Melatonin (N-acetyl-5-methoxytryptamine, C₁₃H₁₆N₂O₂) is synthesized by the pineal gland from serotonin in two enzymatic steps: serotonin → N-acetylserotonin (by AANAT, the light-regulated rate-limiting enzyme) → melatonin (by HIOMT adding the –OCH₃ group). The result is a molecule more lipophilic than serotonin — it diffuses freely through membranes and acts on all tissues.
The retina-to-pineal circuit
Melanopsin-expressing retinal ganglion cells (peak sensitivity ~480 nm, blue light) project directly to the suprachiasmatic nucleus (SCN) — the master circadian clock. In darkness, the inhibitory sympathetic pathway to the pineal ceases, noradrenergic fibers activate β-adrenergic receptors in pinealocytes, AANAT activates, and melatonin secretion begins. Plasma half-life: ~40 minutes.
Receptors MT1 and MT2
MT1 (SCN): inhibits SCN neuronal firing, producing the "night signal" that suppresses wakefulness. MT2 (SCN, retina): regulates phase advance of the circadian rhythm — responds especially to melatonin at dusk, advancing the clock. Selective MT2 agonists are more effective for eastward jet lag than standard melatonin.
What melatonin actually does (and doesn't)
✓ Synchronizes the circadian clock with the light-dark cycle
✓ Advances sleep phase when taken 2–3 h before desired sleep time
✓ Reduces jet lag adaptation time (especially eastward flights)
✓ Facilitates sleep in circadian rhythm disorders (delayed sleep phase syndrome, shift workers)
✗ Does NOT significantly reduce sleep latency in non-circadian insomnia
✗ Does NOT increase total sleep duration in healthy adults without circadian disruption
Blue light and circadian disruption
Melanopsin has peak sensitivity at ~480 nm — exactly the blue range emitted by LED screens. Screen use 2–3 hours before bedtime suppresses melatonin by 50–80%, delaying DLMO (dim light melatonin onset) by 30–90 minutes — contributing to "social jet lag" associated with worse metabolic health and higher depression risk.