Does Biochemical Life Exist for a Receptor Agonist Outside Its Receptor? The Case of Melatonin

Melatonin is reported to exert two types of actions: those based on its interaction with cognate receptors (characterized by very high affinities—1 nM and below), and those mediated by unknown targets (characterized by high concentrations—100 µM and above). Whereas receptor-mediated activities are known to regulate circadian rhythm, the high-dose effects are reported to be independent of these receptors and to produce literally dozens of beneficial effects in almost all human diseases, including cancer, neurodegenerative disorders, viral infections, obesity and many others. In the present opinion paper, we discuss this extensive set of claims and place them in perspective with a sum of evidence that collectively challenges the validity of these alleged beneficial effects.