Melatonin

also known as: N-acetyl-5-methoxytryptamine, 5-methoxy-N-acetyltryptamine, Circadin, MT

A pineal-gland hormone that regulates circadian rhythms, widely used as an OTC sleep supplement and increasingly investigated for antioxidant, oncostatic, and longevity applications.

An indoleamine hormone produced rhythmically by the pineal gland with nighttime peaks, acting through MT1 and MT2 G-protein-coupled receptors to synchronize circadian physiology — and widely used, often at overdoses, as a popular consumer sleep aid.

Mechanism of action

Synthesized from serotonin via N-acetyltransferase and HIOMT in the pineal gland, with secretion entrained by the suprachiasmatic nucleus under light-dark cycle control. Activates two high-affinity G-protein-coupled receptors — MT1 (primarily involved in REM sleep regulation and acute sleep onset) and MT2 (NREM sleep and circadian phase-shifting). Also has direct free-radical scavenging and antioxidant properties, and modulates mitochondrial function; these non-receptor effects are the basis for much of the longevity-interest research. Supraphysiological doses (common in OTC products) saturate receptors and may produce paradoxical or diminishing effects.

Primary uses

Primary insomnia and sleep onset difficulty
Jet lag and circadian rhythm sleep disorders
Delayed sleep phase syndrome
Shift-work sleep disorder (adjunct)
Adjunct in chemotherapy (antioxidant / anti-cachexia; investigational)
Longevity and antioxidant protocols (unestablished)

Typical dosing

0.3–10 mg 30–60 minutes before bedtime (oral (most common); sublingual, transdermal, or injectable (less common))

Physiological doses (0.3–1 mg) are often as effective as higher OTC doses (3–10 mg) for sleep onset. Injectable compounded melatonin is uncommon but included in some wellness IV protocols. US OTC products frequently exceed labeled content by wide margins.

Regulatory status

Regulatory status varies widely. In the US, melatonin itself is sold as an OTC dietary supplement (not regulated as a drug). In the EU and UK, prolonged-release melatonin (Circadin) is prescription-only and approved for primary insomnia in patients ≥55. Synthetic analogs ramelteon (Rozerem), tasimelteon (Hetlioz), and agomelatine (Valdoxan, EU only) are FDA- or EMA-approved drugs for specific sleep and mood indications.

References

[review] Liu J, Clough SJ, Hutchinson AJ, et al. "MT1 and MT2 melatonin receptors: a therapeutic perspective." Annu Rev Pharmacol Toxicol, 2016;56:361-383. PMID: 26514204.
[review] Comai S, et al. "Melatonin, melatonin receptors and sleep: moving beyond traditional views." J Pineal Res, 2024;76(1):e13011.
[clinical-trial] Wade AG, Ford I, Crawford G, et al. "Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years." Curr Med Res Opin, 2007;23(10):2597-2605.

Related peptides

DSIP

An endogenous 9-amino-acid peptide named for its ability to induce delta-wave sleep in early rabbit experiments, with broader effects on stress response, pain modulation, and circadian regulation.

Epithalon

A synthetic pineal tetrapeptide from the Khavinson group (St. Petersburg) — the only peptide with published data claiming telomerase activation and telomere elongation in human cell models.

Oxytocin

An endogenous nine-amino-acid hormone with roles in labor, lactation, and social-affiliative behavior; also explored off-label for social/anxiety research.

Quick facts

Class

Note: Melatonin is an indoleamine hormone synthesized from tryptophan (via serotonin), not a peptide. It is included here because it is ubiquitously stacked with peptide therapeutics in sleep, longevity, and circadian-health protocols.

Subcategory

pineal indoleamine hormone

Sequence

Not applicable — Melatonin is an indoleamine (N-acetyl-5-methoxytryptamine) synthesized from tryptophan via serotonin, not a peptide.

Molecular formula

C13H16N2O2

Molecular weight

232.28 Da

Half-life

20–50 minutes (immediate-release); several hours (sustained-release) — Short plasma half-life is a central reason for the development of slow-release formulations (Circadin) and synthetic MT1/MT2 agonists (ramelteon, tasimelteon, agomelatine) with longer effective durations.

Evidence level

Medium

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.