COVID-19 has infected hundreds of thousands and killed tens of thousands of people worldwide and it continues to ravage societies as well as fiscal and economic stability of several countries.  Currently, several drugs that were designed for other conditions have been repurposed to counter the COVID-19 pandemic.  Some have modest efficacy in resisting this disease, but all of them have significant toxicity.  Several pharmaceutical companies are rushing to develop vaccines, but their availability is 8 to 12 months in the future.  In the meantime, readily available and affordable molecules that will have utility as COVID-19 antidotes are being sought.

Recently, several groups independently and almost simultaneously proposed that melatonin should be considered for this purpose and several trials are underway to test whether melatonin is a reliable candidate drug for COVID-19 treatment.  In this brief review, we described some potential mechanisms by which melatonin may work to protect against a COVID-19 infection.  Of particular note is the likely ability of melatonin to force activated immune cells to abandon aerobic glycolysis in favor of mitochondrial oxidative phosphorylation.  Aerobic glycolysis gives proinflammatory activated immune cells, for example, macrophages, an opportunity to produce increased amounts of cytokines which are released as the cytokine storm.  The associated significant increase in oxidative stress is accepted as a major contributing factor to the bronchoalveolar dysfunction and pneumonia that occurs in COVID-19-infected individuals.  Melatonin, via similar processes, may reduce the formation of proinflammatory M1 macrophages and convert them to macrophages of the M2 phenotype, which are anti-inflammatory.  These are not the only mechanisms by which melatonin may protect against the deadly COVID-19 pandemic.  Melatonin could also be given as an adjuvant with other toxic pharmaceutical agents with a high likelihood it would reduce their side effects.