Evidence Trace, complete trial record

In plain terms

In plain terms: Melatonin has some human trial evidence supporting it, but the evidence is not yet strong enough for EBL to call it established. It is worth knowing about and worth discussing with your clinician.

Melatonin

B Supported: a good trial, backed by more

Category Supplements

Evidence Meta-analyses of randomized trials, with per-use rows

Reviewed July 2026

PMIDs 15649737 · 23691095 · 16423108 · 36179487 · 37434463 · 12076414 · 10484950 · 42346809 · 38888087 · 29912983 · 11211063 · 1674014 · 16295212

The endpoint this grade is based on: Objectively measured functional outcome, Sleep onset timing in delayed sleep phase disorder (B) and jet lag symptoms after flights across five or more time zones (B). In ordinary adult insomnia the effect on sleep onset is a few minutes and the adult-only pooled analysis is null, so that use is C. The antioxidant claim rests on no randomized clinical trial and carries no letter.

The evidence as the record states it

Evidence record

PMID 15649737 PMID 23691095 PMID 16423108 PMID 36179487 PMID 37434463 PMID 12076414 PMID 10484950 PMID 42346809 PMID 38888087 PMID 29912983 PMID 11211063 PMID 1674014 PMID 16295212

Buscemi et al. (J Gen Intern Med, 2005; PMID 16423108), an AHRQ-funded meta-analysis: sleep onset latency shortened by 7.2 minutes in insomnia (12 trials) and by 38.8 minutes in delayed sleep phase syndrome (2 trials); the authors conclude melatonin is not effective for most primary sleep disorders with short-term use but is effective in delayed sleep phase syndrome. Brzezinski et al. (Sleep Med Rev, 2005; PMID 15649737): 17 small studies, 284 subjects, most in healthy people or people without a relevant illness; sleep onset shortened by about 4 minutes. Ferracioli-Oda et al. (PLoS One, 2013; PMID 23691095): 19 trials, 1,683 adults and children with primary sleep disorders; sleep onset shortened by 7 minutes and total sleep lengthened by 8 minutes, larger effects at higher doses. Choi et al. (Sleep Med Rev, 2022; PMID 36179487): 24 trials in chronic insomnia; in adults melatonin did not significantly improve sleep onset, total sleep time or sleep efficiency. Maruani et al. (J Sleep Res, 2023; PMID 37434463): prolonged-release melatonin, small objective effect on sleep onset in adults. Delayed sleep phase: Kayumov et al. (Psychosom Med, 2001; PMID 11211063), Dahlitz et al. (Lancet, 1991; PMID 1674014), Mundey et al. (Sleep, 2005; PMID 16295212) and Sletten et al. (PLoS Med, 2018; PMID 29912983). Jet lag: Herxheimer and Petrie (Cochrane, 2002; PMID 12076414), nine of ten trials positive on self-rated jet lag after flights across five or more time zones; Spitzer et al. (Am J Psychiatry, 1999; PMID 10484950), the largest single trial, 257 travelers, null. Dose and safety: Cruz-Sanabria et al. (J Pineal Res, 2024; PMID 38888087), dose-response meta-analysis, efficacy rising to about 4 mg and larger when taken earlier; Qian et al. (Diabetes Care, 2026; PMID 42346809), a single 5 mg dose impaired glucose tolerance in MTNR1B risk-allele carriers. Grade B, the best letter any use carries: delayed sleep phase B, jet lag B, adult insomnia C, delirium prevention C to D by setting.

PMID 15649737 PMID 23691095 PMID 16423108 PMID 36179487 PMID 37434463 PMID 12076414 PMID 10484950 PMID 42346809 PMID 38888087 PMID 29912983 PMID 11211063 PMID 1674014 PMID 16295212

Evidence by specific use

Sleep onset latency and sleep quality (primary sleep disorders)

Grade C

Mixed. Pooled randomized trials find a small shortening of sleep onset: 7.2 minutes in insomnia (Buscemi et al., J Gen Intern Med, 2005; PMID 16423108), about 4 minutes across 17 small studies mostly in healthy people (Brzezinski et al., Sleep Med Rev, 2005; PMID 15649737), 7 minutes across 19 trials of adults and children with primary sleep disorders (Ferracioli-Oda et al., PLoS One, 2013; PMID 23691095), and about 5 minutes objectively for prolonged-release melatonin (Maruani et al., J Sleep Res, 2023; PMID 37434463). The adult-only analysis of chronic insomnia found no significant effect on sleep onset, total sleep time or sleep efficiency (Choi et al., Sleep Med Rev, 2022; PMID 36179487), and Buscemi concluded melatonin is not effective for most primary sleep disorders with short-term use. Most pooled outcomes are polysomnographic or actigraphic, so the endpoint is measured function rather than self-report, but an effect of a few minutes that an adult-only analysis cannot detect is mixed evidence: C. The pooled trials span doses; this use does not grade a specific dose.

PMID 16423108 PMID 15649737 PMID 23691095 PMID 36179487 PMID 37434463

Sleep onset timing in delayed sleep phase disorder

Grade B

Sleep onset measured by polysomnography or actigraphy is a qualifying endpoint, and the trials point the same way. Buscemi et al. (J Gen Intern Med, 2005; PMID 16423108) pooled two trials: sleep onset 38.8 minutes earlier. Sletten et al. (PLoS Med, 2018; PMID 29912983): 116 patients, 0.5 mg one hour before desired bedtime with behavioral scheduling against placebo with the same scheduling, actigraphic sleep onset 34 minutes earlier. Kayumov et al. (Psychosom Med, 2001; PMID 11211063): 22 patients, 5 mg, double-blind crossover, polysomnographic sleep onset latency shorter than on placebo. Dahlitz et al. (Lancet, 1991; PMID 1674014): 8 patients, 5 mg, sleep onset 82 minutes earlier on sleep logs. Mundey et al. (Sleep, 2005; PMID 16295212): 13 patients, 0.3 or 3 mg, circadian phase advanced. EBL's published update rule requires more than 30 participants in a trial before it can move a grade. Only Sletten et al. meets it; the trials that repeat its finding have 8 to 22 participants. One qualifying trial supported by smaller trials that agree is the written B definition, not a replicated A. Limits stated beside the letter: 4 weeks per trial, one crossover, and the largest trial gave melatonin alongside a sleep-scheduling program that both arms received.

PMID 16423108 PMID 11211063 PMID 1674014 PMID 16295212 PMID 29912983

Jet lag symptoms after flights across five or more time zones

Grade B

Herxheimer and Petrie (Cochrane Database Syst Rev, 2002; PMID 12076414): ten randomized placebo-controlled trials; nine found melatonin taken at the destination bedtime reduced self-rated jet lag after flights across five or more time zones, doses of 0.5 to 5 mg similarly effective with faster sleep onset at 5 mg, benefit larger eastward and with more time zones. The one null trial is the largest: Spitzer et al. (Am J Psychiatry, 1999; PMID 10484950), 257 travelers, 0.5 and 5 mg, no effect on a validated jet lag scale. Nine independent positive trials against one null are replicated evidence, and the endpoint is self-rated, which caps the letter at B.

PMID 12076414 PMID 10484950

Prevention of delirium in older hospitalized/medical-ward patients

Grade C

Al-Aama et al. (Int J Geriatr Psychiatry, 2011; PMID 20845391): randomized placebo-controlled trial, 145 adults aged 65 and over on a medical ward, 0.5 mg melatonin nightly; delirium 12.0% against 31.0%. Jaiswal et al. (Am J Med, 2018; PMID 29729237): 69 inpatients on medical wards, 3 mg nightly; delirium 22.2% on melatonin against 9.1% on placebo, not significant. Al Alawi et al. (RESTORE, BMJ Open, 2026; PMID 41592826): 109 patients on general medical wards, 5 or 8 mg nightly, stopped for futility. Chen et al. (Molecular Neurobiology, 2016; PMID 26189834): meta-analysis of four randomized trials, 669 patients; pooled delirium incidence not significant (RR 0.41, 95% CI 0.15 to 1.13, P=0.08), medical-ward subgroup significant (RR 0.25). Campbell et al. (BMC Geriatr, 2019; PMID 31619178): six studies in older surgical patients, delirium reduced (OR 0.63) with high heterogeneity. Intensive care and cardiac surgery are graded on their own rows below. On the medical ward, which is this use: one positive trial (Al-Aama 2011) and two null trials (Jaiswal 2018, RESTORE 2026), with the pooled primary of the cited meta-analysis missed. Mixed randomized evidence is C. Delirium by the Confusion Assessment Method is a clinician-rated scale.

PMID 26189834 PMID 31619178 PMID 20845391 PMID 29729237 PMID 41592826

Prevention of delirium in the general intensive care unit

Grade D

Tested in general intensive care and no benefit. Wibrow et al. (Intensive Care Med, 2022; PMID 35220473), Pro-MEDIC: 847 patients across 12 Australian units, 4 mg nightly; delirium-free assessments 79.2 against 80.0 percent, no difference in stay, mortality or sleep. Mekontso Dessap et al. (Intensive Care Med, 2025; PMID 40608082), DEMEL: 355 ventilated patients in 20 French centers, 0.3 or 3 mg; delirium 55 percent either way, risk ratio 0.99. Bandyopadhyay et al. (Crit Care Sci, 2024; PMID 38656078): 108 patients, 3 mg, 29.6 against 46.2 percent, not significant. Lakbar et al. (Intensive Care Med, 2025; PMID 41051561) pool the low-bias trials, 2,209 patients, RR 0.89 crossing 1, and all 13 trials, RR 0.86 crossing 1; Duan et al. (Front Endocrinol, 2023; PMID 37564987) find no effect in general units (OR 1.14) and an effect only in cardiovascular units; Zhao et al. (Altern Ther Health Med, 2024; PMID 38518134) pool 10 trials and find no significant reduction overall (RR 0.85). Two 2026 poolings that include smaller and higher-bias trials report a reduction (Wu et al., Front Pharmacol, 2026; PMID 41602948, RR 0.75; Chaves-Filho et al., Crit Care, 2026; PMID 42310686, RR 0.77, low certainty), with no effect on duration, stay or mortality. The two largest trials and the lowest-bias pooling are null: D on Route 2 for the general unit. Cardiac surgery, where the trials point the other way, is graded on its own row.

PMID 35220473 PMID 40608082 PMID 38656078 PMID 41051561 PMID 37564987 PMID 38518134 PMID 41602948 PMID 42310686

Prevention of delirium after cardiac surgery

Grade C

Mixed. Ford et al. (J Am Geriatr Soc, 2020; PMID 31595489), the Healthy Heart-Mind trial: 210 adults aged 50 or over having bypass or valve surgery in Perth, 3 mg nightly for 7 days from 2 days before surgery; delirium 21.4 against 20.2 percent, no difference, the largest single trial. Javaherforoosh Zadeh et al. (Iran J Med Sci, 2021; PMID 33753956): 60 on-pump bypass patients, 3 mg; delirium 13 against 37 percent on day one and 10 against 47 percent on day two. Han et al. (Front Cardiovasc Med, 2022; PMID 35665270) pool eight randomized trials and two cohorts, 1,714 patients, melatonin or ramelteon; delirium lower (OR 0.46), with the authors noting modest numbers and heterogeneity. Duan et al. (Front Endocrinol, 2023; PMID 37564987) find the effect confined to cardiovascular units (OR 0.52) and absent in general units. Small positive trials and a positive pooling against a null trial that is larger than most of the pooled ones: C. Delirium by the Confusion Assessment Method is a clinician-rated scale.

PMID 31595489 PMID 33753956 PMID 35665270 PMID 37564987

Why Grade B and not Grade A

Grade B reflects moderate human evidence -- typically a single strong trial, multiple smaller trials, or surrogate endpoint data without hard clinical outcome replication. To reach Grade A, Melatonin would require at least one additional independent randomized trial demonstrating a hard clinical endpoint or objectively measured functional outcome in a comparable population.

What would move this grade

An independent randomized trial demonstrating a hard clinical endpoint -- mortality, major adverse event, or objectively confirmed functional improvement -- in an adequately powered sample, with results independently replicated, would support Grade A.

How to track whether this is working Sleep onset latency, sleep efficiency, morning alertness, DLMO test if circadian assessment needed; for jet lag, a daily jet lag rating for the first week.