Safety of higher doses of melatonin in adults: A systematic review and meta-analysis.

IMPORTANCE: Melatonin is commonly used for sleep and jetlag at low doses. However, there is less documentation on the safety of higher doses which are being increasingly used for a wide variety of conditions, including more recently COVID-19 prevention and treatment. OBJECTIVE: To investigate the safety of higher doses of melatonin in adults. DATA SOURCES: Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020. STUDY SELECTION: Randomised controlled trials investigating high-dose melatonin (≥10mg) in human adults over 30 years of age. DATA EXTRACTION AND SYNTHESIS: 2 investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of 3 investigators. 79 studies were identified with a total of 3861 participants. Studies included a large range of medical conditions. The meta-analysis was pooled data using a random effects model. MAIN OUTCOMES AND MEASURES: The number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs. RESULTS: 29 studies (37%) made no mention of the presence or absence of AEs. Overall, only 4 studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset melatonin did not cause a detectable increase in SAEs (Rate Ratio=0.88 [0.52, 1.50], p=0.64) or withdrawals due to AEs (0.93 [0.24, 3.56], p=0.92), but did appear to increase the risk of AEs such as drowsiness, headache, and dizziness (1.40, [1.15, 1.69], p<0.001). CONCLUSIONS AND RELEVANCE: Overall, there has been limited AE reporting from large-dose melatonin studies. Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this as our confidence limits were very wide due to the paucity of suitable data.