5-Methoxytryptamine (5-MT, 5-MeO-T, or 5-OMe-T), also known as serotonin methyl ether or O-methylserotonin and as mexamine, is a tryptamine derivative closely related to the neurotransmitters serotonin and melatonin. It has been shown to occur naturally in the body in low levels, especially in the pineal gland. It is formed via O-methylation of serotonin or N-deacetylation of melatonin. 5-MT is a highly potent and non-selective serotonin receptor agonist and shows serotonergic psychedelic-like effects in animals. However, it is inactive in humans, at least orally, likely due to rapid metabolism by monoamine oxidase (MAO). The levels and effects of 5-MT are dramatically potentiated by monoamine oxidase inhibitors (MAOIs) in animals.

Biosynthesis

5-MT can be formed by O-methylation of serotonin mediated by hydroxyindole O-methyltransferase (HIOMT) or by N-deacetylation of melatonin. It is also a precursor of 5-MeO-DMT in some species.

Pharmacology

Pharmacodynamics

5-MT acts as an agonist of the serotonin 5-HT1, 5-HT2, 5-HT4, 5-HT6, and 5-HT7 receptors. It is an extremely potent serotonin 5-HT2A receptor agonist in vitro, with an EC50 of 0.503nM. This was more potent than any other tryptamine evaluated in two large series of compounds. For comparison, 5-MeO-DMT had an EC50 of 3.87nM (7.7-fold lower) and dimethyltryptamine (DMT) had an EC50 of 38.3nM (76-fold lower). 5-MT has been said to be 25- and 400-fold selective for the serotonin 5-HT2B receptor over the serotonin 5-HT2A and 5-HT2C receptors, respectively. 5-MT, in contrast to the closely related melatonin, has no affinity for the melatonin receptors. However, it may be converted into melatonin in the body, and hence may indirectly act as a melatonin receptor agonist. 5-MT shows dramatically reduced activity as a monoamine releasing agent compared to tryptamine and serotonin.

Effects in animals and humans

5-MT dose-dependently induces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents, and this effect is reversed by serotonin 5-HT2A receptor antagonists. As such, it may be a hallucinogen in humans. 5-MT is only briefly mentioned in several places in Alexander Shulgin's TiHKAL and its psychoactive effects are not described. Besides psychedelic-like effects, 5-MT produces a "hyperactivity syndrome" in rodents. It produces various other effects in animals as well.

Pharmacokinetics

Distribution

5-MT is able to cross the blood–brain barrier and enter the central nervous system with peripheral administration in animals.

Metabolism

5-MT is metabolized by deamination by monoamine oxidase (MAO), specifically monoamine oxidase A (MAO-A) and to a much lesser extent by monoamine oxidase B (MAO-B). Brain levels of 5-MT following central administration of 5-MT in rats were potentiated by 20-fold by the MAO-A inhibitor clorgyline and by 5.5-fold by the MAO-B inhibitor selegiline. Similarly, levels of serotonin and phenethylamine were also greatly elevated by these drugs. In accordance with the potentiation of brain levels of 5-MT by MAOIs, the behavioral effects of centrally administered 5-MT in rats, for instance in the conditioned avoidance response test, are markedly enhanced by MAOIs, including by the dual MAO-A and MAO-B inhibitor iproniazid and by clorgyline and selegiline. Similarly to rat findings, pineal gland levels of endogenous 5-MT are dramatically elevated by the MAO-A inhibitor clorgyline and by the dual MAO-A and MAO-B inhibitor pargyline in hamsters, and plasma levels of exogenous 5-MT are greatly elevated by these MAOIs as well. Conversely, selegiline was ineffective in elevating brain or plasma 5-MT levels in hamsters. The non-selective MAO-A and MAO-B inhibitor tranylcypromine has been frequently used to potentiate the effects of 5-MT in animal studies. 5-MT is orally inactive in humans presumably due to rapid metabolism by MAO-A. Metabolites of 5-MT include 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptophol. It may also be metabolized into melatonin.

Chemistry

5-MT, also known as 5-methoxytryptamine or as 5-hydroxytrypamine O-methyl ether, is a substituted tryptamine and a derivative of serotonin (5-hydroxytryptamine) and precursor of melatonin (N-acetyl-5-methoxytryptamine). It is closely related to other 5-methoxylated tryptamines such as 5-MeO-NMT, 5-MeO-DMT, 5-MeO-DPT, 5-MeO-DiPT, 5-MeO-MiPT, 5-MeO-DALT, and 5-MeO-AMT. 5-MeO-AMT is orally active in humans, in contrast to 5-MT, and could be thought of as a sort of orally active form of 5-MT. Some other notable analogues of 5-MT include tryptamine, 2-methyl-5-hydroxytryptamine, 5-benzyloxytryptamine, 5-carboxamidotryptamine, 5-(nonyloxy)tryptamine, α-methyl-5-hydroxytryptamine, acetryptine (5-acetyltryptamine), and isamide (N-chloroacetyl-5-methoxytryptamine), among others. The predicted log P of 5-MT is 0.5 to 1.41.