Serotonin → N-acetylserotonin [by arylalkylamine N-acetyltransferase, AANAT]
N-acetylserotonin → Melatonin [by acetylserotonin O-methyltransferase, ASMT, formerly HIOMT]
The first step, N-acetylation, is the rate-limiting step controlled by light. AANAT is active in the dark and is rapidly degraded in light (its half-life drops from hours to minutes). The second step, O-methylation at position 5 of the indole ring, adds the methoxy group (–OCH₃) that structurally distinguishes melatonin from serotonin.
Compare the two structures in Studio: serotonin has a free –OH at position 5 and a free –NH₂ on the side chain. In melatonin, that –OH has become –OCH₃ (more hydrophobic) and the –NH₂ has become –NHCOCH₃ (an amide, also more hydrophobic). The result is a more lipophilic molecule than serotonin, which lets it diffuse freely through membranes and act in every tissue.
The control circuit: from retina to pineal
The signalling chain from ambient light to melatonin secretion is elegant in its simplicity:
1. Retina. Retinal ganglion cells containing melanopsin (a blue-sensitive photopigment with peak absorption at ~480 nm) detect ambient light, especially blue-rich broad-spectrum light.
2. Retinohypothalamic tract. These cells project directly to the suprachiasmatic nucleus (SCN) of the hypothalamus, the master circadian clock, which keeps its ~24-hour rhythm even in total isolation.
3. SCN → paraventricular nucleus → spinal cord. The SCN controls the pineal gland through a multi-synapse route running through the hypothalamic paraventricular nucleus and the spinal cord. In light, the SCN suppresses this pathway.
4. Spinal cord → superior cervical ganglion → pineal. In darkness, the SCN releases the brake and sympathetic noradrenergic fibres from the superior cervical ganglion activate β-adrenergic receptors on pinealocytes, stimulating AANAT synthesis and melatonin production.
5. Blood → every tissue. Secreted melatonin diffuses freely into the blood and reaches all tissues. Its plasma half-life is about 40 minutes.
In healthy adults, melatonin starts rising about 2 hours before usual bedtime (the DLMO, dim light melatonin onset), peaks between 2 and 4 a.m., and falls to baseline at dawn.
MT1 and MT2 receptors: timing and sleep
Melatonin acts through two G-protein-coupled receptors:
MT1 (mainly in the SCN): inhibits SCN neuronal firing, producing the "night signal" that dampens the wake-promoting drive. In seasonally breeding animals, melatonin also regulates the reproductive axis according to the length of the night.
MT2 (in the SCN and the retina): mainly mediates phase shifts of the circadian rhythm; melatonin taken in the early evening moves the clock earlier.
Both receptors become less sensitive with continuous exposure to melatonin, so for shifting the clock small immediate-release doses are usually preferred over formulations that keep levels high for hours.
What melatonin really does (and does not do)
What it does:
- Synchronises the circadian clock with the light-dark cycle (it is a chronobiotic)
- Brings sleep timing earlier when taken 2–3 hours before the desired bedtime
- Shortens adaptation to jet lag on long-haul flights (especially eastward)
- Helps people with circadian rhythm disorders (delayed sleep phase syndrome, shift workers)
What it does not do (or does only slightly):
- It is not a sleeping pill that directly induces sleep in people with a normal circadian rhythm
- In chronic non-circadian insomnia it shortens the time to fall asleep only slightly (by minutes, in meta-analyses)
- It does not increase total sleep time in healthy adults whose clocks are in sync
The confusion comes from mixing two different things: synchronising the biological clock (what melatonin does) and promoting sleep as such (what hypnotics such as benzodiazepines or Z-drugs do by acting on GABA-A receptors).
Blue light from screens: the modern clock disruptor
Melanopsin is most sensitive at ~480 nm, right in the blue range emitted by the LED screens of phones, tablets and monitors. Using screens for hours before bed can suppress melatonin: in laboratory studies, reading for several hours on a bright tablet cut night-time melatonin by about 50 %. With typical brightness and viewing times the effect is usually smaller.
The result can be a delay in DLMO of up to an hour and a half: the person feels sleepy later and their clock drifts away from their waking schedule. Accumulated over weeks, this contributes to social jet lag (the mismatch between the biological clock and the schedule society imposes), which is linked to poorer metabolic health, higher risk of depression and lower cognitive performance.
Software blue-light filters (night mode) partly help by shifting the spectrum towards orange-red (620–700 nm, to which melanopsin is barely sensitive). The most effective fix, though, is to reduce overall screen brightness and viewing time, not just the colour.
Melatonin in plants and evolution
Melatonin is not unique to animals: it is found in practically all living things, including plants, fungi, bacteria and algae, where it acts as an antioxidant and in stress responses. In plants its possible roles in growth, stress responses and, according to some studies, flowering are being investigated.
This universality suggests that melatonin, as an antioxidant and darkness signal, is evolutionarily ancient, older than the split between kingdoms, and that its role in animal circadian regulation was built on a much older molecular scaffold.
From serotonin to melatonin
Load both in Studio. Melatonin has the same indole ring as serotonin, but the –OH at position 5 has become –OCH₃ and the ethylamine chain carries an N-acetyl group. Two changes that turn a daytime neurotransmitter into a night-time hormone.
The next block leaves neuroscience for the chemistry of the world's most widely used drugs, starting with the molecule that opened the era of modern pharmacology: aspirin.