Abstract: Chih-Cheng Lai ORCID iD: 0000-0002-6334-2388 Efficacy of Melatonin in the Treatment of Patients With COVID-19: A Systematic Review and Meta-Analysis of Accepted Article Randomized Controlled Trials Shao-Huan Lan,1,# Hong-Zin Lee,2,# Chien-Ming Chao,3, # Shen-Peng Chang,4 Li-Chin Lu,5 Chih-Cheng Lai6,* 1 School of Pharmaceutical Sciences and Medical Technology, Putian University, Putian 351100, China. shawnlan0713@gmail.com 2 School of Pharmacy, China Medical University, Taichung. hong@mial.cou.edu.tw 3 Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan. ccm870958@yahoo.com.tw 4 Yijia Pharmacy, Tainan 70846, Taiwan. httremoon@ms.szmc.edu.tw 5 School of Management, Putian University, Putian 351100, China. jane90467@gmail.com 6 Department of Internal Medicine, Kaohsiung Veterans General Hospital, Tainan Branch, Tainan, Taiwan. dtmed141@gmail.com # The two authors contributed equally This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.27595. This article is protected by copyright. All rights reserved. *Corresponding author: Dr. Chih-Cheng Lai, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Tainan Branch, Tainan, Taiwan. Accepted Article dtmed141@gmail.com Abstract This study investigated the effect of melatonin on clinical outcomes in patients with COVID-19. We searched PubMed, the Web of Science, the Cochrane Library, Ovid MEDLINE, and Clinicaltrials.gov for randomized controlled trials (RCTs) published before September 11, 2021. Only RCTs that compared the clinical efficacy of melatonin with a placebo in the treatment of patients with COVID-19 was included. The primary outcome measure was the clinical recovery rate. We included 3 RCTs in this meta-analysis. Melatonin 3 mg thrice daily was administered in one RCT, and 3 or 6 mg daily before bedtime in other two trials. Treatment duration was 14 days in two RCTs and 7 days in one trial. The clinical recovery rates were 94.2% (81/86) and 82.4% (70/85) in the melatonin and control groups, respectively. Overall, patients receiving melatonin had a higher clinical recovery rate than did the controls (odds ratio [OR], 3.67; 95% CI, 1.21-11.12; I2 = 0%, P = .02). The risk of intensive care unit admission was numerically lower in the melatonin group than in the control group (8.3% [6/72] vs 17.6% [12/68], OR, 0.45; 95% CI, 0.16-1.25; I2 = 0%, P = .13), and the risk of mortality was numerically lower in the melatonin group than in the control group (1.4% [1/72] vs 4.4% [3/68], OR, 0.32; 95% CI, 0.03-3.18; I2 = 0%, P = .33). In conclusion, melatonin may help improve the clinical outcomes of patients with COVID-19. Keywords: COVID-19, melatonin, outcome, SARS-CoV-2 Highlight  This study investigated the effect of melatonin on clinical outcomes in patients with COVID-19.  Patients receiving melatonin had a higher clinical recovery rate than did the controls (odds ratio [OR], 3.67; 95% CI, 1.21-11.12; I2 = 0%, P = .02).  The risk of intensive care unit admission was only insignificantly lower in This article is protected by copyright. All rights reserved. the melatonin group than in the control group  The risk of mortality was insignificantly lower in the..