Melatonin

Melatonin is not a peptide. It is a small molecule made from the amino acid tryptophan by way of serotonin, produced mainly by the pineal gland, and its role is to report the time of day. Production rises a couple of hours before habitual sleep, peaks in the middle of the night and falls before waking, and light falling on the retina suppresses it directly.

The single most useful thing to understand about it is that it is a signal rather than a sedative. It does not act on the machinery that conventional sleep medication targets, and it does not produce sedation in the way those compounds do. What it does is tell the body's clock what time the external world thinks it is.

That distinction explains almost everything about how it is studied. It is not measured as a hypnotic — how quickly it puts an animal to sleep — but as a phase-shifting signal, moving the timing of the clock earlier or later. And crucially, whether it advances or delays the clock depends entirely on when it arrives.

• Phase response: The same signal shifts the clock in opposite directions depending on the time it is received. That relationship, mapped as a phase response curve, is the central concept in circadian pharmacology.

• Two receptors, two jobs: MT1 and MT2 are distributed differently, and the evidence suggests one is more involved in the direct effect on alertness and the other in shifting the clock — a clean separation of two functions.

• Suppression by light: Production is switched off by light reaching the retina, particularly at short wavelengths. This makes it the most direct measurable link between the light environment and internal timing.

• Signalling outside the brain: Receptors occur in the retina, blood vessels and immune tissue, so the compound is studied well beyond sleep — which is often overlooked.

The body keeps time with a cluster of about twenty thousand neurons in the hypothalamus called the suprachiasmatic nucleus. Left alone it runs on a cycle of roughly, but not exactly, twenty-four hours, so it has to be reset continually against the outside world. Light is the main resetting signal, arriving directly from the retina.

Melatonin is the clock's output rather than its input — the pineal gland releases it on instruction from the nucleus, and it circulates as a message that the dark phase has begun. It also feeds back onto the clock itself, because the suprachiasmatic nucleus carries melatonin receptors. So it is both a broadcast of the time and a correction to the timekeeper.

The direction of that correction depends on timing, which is the part most often misunderstood. Received in the evening before natural onset, it advances the clock, shifting everything earlier. Received in the early morning, it delays it. Received in the middle of the biological night, it does little. This is why the same molecule can help or hinder depending only on when it arrives, and why circadian research is so insistent about timing.

The circadian biology is thoroughly established: melatonin's synthesis pathway, its receptors, its suppression by light and its phase-shifting effect are supported by decades of independent work in animals and people, and the phase response curve has been mapped directly in humans.

Controlled studies generally show a modest reduction in the time taken to fall asleep and little effect on total sleep, and it performs better in circadian misalignment than in ordinary insomnia. Regulatory status varies — prescription-only in the UK, a supplement in the US — and it is supplied for laboratory research only. Its research value is the phase response curve: the direction of its effect depends on timing, and that relationship has been mapped directly in humans.

DSIP is the instructive contrast: a nine-residue peptide isolated from the blood of sleeping animals, studied for the same subject through an entirely different question — whether a sleep signal can be carried in circulation at all.

Epithalon comes from research on the same gland, approaching it from the bioregulator tradition rather than through a defined hormone and receptor.