Objectives: To assess the evidence for adverse events (AEs) associated with short-term and longer-term melatonin treatment for sleep disorders. Background: Melatonin is widely available either on prescription for the treatment of sleep disorders or as an overthe-counter dietary supplement. Melatonin has also recently been licensed in the UK for the short-term treatment of jet-lag. Little is known about the potential for AEs, in particular AEs resulting from long-term use. Particular concern has been raised over the possible risks of exposure in certain populations including pre-adolescent children and patients with epilepsy or asthma. Methods: A literature search of the PubMed/Medline database and Google Scholar was conducted to identify randomised, placebo-controlled trials (RCTs) of exogenous melatonin administered for primary or secondary sleep disorders. Studies were included if they reported on both the types and frequencies of AEs. Studies of pre-term infants, studies of less than one week in duration or involving single doses of melatonin and studies in languages other than English were excluded. Findings from open-label studies that raised particular concerns relating to AE reports in patients were also examined. Studies were assessed for quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist and for risk of bias against the Cochrane Collaboration risk of bias criteria. Results: Thirty-seven RCTs met criteria for inclusion. Daily melatonin doses were from 0.15 to 12 mg/day. Subjects were monitored for up to 29 weeks, but most studies were of much shorter duration (four weeks or less). The most frequently reported AEs were daytime sleepiness (1.66%), headache (0.74%), other sleep-related AEs (0.74%), dizziness (0.74%) and hypothermia (0.62%).. Very few AEs that were considered to be serious or of clinical significance were reported. These included agitation, fatigue, mood swings, nightmares, skin irritation and palpitations. The large majority of AEs either resolved spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment. Melatonin was generally regarded as safe and well-tolerated. Many studies predated publication of the CONSORT checklist and consequently did not conform closely to the guidelines. Similarly, only eight studies were judged 'good' overall with respect to the Cochrane risk of bias criteria. Of the remaining papers 16 were considered 'fair' and 13 'poor' but publication of almost half of the papers preceded that of the earliest version of the guidelines. Conclusion: Few, generally mild to moderate, AEs were associated with exogenous melatonin. No AEs that were life threatening or of major clinical significance were identified. The scarcity of evidence from long-term RCTs, however, limits the conclusions regarding the safety of continuous melatonin therapy over extended periods. There are insufficient robust data to allow a meaningful appraisal of concerns that melatonin may result in more clinicallys...