Brief Communication

A Pilot Study on Controlling Coronavirus Disease 2019 (COVID-19) Inflammation Using Melatonin Supplement


No effective antiviral drugs and vaccines are available for the treatment of patients with severe coronavirus 2019 (COVID-19). Therefore, available, safe, and inexpensive drugs and supplements such as melatonin are among the proposed options for controlling inflammation.
We did a randomized, single-blind study in Imam Khomeini Hospital between June 30, 2020, and August 5, 2020. Mild to moderate COVID-19 patients aged 25-65 years were eligible to enter the study based on chest CT scan, clinical symptoms, and physician diagnosis. The intervention group was prescribed 6 mg of oral melatonin for 2 weeks, which consumed half an hour before bedtime every night in low light conditions. Clinical symptoms and C-reactive protein (CRP) were measured before and after treatment in the melatonin received and control (regular medications) groups. Among screened patients with COVID-19, 14 patients were assigned to receive melatonin, and 17 patients were considered as controls.
A significant difference (p=0.005) between CRP 1 and CRP 2 levels (before and after using melatonin) was found in the melatonin group while this difference (p=0.069) was not significant in the control group. Also, the percentage of recovery (based on symptoms) in patients who took melatonin was higher than that of patients in the control group (85.7% VS 47.1%).
The result of this study confirmed the effectiveness of melatonin in mild to moderate outpatients with COVID-19. More clinical trials on elderly, diabetic, obese patients and severe cases are suggested in future studies.   

1. 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):448-52.
2. 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.
3. Im H, Ammit AJ. The NLRP3 inflammasome: role in airway inflammation. Clin Exp Allergy. 2014;44(2):160-72.
4. 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.
5. Danielski LG, Giustina AD, Bonfante S, Barichello T, Petronilho F. The NLRP3 Inflammasome and Its Role in Sepsis Development. Inflammation. 2020;43(1):24-31.
6. Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al. COVID-19: Melatonin as a potential adjuvant treatment.Life Sci. 2020:117583.
7. Bahrampour Juybari K, 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.
8. ÖztÜrk G, Akbulut KG, GÜney Ş. Melatonin, Aging and COVID-19: Could melatonin be beneficial for COVID-19 treatment in elderly? Turk J Med Sci. 2020;50(6):504-12.
9. 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.
10. Essa MM, Hamdan H, Chidambaram SB, Al-Balushi B, Guillemin GJ, Ojcius DM, et al. Possible role of tryptophan and melatonin in COVID-19. Int J Tryptophan Res. 2020;13:1178646920951832.
11. Feitosa EL, Júnior F, Nery Neto JAO, Matos LFL, Moura MHS, Rosales TO, et al. 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.
12. Kow CS, Hasan SS. Could melatonin be used in COVID-19 patients with laryngopharyngeal reflux disease? J Med Virol. 2020;93(1):92-3.
13. NaveenKumar SK, Hemshekhar M, Jagadish S, Manikanta K, Vishalakshi GJ, Kemparaju K, et al. Melatonin restores neutrophil functions and prevents apoptosis amid dysfunctional glutathione redox system. J Pineal Res. 2020;69(3):e12676.
14. 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.
15. Salles C. Correspondence COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020;253:117716.
16. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers.J Pineal Res. 2016;61(3):253-78.
17. Volt H, Garcia JA, Doerrier C, Diaz-Casado ME, Guerra-Librero A, Lopez LC, et al. Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. J Pineal Res. 2016;60(2):193-205.
18. Hu W, Deng C, Ma Z, Wang D, Fan C, Li T, et al. Utilizing melatonin to combat bacterial infections and septic injury. Br J Pharmacol. 2017;174(9):754-68.
19. Har-deland R. Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks. Int J Mol Sci. 2019;20(5):8-12.
20. Rahim I, Djerdjouri B, Sayed RK, Fernandez-Ortiz M, Fernandez-Gil B, Hidalgo-Gutierrez A, et al. Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis. JPineal Res. 2017;63(1):12-4.
21. Peng Z, Zhang W, Qiao J, He B. Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1beta in rats with COPD. Int Immunopharmacol. 2018;62:23-8.
22. Ahn M, Anderson DE, Zhang Q, Tan CW, Lim BL, Luko K, et al. Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host. Nat Microbiol. 2019;4(5):789-99.
23. Zhang J, Lu X, Liu M, Fan H, Zheng H, Zhang S, et al. Melatonin inhibits inflammasome-associated activation of endothelium and macrophages attenuating pulmonary arterial hypertension. Cardiovasc Res. 2020;116(13):2156-69.
24. Wirtz PH, Spillmann M, Bärtschi C, Ehlert U, von Känel R. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res. 2008;44(2):127-33.
25. Prado NJ, Ferder L, Manucha W, Diez ER. Anti-Inflammatory Effects of Melatonin in Obesity and Hypertension. Curr Hypertens. 2018;20(5):45-8.
26. Szewczyk-Golec K, Rajewski P, Gackowski M, Mila-Kierzenkowska C, Wesołowski R, Sutkowy P, et al. Melatonin Supplementation Lowers Oxidative Stress and Regulates Adipokines in Obese Patients on a Calorie-Restricted Diet. Oxid Med Cell Longev. 2017;2017:8494107.
27. Rodríguez-Rubio M, Figueira JC, Acuña-Castroviejo D, Borobia AM, Escames G, de la Oliva P. A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive care unit (MelCOVID study): a structured summary of a study protocol for a randomized controlled trial. Trials. 2020;21(1):699-702.
28. Ziaei A, Davoodian P, Dadvand H, Safa O, Hassanipour S, Omidi M, et al. Evaluation of the efficacy and safety of Melatonin in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020;21(1):882-4.
IssueVol 20 No 4 (2021) QRcode
SectionBrief Communication
COVID-19 Inflammation Melatonin

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Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
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):494-499.