Therapeutic Efficacy of Melatonin in Patients with Coronavirus 2019: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Authors

  • Maryam Akbari Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
  • Kamran Bagheri Lankarani Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
  • Reza Homayounfar National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Reza Tabrizi Noncommunicable Diseases Research Center, Fasa University of Medical Science, Fasa, Iran; Clinical Research Development Unit, Fasa University of Medical Science, Fasa, Iran; USERN Office, Fasa University of Medical Sciences, Fasa, Iran
  • Mohebat Vali Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
  • Mohamad- Reza Zakeri Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
  • Mojtaba Farjam Noncommunicable Diseases Research Center, Fasa University of Medical Science, Fasa, Iran
  • Mahmoud Khodadost Department of Public Health, School of Health, Larestan University of Medical Sciences, Larestan, Iran
  • Fariba Ahmadizar Department of Data Science and Biostatistics, University Medical Center Utrecht, Utrecht, The Netherlands

DOI:

https://doi.org/10.31661/gmj.v11i.2562

Keywords:

Coronavirus 2019, Melatonin, Mortality, C-reactive Protein

Abstract

The efficacy of melatonin in the treatment of patients with coronavirus 2019 (COVID-19) is controversial. This review has summarized the evidence on the efficacy of oral melatonin compared to placebo in patients with mild to moderate COVID-19 infection. We searched four international online databases and all randomized clinical trials (RCTs) that investigated the effects of melatonin compared with the placebo on clinical outcomes, including mortality, discharge time, O2 saturation (SaO2), and c-reactive protein (CRP) levels in patients with COVID-19 infection, were included. The standard random-effects model with hybrid continuity correction was used to pool the risk ratio (RR), weighted mean difference (WMD), and the I2 index to assess the heterogeneity. A total of 272 patients from five RCTs were included. Our meta-analysis showed melatonin compared to placebo, decreased discharge time (WMD=-0.93 days; 95% confidence interval [CI]:-2.94 to 1.07, P=0.36; I2=56.78%) and the risk of mortality (RR=0.72; 95% CI:0.25 to 2.13, P=0.56; I2=0.0%) in COVID-19 patients. Melatonin intake compared to placebo significantly increased SaO2 (WMD=1.38%; 95% CI:0.09 to 2.68, P=0.04; I2=49.82%) and decreased the CRP levels (WMD=-7.24 mg/l; 95% CI:-11.28 to -3.21, P<0.001) in a sensitivity analysis. Our findings showed the efficacy of melatonin compared to placebo in patients with mild to moderate COVID-19 infection.

References

Merad M, Martin JC. Author Correction: Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20(7):448. https://doi.org/10.1038/s41577-020-0353-yPMid:32488203 PMCid:PMC7265161 Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19):a review. JAMA. 2020;324(8):782-93. https://doi.org/10.1001/jama.2020.12839PMid:32648899 Im H, Ammit AJ. The NLRP 3 inflammasome: role in airway inflammation. Clin Exp Allergy. 2014;44(2):160-72. https://doi.org/10.1111/cea.12206PMid:24118105 Lin L, Xu L, Lv W, Han L, Xiang Y, Fu L, et al. An NLRP3 inflammasome-triggered cytokine storm contributes to Streptococcal toxic shock-like syndrome (STSLS). PLoS Pathog. 2019;15(6):e1007795. https://doi.org/10.1371/journal.ppat.1007795PMid:31170267 PMCid:PMC6553798 Danielski LG, Della Giustina A, Bonfante S, Barichello T, Petronilho F. The NLRP3 inflammasome and its role in sepsis development. Inflammation. 2020;43(1):24-31. https://doi.org/10.1007/s10753-019-01124-9PMid:31741197 Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL. Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Med Rev. 2017;34:10-22. https://doi.org/10.1016/j.smrv.2016.06.005PMid:28648359 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. https://doi.org/10.1016/j.lfs.2020.117583PMid:32217117 PMCid:PMC7102583 Juybari KB, Pourhanifeh MH, Hosseinzadeh A, Hemati K, Mehrzadi S. Melatonin potentials against viral infections including COVID-19:Current evidence and new findings. Virus Res. 2020;287:198108. https://doi.org/10.1016/j.virusres.2020.198108PMid:32768490 PMCid:PMC7405774 Öztürk G, Akbulut KG, Güney Åž. Melatonin, aging, and COVID-19:Could melatonin be beneficial for COVID-19 treatment in the elderly? Turk J Med Sci. 2020;50(6):1504-12. https://doi.org/10.3906/sag-2005-356PMid:32777902 PMCid:PMC7605095 El-Missiry MA, El-Missiry ZMA, Othman AI. Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19. Eur J Pharmacol. 2020;882:173329. https://doi.org/10.1016/j.ejphar.2020.173329PMid:32615182 PMCid:PMC7324339 Essa MM, Hamdan H, Chidambaram SB, Al-Balushi B, Guillemin GJ, Ojcius DM, Qoronfleh MW. Possible role of tryptophan and melatonin in COVID-19. Int J Tryptophan Res. 2020;13:1178646920951832. https://doi.org/10.1177/1178646920951832PMid:32913393 PMCid:PMC7443751 Feitosa EL, Júnior FTDSS, Nery Neto JAO, Matos LFL, Moura MHS, Rosales TO, De Freitas GBL. COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor. Int J Med Sci. 2020;17(14):2133-46. https://doi.org/10.7150/ijms.48053PMid:32922174 PMCid:PMC7484667 Kow CS, Hasan SS. Could melatonin be used in COVID-19 patients with laryngopharyngeal reflux disease? J Med Virol. 2020;93(1):92-3. https://doi.org/10.1002/jmv.26150PMid:32519764 PMCid:PMC7300529 NaveenKumar SK, Hemshekhar M, Jagadish S, Manikanta K, Vishalakshi GJ, Kemparaju K, Girish KS. Melatonin restores neutrophil functions and prevents apoptosis amid dysfunctional glutathione redox system. J Pineal Res. 2020;69(3):e12676. https://doi.org/10.1111/jpi.12676PMid:32597503 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. https://doi.org/10.1016/j.medidd.2020.100044PMid:32395713 PMCid:PMC7211589 Salles C. Correspondence COVID-19:Melatonin as a potential adjuvant treatment. Life Sci. 2020;253:117716. https://doi.org/10.1016/j.lfs.2020.117716PMid:32334009 PMCid:PMC7195414 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Moher D. Updating guidance for reporting systematic reviews: development of the PRISMA 2020 statement. J Clin Epidemiol. 2021;134:103-12. https://doi.org/10.1016/j.jclinepi.2021.03.001https://doi.org/10.1016/j.jclinepi.2021.02.003PMid:33577987 Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. https://doi.org/10.1136/bmj.d5928PMid:22008217 PMCid:PMC3196245 Wei JJ, Lin EX, Shi JD, Yang K, Hu ZL, Zeng XT, Tong TJ. Meta-analysis with zero-event studies: a comparative study with application to COVID-19 data. Mil Med Res. 2021;8(1):41. https://doi.org/10.1186/s40779-021-00331-6https://doi.org/10.21203/rs.3.rs-365606/v1PMid:34217371 PMCid:PMC8254431 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. https://doi.org/10.1016/j.arcmed.2021.06.006PMid:34229896 PMCid:PMC8220995 Alizadeh Z, Keyhanian N, Ghaderkhani S, Dashti-Khavidaki S, Shokouhi Shoormasti R, Pourpak Z. A Pilot Study on Controlling Coronavirus Disease 2019 (COVID-19) Inflammation Using Melatonin Supplement. Iran J Allergy Asthma Immunol. 2021;20(4):494-9. https://doi.org/10.18502/ijaai.v20i4.6959PMid:34418903 Darban M, Malek F, Memarian M, Gohari A, Kiani A, Emadi A, et al. Efficacy of High Dose Vitamin C, Melatonin and Zinc in Iranian Patients with Acute Respiratory Syndrome due to Coronavirus Infection: A Pilot Randomized Trial. J Cell Mol Anesth. 2020;6(2):164-7. Mousavi SA, Heydari K, Mehravaran H, Saeedi M, Alizadeh-Navaei R, Hedayatizadeh-Omran A, Shamshirian A. 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. https://doi.org/10.1002/jmv.27312PMid:34460132 PMCid:PMC8662261 https://ssrn.com/abstract=3878090https://doi.org/10.2139/ssrn.3878090 Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, Li HB. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017;8(24):39896-921. https://doi.org/10.18632/oncotarget.16379PMid:28415828 PMCid:PMC5503661 Huang SH, Liao CL, Chen SJ, Shi LG, Lin L, Chen YW, et al. melatonin possesses an anti-influenza potential through its immune modulatory effect. J Funct Foods. 2019;58:189-98. https://doi.org/10.1016/j.jff.2019.04.062 Biancatelli RMLC, Berrill M, Mohammed YH, Marik PE. Melatonin for the treatment of sepsis:the scientific rationale. J Thorac Dis. 2020;12(Suppl 1):S54-65. https://doi.org/10.21037/jtd.2019.12.85PMid:32148926 PMCid:PMC7024751 KleszczyÅ„ski K, Slominski AT, Steinbrink K, Reiter RJ. Clinical trials for use of melatonin to fight against COVID-19 are urgently needed. Nutrients. 2020;12(9):2561. https://doi.org/10.3390/nu12092561PMid:32847033 PMCid:PMC7551551 Anderson G, Reiter RJ. Melatonin:roles in influenza, Covidâ€19, and other viral infections. Rev Med Virol. 2020;30(3):e2109. https://doi.org/10.1002/rmv.2109PMid:32314850 PMCid:PMC7235470 Shneider A, Kudriavtsev A, Vakhrusheva A. Can melatonin reduce the severity of COVID-19 pandemic? Int Rev Immunol. 2020;39(4):153-62. https://doi.org/10.1080/08830185.2020.1756284PMid:32347747 Habtemariam S, Daglia M, Sureda A, Selamoglu Z, Gulhan MF, Nabavi SM. Melatonin and Respiratory Diseases: A Review. Curr Top Med Chem. 2017;17(4):467-88. https://doi.org/10.2174/1568026616666160824120338PMid:27558675 Ramlall V, Zucker J, Tatonetti N. Melatonin is significantly associated with survival of intubated COVID-19 patients. MedRxiv. 2020. https://doi.org/10.1101/2020.10.15.20213546 Zinchuk VV, Poluyan IA, Hlutkin SV. Effects of Melatonin on the Oxygen Transport in Blood, Gas Transmitters, and Prooxidant-Antioxidant Balance in the Exercise. Hum Physiol. 2019;45(6):693-700. https://doi.org/10.1134/S0362119719050219 Zinchuk VV, Firago ME. Participation of melatonin in regulation of blood oxygen-transport function in oxidative stress induced by injection of lipopolisaccharide. Biomed Khim. 2017;63(6):520-6. https://doi.org/10.18097/PBMC20176306520PMid:29251613 Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59(4):403-19. https://doi.org/10.1111/jpi.12267PMid:26272235 Hlutkin S, Zinchuk V. Effect of melatonin on the blood oxygen transport during hypothermia and rewarming in rats. Adv Med Sci. 2008;53(2):234. https://doi.org/10.2478/v10039-008-0035-7PMid:18930873 Liu F, Li L, Xu M, Wu J, Luo D, Zhu Y,et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol. 2020;127:104370. https://doi.org/10.1016/j.jcv.2020.104370PMid:32344321 PMCid:PMC7194648 Potempa LA, Rajab IM, Hart PC, Bordon J, Fernandez-Botran R. Insights into the use of C-reactive protein as a diagnostic index of disease severity in COVID-19 infections. Am J Trop Med Hyg. 2020;103(2):561. https://doi.org/10.4269/ajtmh.20-0473PMid:32588812 PMCid:PMC7410479 Wichniak A, Kania A, SiemiÅ„ski M, CubaÅ‚a WJ. Melatonin as a Potential Adjuvant Treatment for COVID-19 beyond Sleep Disorders. Int J Mol Sci. 2021;22(16):8623. https://doi.org/10.3390/ijms22168623PMid:34445329 PMCid:PMC8395320

Published

2022-12-20

How to Cite

Akbari , M. ., Bagheri Lankarani , K. ., Homayounfar, R. ., Tabrizi , R. ., Vali , M. ., Zakeri , M.-. R. ., … Ahmadizar , F. . (2022). Therapeutic Efficacy of Melatonin in Patients with Coronavirus 2019: A Systematic Review and Meta-Analysis of Randomized Controlled Trials : . Galen Medical Journal, 11, e2562. https://doi.org/10.31661/gmj.v11i.2562

Issue

Section

Review Article