3,4,5-Trimethoxyamphetamine

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Wikipedia

TMA
Clinical data
Other namesTrimethoxyamphetamine; TMA; TMA-1; 3,4,5-TMA; α-Methylmescaline; alpha-Methylmescaline; AMM; Mescalamphetamine; 3,4,5-Trimethoxy-α-methylphenethylamine; EA‐1319; EA1319; 3C-Mescaline; 3C-M
Routes of
administration		Oral[1][2]
Drug classSerotonergic psychedelic; Hallucinogen; Serotonin 5-HT2A receptor agonist
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Duration of action6–8 hours[1][2]
Identifiers
  • 1-(3,4,5-trimethoxyphenyl)propan-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC12H19NO3
Molar mass225.288 g·mol−1
3D model (JSmol)
  • CC(CC1=CC(=C(C(=C1)OC)OC)OC)N
  • InChI=1S/C12H19NO3/c1-8(13)5-9-6-10(14-2)12(16-4)11(7-9)15-3/h6-8H,5,13H2,1-4H3
  • Key:WGTASENVNYJZBK-UHFFFAOYSA-N

3,4,5-Trimethoxyamphetamine (TMA, TMA-1, or 3,4,5-TMA), also known as α-methylmescaline (3C-mescaline or 3C-M) or mescalamphetamine, is a psychedelic drug of the phenethylamine and amphetamine families.[1][2] It is one of the trimethoxyamphetamine (TMA) series of positional isomers.[1][2] The drug is notable in being the amphetamine (i.e., α-methylated) analogue of mescaline (3,4,5-trimethoxyphenethylamine).[1][2]

Use and effects

In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists TMA's dose as 100 to 250 mg orally and its duration as 6 to 8 hours.[1][2][4][5] For comparison, mescaline is typically used at doses of 200 to 500 mg orally and is said to have a duration of 10 to 12 hours or longer.[6] TMA's positional isomer 2,4,5-trimethoxyamphetamine (2,4,5-TMA or TMA-2) is much more potent than TMA, with a dose of 20 to 40 mg orally and a duration of 8 to 12 hours.[7]

The effects of TMA have been reported to include closed-eye imagery, introspection, music enhancement, emotional volatility, annoyance and irritability, feeling violent, lightheadedness, giddiness, and nausea, among others.[1] It is said to lack mescaline's color changes and to have a "thread of negativity" at higher doses and a possible "antisocial nature" that has limited interest in the drug.[1]

Interactions

Pharmacology

Pharmacodynamics

TMA activities
TargetAffinity (Ki, nM)
5-HT1A1,678–>5,600
5-HT1B2,855
5-HT1D3,035
5-HT1E3,369
5-HT1FND
5-HT2A>10,000 (Ki)
41.3–1,700 (EC50Tooltip half-maximal effective concentration)
40–96% (EmaxTooltip maximal efficacy)
5-HT2B477 (Ki)
>10,000 (EC50)
5-HT2C4,600–>10,000 (Ki)
47.4 (EC50)
92% (Emax)
5-HT3>10,000
5-HT4ND
5-HT5A>10,000
5-HT6>10,000
5-HT7749
α1A, α1B>10,000
α1DND
α2A2,071–4,030
α2B>10,000
α2C5,014
β1, β2>10,000
D1–D5>10,000
H1–H4>10,000
M1, M3, M4ND
M2, M5>10,000
nACh260–>10,000
TAAR11,800 (Ki) (mouse)
3,200 (Ki) (rat)
>10,000 (EC50) (human)
I1>10,000
σ1537
σ2537
SERTTooltip Serotonin transporter>10,000 (Ki)
>100,000 (IC50Tooltip half-maximal inhibitory concentration)
16,000 (EC50) (rat)
NETTooltip Norepinephrine transporter>10,000 (Ki)
>100,000 (IC50)
>100,000 (EC50) (rat)
DATTooltip Dopamine transporter>10,000 (Ki)
>100,000 (IC50)
>100,000 (EC50) (rat)
MAO-ATooltip Monoamine oxidase A>200,000 (IC50)
MAO-BTooltip Monoamine oxidase B>200,000 (IC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [8][9][10][11][12][13][14][15]

TMA is a low-potency serotonin 5-HT2A receptor partial agonist, with an affinity (Ki) of >12,000 nM, an EC50Tooltip half-maximal effective concentration of 1,700 nM, and an EmaxTooltip maximal efficacy of 40%.[11] Conversely, it was inactive at the serotonin 5-HT1A, 5-HT2B and 5-HT2C receptors and at several other receptors, at least at the assessed concentrations (up to 10,000 nM).[11] It showed affinity for the mouse and rat trace amine-associated receptor 1 (TAAR1) (Ki = 1,800 nM and 3,200 nM, respectively), whereas it was inactive at the human TAAR1 (EC50 > 10,000 nM).[11]

TMA is also a very low-potency serotonin releasing agent (SRA), with an EC50 value of 16,000 nM.[12] In contrast, it is inactive as a releasing agent and reuptake inhibitor of dopamine and norepinephrine (EC50 > 100,000 nM).[12] Despite its apparent SRA activity in vitro, TMA did not increase brain serotonin or dopamine levels in rodents in vivo.[15] TMA is similarly inactive as a monoamine oxidase inhibitor (MAOI), including of both monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) (IC50Tooltip half-maximal inhibitory concentration > 200,000 nM).[14][15]

The low potency of TMA as a serotonin 5-HT2A receptor agonist is analogous to the case of mescaline, which is a well-known and widely used psychedelic but is likewise a very low-potency agonist of this receptor, showing an affinity (Ki) of 9,400 nM, an EC50 of 10,000 nM, and an Emax of 56% in the same study.[11] For comparison, DOM has shown an affinity (Ki) of 88 nM and an EC50 of 4 to 24 nM.[16]

Chemistry

Synthesis

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

Derivatives

A variety of derivatives of TMA, known as the 3C series, have been studied and described.[1][2][11]

History

TMA was first synthesized by Gordon Alles around 1937.[17][18] He assessed it in both animal studies and self-experiments and documented its effects, but these were not reported until 1959.[17][18] The drug was first described in the scientific literature in 1947 and its psychedelic effects were first described in 1955.[19][20][21][22] TMA was studied at Edgewood Arsenal under the code name EA‐1319 in 1953 and 1954.[17] The drug was further characterized by Alexander Shulgin and described in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved).[1][2]

Society and culture

TMA is a Schedule I controlled substance in the United States.[2][3]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Shulgin AT, Shulgin A (1991). "#157 TMA 3,4,5-TRIMETHOXYAMPHETAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN 978-0-9630096-0-9. OCLC 25627628.
  2. 1 2 3 4 5 6 7 8 9 10 Shulgin A, Manning T, Daley PF (2011). "#117. TMA". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. ISBN 978-0-9630096-3-0.
  3. 1 2 "Controlled Substances" (PDF). www.deadiversion.usdoj.gov.
  4. ↑ Halberstadt AL, Luethi D, Hoener MC, Trachsel D, Brandt SD, Liechti ME (January 2023). "Use of the head-twitch response to investigate the structure-activity relationships of 4-thio-substituted 2,5-dimethoxyphenylalkylamines". Psychopharmacology. 240 (1): 115–126. doi:10.1007/s00213-022-06279-2. PMC 9816194. PMID 36477925. For example, 3,4,5-trimethoxyamphetamine (TMA) is active at a dose range of 100–250 mg, whereas its 2,4,5-regioisomer (2,4,5-trimethoxyamphetamine, TMA-2) is active at 20–40 mg (Shulgin and Shulgin 1991).
  5. ↑ Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD (May 2020). "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology. 167 107933. doi:10.1016/j.neuropharm.2019.107933. PMC 9191653. PMID 31917152. Table 4 Human potency data for selected hallucinogens. [...]
  6. ↑ Vamvakopoulou IA, Narine KA, Campbell I, Dyck JR, Nutt DJ (January 2023). "Mescaline: The forgotten psychedelic". Neuropharmacology. 222 109294. doi:10.1016/j.neuropharm.2022.109294. PMID 36252614.
  7. ↑ Shulgin AT, Shulgin A (1991). "#158 TMA-2 2,4,5-TRIMETHOXYAMPHETAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN 978-0-9630096-0-9. OCLC 25627628.
  8. ↑ "PDSP Database". UNC (in Zulu). Retrieved 15 March 2025.
  9. ↑ Liu T. "BDBM50005256 (+/-)1-Methyl-2-(3,4,5-trimethoxy-phenyl)-ethylamine::1-Methyl-2-(3,4,5-trimethoxy-phenyl)-ethylamine::CHEMBL30336::TMA". BindingDB. Retrieved 14 March 2025.
  10. ↑ Ray TS (February 2010). "Psychedelics and the human receptorome". PLOS ONE. 5 (2) e9019. Bibcode:2010PLoSO...5.9019R. doi:10.1371/journal.pone.0009019. PMC 2814854. PMID 20126400.
  11. 1 2 3 4 5 6 Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, Liechti ME (2021). "Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines". Frontiers in Pharmacology. 12 794254. doi:10.3389/fphar.2021.794254. PMC 8865417. PMID 35222010.
  12. 1 2 3 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. ↑ Whiteaker P, Sharples CG, Wonnacott S (May 1998). "Agonist-induced up-regulation of alpha4beta2 nicotinic acetylcholine receptors in M10 cells: pharmacological and spatial definition". Molecular Pharmacology. 53 (5): 950–962. doi:10.1016/S0026-895X(24)13263-4. PMID 9584223.
  14. 1 2 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.
  15. 1 2 3 Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, et al. (August 2014). "5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis". European Neuropsychopharmacology. 24 (8): 1362–1370. doi:10.1016/j.euroneuro.2014.04.009. PMID 24862256.
  16. ↑ Luethi D, Rudin D, Hoener MC, Liechti ME (2022). "Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines". The FASEB Journal. 36 (S1) fasebj.2022.36.S1.R2691. doi:10.1096/fasebj.2022.36.S1.R2691. ISSN 0892-6638.
  17. 1 2 3 Passie T, Benzenhöfer U (January 2018). "MDA, MDMA, and other "mescaline-like" substances in the US military's search for a truth drug (1940s to 1960s)". Drug Testing and Analysis. 10 (1): 72–80. doi:10.1002/dta.2292. PMID 28851034.
  18. 1 2 Alles GA (1959). "Some Relations Between Chemical Structure and Physiological Action of Mescaline and Related Compounds / Structure and Action of Phenethylamines". In Abramson HA (ed.). Neuropharmacology: Transactions of the Fourth Conference, September 25, 26, and 27, 1957, Princeton, N. J. New York: Josiah Macy Foundation. pp. 181–268. OCLC 9802642. Archived from the original on 21 March 2025.
  19. ↑ Peretz DI, Smythies JR, Gibson WC (April 1955). "A new hallucinogen: 3,4,5-trimethoxyphenyl-beta-aminopropane with notes on the stroboscopic phenomenon". The Journal of Mental Science. 101 (423): 317–329. doi:10.1192/bjp.101.423.317. PMID 13243046.
  20. ↑ Shulgin AT, Bunnell S, Sargent T (1961). "The Psychotomimetic Properties of 3,4,5-Trimethoxyamphetamine". Nature. 189 (4769): 1011–1012. Bibcode:1961Natur.189.1011S. doi:10.1038/1891011a0. ISSN 0028-0836.
  21. ↑ Hey P (1947). "The synthesis of a new homologue of mescaline". Quarterly Journal of Pharmacy and Pharmacology. 20 (2): 129–134. PMID 20260568. Archived from the original on 19 July 2019.
  22. ↑ 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.