5-Methoxytryptamine

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.^[3] It has been shown to occur naturally in the body in low levels, especially in the pineal gland.^[3][4] It is formed via O-methylation of serotonin or N-deacetylation of melatonin.^[3][5][4]

5-Methoxytryptamine

Clinical data
Other names	5-MeO-T; 5-OMe-T; 5-MeOT; 5-MeO-TPA; 5-MT; MT; 5-Hydroxytryptamine methyl ether; Serotonin methyl ether; O-Methylserotonin; O-Methyl-5-HT; Mexamine; Meksamin; Mekasamin; PAL-234
Routes of administration	Orally inactive[1][2]
Drug class	Non-selective serotonin receptor agonist; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen
Pharmacokinetic data
Metabolism	MAO-ATooltip Monoamine oxidase A
Identifiers
IUPAC name 2-(5-Methoxy-1H-indol-3-yl)ethanamine
CAS Number	608-07-1 Y
PubChem CID	1833
IUPHAR/BPS	107
ChemSpider	1767 Y
UNII	3VMW6141KC
KEGG	C05659 Y
ChEBI	CHEBI:2089 Y
ChEMBL	ChEMBL8165 Y
CompTox Dashboard (EPA)	DTXSID60209638
ECHA InfoCard	100.009.231
Chemical and physical data
Formula	C11H14N2O
Molar mass	190.246 g·mol−1
3D model (JSmol)	Interactive image
SMILES O(c1cc2c(cc1)[nH]cc2CCN)C
InChI InChI=1S/C11H14N2O/c1-14-9-2-3-11-10(6-9)8(4-5-12)7-13-11/h2-3,6-7,13H,4-5,12H2,1H3 Y Key:JTEJPPKMYBDEMY-UHFFFAOYSA-N Y
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5-MT is a highly potent and non-selective serotonin receptor agonist^[6][7][8][9] and shows serotonergic psychedelic-like effects in animals.^[10] However, it is inactive in humans, at least orally, likely due to rapid metabolism by monoamine oxidase (MAO).^[1][2] The levels and effects of 5-MT are dramatically potentiated by monoamine oxidase inhibitors (MAOIs) in animals.^{[11][12][13][14][15][16]}

Biosynthesis

5-MT can be formed by O-methylation of serotonin mediated by hydroxyindole O-methyltransferase (HIOMT) or by N-deacetylation of melatonin.^[3][5] It is also a precursor of 5-MeO-DMT in some species.^[3]

Pharmacology

Pharmacodynamics

5-MT activities

Target	Affinity (Ki, nM)
5-HT1A	3.2–4.8 (Ki) 183–535 (EC50Tooltip half-maximal effective concentration) 66–135% (EmaxTooltip maximal efficacy)
5-HT1B	0.75–38
5-HT1D	1.7–34
5-HT1E	3,151
5-HT1F	1,166
5-HT2A	4.8–724 (Ki) 0.503 (EC50) 96–119% (Emax)
5-HT2B	0.51–16 (Ki) 1.62 (EC50) (rat) 101% (Emax) (rat)
5-HT2C	7.1–943 100% (Emax)
5-HT3	>10,000 (non-human)
5-HT4	27–2,443 (Ki) 437 (EC50) (pig) 107% (Emax) (pig)
5-HT5A	98 (unknown)
5-HT6	18–88
5-HT7	0.5–5.0
MT1	>10,000
MT2	>10,000
SERTTooltip Serotonin transporter	4,000 (IC50Tooltip half-maximal inhibitory concentration) 2,169 (EC50)
NETTooltip Norepinephrine transporter	>10,000 (IC50) >10,000 (EC50)
DATTooltip Dopamine transporter	>10,000 (IC50) 11,031 (EC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [6][7][8][9][17][18][19][20][21]

5-MT acts as an agonist of the serotonin 5-HT₁, 5-HT₂, 5-HT₄, 5-HT₆, and 5-HT₇ receptors.^{[22][23][24][25][26][27][28][29]}

It is an extremely potent serotonin 5-HT_2A receptor agonist in vitro, with an EC₅₀Tooltip half-maximal effective concentration of 0.503 nM.^[8] This was more potent than any other tryptamine evaluated in two large series of compounds.^[8][9] For comparison, 5-MeO-DMT had an EC₅₀ of 3.87 nM (7.7-fold lower) and dimethyltryptamine (DMT) had an EC₅₀ of 38.3 nM (76-fold lower).^[9]

5-MT has been said to be 25- and 400-fold selective for the serotonin 5-HT_2B receptor over the serotonin 5-HT_2A and 5-HT_2C receptors, respectively.^[30]

5-MT, in contrast to the closely related melatonin, has no affinity for the melatonin receptors.^[31][32] However, it may be converted into melatonin in the body, and hence may indirectly act as a melatonin receptor agonist.^[3][5]

5-MT shows dramatically reduced activity as a monoamine releasing agent compared to tryptamine and serotonin.^[8]

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-HT_2A receptor antagonists.^{[10][33][34][35][36][15][16]} As such, it may be a hallucinogen in humans.^[37] 5-MT is only briefly mentioned in several places in Alexander Shulgin's TiHKAL and its psychoactive effects are not described.^[38][39] Besides psychedelic-like effects, 5-MT produces a "hyperactivity syndrome" in rodents.^[3][11][40] It produces various other effects in animals as well.^[3]

Pharmacokinetics

Distribution

5-MT is able to cross the blood–brain barrier and enter the central nervous system with peripheral administration in animals.^[11] 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.^[41]

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).^{[12][13][14][42]}

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.^[13][12] Similarly, levels of serotonin and phenethylamine were also greatly elevated by these drugs.^[12][13] 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.^[13]

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.^[14] Conversely, selegiline was ineffective in elevating brain or plasma 5-MT levels in hamsters.^[14]

The non-selective MAO-A and MAO-B inhibitor tranylcypromine has been frequently used to potentiate the effects of 5-MT in animal studies.^{[11][34][36][15][16]}

5-MT is orally inactive in humans presumably due to rapid metabolism by MAO-A.^[1][2]

Metabolites of 5-MT include 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptophol.^[3][14] It may also be metabolized into melatonin.^[3][5]

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).^[43]

The predicted log P of 5-MT is 0.5 to 1.41.^[43][44][45]

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.^[2] Some other notable analogues of 5-MT include tryptamine, 2-methyl-5-hydroxytryptamine, 5-benzyloxytryptamine, 5-carboxamidotryptamine, 5-methyltryptamine, 5-(nonyloxy)tryptamine, α-methyl-5-hydroxytryptamine, acetryptine (5-acetyltryptamine), and isamide (N-chloroacetyl-5-methoxytryptamine), among others.