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2,4,6-Trimethoxyamphetamine

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2,4,6-Trimethoxyamphetamine
Clinical data
Other names2,4,6-TMA; TMA-6; ψ-TMA-2; NSC-367445
Routes of
administration		Oral[1]
Drug classSerotonin receptor modulator; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Identifiers
  • 1-(2,4,6-trimethoxyphenyl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC12H19NO3
Molar mass225.288 g·mol−1
3D model (JSmol)
  • CC(CC1=C(C=C(C=C1OC)OC)OC)N
  • 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

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

Use and effects

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In his 1991 book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin gave a dose range for TMA-6 of 25 to 50 mg and a duration of 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]

Its effects at 25 to 50 mg included 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

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See also: Psychedelic drug § Interactions, and Trip killer § Serotonergic psychedelic antidotes

Pharmacology

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Pharmacodynamics

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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-HT1A or dopamine D2 receptors (Ki = >10,000 nM).[10] It 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).[11][12][13] The drug is a potent monoamine oxidase A (MAO-A) inhibitor, with an IC50Tooltip half-maximal inhibitory concentration of 400 nM.[14] This is in contrast to TMA (3,4,5-TMA) and TMA-2 (2,4,5-TMA), which are inactive in this regard.[14]

TMA-6 fully substitutes for the psychedelic drugs DOM and 5-MeO-DMT in rodent drug discrimination tests.[2][15][16] It also partially substitutes for dextroamphetamine in rodent drug discrimination tests.[2][17]

Chemistry

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Analogues

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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][18][19][20][21] Alexander Shulgin only limitedly explored the 2,4,6- substitution pattern.[22][20]

History

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TMA-6 was first described in the scientific literature by 1954.[2][3][23] 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.[24][5][25][26] Shulgin subsequently gave the drug the name TMA-6 in 1970.[25] He more thoroughly described TMA-6 in PiHKAL in 1991.[1] The drug was encountered as a novel designer drug in Europe in 2009.[27]

Society and culture

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

See also

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References

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  1. ^ a b c d e f g Shulgin, Alexander; Shulgin, Ann (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN 0-9630096-0-5. OCLC 25627628.
  2. ^ a b c d e f g 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. ^ a b c d e 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. ^ a b 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 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. ^ a b Shulgin AT, Sargent T, Naranjo C (February 1969). "Structure--activity relationships of one-ring psychotomimetics". Nature. 221 (5180): 537–541. 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". J Med Chem. 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". Eur J Pharmacol. 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, Smith C, Egan C, Davis K, Mattson MV (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 Alcohol Depend. 60 (2): 121–132. doi:10.1016/s0376-8716(99)00148-9. PMID 10940539.
  11. ^ Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". Eur J Pharmacol. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101.
  12. ^ Benington F, Morin RD (July 1968). "The chemorelease of norepinephrine from mouse hearts by substituted amphetamines". J Med Chem. 11 (4): 896–897. doi:10.1021/jm00310a048. PMID 5677681.
  13. ^ Tseng LF, Loh HH (April 1977). "Effects of methoxyamphetamines on the uptake and release of [3H]5-hydroxytryptamine by human blood platelets". Biochem Pharmacol. 26 (7): 647–649. doi:10.1016/0006-2952(77)90041-7. PMID 577148.
  14. ^ a b Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol. 10: 1590. doi:10.3389/fphar.2019.01590. PMC 6989591. PMID 32038257.
  15. ^ Glennon RA, Young R (October 1982). "Comparison of behavioral properties of di- and tri-methoxyphenylisopropylamines". Pharmacol Biochem Behav. 17 (4): 603–607. doi:10.1016/0091-3057(82)90330-6. PMID 6965276.
  16. ^ Glennon RA, Rosecrans JA, Young R (December 1981). "Behavioral properties of psychoactive phenylisopropylamines in rats". Eur J Pharmacol. 76 (4): 353–360. doi:10.1016/0014-2999(81)90106-0. PMID 7327208.
  17. ^ Glennon RA, Young R, Hauck AE (May 1985). "Structure-activity studies on methoxy-substituted phenylisopropylamines using drug discrimination methodology". Pharmacol Biochem Behav. 22 (5): 723–729. doi:10.1016/0091-3057(85)90520-9. PMID 3839309.
  18. ^ 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 trisubstirurion 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-subscituted series, one might anticipate that more hydrophobic 4 substituenrs 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.
  19. ^ Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Research Monograph. 146: 74–91. PMID 8742795. 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.
  20. ^ a b 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.
  21. ^ Trachsel D (2012). "Fluorine in psychedelic phenethylamines". Drug Test Anal. 4 (7–8): 577–590. doi:10.1002/dta.413. PMID 22374819.
  22. ^ "Ask Dr. Shulgin Online". keeping freedom in mind -. 14 March 2002. Retrieved 4 July 2025.
  23. ^ Benington, F.; Morin, R. D.; Clark, Leland C. (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.
  24. ^ 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.
  25. ^ a b Alexander Shulgin (1970). "Chemistry and Structure-Activity Relationships of the Psychotomimetics". In D. H. Efron (ed.). Psychotomimetic Drugs (PDF). New York: Raven Press. pp. 21–41.
  26. ^ Shulgin, Alexander T. (1966). "The Six Trimethoxyphenylisopropylamines (Trimethoxyamphetamines)". Journal of Medicinal Chemistry. 9 (3): 445–446. doi:10.1021/jm00321a058. ISSN 0022-2623.
  27. ^ https://bitnest.netfirms.com/external/EMCDDA/New-Drugs-In-Europe-2009
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