Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine hormone synthesized and secreted principally by the pineal gland at night under normal light/dark conditions. ^{[1] [2]} Its endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle, so it is a core output of the circadian system. ^[1] Smaller amounts are also produced outside the pineal gland, by the retina, lymphocytes, bone marrow, gastrointestinal tract and thymus. ^[3] Exogenous melatonin is a pharmaceutical ingredient in medicines, over-the-counter medicines, nutraceuticals and dietary supplements, and it has become a popular supplement best known as a chronobiotic and for establishing healthy sleep. ^{[4] [5]} In the United States, melatonin is not an FDA-approved hypnotic although it is commonly used for insomnia, whereas ramelteon, a melatonin receptor agonist, is FDA-approved for insomnia. ^{[6] [7]} Clinically, it is used as a resynchronisation agent in jet lag and is one of the common treatments for circadian rhythm sleep-wake disorders, alongside light therapy, sleep health education and hypnotics. ^{[8] [9]}

Melatonin acts mainly through the MT1 and MT2 receptors, which are expressed by many mammalian organs. ^[3] Its primary physiological function is to convey information about the daily cycle of light and darkness to body structures, with secretion adjusting to night length, and light can either suppress or synchronize its production. ^[1] There is some evidence that melatonin stabilises and strengthens the coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms, although its functions in humans rest mainly on correlations between clinical observations and melatonin secretion. ^[1] Short-wavelength (blue) light is the strongest synchronizing agent for the circadian system, and daytime exposure suppresses melatonin secretion, whereas chronic low-intensity blue light directly before bedtime may impair sleep quality and circadian phase. ^[10] Melatonin directly detoxifies reactive oxygen and nitrogen species and indirectly stimulates antioxidant enzymes, and it reaches high concentrations in mitochondria, which has led some authors to propose classifying it as a mitochondria-targeted antioxidant against oxidative stress, with much of the support coming from experimental ischemia/reperfusion studies. ^[11] Melatonin production decreases with age, which has suggested that an age-related deficit contributes to poor sleep, but little scientific evidence supports a benefit of this substitutive therapy.

In a network meta-analysis of 154 double-blind randomised trials (44 089 participants) of insomnia drugs in adults, benzodiazepines, eszopiclone, zolpidem and zopiclone were more efficacious than melatonin, and melatonin did not show overall material benefits. ^[14] A systematic review of 24 randomised trials in chronic insomnia found that melatonin did not significantly improve sleep onset latency, total sleep time or sleep efficiency in adults, while it might be effective in children and adolescents. ^[15] An earlier meta-analysis in 1683 subjects with primary sleep disorders found that melatonin reduced sleep latency by 7.06 minutes and increased total sleep time by 8.25 minutes versus placebo, effects its authors described as modest and smaller than those of other insomnia drugs. ^[16] A dose-response meta-analysis of 26 randomised trials found that effects on sleep onset latency and total sleep time peaked at 4 mg/day and suggested that dosing about 3 h before the desired bedtime may work better than the common schedule of 2 mg 30 min before bedtime. ^[17] Guidelines diverge by formulation: the American Academy of Sleep Medicine suggests not using melatonin for sleep onset or sleep maintenance insomnia in adults (weak recommendation), and the 2023 European Insomnia Guideline does not recommend fast-release melatonin but allows prolonged-release melatonin for up to 3 months in patients aged 55 years or older. ^[18]

Short-term use of melatonin appears safe, even in extreme doses, with only mild adverse effects such as dizziness, headache, nausea and sleepiness reported. ^[22] Randomised studies indicate that long-term treatment causes only mild adverse effects comparable to placebo, but long-term safety in children and adolescents requires further investigation and pregnant or breast-feeding women are advised not to take it for lack of human studies. ^[22] Product quality and efficacy may vary: one analysis of 31 over-the-counter products found melatonin content ranging from 83% below to 478% above the labelled amount. ^{[5] [6]} Timing determines the circadian effect: taken at bedtime, a 0.5 mg dose did not shift the circadian rhythm whereas a 3.0 mg dose caused a phase delay, which may explain occasional paradoxical effects on sleep. ^[5] Melatonin is metabolized mainly by hepatic CYP1A2, so the CYP1A2 inhibitor fluvoxamine can potentiate melatonin levels, and caution is advised with co-medications to avoid adverse effects such as extreme sedation. ^[5] Reported adverse effects also include nightmares and grogginess, and the evidence base is limited by inconsistent methodologies, small sample sizes and limited data on long-term effects.