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.
Highlights
The most evident hormonal action of melatonin was its effects on the body circadian rhythm: oral administration during the morning shortly after waking led to a delay in body rhythms the day, while administration prior to going to bed led to a rhythm advance
This effect was followed by its use in the delayed-phase sleep disorder and jet lag, often in combination with controlled lighting, which has effects on rhythms that are the inverse of melatonin [4]
This first randomly controlled randomized clinical trial (RCT) strongly indicates that melatonin warrants attention as a treatment adjuvant that has improved both clinical and laboratory findings
Summary
The most evident hormonal action of melatonin was its effects on the body circadian rhythm: oral administration during the morning shortly after waking led to a delay in body rhythms the day, while administration prior to going to bed led to a rhythm advance. This effect was followed by its use in the delayed-phase sleep disorder and jet lag, often in combination with controlled lighting, which has effects on rhythms that are the inverse of melatonin [4]. Melatonin has a two-faced action on immunity, reducing innate immunity and preventing tissue overreaction, while at the same time boosting resistance to external pathogens [23]
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