The clinical efficacy of melatonin in the treatment of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials

Abstract

BackgroundThe COVID-19 pandemic has resulted in significant morbidity and mortality worldwide, with cytokine storm leading to exaggerating immune response, multi-organ dysfunction and death. Melatonin has been shown to have anti-inflammatory and immunomodulatory effects and its effect on COVID-19 clinical outcomes is controversial. This study aimed to conduct a meta-analysis to evaluate the impact of melatonin on COVID-19 patients.MethodsPubMed, Embase, and Cochrane Central Register of Controlled Trials were searched without any language or publication year limitations from inception to 15 Nov 2022. Randomized controlled trials (RCTs) using melatonin as therapy in COVID-19 patients were included. The primary outcome was mortality, and the secondary outcomes included were the recovery rate of clinical symptoms, changes in the inflammatory markers like C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophil to lymphocyte ratio (NLR). A random-effects model was applied for meta-analyses, and further subgroup and sensitivity analyses were also conducted.ResultsA total of nine RCTs with 718 subjects were included. Five studies using melatonin with the primary outcome were analyzed, and the pooled results showed no significant difference in mortality between melatonin and control groups with high heterogeneity across studies identified (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.47–1.11, p = 0.14, I2 = 82%). However, subgroup analyses revealed statistically significant effects in patients aged under 55 years (RR 0.71, 95% CI 0.62–0.82, p < 0.01) and in patients treated for more than 10 days (RR 0.07, 95% CI 0.01–0.53, p = 0.01). The recovery rate of clinical symptoms and changes in CRP, ESR, and NLR were not statistically significant. No serious adverse effects were reported from melatonin use.ConclusionIn conclusion, based on low certainty of evidence, the study concluded that melatonin therapy does not significantly reduce mortality in COVID-19 patients, but there are possible benefits in patients under 55 years or treated for more than 10 days. With a very low certainty of evidence, we found no significant difference in the recovery rate of COVID-19 related symptoms or inflammatory markers in current studies. Further studies with larger sample sizes are warranted to determine the possible efficacy of melatonin on COVID-19 patients.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022351424.

Assessing the antiviral potential of melatonin: A comprehensive systematic review

“…By targeting the entry of the virus into the brain and other cells possessing the ACE2 enzyme, melatonin holds promise as potential therapeutic agent to mitigate the body‐wide impact of COVID‐19. These data are supported by the suggestions of a broad‐spectrum scientists that melatonin, based on its mechanisms of action, would very likely have value in attenuating the severity of a SARS‐CoV‐2 infection 8,9,31 …”

“…These data are supported by the suggestions of a broad-spectrum scientists that melatonin, based on its mechanisms of action, would very likely have value in attenuating the severity of a SARS-CoV-2 infection. 8,9,31 The efficacy of melatonin as a protective agent against H1N1 influenza A virus (IAV) infection, a highly communicable disease, was examined in mice. The study found that local melatonin levels in the nose and lung tissue were inversely associated with the death rate of H1N1-infected mice, indicating a protective role of melatonin against the common flu.…”

A mid‑pandemic night's dream: Melatonin, from harbinger of anti‑inflammation to mitochondrial savior in acute and long COVID‑19 (Review)

“…Melatonin supplementation has the potential to target and benefit the host by reducing the exaggeration of the innate immune system, which is essential for improving tolerance against the invasion of pathogens ( 156 ). There is a substantial association between the immunological response of the host, particularly the innate immune network, and the symptoms and the results of viral infections with the host ( 156 , 157 ). The overwhelming inflammatory response that is triggered by the cytokine storm is responsible for the majority of the detrimental effects caused by SARS-CoV-2 ( 36 , 114 , 156 , 157 ).…”

“…There is a substantial association between the immunological response of the host, particularly the innate immune network, and the symptoms and the results of viral infections with the host ( 156 , 157 ). The overwhelming inflammatory response that is triggered by the cytokine storm is responsible for the majority of the detrimental effects caused by SARS-CoV-2 ( 36 , 114 , 156 , 157 ). Consequently, this excessive production of cytokines is harmful to organs and tissues, which ultimately results in oxidative damage to several organs ( 36 , 114 , 157 , 158 ).…”

“…The overwhelming inflammatory response that is triggered by the cytokine storm is responsible for the majority of the detrimental effects caused by SARS-CoV-2 ( 36 , 114 , 156 , 157 ). Consequently, this excessive production of cytokines is harmful to organs and tissues, which ultimately results in oxidative damage to several organs ( 36 , 114 , 157 , 158 ). A considerable improvement in the outcomes of patients with SARS-CoV-2 infection may be achieved by downregulating the innate immune response and reducing the inflammatory reaction.…”