Melatonin

Melatonin is a prescription medicine in some countries and an over-the-counter supplement in others, including the US. Its best evidence is for circadian problems rather than general insomnia.

For jet lag, nine of ten trials found that melatonin taken close to bedtime at the destination reduced jet lag after flights crossing five or more time zones [1]. For primary sleep disorders, a meta-analysis of 19 studies (1,683 people) found reduced sleep latency and increased total sleep time, and the effects did not fade with continued use [2]. A 2024 dose-response meta-analysis found the benefits peaked at around 4 mg a day, with earlier dosing working better [3].

Melatonin is a timing signal rather than a sedative. Released at night, it tells the brain's master clock that it is dark. That is why timing decides whether a dose helps. Taken early in the day, melatonin can cause sleepiness and delay adaptation to local time [1].

Pharmacokinetically it is short-lived. Oral immediate-release doses peak at about 50 minutes and have a half-life of about 45 minutes, and oral bioavailability is 9 to 33% [4]. In the jet lag data, 2 mg slow-release melatonin worked relatively poorly, which suggests a short, high peak works better [1].

Side effects are infrequent in trials [1]. The Cochrane review flagged case reports suggesting people with epilepsy and people taking warfarin may come to harm [1].

The bigger practical problem is product quality. In an analysis of 31 supplements, melatonin content ranged from 83% below to 478% above the label, and it varied by up to 465% between lots of the same product. A quarter of the products also contained serotonin [5].

Melatonin's pharmacokinetics are affected by age, caffeine, smoking, oral contraceptives, feeding status and fluvoxamine [4]. Fluvoxamine, a strong CYP1A2 inhibitor, is the one most worth knowing about.