 minutes (0.3 mg); 6 minutes (1 mg)

Time-specific effects & time to “stage 2” sleep reductions

• 6 PM: 65.3 minutes (placebo); 19 minutes (0.3 mg); 14 minutes (1 mg)
• 8 PM: 33.8 minutes (placebo); 7.2 minutes (0.3 mg); 11.4 minutes (1 mg)
• 9 PM: 61.25 minutes (placebo); 10.1 minutes (0.3 mg); 11.3 minutes (1 mg)

Individuals with prolonged sleep onset latencies appear to exhibit strongest responses to exogenous melatonin administration.

Self-reports from study participants indicated that latency to the hypnotic effect of melatonin was 25-60 minutes.

Zhdanova et al. concluded that low oral doses of melatonin produce acute hypnotic effects when given in the evening – and that these effects are discernable via subjective assessment and polysomnography.

Effects of Long-Term, Low-Dose, Time-Specified Melatonin on Endocrine & Cardiovascular Variables in Adult Men (R)

• Date: 1990
• Authors: Terzolo et al.
• Methods: Blood samples were routinely collected from 6 healthy adult male volunteers to determine the effect of melatonin (2 mg) at 6:00 PM – over a 2-month period.
• Measures: Melatonin; Prolactin; Cortisol; Testosterone; T3; T4; LH; FSH; PRL; TSH; Aldosterone
• Results: Treatment led to marked elevations in serum melatonin with a significant phase-advance of its circadian rhythm. Melatonin signaling may cue neuroendocrine systems for organization of testicular function.

Note: Researchers in this study referred to “2 mg” as “low dose” melatonin – hence its inclusion in this article. However, 2 mg isn’t really considered “low dose” by most.

Excerpts from melatonin researchers & medical professionals…

Why does Dr. Richard Wurtman (MIT) think that melatonin dosages below 1 mg are ideal for sleep?

• No tolerance induction with chronic use (such as via receptor desensitization – which he has either observed or suspects at higher doses).
• No circadian dysregulation with chronic use (high doses can accumulate systemically such that melatonin concentrations remain high in the daytime – and dysregulate the circadian rhythm)
• No discrepancies in long-term effect based on CYP1A2 metabolism (higher doses can cause significant circadian dysregulation in slow CYP1A2 metabolizers)
• Clinically relevant effect in reducing sleep onset latency and regulating the circadian rhythm (relative to a placebo) with lower risk of/magnitude of – side effects (relative to higher doses).

Who is best suited for low-dose melatonin?

Anyone can use low-dose melatonin – as long as it is safe (based on health/medical status) and beneficial (in terms of treating a medical condition or enhancing quality of life).

In fact, I’d say that everyone who plans to use melatonin chronically – should be using the minimal effective dose (MED), or lowest-possible amount to get significant benefit.

Why? Lower doses generally tend to decrease risk of side effects, adverse reactions, interactions (with medications, supplements, and medical conditions) – and are unlikely to cause tolerance or circadian dysregulation.

Finding the minimal effective dose for your specific physiology may require a bit of experimentation.

Reasons to Use Low Dose Melatonin (0.1 mg, 0.3 mg, 0.5 mg, 1 mg)

Included below are reasons to use low-dose melatonin (instead of standard-dose or high-dose).

Just as effective as standard & high-doses

Lower dosages such as 0.1 mg, 0.3 mg, 0.5 mg, and 1 mg – have been shown in scientific literature to work just as well as high-doses for circadian modulation and sleep induction, sleep maintenance, and sleep enhancement.

Therefore, many would ask – why use more than this amount?

Dysregulation of circadian rhythm & sleep problems

Research suggests that melatonin at standard-to-high doses can systemically accumulate in CYP1A2 slow metabolizers (usually in ~4 weeks).

After accumulating systemically, further supplementation actually dysregulates the circadian rhythm and worsens sleep (relative to pre-melatonin baseline).

In CYP1A2 slow metabolizers, using low dose melatonin (100-300 mcg) prevents circadian dysregulation while providing indefinite therapeutic benefit.

Protection from tolerance onset

While melatonin at standard (e.g. 1-5 mg) and high doses (10+ mg) hasn’t been shown to induce tolerance, some experts argued that it may eventually occur (such as via receptor desensitization).

“A possible explanation for the decline in hypnotic effects after 3 months may also be altered melatonin receptor sensitivity or decreased receptor density.” – Russcher et al. (R)

Low dose melatonin ensures that melatonin concentrations remain within a physiologically homeostatic range – and thus physiological tolerance is thought to be impossible or unlikely.

Read: Melatonin Tolerance.

Decreases risk of side effects & adverse events

The lower the dose melatonin taken – the lower the risk of side effects and adverse events.

If you do experience any side effects/adverse events – their severities should theoretically be much lower at lower doses relative to high doses.

Related: Melatonin Overdose.

Lowers risk of interaction effects (pharmacokinetic & pharmacodynamic)

The lower the dose of melatonin taken, the lower the risk of melatonin interacting with, potentiating the effects of, or being potentiated by – another co-ingested substance.

For example: If you take a prescription medication or over-the-counter medication that happens to interact somewhat with melatonin – the interaction effect probably shouldn’t be as pronounced/problematic if the dose is low.

Related: Melatonin & Xanax Combination.

Minimizes risk of hormone disruption

There is some evidence that chronic melatonin use might disrupt hormones (such as testosterone production) – especially at high doses.

To minimize the risk of melatonin disrupting hormones, low doses are best.

Some think that supraphysiological doses of melatonin may shrink testicles and ovaries (i.e. gonads).

Prevents melatonin “hangovers” (?)

Many people report lingering effects (akin to a hangover) the morning after taking melatonin.

These include things like: brain fog, cognitive impairment, depression, drowsiness, sleepiness, and fatigue/lethargy. Lower doses may prevent these hangovers.

Note: In addition to CYP1A2 slow metabolizers, melatonin may accumulate in persons with impaired kidney (renal) and/or liver (hepatic) function – and possibly end up stored in fat (adipose) tissue.

What is the optimal dose of melatonin to start with?

If you’re new to melatonin, talk to your doctor and pharmacist about this.

Determine whether melatonin: (A) might interact with medications and/or supplements that you take – and (B) is safe to take (given your health & medical conditions); and (C) might be useful or beneficial.

Assuming you’re purchasing your own melatonin supplements and plan on taking the minimal effective dose for sleep enhancement and/or circadian optimization, I’d personally start with 0.1 mg or 0.3 mg.

Try it for several weeks about 1 hour before your desired bedtime (e.g. 9 PM for a 10 PM bedtime).

Melatonin actually strengthens the circadian rhythm with chronic administration (such that effects often become more pronounced after using for several weeks) – hence start slow for several weeks and see how you fair.

If you don’t experience any significant subjective improvement (e.g. reduction in the time it takes to fall asleep) – increase the dose slightly and maintain for several more weeks.

Keep increasing the dose until you find the minimal effective dose – or the smallest amount that subjectively enhances sleep quality or quality of life.

When to take high dose melatonin (instead of low-dose)?

There may be specific therapeutic “use cases” for high-dose melatonin wherein health/medical impact may be significantly greater than low-dose melatonin.

• Recovery from nerve injury: Preliminary data indicate that high-dose melatonin may be more useful than low-dose melatonin in promotion of recovery following nerve (i.e. neurological) injury.
• Toxicity prevention, protection, reduction: High-dose melatonin may be more effective than low-dose melatonin at protecting the body from toxins.
• Anti-inflammatory & antioxidant effect: High-dose melatonin seems to be more effective for reducing inflammation and oxidative stress than low-dose melatonin.
• Immunomodulatory effect: High-dose melatonin may have a favorable immunomodulatory effect while sick with infection – relative to low-dose melatonin (which may not have a therapeutically relevant effect).
• Sleep enhancement (?): Some individuals claim that they experience a significantly more robust sleep enhancement effect from high-dose melatonin relative to low-dose melatonin.

Note: Keep in mind that high-dose melatonin should only be administered with approval of a medical doctor and pharmacist – as it may interact with medications, exacerbate medical conditions, or disrupt homeostatic physiology to cause adverse events (e.g. circadian dysregulation).

Problems with suggesting a “universally optimal” melatonin dose…

Supplements differ significantly in actual melatonin content

An analysis of 31 melatonin supplements in Canada found that melatonin content varied from 83% less than to 478% more than – what was listed on the label.

70% of supplements had melatonin concentrations that weren’t even within 10% of the amount claimed. (R)

For this reason, if you’ve calibrated your dose with a particular melatonin brand – I recommend sticking with that brand.

(Although untrustworthy brands may have significant differences in melatonin content between batches).

Melatonin bioavailability differs between users

The reason it’s best to self-experiment with melatonin supplements is because inter-individual bioavailability has been shown to vary from 3% to 76% – with the same supplement.

Variance in bioavailability of oral melatonin is probably due to discrepancies between users in: absorption and first-pass metabolism (mediated by CYP1A2 enzyme activity & liver function).

DeMuro et al. (2000): “Both 2 mg and 4 mg oral dosages showed an absolute bioavailability of ~15%.” (R)

The inter-individual range of melatonin oral bioavailability (among 12 persons) was: 3% to 76%. (R)

Why it may be best to self-experiment with melatonin…

Considering that the melatonin supplement you decide to take may differ in melatonin content (mg) relative to another supplement someone else takes – it’s possible that your dose of 1 mg might actually be significantly higher or lower than what you’d expect.

Additionally, the bioavailability of melatonin (the amount that’s biologically active) may be lower with certain melatonin preparations and/or in specific users – relative to other preparations in other users.

Therefore, it may be optimal to conduct self-experiments with melatonin by: (1) using reliable melatonin brands; (2) ensuring that only melatonin is in the melatonin supplement (many contain psychoactive additives like 5-HTP); and (3) gauging how you feel at specific dosage increments (as the bioavailability of melatonin for you may differ relative to another user).

Do you use low dose melatonin?

• What dosage of melatonin do you use?
• What brand of melatonin do you take?
• Do you use any other supplements or drugs (prescription, OTC, etc.)?
• What subjective benefits do you experience from melatonin?
• Have you ever tried higher doses of melatonin? (Any difference in effect vs. low dose melatonin?)