Melatonin

What Is Melatonin?

Melatonin (N-acetyl-5-methoxytryptamine) is the pineal hormone secreted in darkness to signal biological night to the rest of the body. It is synthesised in pinealocytes from serotonin in two enzymatic steps (AANAT acetylates serotonin to N-acetylserotonin, then HIOMT methylates it to melatonin), with secretion gated by the suprachiasmatic nucleus through a sympathetic pathway that fires only when retinal light input drops.

Once released, melatonin acts on two high-affinity G-protein-coupled receptors, MT1 (MTNR1A) and MT2 (MTNR1B), distributed across the suprachiasmatic nucleus, retina, vasculature, immune cells, gut, and reproductive tissue. MT1 binding suppresses SCN neuronal firing, the lights-out signal to the master clock, while MT2 mediates the phase-shifting effects that allow the circadian curve to be advanced or delayed. Beyond receptor signalling, melatonin and its metabolites (AFMK, AMK, 6-hydroxymelatonin) are direct free-radical scavengers and indirect antioxidants, upregulating glutathione, superoxide dismutase, and catalase, and protecting mitochondrial DNA from oxidative damage.

This dual role, chronobiotic hormone plus mitochondrial antioxidant, is why melatonin appears in three separate research literatures: sleep onset, circadian phase shifting (jet lag, shift work, delayed sleep phase), and high-concentration oncology and longevity studies. A pharmacological point often overlooked is that the sleep-onset dose-response curve is an inverted U: concentrations that match the endogenous nocturnal pulse give the cleanest effect, while supraphysiological levels saturate and downregulate MT1/MT2 and are associated with next-day sedation and tolerance in the trial data.