Melatonin Physiology
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Direct answer
Darkness, relayed from the retina to the pineal gland, is the sole physiological stimulus for melatonin secretion: plasma levels rise from a daytime baseline near 5-20 pg/mL to a night peak of roughly 60-200 pg/mL between 2 and 4 AM, then fall again, with a plasma half-life of only 30-60 minutes. The synthetic chain inside pinealocytes runs serotonin to N-acetylserotonin via arylalkylamine N-acetyltransferase (AANAT, the rate-limiting enzyme) and then to melatonin via ASMT. Light reaches the gland through a fixed polyneuronal route — retina, retinohypothalamic tract, suprachiasmatic nucleus, paraventricular nucleus, intermediolateral column T1-T2, superior cervical ganglion — which is why lesions anywhere along it abolish the rhythm. Exogenous melatonin in 0.5-5 mg doses is used to rephase rhythms in jet lag and non-24-hour disorder of the blind.
What you must remember
- Synthesis sequence: L-tryptophan, serotonin, N-acetylserotonin (AANAT — rate-limiting, induced 10-fold or more at night), melatonin (ASMT/HIOMT); the pineal concentrates serotonin beyond any other tissue.
- Light pathway in full: photoreceptors or melanopsin ganglion cells, retinohypothalamic tract, suprachiasmatic nucleus (SCN), PVN, descending fibres to the intermediolateral column at T1-T2, superior cervical ganglion, postganglionic noradrenergic fibres to pinealocytes acting on beta-1 receptors.
- Numbers: night peak 60-200 pg/mL at 2-4 AM in young adults, daytime under about 20 pg/mL, half-life 30-60 minutes; secretion declines steeply with age — pineal calcification is near-universal by the sixth decade.
- Receptors: MT1 (sleep induction) and MT2 (phase shifting) — G-protein coupled, acting through Gi to reduce cAMP; ramelteon is a selective agonist.
- Clinical dosing logic: 0.5 mg shifts phase, 2-5 mg hypnotic; for eastward jet lag, take it at local bedtime on arrival; the blind with non-24-hour disorder are the clearest indication.
- Pineal region tumours: compress the tectum producing Parinaud syndrome — vertical gaze palsy, light-near dissociation of pupils — a classic neuro-ophthalmology link.
- Vegetative marker: melatonin is the hormonal hand of the SCN — measuring its rhythm (or its urinary metabolite 6-sulphatoxymelatonin) is how circadian phase is assessed objectively.
How the rhythm is built and broken
Start with a healthy volunteer in constant dim light: melatonin still rises each evening, because the SCN generates the rhythm endogenously — light only entrains it. The onset of melatonin secretion in dim light (DLMO) occurs about 2 hours before habitual sleep and is the reference marker of circadian phase. Now expose the volunteer to bright light at 10 PM: the onset is pushed later, a phase delay. Bright light at 5 AM does the opposite, advancing the clock — the asymmetry exploited in jet lag and delayed sleep phase protocols.
Then take shift work: a night-duty doctor under bright ward lighting suppresses melatonin acutely, then sleeps in a lit morning bedroom while the rhythm drifts. Chronic mismatch of this kind degrades sleep, glucose control and alertness. The blind patient carries the extreme case — without retinal input the SCN free-runs at its intrinsic period slightly above 24 hours, so sleep drifts in and out of alignment with the clock day; low-dose melatonin at a fixed bedtime is the one therapy that anchors the rhythm, a beautiful example of physiology prescribing itself.
Where students slip
Students say light stimulates melatonin — it is darkness, with light inhibiting secretion through the sympathetic chain; the viva probe is to name every station from retina to pineal, and the T1-T2 intermediolateral relay is where most answers fail. The second error is calling melatonin a sleeping tablet: it is a chronobiotic — a phase shifter — so timing matters more than dose, and taking it in the morning can shift rhythms the wrong way. A third slip is forgetting that the pineal is outside the blood-brain barrier and lies at the posterior third ventricle, so pineal tumours present with hydrocephalus and Parinaud gaze signs, not endocrine syndromes.
Frequently asked questions
Which enzyme is rate-limiting in melatonin synthesis?
Arylalkylamine N-acetyltransferase (AANAT), which converts serotonin to N-acetylserotonin and rises many-fold at night under noradrenergic control from the superior cervical ganglion.
How does light information reach the pineal gland?
Through the retinohypothalamic tract to the suprachiasmatic nucleus, then via the paraventricular nucleus and intermediolateral column T1-T2 to the superior cervical ganglion, whose noradrenergic fibres innervate the pinealocytes.
What are normal melatonin levels by time of day?
Daytime plasma levels are near 5-20 pg/mL, rising to a peak of roughly 60-200 pg/mL between 2 and 4 AM in young adults, with secretion declining markedly with age.
Which melatonin receptor does ramelteon act on?
Ramelteon is a selective MT1 and MT2 agonist used for sleep-onset insomnia, avoiding the receptor promiscuity that limits melatonin's own hypnotic use.
Why is melatonin used in non-24-hour sleep-wake disorder?
Blind patients cannot entrain the SCN by light, so their rhythm free-runs slightly longer than 24 hours; correctly timed melatonin entrains the clock pharmacologically, realigning sleep with the solar day.