Melatonin
Also known as: N-Acetyl-5-methoxytryptamine, MT, Circadin, Slenyto
Pineal Hormone | Sleep & Circadian Rhythm Regulator
Overview
Melatonin is an indolamine hormone synthesised primarily by the pineal gland from serotonin in response to darkness. It is the principal endogenous signal of biological night, peaking 4-5 hours after lights-out and declining rapidly toward dawn. Endogenous production is suppressed by light exposure (particularly short-wavelength blue light), which is why screen use late in the evening can shift sleep onset later. Supplemental melatonin is one of the most-used sleep aids globally, available without prescription in the US and as a regulated medicine in much of Europe. Its evidence base is strongest for circadian-rhythm sleep disorders (jet lag, shift-work disorder, delayed sleep-phase syndrome) and for sleep onset in older adults whose endogenous melatonin production has declined. Effects in younger adults with primary insomnia are more modest. The popular consumer perception that more is better is wrong — physiologic doses of 0.3-1 mg often outperform the 5-10 mg products on store shelves, both for efficacy and because high doses produce supraphysiologic plasma levels that persist into the morning, causing next-day grogginess. Beyond sleep, melatonin is a potent free-radical scavenger and modulates immune function; its longevity-research interest stems from these antioxidant and anti-inflammatory effects.
Key benefits
- Reduced sleep-onset latency in older adults and circadian-disorder patients
- Effective phase-shifting for jet lag (eastward travel) and shift-work adaptation
- Useful in delayed sleep-phase syndrome (DSPS) — adolescents and young adults
- Potent free-radical scavenger with mitochondrial-protective effects
- Modest immune-modulating effects (anti-inflammatory in chronic settings)
- Reduces oxidative damage in animal models of neurodegeneration
- Non-habit-forming, no withdrawal, no rebound insomnia
- Available OTC; very wide therapeutic window
Mechanism of action
Melatonin acts via two G-protein-coupled receptors: MT1 and MT2. MT1 is concentrated in the suprachiasmatic nucleus (SCN, the master circadian pacemaker) and mediates the soporific effect — activation reduces SCN firing and lowers core body temperature, both pro-sleep signals. MT2 is more involved in phase-shifting circadian rhythms; activation in the early evening shifts the circadian clock earlier (advancing sleep onset), while activation late at night or early morning shifts it later. This biphasic phase-response curve is why melatonin works for jet lag — the timing of the dose matters as much as the dose itself. Beyond receptor binding, melatonin is a potent antioxidant that directly scavenges hydroxyl radicals and peroxynitrite and stimulates the activity of antioxidant enzymes including superoxide dismutase and glutathione peroxidase. It is highly lipophilic and crosses the blood-brain barrier and mitochondrial membranes readily, where it reduces oxidative damage to mitochondrial DNA. Immunomodulation occurs via melatonin receptors on T-cells and macrophages — the relevance of these effects to disease prevention or treatment is still being characterised.
Molecular data
- Type
- Indolamine — N-acetyl-5-methoxytryptamine (C13H16N2O2)
- Half-life
- ~30-50 minutes (immediate release); ~3-4 hours (sustained release)
Indications
What the research community uses this compound for, with self-reported effectiveness.
Sleep
Sleep Onset in Older Adults
ModerateEndogenous melatonin declines significantly with age. Low-dose supplementation (0.3-2 mg) at bedtime reduces sleep-onset latency by 5-15 minutes and modestly improves sleep efficiency. Effect is more reliable than in younger adults.
Primary Insomnia (Younger Adults)
LimitedModest reductions in sleep-onset latency in some trials, but the effect is small (typically <8 minutes) and clinically marginal. Not a first-line treatment. CBT-I remains gold standard.
Circadian Rhythm Disorders
Jet Lag (Eastward Travel)
EffectiveStrongest evidence base. 0.5-3 mg taken in the early evening at the destination, for 3-5 days, accelerates phase advance and reduces jet lag symptoms. Eastward travel is harder than westward; melatonin helps most with east.
Shift-Work Sleep Disorder
ModerateHelpful when timed correctly relative to the shift schedule — typically 30-60 min before the desired sleep period. Effect on alertness during the shift itself is not the goal; the aim is improving daytime sleep quality.
Delayed Sleep-Phase Syndrome
EffectiveLow-dose melatonin (0.3-1 mg) taken 5-7 hours before the natural (delayed) sleep onset is used to advance the circadian clock. Best done under sleep-medicine guidance for chronic cases.
Other Investigational
Antioxidant / Mitochondrial Support
Under researchStrong preclinical antioxidant and mitochondrial-protective effects. Some clinical interest in neurodegenerative disease and cardiovascular protection but no consensus indication yet.
Migraine Prophylaxis
ModerateSome small RCTs suggest 3 mg melatonin nightly reduces migraine frequency. Effect size is modest; magnesium has more consistent evidence.
Dosing protocols
Common protocols by delivery method. Adjust the curve below to model accumulation in your own cycle.
Oral
Bioavailability: ~15% systemic for immediate-release (high first-pass); higher for sublingualTake 30-60 min before desired sleep onset. Avoid blue light after dosing. Start low — 0.3-1 mg often more effective than 5-10 mg.
| Protocol | Dose | Frequency | Route / duration |
|---|---|---|---|
| Sleep onset (low-dose physiologic) Closer to natural overnight peak. Less next-day grogginess. | 0.3-1 mg | 30-60 min before bed | Ongoing or as-needed |
| Sleep onset (pharmacologic) Common consumer dose; may produce supraphysiologic plasma levels and morning grogginess in some users. | 3-5 mg | 30-60 min before bed | Avoid prolonged daily use |
| Jet lag (eastward) Time relative to destination, not origin. | 0.5-3 mg | 30 min before destination bedtime, for 3-5 days | 3-5 days |
Interactions
Pairwise interactions with other compounds you might be cycling — the same data behind the cycle builder's safety check.
Fluvoxamine
AvoidFluvoxamine inhibits CYP1A2, which metabolises melatonin. Combination raises melatonin plasma levels significantly. Avoid or use much lower doses.
Sedatives / CNS depressants (benzodiazepines, alcohol, opioids)
MonitorAdditive sedation. Effect is modest with melatonin alone but compounds with stronger sedatives.
Anticoagulants (warfarin)
MonitorSome reports of altered INR. Monitor if combined.
Magnesium glycinate
SynergisticCommon evening sleep stack. Magnesium calms; melatonin shifts circadian timing. Mechanisms don't overlap.
L-Theanine
SynergisticTheanine reduces anxious arousal at sleep onset; melatonin shifts circadian timing. Common combined-sleep stack.
Safety
Reported adverse effects, contraindications, and what to monitor on cycle.
Common side effects
- Next-morning grogginess (especially at higher doses)
- Vivid dreams or nightmares
- Headache
- Mild dizziness
Uncommon side effects
- Mood changes (irritability, depressive symptoms)
- Reduced sex drive
- Hypotension (mild)
Rare side effects
- Worsened seizure control in epilepsy patients (mixed evidence)
Contraindications
- Pregnancy and breastfeeding (safety not established)
- Autoimmune disease (theoretical immune-modulating effect)
Monitoring
- None required for typical use. Reassess if morning grogginess persists — drop the dose.
References
Primary literature and clinical-trial data informing this entry.
Auld F et al. Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Med Rev. 2017;34:10-22.
Comprehensive sleep-disorder review.
Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520.
Foundational Cochrane review on jet lag.
Reiter RJ et al. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61(3):253-78.
Antioxidant mechanism review.
Last updated . How this page was sourced is described in the methodology.