Hormone

Melatonin

N-acetyl-5-methoxytryptamine

Evidence TierAWADA NOT PROHIBITED

tuneTypical Dose

0.5–5 mg

watchEffect Window

Acute (same night for sleep onset).

check_circleCompliance

WADA NOT PROHIBITED

Overview

Clinical Summary

Melatonin is a hormone that regulates circadian timing and sleep onset. It is used for jet lag, delayed sleep phase patterns, and sleep onset insomnia, where timing of use is central.

Evidence supports reduced sleep onset latency and improved circadian alignment, especially for jet lag and delayed sleep-wake phase disorder. Benefits are often stronger in older adults with lower endogenous melatonin, and recent meta-analysis in cognitive-impairment populations suggests modest total-sleep-time benefit as well. Minority evidence suggests migraine prevention and modest improvements in some inflammatory or metabolic markers. Effects depend heavily on timing relative to light exposure, and sleep maintenance benefits are less consistent.

Acts on MT1/MT2 receptors in the suprachiasmatic nucleus to signal darkness and promote sleep-wake cycle transition. Secondary antioxidant and immune-modulating activity.

Outcomes

What This Is Expected To Influence

Primary Outcomes

  • Reduces sleep onset latency by 7–12 minutes
  • Effective for jet lag recovery and circadian re-entrainment

Secondary Outcomes

  • Antioxidant neuroprotection
  • Mild immune modulation
  • May improve overall sleep quality

Safety

Contraindications and Interactions

Contraindications

  • Autoimmune diseases (melatonin has immune-stimulating properties)
  • Severe depression (may worsen symptoms in some individuals)
  • Pregnancy (caution)

Side effects

  • Drowsiness - Both immediately after a dose and the next day, potentially affecting daytime alertness
  • Headache
  • Nausea
  • Dizziness
  • Nightmares
  • Abnormal dreams
  • Insomnia
  • Reduced body temperature

Interactions

  • Drugs that cause drowsiness/sedation (Probable/Moderate) - Melatonin can cause drowsiness and may have additive sedative effects when combined with other sedatives.
  • Fluvoxamine (Probable/Moderate) - Strong CYP1A2 inhibition can markedly increase melatonin exposure. Avoid combination or use a substantially lower melatonin dose only with clinician guidance.
  • Drugs that inhibit CYP1A2 (Probable/Moderate) - Melatonin is predominantly metabolized by CYP1A2, so inhibitors can increase melatonin levels.
  • Drugs that induce CYP1A2 (Probable/Moderate) - Induction of CYP1A2 can reduce circulating melatonin levels.
  • Tobacco (Probable/Moderate) - Substances in tobacco smoke may increase the metabolism of supplemental melatonin, leading to reduced melatonin levels in the blood.
  • Nifedipine (Possible/Moderate) - Melatonin may reduce the effectiveness of nifedipine, a blood-pressure-lowering medication.
  • Blood-pressure-lowering drugs (Possible/Minor) - Melatonin (controlled release) lowering drugs may further lower blood pressure at night when combined with antihypertensive medications.
  • Anticoagulants (Possible/Minor) - Melatonin may have mild antiplatelet effects. Monitor for bleeding or INR changes in anticoagulated patients.
  • Immunosuppressants (Possible/Moderate) - Melatonin's immune-modulating effects may counter immunosuppressive therapy.
  • Caffeine (Probable/Unknown) - Caffeine may reduce the metabolism of melatonin, leading to increased melatonin levels in the blood.

Avoid if

  • Pregnant or breastfeeding people
  • Operating machinery or driving within 4–5 hours of dosing
  • Autoimmune disease without clinician supervision
  • Severe depression without clinician supervision
  • Concurrent use of fluvoxamine, nifedipine, anticoagulants, or immunosuppressants without clinician guidance
  • Concurrent use of multiple sedatives/CNS depressants without clinician guidance

Evidence

Study-level References

melatonin-SRC-001Meta-analysis of RCTs
Sourceopen_in_new

Ferracioli-Oda E, et al. "Meta-analysis: melatonin for the treatment of primary sleep disorders." PLoS One. 2013.

Population: Adults with primary sleep disorders

Key findings: Melatonin decreases sleep onset latency, increases total sleep time, and improves overall sleep quality.

Paper content

Melatonin decreases sleep onset latency, increases total sleep time, and improves overall sleep quality.

melatonin-SRC-002Systematic review and meta-analysis
Sourceopen_in_new

Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep parameters: meta-analysis. 2024. PMID:38856072.

Population: Adults with secondary sleep disorders across pooled intervention studies.

Dose protocol: Dosing and formulation varied across included studies.

Key findings: Updated meta-analysis supported improvement in sleep parameters, especially sleep onset and global sleep quality, while effect size varied by disorder type and study design.

Notes: Secondary sleep-disorder populations are heterogeneous, so effect sizes should not be generalized blindly.

Paper content

Updated meta-analysis supported improvement in sleep parameters, especially sleep onset and global sleep quality, while effect size varied by disorder type and study design.

melatonin-SRC-003Scoping review of systematic reviews and meta-analyses
Sourceopen_in_new

Iyer S, Monk V, Slater R, Baxter L. Exogenous Melatonin and Sleep Quality: A Scoping Review of Systematic Reviews. J Clin Pharmacol. 2026;66(2):e70115. doi:10.1002/jcph.70115. PMID:41014554.

Population: People with varied sleep disorders across pooled review-level evidence.

Dose protocol: Review-level synthesis across varied melatonin formulations and sleep disorders.

Key findings: Review-of-reviews reinforced that melatonin's clearest benefit is sleep-onset support, with more mixed evidence for broader sleep outcomes.

Notes: Useful for keeping the recommendation narrow despite a large secondary literature.

Paper content

Review-of-reviews supported melatonin's most consistent benefit for sleep-onset and selected sleep-quality outcomes, while emphasizing condition-specific heterogeneity and formulation differences.

melatonin-SRC-004Systematic review and meta-analysis of randomized controlled trials
Sourceopen_in_new

Mdluli NT, Banda KJ, Chang YC. Melatonin for sleep and cognitive outcomes in older adults with cognitive impairment: a meta-analysis of randomised controlled trials. Age Ageing. 2025;54(11):afaf333. doi:10.1093/ageing/afaf333. PMID:41240058.

Population: Older adults aged 65 years or older with mild cognitive impairment or dementia across 10 randomized placebo-controlled trials.

Dose protocol: Varied melatonin formulations in adults aged 65 years or older with cognitive impairment.

Key findings: Meta-analysis in older adults with cognitive impairment found modest total-sleep-time improvement, while broader sleep-maintenance outcomes remained small or nonsignificant.

Notes: Supports cautious wording that melatonin can help some older adults beyond sleep onset, but not uniformly across all sleep domains.

Paper content

This older-adult cognitive-impairment meta-analysis supports melatonin as a modest sleep-duration aid, with some possible cognitive or neuropsychiatric benefit in this specific population, while broader sleep-maintenance effects remained small or nonsignificant.

melatonin-SRC-005Cochrane systematic review and meta-analysis of randomized controlled trials.
Sourceopen_in_new

Madsen BK, Zetner D, Moller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database Syst Rev. 2020;12(12):CD009861. doi:10.1002/14651858.CD009861.pub3. PMID:33319916.

Population: 2,319 adults aged 15-90 years undergoing surgical procedures requiring general, regional, or topical anesthesia.

Dose protocol: Oral or sublingual melatonin as preoperative anxiolytic across 27 RCTs (2,319 adults).

Key findings: Cochrane review found melatonin reduces preoperative anxiety by about 12 points on a 0-100 VAS versus placebo (moderate certainty), with comparable efficacy to benzodiazepines.

Notes: Demonstrates a quantified anxiolytic effect beyond sleep, positioning melatonin as a non-addictive alternative to benzodiazepine premedication.

Paper content

This Cochrane review of 27 RCTs (2,319 adults) found that melatonin significantly reduces preoperative anxiety compared with placebo (MD = -11.69 on a 0-100 VAS, moderate certainty). Melatonin performed comparably to benzodiazepines for preoperative anxiolysis, with little or no difference between the two (MD = 0.78). Postoperative anxiety effects were smaller and less certain. This review is notable because it demonstrates a quantified anxiolytic effect of melatonin beyond its established sleep-onset role, and positions melatonin as a non-addictive alternative to benzodiazepine premedication.

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