Melatonin as an Add-On Treatment of COVID-19 Infection: Current Status

Abstract

This brief review was written to provide a perspective on the flurry of reports suggesting that melatonin can be an important add-on therapy for COVID-19. Despite the passage of more than 60 years since its discovery and much evidence representing the contrary, there has been great reluctance to conceive melatonin as anything other than a hormone. Many other body chemicals are known to have multiple roles. Melatonin was first shown to be a hormone derived from the pineal gland, to be actively synthesized there only at night, and to act on targets directly or via the G-protein-coupled receptors (GPCRs) superfamily. It is of note that over 40 years ago, it was also established that melatonin is present, synthesized locally, and acts within the gastrointestinal tract. A wider distribution was then found, including the retina and multiple body tissues. In addition, melatonin is now known to have non-hormonal actions, acting as a free radical scavenger, an antioxidant, and as modulating immunity, dampening down innate tissue responses to invaders while boosting the production of antibodies against them. These actions make it a potentially excellent weapon against infection by the SARS-CoV-2 virus. Early published results support that thesis. Recently, a randomized controlled study reported that low doses of melatonin significantly improved symptoms in hospitalized COVID-19 patients, leading to more rapid discharge with no side effects, while significantly decreasing levels of CRP, proinflammatory cytokines, and modulating dysregulated genes governing cellular and humoral immunity. It is now critical that these trials be repeated, with dose-response studies conducted and safety proven. Numerous randomized controlled trials are ongoing, which should complete those objectives while also allowing for a more thorough evaluation of the mechanisms of action and possible applications to other severe diseases.

A Pilot of a Randomized Control Trial of Melatonin and Vitamin C for Mild-to-Moderate COVID-19

“…A delay from diagnosis to treatment has been shown to minimize any positive effect of treatment. 8,16,17 Nevertheless, the concept of this study is generalizable because many patients do not present for evaluation on the first day of symptoms and there may be a lag time while accessing and awaiting laboratory test results. The strengths of this study include accessibility of our surveys, in English and Spanish, and to those isolated in their homes.…”

“…Vitamin C (ascorbic acid) and melatonin (N-acetyl-5-methoxytryptamine) have been suggested as potential therapies to protect against the acute lung injury and other sequelae characteristic of COVID-19 infection. [2][3][4] These antioxidizing agents may disrupt the cytokine cascade to prevent further end organ damage in the setting of acute infection.…”

“…15 Melatonin supplementation is available over the counter in the United States and there is interest in melatonin's therapeutic potential for treatment of those infected with COVID-19. [16][17] Family physicians would like to know how best to advise patients about use of over the counter supplements during infection with COVID-19.…”

Does melatonin protect fetal brain during maternal hypothyroidism? An experimental study

“… 6 , 7 Although it is primarily synthesized in the pineal gland, but other organs of the body, including the brain, lymphocytes, skin, the gastrointestinal tract, thymus, eye and bone marrow also contribute to its synthesis. 8 It has been recently reported that melatonin specifically targets mitochondria of all cells, as it is mainly synthesized here. 9 It is also known that mitochondria is the main organelle involved in the initiation of intrinsic pathway of apoptosis.…”

Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia

“…A possible role in protecting pulmonary endothelial cells can be also hypothesized, as observed in pre-eclampsia [ 273 ]. Several authors have proposed melatonin as a useful therapeutic tool in contrasting neurological complications and super-infections for both COVID-19 and PACS patients [ 274 , 275 , 276 , 277 , 278 ], and a significant vantage in mortality and recovery rate has been observed in severe cases [ 279 , 280 , 281 ]. Validation of the therapeutic role of melatonin and its metabolites in COVID-19 and PACS is needed, and clinical trials and the use of reliable animal models are warranted [ 282 , 283 , 284 , 285 , 286 , 287 ].…”