Melatonin multifaceted pharmacological actions on melatonin receptors converging to abrogate COVID-19

Data indicate that controlling inflammatory responses to COVID-19 may be as important as antiviral therapies or could be an important adjunctive approach. Melatonin possesses anti-inflammation, antioxidation, and immune-enhancing features directly and/or indirectly through its own receptor signaling and is therefore well suited to reduce the severity of COVID-19. Studies have proposed that melatonin regulates COVID-19–associated proteins directly through regulation of molecules such as calmodulin (CALM) 1 and CALM 2, calreticulin (CalR), or myeloperoxidase (MPO) and/or indirectly through actions on GPCR (eg, MTNR1A, MTNR1B) and nuclear (eg, RORα, RORβ) melatonin receptor signaling. However, the exact mechanism(s) and doses by which melatonin reduces the severity of COVID-19 is still open for debate, warranting the need for further testing of melatonin in placebo-controlled randomized clinical trials for COVID-19.