2,4,6-Trimethoxyamphetamine

Pharmaceutical compound From Wikipedia, the free encyclopedia

2,4,6-Trimethoxyamphetamine (2,4,6-TMA), also known as TMA-6 or ψ-TMA-2, is a psychedelic drug of the phenethylamine, amphetamine, and Ψ-PEA families.^[1]^[2]^[3] It is one of the positional isomers of trimethoxyamphetamine (TMA).^[1]^[2]^[3]

Other names2,4,6-TMA; TMA-6; ψ-TMA-2; NSC-367445

Routes of
administrationOral^[1]

Drug classSerotonin receptor modulator; Serotonin 5-HT_2A receptor agonist; Serotonergic psychedelic; Hallucinogen

ATC code

None

Quick facts Clinical data, Other names ...

TMA-6
Clinical data


Other names	2,4,6-TMA; TMA-6; ψ-TMA-2; NSC-367445
Routes of administration	Oral^[1]
Drug class	Serotonin receptor modulator; Serotonin 5-HT_2A receptor agonist; Serotonergic psychedelic; Hallucinogen
ATC code	None
Pharmacokinetic data
Duration of action	12–16 hours^[1]
Identifiers
IUPAC name 1-(2,4,6-trimethoxyphenyl)propan-2-amine
CAS Number	15402-79-6
PubChem CID	31015
ChemSpider	28774
UNII	2X84DCO6GA
ChEMBL	ChEMBL34108
CompTox Dashboard (EPA)	DTXSID40874363
Chemical and physical data
Formula	C₁₂H₁₉NO₃
Molar mass	225.288 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CC(CC1=C(C=C(C=C1OC)OC)OC)N
InChI InChI=1S/C12H19NO3/c1-8(13)5-10-11(15-3)6-9(14-2)7-12(10)16-4/h6-8H,5,13H2,1-4H3 Key:DDGNOUVDFKXADP-UHFFFAOYSA-N

Use and effects

In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists TMA-6's dose as 25 to 50 mg orally and its duration as 12 to 16 hours.^[1] Threshold effects occur at 20 mg, a full hallucinogenic state occurs at 30 to 40 mg, and erratic results have been reported for 40 to 80 mg.^[3] The drug is said to have about 8 to 10 times the potency of mescaline.^[4]^[5]^[6]

The effects of TMA-6 have been reported to include ease with concepts and writing, body tingling, walking unsteadiness, thinking difficulty or intoxication, difficulty with tasks, funniness, hilarity, and laughter, difficulty sleeping, inner chill, visual sparkle, stomach queasiness, diarrhea, reduced appetite, fluctuating emotions, personal insights, visuals, colors, and feelings of "energy flow".^[1] Additional reported effects include enjoyable lightheadedness, euphoria, perceptual distortion, synesthesia, and nausea.^[4]^[7]

Interactions

Pharmacology

Pharmacodynamics

TMA-6 shows affinity for serotonin receptors in rat stomach fundus strips (A₂ = 525 nM) as well as in rat brain membranes (IC₅₀Tooltip half-maximal inhibitory concentration = 25,000 nM).^[2]^[8]^[9] In a later study, it showed no affinity for the serotonin 5-HT_1A or dopamine D₂ receptors (K_i = >10,000 nM).^[10] Subsequently, it was reported to be a potent serotonin 5-HT_2A receptor full agonist, with an EC₅₀Tooltip half-maximal effective concentration of 29.2 nM and an E_maxTooltip maximal efficacy of 107%.^[11] The drug was inactive as a monoamine reuptake inhibitor and releasing agent in rat brain synaptosomes (IC₅₀Tooltip half-maximal inhibitory concentration and EC₅₀Tooltip half-maximal effective concentration = >100,000 nM, respectively).^[12]^[13]^[14] The drug is a potent monoamine oxidase A (MAO-A) inhibitor, with an IC₅₀Tooltip half-maximal inhibitory concentration of 400 nM.^[15] This is in contrast to TMA (3,4,5-TMA) and TMA-2 (2,4,5-TMA), which are inactive in this regard.^[15]

TMA-6 fully substitutes for the psychedelic drugs DOM and 5-MeO-DMT in rodent drug discrimination tests.^[2]^[16]^[17] It also partially substitutes for dextroamphetamine in rodent drug discrimination tests.^[2]^[18]

Chemistry

Synthesis

The chemical synthesis of TMA-6 has been described.^[1]

Analogues

A number of analogues of TMA-6 with a 2,4,6- substitution pattern have been described, such as Ψ-DOM and ψ-2C-T-4, among others.^[1]^[19]^[20]^[21]^[22] Alexander Shulgin only limitedly explored the 2,4,6- substitution pattern.^[23]^[21]

History

TMA-6 was first described in the scientific literature by 1954.^[2]^[3]^[24] Alexander Shulgin discovered its psychedelic effects in 1964^[3] and first described its hallucinogenic effects in the literature in 1969, where he stated its potency relative to mescaline and noted that these findings were previously unpublished.^[25]^[5]^[26]^[27] Shulgin subsequently gave the drug the name TMA-6 in 1970.^[26] He more thoroughly described TMA-6 in PiHKAL in 1991.^[1] The drug was encountered as a novel designer drug in Europe in 2009.^[28]

Society and culture

Legal status

Canada

TMA-6 is a controlled substance in Canada under phenethylamine blanket-ban language.^[29]

United States

As a positional isomer of TMA, TMA-6 is a Schedule I controlled substance in the United States.^[30] ^[2]

References

[1]
Shulgin A, Shulgin A (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN 0-9630096-0-5. OCLC 25627628.
[2]
Shulgin A, Manning T, Daley PF (2011). "#122. TMA-6". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley, CA: Transform Press. pp. 302–305. ISBN 978-0-9630096-3-0. OCLC 709667010.
[3]
Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN 978-1-4757-0512-6. 3.1.10. 2,4,6-Trimethoxyphenylisopropylamine: The symmetrical, sixth isomer of trimethoxyphenylisopropylamine is TMA-6 (43, 2,4,6-trimethoxyphenylisopropylamine, 2,4,6-trimethoxyamphetamine). This base was first synthesized over 20 years ago (Benington et al., 1954) and its psychotomimetic properties were discovered 10 years later (Shulgin, 1964, unpublished data). A threshold of central activity is apparent at an oral dose of 20 mg, and the dosage range for a fully developed psychotomimetic intoxication state is 30-40 mg. There is a visually entertaining aspect to the experience, although its extended action (maximum effects can persist into the sixth hour) can be both tiring and anxiety-provoking. Naranjo (1967, personal communication) has investigated TMA-6 with 13 subjects in the 40-80 mg range and has found that these higher doses lead to erratic results. With several patients there was neither a prolongation nor an intensification of effects; and with at least one, there was the generation of a convincing psychotic episode. The recorded potency of TMA-6 (ten times that of mescaline; effective dose about 30 mg) can be used in quantitative comparisons with confidence (Shulgin et at., 1969).
[4]
Shulgin AT (March 1973). "Mescaline: the chemistry and pharmacology of its analogs". Lloydia. 36 (1): 46–58. PMID 4576313. The symmetrical isomer (2,4,6-trimethoxyphenylisopropylamine, TMA-6, 17) is without known analogy in the essential oils, but this ring substitution pattern is extremely common throughout the many plant products related to the chromones and the flavonoids. The styles of central activity of 15 and 17 are similar to one another in that at threshhold [sic?] levels there is noted only an enjoyable light-headedness coupled with distinct euphoria and a minimum of perceptive distortion. At effective dosages there again is the nausea reminiscent of that seen with mescaline, and the visual distortions can become quite extensive. The sensory disturbances and syntheses so often found to be entertaining or instructive in the case of mescaline intoxication, are found to be disturbing with these latter drugs. TMA-6, 17, is about half as potent as 15, thus having some ten times the effectiveness of mescaline.
[5]
Shulgin AT, Sargent T, Naranjo C (February 1969). "Structure--activity relationships of one-ring psychotomimetics". Nature. 221 (5180): 537–541. Bibcode:1969Natur.221..537S. doi:10.1038/221537a0. PMID 5789297.
[6]
Brimblecombe RW, Pinder RM (1975). "Phenylalkylamines and Their Derivatives". Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 55–97.
[7]
Shulgin AT (1976). "Psychotomimetic Agents". In Gordon M (ed.). Psychopharmacological Agents: Use, Misuse and Abuse. Medicinal Chemistry: A Series of Monographs. Vol. 4. Academic Press. pp. 59–146. doi:10.1016/b978-0-12-290559-9.50011-9. ISBN 978-0-12-290559-9. The symmetrical isomer [2,4,6-trimethoxyphenylisopropylamine, TMA-6 (LXVII)] has a substitution pattern common throughout the many plant products related to the chromones and the flavanoids. The central activity of (LXIII) and (LXVII) are similar to one another in that at threshold levels there is noted only an enjoyable light-headedness coupled with distinct euphoria and a minimum of perceptive distortion. At effective dosages there again is the nausea reminiscent of that seen with mescaline, and the visual distortions can become quite extensive; (LXVII) is about half as potent as (LXIII).
[8]
Glennon RA, Liebowitz SM, Anderson GM (March 1980). "Serotonin receptor affinities of psychoactive phenalkylamine analogues". Journal of Medicinal Chemistry. 23 (3): 294–299. doi:10.1021/jm00177a017. PMID 7365744.
[9]
De Jong AP, Huggins F, Fournier D, Makriyannis A (September 1982). "Inhibition of [3H]5-HT binding to rat brain membranes by psychotomimetic amphetamines". European Journal of Pharmacology. 83 (3–4): 305–308. doi:10.1016/0014-2999(82)90266-7. PMID 7173311.
[10]
Glennon RA, Dukat M, Grella B, Hong S, Costantino L, Teitler M, et al. (August 2000). "Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors". Drug and Alcohol Dependence. 60 (2): 121–132. doi:10.1016/s0376-8716(99)00148-9. hdl:11380/17721. PMID 10940539.
[11]
Stalberga D, Kronstrand R, Schranz B, van Zijl N, Karlman S, Aref S, et al. (July 2026). "Comprehensive in vitro profiling of traditional and emerging stimulants at monoamine transporters and the 5-HT2A receptor". Br J Pharmacol. doi:10.1111/bph.70587. PMID 42449077.
[12]
Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101.
[13]
Benington F, Morin RD (July 1968). "The chemorelease of norepinephrine from mouse hearts by substituted amphetamines". Journal of Medicinal Chemistry. 11 (4): 896–897. doi:10.1021/jm00310a048. PMID 5677681.
[14]
Tseng LF, Loh HH (April 1977). "Effects of methoxyamphetamines on the uptake and release of [3H]5-hydroxytryptamine by human blood platelets". Biochemical Pharmacology. 26 (7): 647–649. doi:10.1016/0006-2952(77)90041-7. PMID 577148.
[15]
Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Frontiers in Pharmacology. 10 1590. doi:10.3389/fphar.2019.01590. PMC 6989591. PMID 32038257.
[16]
Glennon RA, Young R (October 1982). "Comparison of behavioral properties of di- and tri-methoxyphenylisopropylamines". Pharmacology, Biochemistry, and Behavior. 17 (4): 603–607. doi:10.1016/0091-3057(82)90330-6. PMID 6965276.
[17]
Glennon RA, Rosecrans JA, Young R (December 1981). "Behavioral properties of psychoactive phenylisopropylamines in rats". European Journal of Pharmacology. 76 (4): 353–360. doi:10.1016/0014-2999(81)90106-0. PMID 7327208.
[18]
Glennon RA, Young R, Hauck AE (May 1985). "Structure-activity studies on methoxy-substituted phenylisopropylamines using drug discrimination methodology". Pharmacology, Biochemistry, and Behavior. 22 (5): 723–729. doi:10.1016/0091-3057(85)90520-9. PMID 3839309.
[19]
Nichols DE, Glennon RA (1984). "Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". In Jacobs BL (ed.). Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. pp. 95–142. ISBN 978-0-89004-990-7. OCLC 10324237. The 2,4,6 trisubstitution pattern has received very little attention, but appears quite interesting. The 2,4,6-trimethoxyamphetamine 38 appears to be active in humans in the 30-40 mg range, not too far removed from the potency of 2,4,5-trimethoxyamphetamine (Shulgin and Shulgin, 1991). Further, 2,6-dimethoxy-4-methylamphetamine (39), a positional isomer of DOM, has been reported to be active in humans in the 15-25 mg range (Shulgin and Shulgin, 1991). Based on the known structure-activity relationships in the 2,4,5-substituted series, one might anticipate that more hydrophobic 4 substituents in this series would lead to quite active compounds. However, no additional members of the series have been reported, nor have any animal or biochemical pharmacological studies been carried out to indicate whether the mechanism of action of the 2,4,6-substituted series is similar to that of compounds with the other substituent orientations.
[20]
Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Research Monograph. 146: 74–91. PMID 8742795. Archived from the original (PDF) on 2023-08-05. Retrieved 2025-07-04. The second group has a 2,4,6-substitution pattern. The majority of the compounds listed in the last few tables has carried the 3,4,5- or the 2,4,5-substitution pattern. The similarity of potency between TMA-2 and TMA-6 (the latter with the 2,4,6 substitution pattern, see table 5) has opened up a new family of hallucinogenic amphetamines, one of the authors' current areas of research. With this group also, the 4-position appears to dictate the potency and nature of response. It seems that each of the 2,4,5-substituted materials may have an active 2,4,6-counterpart. The isomer that corresponds to DOM (2,6-dimethoxy-4-methylamphetamine [pseudo-DOM]) is active at 15 to 25 mg orally. Synthetic procedures are now in hand to prepare the pseudo analogs of the 2C-T family with various alkylthio groups at the 4-position.
[21]
Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN 978-0-12-433951-4. This review to date has considered the relatives of the 3,4,5-trisubstitution ring pattern (modest activity) and the considerably more potent 2,4,5-trisubstitution pattern. As was noted in the comments comparing TMA-2 with TMA-6, the 2,4,6-orientation bids fair to be every bit as important as the 2,4,5-system, although it has as yet been almost unexplored, either chemically or pharmacologically. A nomenclature that has been used to refer to this branch which is parallel to the 2,4,5-group, is to use the code name of the drug and precede it with the Greek letter psi. This was introduced above with the compound Ψ-2C-T-4. Thus, the lead drug of this section (DOM or 2,5-dimethoxy-4-methylamphetamine) becomes Ψ-DOM (2,6-dimethoxy-4-methylamphetamine). Clinical studies have shown it to be active as a hallucinogen in the 15—25mg range, with a mescaline equivalency of 15. There is too little data at the present time to determine any quantitative relationship between the 2,4,5-normal series and the but it appears quite possible that the two parallel families are, at least as to their quantitative properties, quite similar.
[22]
Trachsel D (2012). "Fluorine in psychedelic phenethylamines". Drug Testing and Analysis. 4 (7–8): 577–590. doi:10.1002/dta.413. PMID 22374819.
[23]
"Ask Dr. Shulgin Online". keeping freedom in mind -. 14 March 2002. Retrieved 4 July 2025.
[24]
Benington F, Morin RD, Clark LC (1954). "MESCALINE ANALOGS. I. 2,4,6-TRIALKOXY-β-PHENETHYLAMINES". The Journal of Organic Chemistry. 19 (1): 11–16. doi:10.1021/jo01366a003. ISSN 0022-3263. Retrieved 4 July 2025.
[25]
Shulgin AT (1982). "Chemistry of Psychotomimetics". In Hoffmeister F, Stille G (eds.). Psychotropic Agents, Part III: Alcohol and Psychotomimetics, Psychotropic Effects of Central Acting Drugs. Handbook of Experimental Pharmacology. Vol. 55. Berlin: Springer Berlin Heidelberg. pp. 3–29. doi:10.1007/978-3-642-67770-0_1. ISBN 978-3-642-67772-4. OCLC 8130916.
[26]
Shulgin A (1970). "Chemistry and Structure-Activity Relationships of the Psychotomimetics". In Efron DH (ed.). Psychotomimetic Drugs (PDF). New York: Raven Press. pp. 21–41.
[27]
Shulgin AT (1966). "The Six Trimethoxyphenylisopropylamines (Trimethoxyamphetamines)". Journal of Medicinal Chemistry. 9 (3): 445–446. doi:10.1021/jm00321a058. ISSN 0022-2623. PMID 5960939.
[28]
"EMCDDA–Europol 2009 Annual Report on the implementation of Council Decision 2005/387/JHA". European Monitoring Centre for drug and Drug Addiction (EMCDDA).
[29]
"Controlled Drugs and Substances Act". Department of Justice Canada. Retrieved 19 January 2026.
[30]
Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026) (PDF), United States: U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division, January 2026