5-Methoxytryptamine

Use and effects

5-MT is said to produce mild psychoactive effects in humans. It can reportedly potentiate the effects of other drugs such as LSD and THC.

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 a of 0.5 nM or 0.7 nM. 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. Conversely, one assay reported comparable, low or sub-nanonomolar potencies for all three receptors and the 5-HT1A receptor.

5-MT, in contrast to the closely related melatonin, has no affinity for the melatonin receptors. Conversely, in tango assay it displayed agonist-like activity at MT1. However, it may also 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 (HTR), 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. However, in one recent study subcutaneous injection failed to increase HTRs under any conditions in mice, only inducing 5-HT1A-mediated hypothermia and hypolocomotion. 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. However, it has also been reported that 5-MT shows strong peripheral selectivity in animals comparable to serotonin and bufotenin and that its capacity to exert central effects is limited.

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).

The predicted log P of 5-MT is 0.5 to 1.41.

Analogues and derivatives

5-MT 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-phenoxytryptamine, 5-benzyloxytryptamine, 5-carboxamidotryptamine, 5-methyltryptamine, 5-(nonyloxy)tryptamine, α-methyl-5-hydroxytryptamine, acetryptine (5-acetyltryptamine), and isamide (N-chloroacetyl-5-methoxytryptamine), among others.

History

5-MT was encountered online as a reported designer drug by 2023.

Society and culture

Legal status

Canada

5-MT is not a controlled substance in Canada as of 2025.

United States

5-MT is not an explicitly controlled substance in the United States. However, it could be considered a controlled substance under the Federal Analogue Act if intended for human consumption.

References

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