Melatonin
Evidence Fact Sheet
Melatonin (N-acetyl-5-methoxytryptamine) is a pineal hormone and MT1/MT2 receptor agonist studied chiefly for circadian and sleep-onset research. Meta-analyses show a modest, reliable shortening of time-to-fall-asleep and jet-lag relief, with honest null/mixed results for blood pressure, ICU delirium, and high-quality pain trials.
Also known as: Melatonin · N-acetyl-5-methoxytryptamine · Melatonina
Overview
Melatonin is the endogenous pineal hormone N-acetyl-5-methoxytryptamine that acts as an agonist at the MT1/MT2 (MTNR1A/MTNR1B) receptors regulating circadian rhythm, with additional preclinical free-radical-scavenging and NF-kB-inhibiting activity. In research and supplement use it is taken close to bedtime at roughly 0.3-5 mg/day (low phase-shifting doses several hours before sleep; ~1-2 mg for sleep onset; ≥0.5 mg for jet lag). Regulatory status is sharply fragmented: the US treats it as a freely-sold DSHEA supplement with no statutory cap; the EU authorizes only two EFSA claims (sleep-onset reduction at ≥1 mg and jet-lag relief at ≥0.5 mg) while EMA Rx products (Circadin, Slenyto) exist; China caps health-food use at ≤3 mg/day; and Brazil's ANVISA RDC 587/2021 limits supplements to ≤0.21 mg/day, effectively excluding most international products. Short-term safety is good (drowsiness, headache and dizziness near placebo), but long-term data are limited and it is not advised in pregnancy/lactation. This page frames all findings as research outcomes in studied populations, not disease treatment.
Mechanism of Action
MT1/MT2 receptor (MTNR1A/MTNR1B) activation regulating circadian rhythm (phase-shifting + sleep-onset) · Direct free-radical scavenging with redox-active metabolites (preclinical) · NF-kB inhibition (anti-inflammatory, mechanistic context)
Body systems: Sleep-Wake System · Neurological & Cognitive · Immune System
Evidence-Based Benefits
Each benefit below is anchored to a specific PubMed-indexed study. Effect sizes, sample sizes, and p-values are reported as published; no values are inferred. Honest negatives and null results are kept alongside the positive findings, and disease-research populations are described as such — Melatonin is not characterized as a treatment for any disease.
Sleep-Onset Latency
Meta-analysis supported- −7.06 minsleep latency · 95% CI 4.37-9.75
- 19 studiesn = 1,683 subjects
The most-cited pooled analysis of randomized trials found melatonin modestly shortens the time taken to fall asleep versus placebo. The effect is statistically reliable but small in absolute terms (about 7 minutes), consistent with the single EFSA-authorized sleep-onset claim.
Reported effect: Reduced sleep latency by 7.06 minutes (95% CI 4.37-9.75); 19 studies, 1,683 subjects
“Melatonin demonstrated significant efficacy in reducing sleep latency...by 7.06 minutes (95% CI: 4.37-9.75 minutes); 1,683 subjects across 19 studies”
Source: PMID 23691095 · Ferracioli-Oda 2013 · PLoS One
Total Sleep Time & Sleep Quality
Meta-analysis supported- +8.25 mintotal sleep time · 95% CI 1.74-14.75
The same meta-analysis reported a small increase in total sleep time and significantly improved overall sleep quality versus placebo. Benefits are real but modest relative to prescription hypnotics.
Reported effect: Total sleep time increased (WMD = 8.25 minutes, 95% CI 1.74 to 14.75); overall sleep quality significantly improved
“increasing total sleep time (WMD = 8.25 minutes [95% CI 1.74 to 14.75]... Overall sleep quality was significantly improved in subjects taking melatonin...compared to placebo”
Source: PMID 23691095 · Ferracioli-Oda 2013 · PLoS One
Jet Lag
Meta-analysis supported- 11 RCTs+ 4 systematic reviews
- GRADE"probably reduces" symptoms
A GRADE-based meta-analysis concluded oral melatonin probably reduces jet-lag symptoms, with adverse effects probably mild. This aligns with the second EFSA-authorized claim (≥0.5 mg close to bedtime on travel days). The abstract reports a GRADE judgement rather than a single pooled effect size.
Reported effect: 11 randomized trials + 4 systematic reviews; GRADE conclusion that oral melatonin probably reduces jet-lag symptoms
“the use of oral melatonin probably reduces symptoms associated with jet lag syndrome... 11 randomized trials included; 4 systematic reviews analyzed... adverse effects...probably mild”
Source: PMID 26731279 · Tortorolo 2015 · Medwave
Preoperative Anxiety
Meta-analysis supported- −11.69 mmVAS vs placebo · 95% CI −13.80,−9.59
- 0.78 mmvs midazolam · CI −2.02,3.58
A Cochrane review of 27 RCTs found melatonin probably reduces preoperative anxiety on a 0-100 mm visual-analogue scale versus placebo, with little or no difference compared with benzodiazepines (midazolam). Evidence was moderate-certainty.
Reported effect: vs placebo MD −11.69 mm VAS (95% CI −13.80 to −9.59; 18 studies, 1,264 participants); vs midazolam MD 0.78 mm (95% CI −2.02 to 3.58)
“Melatonin probably results in a reduction in preoperative anxiety measured by a visual analogue scale (VAS, 0 to 100 mm) compared to placebo... Mean difference of -11.69 mm... (95% CI -13.80 to -9.59; 18 studies, 1,264 participants)... vs midazolam Mean difference of 0.78 mm (95% CI -2.02 to 3.58)”
Source: PMID 33319916 · Madsen 2020 · Cochrane Database Syst Rev
Blood Pressure (Nocturnal)
Null / no benefit Meta-analysis supported- −3.57 mmHgasleep SBP · CI −7.88,0.73 (NS)
- I² = 0%controlled-release only
Honest negative: a systematic review found only controlled-release (not immediate-release) melatonin lowered asleep systolic blood pressure, and even that 3.57 mmHg reduction was NOT statistically significant (confidence interval crosses zero). Diastolic changes were also non-significant; no cardiovascular outcomes were reported.
Reported effect: Controlled-release melatonin reduced asleep SBP by 3.57 mmHg (95% CI −7.88 to 0.73; I²=0%) — not statistically significant; diastolic BP changes non-significant
“Only controlled-release melatonin (not an immediate-release preparation) reduced asleep systolic blood pressure by 3.57 mm Hg (95% confidence interval: -7.88 to .73; I2 = 0%)... It also reduced asleep and awake diastolic blood pressure, but these differences were not statistically significant.”
Source: PMID 35388609 · Lee 2022 · J Clin Hypertens
ICU Delirium Prevention
Null / no benefit Meta-analysis supported- OR 0.71delirium · 95% CI 0.46-1.12 (NS)
- 6 RCTsn = 2,374 patients
Honest negative: a meta-analysis of 6 RCTs found melatonin did NOT significantly reduce delirium incidence in ICU patients overall, with no benefit for mortality or length of stay. A cardiac-care-unit subgroup showed benefit (OR 0.52) but the general-ICU subgroup did not (OR 1.14).
Reported effect: Delirium OR 0.71 (95% CI 0.46-1.12, p=0.14, non-significant overall); CCU subgroup OR 0.52 (0.37-0.73); GICU subgroup OR 1.14 (0.86-1.50); mortality OR 0.85 (0.66-1.09)
“melatonin did not reduce the incidence of delirium in ICU patients... Odds Ratio: 0.71 (95% CI: 0.46-1.12; p = 0.14)... CCU patients: OR 0.52 (95% CI: 0.37-0.73; p=0.0001)... GICU patients: OR 1.14 (95% CI: 0.86-1.50; p=0.35); 6 randomized controlled trials involving 2,374 patients”
Source: PMID 37564987 · Duan 2023 · Front Endocrinol (Lausanne)
Pain / Analgesia
Null / no benefit Meta-analysis supported- SMD −0.82acute postop pain · CI −1.40,−0.25
- SMD −0.21high-quality subgroup (NS)
Mixed-to-negative: across 30 trials melatonin reduced chronic pain (SMD −0.65) and acute postoperative pain (SMD −0.82), but the high-quality subgroup showed NO significant analgesic effect (SMD −0.21, CI crosses zero, I²=82%). The authors concluded evidence is insufficient for acute/procedural pain.
Reported effect: Chronic pain SMD −0.65 (95% CI −0.96 to −0.34); acute postop pain SMD −0.82 (95% CI −1.40 to −0.25); high-quality subgroup SMD −0.21 (95% CI −0.66 to 0.24, NS); 30 trials, 1,967 participants
“the subgroup meta-analysis of high-quality RDBPCTs showed no significant association between them (6 studies, SMD −0.21, 95 % CI −0.66 to 0.24, I² = 82.4%)... melatonin might be used in treatment of chronic pain, while there is no sufficient evidence for acute postoperative or procedural pain”
Source: PMID 32455582 · Oh 2020 · J Clin Med
High-Dose Safety / Tolerability
Meta-analysis supported- RR 1.40drowsiness/headache · CI 1.15-1.69
- RR 0.88serious AEs (NS)
A systematic review of 79 high-dose (≥10 mg) studies in adults found no detectable increase in serious adverse events or AE-related withdrawals, but a higher rate of mild effects such as drowsiness, headache and dizziness versus comparator. Reporting quality was a limitation (37% of studies did not mention AEs).
Reported effect: No increase in serious AEs (RR 0.88, 95% CI 0.52-1.50) or withdrawals (0.93, 0.24-3.56); increased mild AEs drowsiness/headache/dizziness (RR 1.40, 95% CI 1.15-1.69, p<.001); 79 studies, 3,861 participants
“melatonin did not cause a detectable increase in SAEs (Rate Ratio = 0.88 [0.52, 1.50], p = .64) or withdrawals due to AEs (0.93 [0.24, 3.56], p = .92)... did appear to increase the risk of AEs such as drowsiness, headache and dizziness (1.40 [1.15, 1.69], p < .001); 79 studies involving 3,861 participants”
Source: PMID 34923676 · Schrire 2022 · J Pineal Res
Dosage (research context · not a recommendation)
0.3-5 mg/day taken close to bedtime (phase-shift: 0.3-0.5 mg several hours pre-sleep; sleep-onset: 1-2 mg; jet-lag per EFSA: >=0.5 mg; dose-response effect peaks ~4 mg/day). Market caps: China <=3 mg (health-food only), Brazil <=0.21 mg, US no statutory limit.
Regulatory Status · 4 Markets
- US · FDA
- Dietary supplement under DSHEA 1994 (freely sold, no prescription); structure/function claims (sleep-onset, sleep quality, jet-lag, rhythm); no statutory daily limit; market norm 0.5-10 mg
- EU · EFSA
- Two authorized Art.13.1 claims: sleep-onset (>=1 mg) and jet-lag (>=0.5 mg). Member-state fragmentation (IT <=1 mg supplement, DE treats as medicine); EMA prescription drugs Circadin (PR 2 mg) and Slenyto (pediatric) exist
- CN · China
- SAMR blue-hat health-food raw material; registered function 'improves sleep'; single-ingredient filing pathway since 2021, cap <=3 mg/day.
- BR · ANVISA
- RDC 587/2021: <=0.21 mg/day as a food supplement; above that regulated as a medicine. The very low cap effectively excludes most international melatonin products from the BR supplement channel
Authorized Claims
EFSA — “Melatonin contributes to the reduction of time taken to fall asleep” (Reg 432/2012)
EFSA — “Melatonin contributes to the alleviation of subjective feelings of jet lag” (Reg 432/2012)
Safety
No formal upper limit; consensus <=5 mg/day for adults. A higher-dose safety review found no rise in serious adverse events/withdrawals, but common effects (drowsiness, headache, dizziness) may be increased vs placebo (PMID 34923676). Long-term data limited. Not for pregnancy/lactation (insufficient data). Drowsiness / driving warning. Drug interactions: warfarin, antihypertensives, immunosuppressants, and notably the CYP1A2 inhibitor fluvoxamine (markedly raises melatonin levels). Pediatric ASD/ADHD use is an EU prescription indication (Slenyto), not OTC.
Related
Goals: cognitive-support
Lifestyles: high-stress · senior-60-plus
References
PubMed-indexed citations anchoring the benefit findings above. Effect sizes are reported as published.
- PMID 23691095 · Ferracioli-Oda 2013 · PLoS One — Sleep-Onset Latency
- PMID 26731279 · Tortorolo 2015 · Medwave — Jet Lag
- PMID 33319916 · Madsen 2020 · Cochrane Database Syst Rev — Preoperative Anxiety
- PMID 35388609 · Lee 2022 · J Clin Hypertens — Blood Pressure (Nocturnal)
- PMID 37564987 · Duan 2023 · Front Endocrinol (Lausanne) — ICU Delirium Prevention
- PMID 32455582 · Oh 2020 · J Clin Med — Pain / Analgesia
- PMID 34923676 · Schrire 2022 · J Pineal Res — High-Dose Safety / Tolerability
Frequently Asked Questions
1. What are the honest negatives for melatonin?
Several. For blood pressure, only controlled-release melatonin lowered asleep systolic BP and even that 3.57 mmHg drop was not statistically significant (Lee 2022, PMID 35388609). For ICU delirium prevention, a meta-analysis found no significant overall benefit (OR 0.71, 95% CI 0.46-1.12; Duan 2023, PMID 37564987). And for pain, although pooled estimates looked favorable, the high-quality-trial subgroup showed no significant analgesic effect (SMD −0.21, CI crosses zero; Oh 2020, PMID 32455582).
2. How much melatonin is typically used in studies, and when?
Per the ingredient card, roughly 0.3-5 mg/day taken close to bedtime. Low doses (0.3-0.5 mg, several hours before sleep) are used for circadian phase-shifting; ~1-2 mg for sleep onset; and ≥0.5 mg for jet lag per EFSA conditions. Note that more is not necessarily better, and timing matters as much as dose.
3. Is melatonin safe, and are there interactions?
Short-term safety is generally good. A review of 79 high-dose (≥10 mg) studies found no detectable rise in serious adverse events but more mild effects — drowsiness, headache, dizziness (RR 1.40; Schrire 2022, PMID 34923676). Long-term data are limited. It carries a drowsiness/driving warning, is not advised in pregnancy or lactation, and can interact with warfarin, antihypertensives, immunosuppressants, and notably the CYP1A2 inhibitor fluvoxamine, which markedly raises melatonin levels.
4. Why is melatonin a supplement in the US but restricted elsewhere?
Regulatory status is highly fragmented. The US treats melatonin as a freely-sold DSHEA dietary supplement with no statutory daily limit. The EU authorizes only two EFSA claims (sleep-onset at ≥1 mg, jet-lag at ≥0.5 mg) and several member states regulate it as a medicine; EMA prescription products (Circadin, Slenyto) also exist. China caps health-food use at ≤3 mg/day, and Brazil's ANVISA limits supplements to ≤0.21 mg/day — a cap so low it excludes most international melatonin products from the Brazilian supplement channel.
Last evidence review: 2026-06-13