Melatonin

The strongest evidence is for jet lag, where the problem is the timing of the clock. A Cochrane review of 10 randomised placebo-controlled trials in air travellers, airline staff and military personnel found that in 9 of them melatonin taken close to the target bedtime at the destination (10 pm to midnight) reduced jet lag after flights crossing five or more time zones, with a number needed to treat of 2 (two travellers treated for one to benefit) [1]. For primary sleep disorders, a 2013 meta-analysis of 19 placebo-controlled trials with 1,683 participants found that melatonin shortened the time taken to fall asleep by 7.06 minutes (95% CI 4.37 to 9.75), lengthened total sleep time by 8.25 minutes (95% CI 1.74 to 14.75) and improved overall sleep quality by a standardised mean difference of 0.22 (95% CI 0.12 to 0.32); trials that lasted longer or used higher doses showed larger effects on sleep latency and total sleep time, and the effects did not fade with continued use [3]. An earlier meta-analysis of 17 studies reported similar figures: sleep onset 4.0 minutes faster (95% CI 2.5 to 5.4), sleep efficiency 2.2% higher (95% CI 0.2 to 4.2) and total sleep 12.8 minutes longer (95% CI 2.9 to 22.8) [4]. Larger effects appear where the body's own melatonin is suppressed. In a randomised double-blind trial of 16 hypertensive patients taking the beta-blockers atenolol or metoprolol, 2.5 mg of melatonin nightly for 3 weeks increased polysomnographic total sleep time by 36 minutes, raised sleep efficiency by 7.6% and shortened the time to stage 2 sleep by 14 minutes compared with placebo, with no rebound sleep disturbance after stopping [2].

In chronic insomnia the absolute benefit of melatonin is smaller than that of other drugs used for insomnia, according to the authors of the 2013 meta-analysis [3], and the pooled trials differed widely in who was enrolled, how sleep was measured, and dose and route [4]. The 2017 American Academy of Sleep Medicine (AASM) guideline suggested that clinicians not use melatonin for sleep onset or sleep maintenance insomnia in adults, a weak recommendation based on trials of 2 mg doses [5]. The content of commercial products is inconsistent: an analysis of 31 supplements found melatonin content ranging from 83% below to 478% above the labelled amount, with lot-to-lot variation within one product of up to 465%; more than 71% of products fell outside 10% of the label claim, and 8 contained serotonin at 1 to 75 micrograms [6]. Timing affects the result, as a dose taken at the wrong time of day can delay rather than advance adaptation, and case reports have raised concerns for people with epilepsy and for people taking warfarin [1].

In the jet-lag trials, daily doses between 0.5 and 5 mg were similarly effective, except that participants fell asleep faster and slept better after 5 mg than after 0.5 mg; doses above 5 mg were no more effective, and 2 mg of slow-release melatonin was relatively ineffective [1]. The beta-blocker trial used 2.5 mg nightly for 3 weeks [2], and the trials behind the AASM recommendation used 2 mg [5].