melatonin

General Information

Melatonin is an endogenous hormone that helps regulate circadian sleep-wake timing. In the United States it is commonly used as an OTC dietary supplement (not FDA-approved as a drug).

It is often used for sleep-onset insomnia and circadian rhythm complaints (e.g., delayed sleep timing, jet lag). In insomnia studies, effect sizes are usually modest; meta-analyses suggest small average improvements in sleep latency and total sleep time versus placebo.

The AASM guideline recommends against routine melatonin use for chronic insomnia in adults (weak recommendation), so treat it as a time-limited adjunct and prioritize CBT-I and treatment of comorbid drivers (mood episodes, substances, pain, sleep apnea, circadian disruption).

A practical safety issue is supplement variability: analyses of OTC products have found large differences between labeled and measured melatonin content, and some products contain serotonin (Erland 2017).

The melatonin compare view, evidence feed, and print page support side-by-side review with prescription alternatives.

Melatonin is widely used because it is accessible, inexpensive, and not a controlled substance. However, OTC supplement variability is a meaningful quality and dosing issue; consider reputable manufacturers and avoid stacking multiple melatonin products.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Melatonin binds MT1 and MT2 receptors, supporting circadian timing and sleep onset by modulating wake-promoting signals.

It is not a GABAergic sedative-hypnotic, so it generally does not produce “knockout” sedation; it works best when sleep-onset difficulty and circadian misalignment are key drivers.

Timing is a core part of the intervention: taking melatonin too late can increase morning sleepiness and reduce usefulness (clinical).

• MT1/MT2 receptor agonist (circadian signaling).
• Not a controlled substance; no GABA-A mechanism.

Metabolism and Pharmacokinetics

• Elimination half-life is relatively short, often ~1–2 hours, and varies with formulation (StatPearls).
• Approximately 90% is metabolized in the liver, primarily via CYP1A2 with a minor CYP2C19 contribution; metabolites are excreted mainly in urine (StatPearls).
• Potent CYP1A2 inhibitors (e.g., fluvoxamine) can increase exposure and next-day sedation risk (StatPearls).

Dosing and Administration

• OTC products are product-dependent; many labels recommend one dose about 30 minutes before bedtime.
• Start low and titrate cautiously. Many clinicians start around 0.5–1 mg for sleep-onset goals and increase only if needed, because higher doses can increase next-day grogginess without clear added benefit (clinical).
• Consider immediate-release for sleep onset and prolonged-release products when sleep maintenance is the main complaint; reassess benefit rather than escalating to polypharmacy.
• For chronic insomnia, prioritize CBT-I and treat comorbid contributors rather than layering sedatives.

Monitoring & Labs

• Daytime sleepiness, dizziness, and next-day impairment (driving safety).
• Timing consistency and product quality (avoid stacking multiple melatonin products).
• Mood and sleep trajectories in depression or bipolar disorder.
• Reassess benefit after 1–2 weeks; discontinue if minimal benefit.

Adverse Effects

Interactions

• Potent CYP1A2 inhibitors (e.g., fluvoxamine) can increase melatonin exposure; consider dose reduction or switching strategies if next-day sedation appears (StatPearls).
• Additive sedation can occur with alcohol, cannabis, benzodiazepines, antihistamines, and other hypnotics; total sedative burden still matters even though melatonin is not GABAergic.

Other Useful Information

• For sleep-onset insomnia with a circadian component, melatonin is often used alongside consistent wake times and morning light exposure; behavioral strategies improve durability.
• When supplement quality is uncertain or a regulated product is desired, consider prescription melatonin receptor agonists such as ramelteon.
• If insomnia persists after a short trial, stop and pivot rather than layering additional sedatives.

References

1. Melatonin tablets (dietary supplement) label — DailyMed (2025)
2. Melatonin (StatPearls) — StatPearls Publishing (NCBI Bookshelf) (2025)
3. Meta Analysis: Melatonin FOR THE Treatment OF Primary Sleep Disorders — PLoS One (PMC) (2013)
4. Melatonin Natural Health Products and Supplements—presence of serotonin and variability of melatonin content — Journal of Clinical Sleep Medicine (PMC) (2017)
5. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline — Journal of Clinical Sleep Medicine (2017)