Melatonin

Melatonin
Abbreviation	MT, MLT
Molecular formula	C₁₃H₁₆N₂O₂
Type	Indoleamine hormone (derived from serotonin)
Administration	Oral (tablets, capsules, liquids), sublingual
Bioavailability	~15% orally (60-80% cleared by kidneys within 15 minutes)
Synonyms	N-acetyl-5-methoxytryptamine, Sleep hormone
Source	Pineal gland (primary), synthesized in inflamed tissues, gut, retina. Commercially: synthetic or animal-derived
Ray's verdict	Generally hurts Cautious, "darkness stress hormone" associated with inflammation, lowers temperature, suppresses progesterone, raises estrogen

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine hormone produced primarily in the pineal gland, though significant amounts are also synthesized in the gastrointestinal tract. It functions as a nighttime-dominant hormone, rising during darkness and falling during daylight. While popularly marketed as a sleep aid and "anti-aging" supplement, bioenergetic research suggests melatonin's role is more nuanced: it serves as a stress-related, hibernation-promoting signal that suppresses metabolic rate and fertility rather than a simple restorative compound. Converting serotonin to melatonin appears to be a detoxification pathway, disposing of the more inflammatory serotonin molecule.

Structure/Chemical Properties

Melatonin is synthesized from tryptophan through a multi-step pathway:

Tryptophan -> 5-Hydroxytryptophan -> Serotonin -> N-acetylserotonin -> Melatonin

Key enzymes:

• Tryptophan hydroxylase (TPH): rate-limiting for serotonin
• Arylalkylamine N-acetyltransferase (AANAT): rate-limiting for melatonin
• Hydroxyindole-O-methyltransferase (HIOMT): final methylation step

The synthesis is driven by noradrenaline acting on beta-adrenergic receptors, which is why darkness (which activates adrenaline) stimulates melatonin production.

History

Etymology

The name combines Greek melas ("black") with a reference to its tonic, skin-lightening effect on melanophores (pigment cells) in amphibians, the effect through which it was first detected.

Aaron Lerner isolated and named melatonin in 1958, extracting it from bovine pineal glands after tracing the skin-lightening factor to that gland.

Melatonin (N-acetyl-5-methoxytryptamine) was first purified and characterized from the bovine pineal gland extract by Aron Lerner and co-workers in 1958.

Its name comes from the ability of melatonin to change the shape of amphibian melanophores from stellate to roundish, essentially describing its skin-lightening ("mela" = melanin, "tonin" = affecting tone) effect observed in frog skin bioassays.

Julius Axelrod and colleagues later demonstrated that the pineal gland acts as a neuroendocrine transducer, converting light signals to hormone synthesis via the brain and noradrenergic nerves.

Function/Mechanism of Action

Circadian regulation

• Peaks around 3:00 AM in humans
• Suppressed by light (especially blue spectrum)
• Acts as darkness signal, promoting sleep onset

Metabolic effects

Melatonin goes up during hibernation, and its function is to lower the body temperature.

— Ray Peat

• Lowers body temperature: hibernation-promoting signal
• Inhibits thyroid hormones: reduces metabolic rate
• Shifts metabolism toward torpor - reduces oxidative phosphorylation

Hormonal effects (in diurnal mammals like pigs and humans)

Based on research by A.V. Sirotkin (1994):

• Suppresses progesterone production
• Stimulates estrogen production
• Raises prolactin (which in humans causes infertility, stress, osteoporosis)
• Creates environment incompatible with fertilization and embryo development

Serotonin detoxification

Melatonin production is a protective mechanism for disposing of serotonin:

When you get rid of serotonin, you turn it into melatonin... I think it's a detoxifying process.

— Ray Peat

Melatonin has been found elevated in:

• Inflamed arthritic joints
• Cancerous breast tissue
• Any stressed or inflamed tissue

This likely represents local serotonin disposal rather than causation of pathology.

Medical Uses/Effects

Conventional uses

• Jet lag - shifting circadian rhythm to new time zone
• Sleep onset - reducing time to fall asleep
• Circadian disorders - in shift workers

Bioenergetic perspective on claims

Claimed benefit	Bioenergetic concern
Anti-aging	Based on rodent studies; rodents are nocturnal and melatonin has opposite effects compared to diurnal humans
Antioxidant	Can act as pro-oxidant at physiological concentrations; increases nitric oxide activity
Immune support	Actually immunosuppressive; causes thymus atrophy
Cancer prevention	Found elevated in cancerous tissue (detoxification response, not cause)

Species differences

The studies that have been used to advocate melatonin's possibly anti-aging effect were done on mice and rats, and it turns out that they are very opposite to human beings and pigs, because they work at night in general and sleep in the daytime, and so melatonin for them has exactly the opposite meaning that it does for people and pigs.

— Ray Peat

In rodents: Melatonin -> Prolactin -> Progesterone (protective)

In humans: Melatonin -> Prolactin -> Suppresses progesterone (harmful)

Dosing

1) Don't

Situation	Ray Peat's View
< 1 mg	"Probably harmless"
10 mg	"Going to be a problem"
> 3-5 mg	Associated with next-day grogginess; may persist for hours after waking

An amount much smaller than a milligram can bring on sleep, but I doubt the safety of larger amounts.

— Ray Peat

Note: Supplement purity varies wildly. Studies have found label claims vary up to 300% from actual content.

Alternatives

• Glycine - inhibitory neurotransmitter, lowers core temperature safely
• Progesterone - GABA agonist, anti-stress
• Cyproheptadine - anti-serotonin, anti-histamine (Ray noted even 1 mg or less can work)
• Sugar before bed - prevents hypoglycemia-driven stress hormones
• Salt - stabilizes blood sugar overnight
• Aspirin - anti-adrenaline at bedtime (up to500 mg )
• Bright light during the day - supports natural circadian function so you don't need to force sleep chemically

More in Sleep

Side/Adverse Effects

"1994 A.V. Sirotkin found that melatonin inhibits progesterone production but stimulates estrogen production, and it's widely recognized that melatonin generally inhibits the thyroid hormones, creating an environment in which fertilization, implantation, and development of the embryo are not possible."

— Ray Peat

Documented concerns

Hormonal disruption:

• Suppresses progesterone
• Raises estrogen
• Inhibits thyroid function
• Raises prolactin

Metabolic effects:

• Lowers body temperature
• Reduces immune function and tissue repair capacity
• May impair glucose tolerance (inhibits insulin secretion via pancreatic melatonin receptors)

Inflammatory associations:

• High melatonin correlates with worsened rheumatoid arthritis symptoms (Italian research)
• RA inflammation is worse at night when melatonin peaks

Reproductive effects:

• Signal for suppressing fertility during stressful winter (evolutionary role)
• Shrinks the testes
• Creates environment incompatible with fertilization, implantation, embryo development
• Causes thymus atrophy

Next-day effects:

• Grogginess
• Requires coffee to "wear off" effects
• Light exposure does not clear exogenous melatonin (only affects pineal production)

Melatonin vs 5-HTP

The difference of toxicity between serotonin and melatonin is so great. It's just sort of an indirect problem. If you take 10 milligrams of melatonin, that's going to be a problem. But a milligram or so is probably harmless. But the 5-hydroxytryptophan turns massively into serotonin. That's where people are going to get the problem.

— Ray Peat

5-HTP is significantly more dangerous than melatonin because it converts directly to serotonin, the more inflammatory precursor.