Melatonin as adjuvant treatment in COVID-19 patients. A meta-analysis of randomized and propensity matched studies

Melatonin is a neurohormone well-known as sleep disorder treatment. A few clinical trials have recently pointed out the biological plausibility of utilising melatonin in the treatment of coronavirus disease 2019 (COVID-19, SARS-CoV-2) patients. Melatonin wide range of activities include anti-inflammatory, antiviral and antioxidant effects. Our meta-analysis aimed to investigate the effect of melatonin on mortality in COVID-19 patients with different disease severity. We searched PubMed, EMBASE, Web of Science with no language restrictions updated on February 2023 for randomized and propensity matched studies, comparing melatonin plus standard COVID-19 therapy vs. standard COVID-19 therapy alone. Patients had to be hospitalised with a confirmed diagnosis of SARS-CoV-2 infection. Primary outcome was mortality at the longest follow-up available. We included 7 randomized and 1 propensity matched studies enrolling 1155 overall patients with a mean age of 61 ± 19.5 years. We found a reduced mortality rate in the overall population (127/575 (22%) vs. 209/580 (36%) Relative Risk: 0.62 (confidence interval (CI): 0.40, 0.96), I2 = 86% p = 0.03, with the results confirmed when pooling the 5 studies which administered melatonin in non-intensive-care-unit patients (26/423 (6.1%) vs. 69/419 (16%) Relative Risk 0.30 (CI: 0.10, 0.86), I2 = 40% p = 0.02). According to recent randomized and propensity matched evidence, melatonin might be a life-saving adjuvant therapy in COVID-19 patients. This effect was mainly driven by non-intensive care unit patients.

Melatonin; COVID-19; SARS-CoV-2; Mortality; Critical care; Intensive care unit

[1] Liu S, Kang M, Zhao N, Zhuang Y, Li S, Song T. Comprehensive narrative review of real-world COVID-19 vaccines: viewpoints and opportunities. Medical Review. 2022; 2: 169–196.

[2] Marzolini C, Kuritzkes DR, Marra F, Boyle A, Gibbons S, Flexner C, et al. Recommendations for the management of drug-drug interactions between the COVID-19 antiviral nirmatrelvir/ritonavir (paxlovid) and comedications. Clinical Pharmacology & Therapeutics. 2022; 112: 1191–1200.

[3] Ahmed F, Soomro AM, Chethikkattuveli Salih AR, Samantasinghar A, Asif A, Kang IS, et al. A comprehensive review of artificial intelligence and network based approaches to drug repurposing in Covid-19. Biomedicine & Pharmacotherapy. 2022; 153: 113350.

[4] Kato Y, Nishiyama K, Nishimura A, Noda T, Okabe K, Kusakabe T, et al. Drug repurposing for the treatment of COVID-19. Journal of Pharmacological Sciences. 2022; 149: 108–114.

[5] RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19. The New England Journal of Medicine. 2021; 384: 693–704.

[6] Hosseini A, Badri T, Esmaeili Gouvarchin Ghaleh H, Hassanpour K, Alishiri G, Akbariqomi M, et al. Melatonin as a complementary and prophylactic agent against COVID-19 in high-risk populations: a narrative review of recent findings from clinical and preclinical studies. Fundamental & Clinical Pharmacology. 2022; 36: 918–929.

[7] Zhou Y, Hou Y, Shen J, Mehra R, Kallianpur A, Culver DA, et al. A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19. PLOS Biology. 2020; 18: e3000970.

[8] D’Angelo G, Marseglia L, Reiter RJ, Buonocore G, Gitto E. Melatonin and neonatal sepsis: a promising antioxidant adjuvant agent. American Journal of Perinatology. 2017; 34: 1382–1388.

[9] Ramlall V, Zucker J, Tatonetti N. Melatonin is significantly associated with survival of intubated COVID-19 patients. medRχiv. 2020.[Preprint].

[10] 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. Journal of Cellular and Molecular Anesthesia. 2020; 6: 164–167.

[11] 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. Journal of Taibah University Medical Sciences. 2022; 17: 454–460.

[12] 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. Iranian Journal of Allergy, Asthma and Immunology. 2021; 20: 494–499.

[13] 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. Archives of Medical Research. 2022; 53: 79–85.

[14] Hasan ZT, Atrakji DMQYMAA, Mehuaiden DAK. The effect of melatonin on thrombosis, sepsis and mortality rate in COVID-19 patients. International Journal of Infectious Diseases. 2022; 114: 79–84.

[15] 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. Journal of Medical Virology. 2022; 94: 263–271.

[16] Sánchez-González MÁ, Mahíllo-Fernández I, Villar-Álvarez F, Llanos L. What if melatonin could help patients with severe COVID-19? Journal of Clinical Sleep Medicine. 2022; 18: 335–336.

[17] Ameri A, Frouz Asadi M, Ziaei A, Vatankhah M, Safa O, Kamali M, et al. Efficacy and safety of oral melatonin in patients with severe COVID-19: a randomized controlled trial. Inflammopharmacology. 2023; 31: 265–274.

[18] Fogleman C, Cohen D, Mercier A, Farrell D, Rutz J, Bresz K, et al. A pilot of a randomized control trial of melatonin and vitamin C for mild-to-moderate COVID-19. Journal of the American Board of Family Medicine. 2022; 35: 695–707.

[19] Lan SH, Lee HZ, Chao CM, Chang SP, Lu LC, Lai CC. Efficacy of melatonin in the treatment of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials. Journal of Medical Virology. 2022; 94: 2102–2107.

[20] Wang XC, Wu GL, Cai YF, Zhang SJ. The safety and efficacy of melatonin in the treatment of COVID-19: a systematic review and meta-analysis. Medicine. 2022; 101: e30874.

[21] Pilia E, Alborino E, Covello RD. Does melatonin reduce mortality in COVID-19? Annals of Medicine and Surgery. 2022; 78: 103817.

[22] Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366: l4898.

[23] Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016; 355: i4919.

[24] Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology. 2014; 14: 135.

[25] 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: 882.

[26] 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: 699.

[27] García IG, Rodriguez-Rubio M, Mariblanca AR, de Soto LM, García LD, Villatoro JM, et al. A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): a structured summary of a study protocol for a randomised controlled trial. Trials. 2020; 21: 466.

[28] Rodrigues L, Bento Cunha R, Vassilevskaia T, Viveiros M, Cunha C. Drug repurposing for COVID-19: a review and a novel strategy to identify new targets and potential drug candidates. Molecules. 2022; 27: 2723.

[29] Cecon E, Fernandois D, Renault N, Coelho CFF, Wenzel J, Bedart C, et al. Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels. Cellular and Molecular Life Sciences. 2022; 79: 361.

[30] Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, et al. Melatonin: pharmacology, functions and therapeutic benefits. Current Neuropharmacology. 2017; 15: 434–443.

[31] Benedict C, Cedernaes J. Could a good night’s sleep improve COVID-19 vaccine efficacy? The Lancet Respiratory Medicine. 2021; 9: 447–448.

[32] Mayo JC, Sainz RM, Antoli I, Herrera F, Martin V, Rodriguez C. Melatonin regulation of antioxidant enzyme gene expression. Cellular and Molecular Life Sciences. 2002; 59: 1706–1713.

[33] Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C, et al. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. Journal of Neuroim-munology. 2005; 165: 139–149.

[34] Cuesta A, Cerezuela R, Esteban MA, Meseguer J. In vivo actions of melatonin on the innate immune parameters in the teleost fish gilthead seabream. Journal of Pineal Research. 2008; 45: 70–78.

[35] Ramos A, Míguez MP, Morgado S, Sanchez-Correa B, Gordillo JJ, Casado JG, et al. Melatonin enhances responsiveness to Dichelobacter nodosus vaccine in sheep and increases peripheral blood CD4 T lymphocytes and IgG-expressing B lymphocytes. Veterinary Immunology and Immunopathology. 2018; 206: 1–8.

[36] Kow CS, Ramachandram DS, Hasan SS. Melatonin: revisited role as vaccine adjuvant during outbreaks of COVID-19 caused by the delta variant. Journal of Neuroimmune Pharmacology. 2022; 17: 425–426.

[37] 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. European Journal of Pharmacology. 2020; 882: 173329.

[38] Cardinali DP. Melatonin and healthy aging. Vitamins and Hormones. 2021; 115: 67–88.

[39] Covello RD, Pasin L, Fresilli S, Tóth K, Damiani C, Hajjar LA, et al. Meta-analysis of glucocorticoids for Covid-19 patients not receiving oxygen. NEJM Evidence. 2023; 2: 1–5.