Role of Melatonin in Management of COVID-19: A Systematic Review


  • Ghada Essam El-din Amin Department of Family Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Salwa Mostafa Mohammad Abdel Rahman Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Ain Shams University, Cairo, Egypt
  • Rehab Mohamed Ali Mohamed Department of Family Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  • Mohamed Farouk Allam Department of Family Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt



Coronavirus disease 2019, severe acute respiratory syndrome, Middle East respiratory syndrome


Background: the COVID-19 pandemic has significantly impacted global healthcare and economic systems. The clinical manifestation of the disease varies from flu-like symptoms to severe pneumonia and, in some cases, death. Melatonin and its metabolites play a crucial role in immunomodulation and possess anti-oxidative properties, capable of directly and indirectly scavenging reactive oxygen species. Objective: the aim of the present systematic review was to assess the effectiveness of melatonin in the management of COVID-19 patients and its role in expediting the return of patients to their baseline health. Methodology: the literature review was conducted up to August 2022, resulting in the identification of 533 articles after sorting them by authors and year of publication. Following the removal of 223 duplicate articles, 310 abstracts were screened, leading to the exclusion of 281. Subsequently, 29 full-text studies were evaluated for eligibility, with 22 being excluded. Finally, seven studies met the inclusion criteria and were included for further qualitative and quantitative analyses. Results: the findings revealed a noteworthy reduction in hospital stay among patients who received melatonin compared to those who received a placebo (standardized mean difference: -0.50, Standard error: 0.15, 95% CI: -0.80, -0.20, P value: 0.001). Melatonin was associated with a significant decrease in mortality in COVID-19 patients when compared to the placebo (Pooled RR: 0.21, 95% CI: 0.08, 0.56, P value: 0.002). However, there were no significant differences between melatonin and placebo regarding the need for hospitalization, ICU admission, artificial ventilation, and the requirement for oxygen therapy. Conclusion: melatonin may decrease the mortality rate among patients with COVID-19. Melatonin may reduce the duration of hospital stay in patients with COVID-19. Melatonin had no effect on the following outcomes in COVID-19 patients: the need for hospitalization, ICU admission, artificial ventilation and the need for oxygen therapy.


Metrics Loading ...


Alizadeh N, Dianatkhah M, Alimohamadi Y, Moradi H, Akbarpour S, Akrami M, et al. High dose melatonin as an adjuvant therapy in intubated patients with COVID-19: A randomized clinical trial. J Taibah Univ Med Sci 2022;17(3):454-60.

Arendt J, Aulinas A. Physiology of the Pineal Gland and Melatonin. [Updated 2022 Oct 30]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-. Available at:

Davoodian N, Sharifimood F, Salarbashi D, Elyasi S, Baniasad A, Bejestani FS. The effect of melatonin as an adjuvant therapy on COVID-19: A randomized clinical trial. SSRN Electron J 2021;1-17.

Dhama K, Khan S, Tiwari R, Sircar S, Bhat S, Malik YS, Singh KP, Chaicumpa W, Bonilla-Aldana DK, Rodriguez-Morales AJ. Coronavirus Disease 2019-COVID-19. Clin Microbiol Rev 2020;33(4):e00028-20. doi: 10.1128/CMR.00028-20.

Farnoosh G, Akbariqomi M, Badri T, Bagheri M, Izadi M, Saeedi-Boroujeni A, et al. Efficacy of a low dose of melatonin as an adjunctive therapy in hospitalized patients with COVID-19: A randomized, double-blind clinical trial. Arch Med Res 2022;53(1):79-85.

García-García I, Seco-Meseguer E, Ruiz-Seco P, Navarro-Jimenez G, Martínez-Porqueras R, Espinosa-Díaz M, et al. Melatonin in the prophylaxis of SARS-CoV-2 infection in healthcare workers (MeCOVID): A randomised clinical trial. J Clin Med 2022;11(4):1139.

Gholizadeh M, Abaj F, Hasani H, Mirzababaei A, Mirzaei K. Does the melatonin supplementation decrease the severity of the outcomes in COVID-19 patients? A mini review of observational data in the in vivo and in vitro studies. Melatonin Research 2021;4(2):348-59.

Gur M, Taka E, Yilmaz SZ, Kilinc C, Aktas U, Golcuk M. Conformational transition of SARS-CoV-2 spike glycoprotein between its closed and open states. J Chem Phys 2020;153(7):075101.

Hardeland R. Melatonin and the pathologies of weakened or dysregulated circadian oscillators. J Pineal Res 2017;62(1):e12377.

Hasan ZT, Atrakji DMQYMAA, Mehuaiden DAK. The effect of melatonin on thrombosis, sepsis and mortality rate in COVID-19 patients. Int J Infect Dis 2022;114:79-84.

Hacışevki A, Baba B. An Overview of Melatonin as an Antioxidant Molecule: A Biochemical Approach [Internet]. Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches. IntechOpen; 2018. Available at:

Hosseini A, Esmaeili Gouvarchin Ghaleh H, Aghamollaei H, Fasihi Ramandi M, Alishiri G, Shahriary A, et al. Evaluation of Th1 and Th2 mediated cellular and humoral immunity in patients with COVID-19 following the use of melatonin as an adjunctive treatment. Eur J Pharmacol 2021;904 (174193):174193.

Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 2022;23(1):3-20.

Kvetnoy I, Ivanov D, Mironova E, Evsyukova I, Nasyrov R, Kvetnaia T, et al. Melatonin as the cornerstone of neuroimmunoendocrinology. Int J Mol Sci 2022;23(3):1835.

Lan S-H, Lee H-Z, Chao C-M, Chang S-P, Lu L-C, Lai C-C. Efficacy of melatonin in the treatment of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials. J Med Virol 2022;94(5):2102-7.

Lankarani KB, Akbari M, Homayounfar R, Tabrizi R, Vali M, Zakeri MR, et al. Therapeutic Efficacy of Melatonin in Patients with Coronavirus 2019: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Galen Medical Journal 2022;11.

Leroy H, Han M, Woottum M, Bracq L, Bouchet J, Xie M, et al. Virus-mediated cell-cell fusion. Int J Mol Sci 2020;21 (24):9644.

Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with Coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77 (6):683-90.

Mousavi SA, Heydari K, Mehravaran H, Saeedi M, Alizadeh-Navaei R, Hedayatizadeh-Omran A, et al. Melatonin effects on sleep quality and outcomes of COVID-19 patients: An open-label, randomized, controlled trial. J Med Virol 2022;94(1):263-71.

Mubashshir M, Ahmad N, Negi T, Rawal R, Singhvi N, Khatoon H, Laxmi V, Dubey O, Sharma RB, Negi G, Ovais M. Therapeutic Benefits of Melatonin against COVID-19. Neuroimmunomodulation 2023;30(1):196-205. doi: 10.1159/000531550.

Pinato L, Ramos D, Hataka A, Rossignoli PS, Granado MD Junior, Mazzetto MC, et al. Day/night expression of MT1 and MT2 receptors in hypothalamic nuclei of the primate Sapajus apella. J Chem Neuroanat 2017;81:10-7.

Reiter RJ, Sharma R, Ma Q, Dominquez-Rodriguez A, Marik PE, Abreu-Gonzalez P. Melatonin inhibits COVID-19-induced cytokine storm by reversing aerobic glycolysis in immune cells: A mechanistic analysis. Med Drug Discov 2020;6(100044):100044.

Reiter RJ, Sharma R, Ma Q, Rosales-Corral S, Acuna-Castroviejo D, Escames G. Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy. Melatonin Res 2019;2(3): 105-19.

Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J 2019;16(1):69.

Suofu Y, Li W, Jean-Alphonse FG, Jia J, Khattar NK, Li J, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci U S A 2017;114(38):E7997-8006.

Tesarik J. After corona: there is life after the pandemic. Reprod Biomed Online 2020;40(6):760-2.

Tian X, Li C, Huang A, Xia S, Lu S, Shi Z, et al. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect 2020;9(1):382-5.

Wang X-C, Wu G-L, Cai Y-F, Zhang S-J. The safety and efficacy of melatonin in the treatment of COVID-19: A systematic review and meta-analysis. Medicine (Baltimore) 2022;101(39):e30874.

Zambrelli E, Canevini M, Gambini O, D'Agostino A. Delirium and sleep disturbances in COVID-19: a possible role for melatonin in hospitalized patients? Sleep Med 2020;70:111.

Zhang Q, Gao F, Zhang S, Sun W, Li Z. Prophylactic use of exogenous melatonin and melatonin receptor agonists to improve sleep and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials. Sleep Breath 2019;23(4):1059-70.

Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci 2020;250(117583):117583.



How to Cite

Amin GEE- din, Abdel Rahman SMM, Mohamed RMA, Allam MF. Role of Melatonin in Management of COVID-19: A Systematic Review. Microbes Infect. Chemother. [Internet]. 2024 Jun. 8 [cited 2024 Jul. 21];4:e1982. Available from:




Most read articles by the same author(s)