Abstract: DOI: 10.1111/jpi.12782 | Revised: 14 December 2021 | Accepted: 14 December 2021 REVIEW Safety of higher doses of melatonin in adults: A systematic review and meta-­analysis Zoe Menczel Schrire1,2,3,4 | Craig L. Phillips4,5 | Julia L. Chapman1,2,3,4 | Shantel L. Duffy2,3,4,5 | Grace Wong4 | Angela L. D’Rozario1,2,3,4 | Maria Comas4 Isabelle Raisin6 | Bandana Saini4,5 | Christopher J. Gordon4,5 | Andrew C. McKinnon1,2,3 | Sharon L. Naismith1,2,3 | Nathaniel S. Marshall4,5 | Ronald R. Grunstein4,5,7 | Camilla M. Hoyos1,2,3,4 | 1 Healthy Brain Ageing Program, Faculty of Science, School of Psychology, The University of Sydney, Sydney, New South Wales, Australia 2 Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia 3 Brain & Mind Centre, The University of Sydney, Sydney, New South Wales, Australia 4 Woolcock Institute of Medical Research, Centre for Sleep and Chronobiology, University of Sydney, Sydney, New South Wales, Australia 5 Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia 6 University Library, The University of Sydney, Sydney, New South Wales, Australia 7 Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Correspondence Camilla M. Hoyos, Charles Perkins Centre, The University of Sydney, Level 2, Building D17, Johns Hopkins Drive, Camperdown, NSW 2050, Australia. Email: camilla.hoyos@sydney.edu.au Funding information CMH and ALD are funded by an NHMRC-­ARC Dementia Research Development Fellowship (APP1104003 and GTN1107716 respectively). ZMS is funded by the Centre of Research Excellence to Optimise Sleep in Brain Ageing and Neurodegeneration (CogSleep CRE) Scholarship. RRG is principally funded by the Australian National Health and Medical Research Council (NHMRC) via a Project Grant (GTN1004528), NHMRC Senior Principal Research Fellowship GTN1152945, RRG), NHMRC Centre for Research Excellence and NeuroSLEEP (GTN1060992, RRG). SLN and CLP are funded by NHMRC Boosting Dementia Leadership Fellowships (SLN GTN1135639, CLP Abstract 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. The aim of this review was to investigate the safety of higher doses of melatonin in adults. Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020. Randomised controlled trials investigating high-­dose melatonin (≥10 mg) in human adults over 30 years of age were included. Two investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of three 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. The outcomes examined were the number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs. A total of 29 studies (37%) made no mention of the presence or absence of AEs. Overall, only four 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 = .64) or withdrawals due to AEs (0.93 [0.24, 3.56], p = .92), but did appear to..