2,4,5-Trimethoxyamphetamine

Last updated
TMA-2
Trimethoxyamphetamine-2.svg
TMA-2 ball-and-stick structure.png
Clinical data
Other namesTMA-2; 2,4,5-TMA; 2,4,5-Trimethoxy-α-methylphenethylamine; 2,5-Dimethoxy-4-methoxyamphetamine; 4-Methoxy-2,5-dimethoxyamphetamine; DOMeO; DOOMe; DOO; β-Aminodihydroasarone
Routes of
administration 		Oral [1] [2] [3]
Drug class Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Onset of action ≥1 hour [3]
Duration of action 8–12 hours [1] [2] [3]
Identifiers
  • 1-(2,4,5-trimethoxyphenyl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C12H19NO3
Molar mass 225.288 g·mol−1
3D model (JSmol)
  • CC(CC1=CC(=C(C=C1OC)OC)OC)N
  • InChI=1S/C12H19NO3/c1-8(13)5-9-6-11(15-3)12(16-4)7-10(9)14-2/h6-8H,5,13H2,1-4H3
  • Key:TVSIMAWGATVNGK-UHFFFAOYSA-N

2,4,5-Trimethoxyamphetamine (2,4,5-TMA), also known as TMA-2 or as 2,5-dimethoxy-4-methoxyamphetamine (DOMeO), is a psychedelic drug of the phenethylamine and amphetamine families. [1] [2] [3] It is one of the trimethoxyamphetamine (TMA) series of positional isomers. [1] [2] The drug is also notable in being the 4-methoxylated member of the DOx (i.e., 4-substituted-2,5-dimethoxyamphetamine) series of drugs. [1] [2]

Contents

Use and effects

In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists TMA-2's dose as 20 to 40 mg orally and its duration as 8 to 12 hours. [1] [2] [3] [5] In earlier publications, it was described that threshold effects occur at a dose of 10 mg orally, an effective dose is 16 to 20 mg orally, its onset of psychoactive effects is after 1 hour, and a plateau of effects occurs from 3 to 6 hours following administration. [3] [6] The drug is much more potent than its positional isomer 3,4,5-trimethoxyamphetamine (3,4,5-TMA, TMA, or TMA-1), which is said to be active at doses of 100 to 250 mg orally and to have a duration of 6 to 8 hours. [7] However, DOM (2,5-dimethoxy-4-methylamphetamine), the analogue of TMA-2 in which its 4-methoxy group has been replaced with a more lipophilic 4-methyl group, is about 10 times more potent than TMA-2. [8] TMA-2 has been said to have a sharp dose–response curve, with several additional toxic symptoms occurring at doses of 25 to 30 mg. [3]

The effects of TMA-2 have been reported to include color and contrast enhancement, closed-eye imagery like kaleidoscopic images, visuals such as visual distortion and movement, auditory enhancement, increased salience of objects in one's environment, cosmic thinking, time dilation, music and erotic enhancement, confusion, lethargy, laziness, sleepiness, lightheadedness, feeling faintish and actual fainting, brief but repeated periods of amnesia, fear of psychosis, pupil dilation, paresthesia, nausea, vomiting, abdominal cramps, diarrhea, and muscle tremors, among others. [1] [2] [3] The drug was described as a "seminal" or "archetypal" psychedelic. [1]

Interactions

Combination of TMA-2 with harmaline or ibogaine has been reported to result in long-lasting episodes complicated by severe psychomotor agitation. [3] [6]

Pharmacology

Pharmacodynamics

TMA-2 activities
Target Affinity (Ki, nM)
5-HT1A >10,000
5-HT1B >10,000
5-HT1D >10,000
5-HT1E >10,000
5-HT1F ND
5-HT2A 57.9–1,300 (Ki)
190–1,860 (EC50 Tooltip half-maximal effective concentration)
84–102% (Emax Tooltip maximal efficacy)
5-HT2B 154–307 (Ki)
270 (EC50)
78% (Emax)
5-HT2C 87.7–5,300
5-HT3 >10,000
5-HT4 ND
5-HT5A >10,000
5-HT6 >10,000
5-HT7 >10,000
α1A, α1B >10,000
α1D ND
α2A–α2C >10,000
β1, β2 >10,000
D1–D5 >10,000
H1 1,407
H2–H4 >10,000
M1, M3, M4 ND
M2, M5 >10,000
TAAR1 >4,400 (Ki) (mouse)
3,100 (Ki) (rat)
ND (EC50) (human)
I1 ND
σ1, σ2 ND
SERT Tooltip Serotonin transporter>10,000 (Ki)
>100,000 (IC50 Tooltip half-maximal inhibitory concentration)
>100,000 (EC50) (rat)
NET Tooltip Norepinephrine transporter>10,000 (Ki)
>100,000 (IC50)
>100,000 (EC50) (rat)
DAT Tooltip Dopamine transporter>10,000 (Ki)
>100,000 (IC50)
>100,000 (EC50) (rat)
MAO-A Tooltip Monoamine oxidase A>100,000 (IC50) (rat)
MAO-B Tooltip Monoamine oxidase B>100,000 (IC50) (rat)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [9] [10] [11] [12] [13] [14] [15] [16] [17]

TMA-2's affinity (Ki) for the serotonin 5-HT2A receptor has been found to be 1,300 nM. [12] Its EC50 Tooltip half-maximal effective concentration at the receptor was 190 nM and its Emax Tooltip maximal efficacy was 84%. [12] The drug was also active at the serotonin 5-HT2B receptor and, to a much lesser extent, at the serotonin 5-HT2C receptor. [12] In an earlier study, its affinities (Ki) were 1,650 nM at the serotonin 5-HT2 receptor and 46,400 nM at the serotonin 5-HT1 receptor. [18] [19] TMA-2 is inactive at the monoamine transporters. [16] [12] It was inactive at the mouse trace amine-associated receptor 1 (TAAR1), whereas it bound to the rat TAAR1 with an affinity (Ki) of 3,100 nM and was not assessed at the human TAAR1. [12]

Pharmacokinetics

In terms of metabolism, TMA-2 is known to be at least partially O-demethylated in animals in vivo . [3] [6] It might produce 2,4,5-trihydroxyamphetamine (THA) as a metabolite. [3] The pharmacokinetics and metabolism of TMA-2 in humans are unknown. [3] [6]

Chemistry

Properties

The chemical properties of TMA-2 have been described. [3]

Synthesis

The chemical synthesis of TMA-2 has been described. [1]

Analogues and derivatives

2,4,5-Trimethoxyamphetamine is very similar in chemical structure to the monoaminergic neurotoxin 6-hydroxydopamine. [3] [6]

A variety of derivatives of TMA-2 have been developed and studied. [12] [20]

History

TMA-2 was first described in the scientific literature by Bruckner in 1933. [21] [2] [3] [22] Subsequently, Alexander Shulgin discovered the hallucinogenic effects of TMA-2 in 1962 and published them in 1964. [3] [21] [23] [24] [2] The drug was later described in further detail by Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). [1]

Society and culture

Canada

TMA-2 is a controlled substance in Canada. [25]

United States

As of 2011, TMA-2 is not an explicitly controlled substance in the United States. [2] [4] However, it is a positional isomer of 3,4,5-trimethoxyamphetamine (TMA), and thus is a Schedule I controlled substance in this country similarly. [2] [3] [4] [26]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 Shulgin AT, Shulgin A (1991). "#158 TMA-2 2,4,5-TRIMETHOXYAMPHETAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN   9780963009609. OCLC   25627628.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 Shulgin A, Manning T, Daley PF (2011). "#118. TMA-2". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley: Transform Press. ISBN   978-0-9630096-3-0.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Shulgin, Alexander T. (1976). "Profiles of Psychedelic Drugs: 1. DMT & 2. TMA-2". Journal of Psychedelic Drugs. 8 (2): 167–169. doi:10.1080/02791072.1976.10471846. ISSN   0022-393X. Theoretical interest in TMA-2 stems from the recognition of 6-hydroxy dopamine as an extremely potent disrupter of the adrenergic nervous system. TMA-2 is structurally related with an identical oxygenation pattern, and has been shown to be partially demethylated in vivo. The end product, 2,4,5-trihydroxyamphetamine, has been studied clinically as an antihypertensive, but has not been reported to produce sensory or perceptual changes in humans even at dosages of 200 mg. The metabolism and fate of TMA-2 in humans is unknown.
  4. 1 2 3 "Controlled Substances" (PDF). www.deadiversion.usdoj.gov.
  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" (PDF). Neuropharmacology. 167 107933. doi:10.1016/j.neuropharm.2019.107933. PMC   9191653 . PMID   31917152. Table 4 Human potency data for selected hallucinogens. [...]
  6. 1 2 3 4 5 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. There is a theoretical interest in TMA-2 stemming from the recognition of 6-hydroxydopamine (38) as a potent disrupting agent within the adrenergic nervous system. The two compounds have an identical oxygen substitution, and TMA-2 (34) has been shown to be partially demethylated in vivo (Mitoma, 1970; Sargent et al., 1976). The totally demethylated product from TMA-2 is 2,4,5-trihydroxyphenylisopropylamine (39), which has been explored as an antihypertensive agent, but which exhibits no mental effects at dosages as high as 200 mg (Stone, 1963).
  7. ↑ Shulgin AT, Shulgin A (1991). "#157 TMA 3,4,5-TRIMETHOXYAMPHETAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN   9780963009609. OCLC   25627628.
  8. ↑ Nichols, David E. (2012). "Structure–activity relationships of serotonin 5-HT2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi: 10.1002/wmts.42 . ISSN   2190-460X.
  9. ↑ "Kᵢ Database". PDSP. 15 March 2025. Retrieved 15 March 2025.
  10. ↑ Liu, Tiqing. "BDBM50005253 (+/-)1-Methyl-2-(2,4,5-trimethoxy-phenyl)-ethylamine::1-(2,4,5-trimethoxyphenyl)propan-2-amine::1-Methyl-2-(2,4,5-trimethoxy-phenyl)-ethylamine::1-Methyl-2-(2,4,5-trimethoxy-phenyl)-ethylamine(2,4,5-TMA)::CHEMBL8389". BindingDB. Retrieved 14 March 2025.
  11. ↑ 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.
  12. 1 2 3 4 5 6 7 Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, Liechti ME (2019). "Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines". Front Pharmacol. 10 1423. doi: 10.3389/fphar.2019.01423 . PMC   6893898 . PMID   31849671.
  13. ↑ Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (January 1999). "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors" . Naunyn Schmiedebergs Arch Pharmacol. 359 (1): 1–6. doi:10.1007/pl00005315. PMID   9933142.
  14. ↑ Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD (April 2021). "Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore". ACS Pharmacol Transl Sci. 4 (2): 488–502. doi:10.1021/acsptsci.0c00063. PMC   8033619 . PMID   33860179.
  15. ↑ 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" (PDF). Psychopharmacology (Berl). 240 (1): 115–126. doi:10.1007/s00213-022-06279-2. PMC   9816194 . PMID   36477925.
  16. 1 2 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.
  17. ↑ 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.
  18. ↑ Glennon RA (January 1987). "Central serotonin receptors as targets for drug research". J Med Chem. 30 (1): 1–12. doi:10.1021/jm00384a001. PMID   3543362. Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
  19. ↑ Shannon M, Battaglia G, Glennon RA, Titeler M (June 1984). "5-HT1 and 5-HT2 binding properties of derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA)". Eur J Pharmacol. 102 (1): 23–29. doi:10.1016/0014-2999(84)90333-9. PMID   6479216.
  20. ↑ Trachsel D (2012). "Fluorine in psychedelic phenethylamines" . Drug Test Anal. 4 (7–8): 577–590. doi:10.1002/dta.413. PMID   22374819.
  21. 1 2 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. 3.1.6. 2,4,5-Trimethoxyphenylisopropylamine This geometric isomer of TMA was first synthesized by Bruckner (1933) and its psychotomimetic properties were first observed some 30 years later (Shulgin, 1964a), 2,4,5-Trimethoxyphenylisopropylamine (34, TMA-2, 2,4,5-trimethoxyamphetamine) was the second of the six possible positional isomers found to be psychotomimetic, and was thus called TMA-2.
  22. ↑ Bruckner, Viktor (24 October 1933). "Über das Pseudonitrosit des Asarons". Journal für Praktische Chemie. 138 (9–10): 268–274. doi:10.1002/prac.19331380907. ISSN   0021-8383.
  23. ↑ Shulgin AT (July 1964). "Psychotomimetic amphetamines: methoxy 3,4-dialkoxyamphetamines". Experientia. 20 (7): 366–367. doi:10.1007/BF02147960. PMID   5855670.
  24. ↑ Shulgin AT (May 1966). "The six trimethoxyphenylisopropylamines (trimethoxyamphetamines)". J Med Chem. 9 (3): 445–446. doi:10.1021/jm00321a058. PMID   5960939.
  25. ↑ "Controlled Drugs and Substances Act". Department of Justice Canada. Retrieved 19 January 2026.
  26. ↑ Drug Enforcement Administration (3 December 2007). "Definition of "Positional Isomer" as It Pertains to the Control of Schedule I Controlled Substances". Federal Register.
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