Menczel Schrire et al. searched Medline, Scopus, Embase, and PsycINFO from inception to December 2019 for randomized controlled trials of high-dose melatonin (10 mg or more) in adults over 30. Of 79 identified studies, 29 (37%) made no mention of adverse events at all. In the four studies meeting low risk-of-bias criteria for meta-analysis, melatonin did not increase serious adverse events or withdrawals due to adverse events compared to placebo, though it did increase minor effects such as drowsiness, headache, and dizziness. The authors concluded melatonin appears to have a good safety profile but called for better safety reporting in future long-term trials.

Lemoine et al. conducted a prospective study of community-dwelling adults who had participated in a prior placebo-controlled trial. Patients received 2 mg prolonged-release melatonin (PRM) nightly for up to 12 months, followed by a 2-week withdrawal period. There was no evidence of tolerance developing over the treatment period, and discontinuation was not associated with rebound insomnia, withdrawal symptoms, or suppression of endogenous melatonin production. The study was published in Therapeutics and Clinical Risk Management.

Wade et al. randomized 791 outpatients with primary insomnia to receive either prolonged-release melatonin (PRM) 2 mg or placebo nightly for up to 26 weeks after initial run-in phases. Most adverse events were mild in severity, and there were no clinically relevant differences between PRM and placebo for any safety outcome. The study, published in BMC Medicine, also found that PRM did not impair next-day psychomotor performance or driving ability.

Buscemi et al. conducted a comprehensive meta-analysis published in the Journal of General Internal Medicine. The review examined RCTs investigating melatonin for primary sleep disorders. While it found melatonin had modest efficacy (reducing sleep onset latency by 11.7 minutes overall, and 38.8 minutes for delayed sleep phase syndrome), there was no evidence of harmful adverse effects. The authors noted the safety data specifically covered use periods of up to 3 months.

Wright et al. published findings in the Journal of Pineal Research demonstrating that the amplitude of endogenous melatonin production is not affected by melatonin treatment in humans. Research has consistently shown that natural melatonin production returns to baseline within 1 to 3 days of stopping supplementation. This finding was subsequently supported by the 2011 Lemoine study, which confirmed no suppression of endogenous production even after 12 months of nightly use.

The European Commission granted marketing authorization for Circadin (2 mg prolonged-release melatonin) on June 29, 2007, based on clinical trials demonstrating both efficacy and safety. The approval represented regulatory confidence in melatonin''s safety profile. Post-approval studies extended the evidence base to 6 to 12 months of use, showing maintained efficacy and safety. Circadin remains the only prescription melatonin product approved across the EU.

Besag et al. searched PubMed/Medline and Google Scholar to identify all randomized, placebo-controlled trials of exogenous melatonin for primary or secondary sleep disorders. The review, published in CNS Drugs, found that the most common adverse effects compared to placebo were minor. The authors concluded that melatonin has a favorable safety profile compared to other sleep medications. However, they noted that the majority of included trials were short-duration (less than 12 weeks), limiting conclusions about long-term safety.

Wade et al. conducted a post hoc analysis of pooled data from four randomized, double-blind trials comparing prolonged-release melatonin to placebo in insomnia patients aged 55 and older who were also taking antihypertensive medications. The analysis included 195 PRM patients and 197 placebo patients for 3 weeks, and 157 PRM vs. 40 placebo patients for 28 weeks. PRM showed no negative interactions with blood pressure medications and was even associated with improvement in nocturnal hypertension. Published in Integrated Blood Pressure Control.