2,4,5-Trimethoxyamphetamine

TMA-2 Trimethoxyamphetamine-2.svg skin-invert-image 225px TMA-2 ball-and-stick structure.png bg-transparent 200px Oral Serotonergic psychedelic; Hallucinogen None Schedule I ≥1 hour 8–12 hours 1083-09-6 31014 28773 713Z3SL0TJ C22746 8389 TMA-2; 2,4,5-TMA; 2,4,5-Trimethoxy-α-methylphenethylamine; 2,5-Dimethoxy-4-methoxyamphetamine; 4-Methoxy-2,5-dimethoxyamphetamine; DOMeO; DOOMe; DOO; MMM; β-Aminodihydroasarone 1-(2,4,5-trimethoxyphenyl)propan-2-amine 12 19 1 3 CC(CC1=CC(=C(C=C1OC)OC)OC)N 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 TVSIMAWGATVNGK-UHFFFAOYSA-N 2,4,5-Trimethoxyamphetamine (2,4,5-TMA), also known as TMA-2, MMM, or 2,5-dimethoxy-4-methoxyamphetamine (DOMeO), is a psychedelic drug of the phenethylamine and amphetamine families. Shulgin AT, Shulgin A #158 TMA-2 2,4,5-TRIMETHOXYAMPHETAMINE PiHKAL: A Chemical Love Story 1991 Transform Press 9780963009609 1st Berkeley, CA 25627628 https://www.erowid.org/library/books_online/pihkal/pihkal158.shtml Shulgin A, Manning T, Daley PF #118. TMA-2 The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds Transform Press Berkeley 1 2011 978-0-9630096-3-0 https://archive.org/details/shulgin-index-vol-1/page/291/mode/1up?view=theater Shulgin Alexander T. Profiles of Psychedelic Drugs: 1. DMT & 2. TMA-2 Journal of Psychedelic Drugs 8 2 1976 0022-393X 10.1080/02791072.1976.10471846 167–169 https://bitnest.netfirms.com/external/10.1080/02791072.1976.10471846 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. It is one of the trimethoxyamphetamine (TMA) series of positional isomers. The drug is also notable in being the 4-methoxylated member of the DOx (i.e., 4-substituted-2,5-dimethoxyamphetamine) series of drugs. Use and effects In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists TMA-2's dose as 20 to 40mg orally and its duration as 8 to 12hours. Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD 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 May 2020 31917152 9191653 10.1016/j.neuropharm.2019.107933 http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Serotonergic%20Psychedelics%2020/Halberstadt%2020%20Neuropharm%20potency%20of%20hallucinogens%20%20head-twitch.pdf Table 4 Human potency data for selected hallucinogens. [...] 2025-03-26 2025-03-26 https://web.archive.org/web/20250326111621/http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Serotonergic%20Psychedelics%2020/Halberstadt%2020%20Neuropharm%20potency%20of%20hallucinogens%20%20head-twitch.pdf dead In earlier publications, it was described that threshold effects occur at a dose of 10mg orally, an effective dose is 16 to 20mg orally, its onset of psychoactive effects is after 1hour, and a plateau of effects occurs from 3 to 6hours following administration. 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 250mg orally and to have a duration of 6 to 8hours. Shulgin AT, Shulgin A #157 TMA 3,4,5-TRIMETHOXYAMPHETAMINE PiHKAL: A Chemical Love Story 1991 Transform Press 9780963009609 1st Berkeley, CA 25627628 https://www.erowid.org/library/books_online/pihkal/pihkal157.shtml 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 10times more potent than TMA-2.Nichols David E. Structure–activity relationships of serotonin 5-HT2A agonists Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1 5 2012 2190-460X 10.1002/wmts.42 free 559–579 TMA-2 has been said to have a sharp dose–response curve, with several additional toxic symptoms occurring at doses of 25 to 30mg. 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, and music and erotic enhancement. Other effects have been reported to include 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. The drug was described as a "seminal" or "archetypal" psychedelic in PiHKAL. Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Combination of TMA-2 with harmaline or ibogaine has been reported to result in long-lasting episodes complicated by severe psychomotor agitation. 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 No data 5-HT2A 57.9–1,300 (Ki)190–1,860 (EC50 half-maximal effective concentration)84–102% (Emax maximal efficacy) 5-HT2B 154–307 (Ki)270 (EC50 half-maximal effective concentration)78% (Emax maximal efficacy) 5-HT2C 87.7–5,300 5-HT3 >10,000 5-HT4 ND No data 5-HT5A >10,000 5-HT6 >10,000 5-HT7 >10,000 α1A, α1B >10,000 α1D ND No data α2A–α2C >10,000 β1, β2 >10,000 D1–D5 >10,000 H1 1,407 H2–H4 >10,000 M1, M3, M4 ND No data M2, M5 >10,000 TAAR1 >4,400 (Ki) (mouse)3,100 (Ki) (rat)ND No data (EC50 half-maximal effective concentration) (human) I1 ND No data σ1, σ2 ND No data SERT Serotonin transporter >10,000 (Ki)>100,000 (IC50 half-maximal inhibitory concentration)>100,000 (EC50 half-maximal inhibitory concentration) (rat) NET Norepinephrine transporter >10,000 (Ki)>100,000 (IC50 half-maximal inhibitory concentration)>100,000 (EC50 half-maximal inhibitory concentration) (rat) DAT Dopamine transporter >10,000 (Ki)>100,000 (IC50 half-maximal inhibitory concentration)>100,000 (EC50 half-maximal inhibitory concentration) (rat) MAO-A Monoamine oxidase A >100,000 (IC50 half-maximal inhibitory concentration) (rat) MAO-B Monoamine oxidase B >100,000 (IC50 half-maximal inhibitory concentration) (rat) Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: Kᵢ Database PDSP 15 March 2025 https://pdsp.unc.edu/kidb2/kidb/web/kis-results/index?KisResultsSearch%5Binput_receptors%5D=&KisResultsSearch%5Binput_sources%5D=&KisResultsSearch%5Binput_species%5D=&KisResultsSearch%5Binput_hot_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=12958&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=15598&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=12962&KisResultsSearch%5Binput_citations%5D=&KisResultsSearch%5BsearchType%5D=&KisResultsSearch%5Bki_val_from%5D=&KisResultsSearch%5Bki_val_to%5D=&KisResultsSearch%5Bcustom_ki_val%5D= 15 March 2025Liu 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 https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50005253 14 March 2025 Ray TS Psychedelics and the human receptorome PLOS ONE 5 2 e9019 February 2010 20126400 2814854 10.1371/journal.pone.0009019 free 2010PLoSO...5.9019R https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=1a083d0a618771af6662e2c6d978855fc09f4c4c Nelson DL, Lucaites VL, Wainscott DB, Glennon RA 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 January 1999 9933142 10.1007/pl00005315 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=598855ff348176de6e6aae050cf17401bab3faeb subscription Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD 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 April 2021 33860179 8033619 10.1021/acsptsci.0c00063 Halberstadt AL, Luethi D, Hoener MC, Trachsel D, Brandt SD, Liechti ME Use of the head-twitch response to investigate the structure-activity relationships of 4-thio-substituted 2,5-dimethoxyphenylalkylamines Psychopharmacology (Berl) 240 1 115–126 January 2023 36477925 9816194 10.1007/s00213-022-06279-2 https://core.ac.uk/download/pdf/543784099.pdf Nagai F, Nonaka R, Satoh Hisashi Kamimura K The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain Eur J Pharmacol 559 2–3 132–137 March 2007 17223101 10.1016/j.ejphar.2006.11.075 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=00665d67c36dcf1777989b70cc901c654420a0c7 subscription Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK Amphetamine Derivatives as Monoamine Oxidase Inhibitors Frontiers in Pharmacology 10 1590 2019 32038257 6989591 10.3389/fphar.2019.01590 free TMA-2's affinity (Ki) for the serotonin 5-HT2A receptor has been found to be 1,300nM. Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, Liechti ME Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines Front Pharmacol 10 1423 2019 31849671 6893898 10.3389/fphar.2019.01423 free Its EC50 half-maximal effective concentration at the receptor was 190nM and its Emax maximal efficacy was 84%. The drug was also active at the serotonin 5-HT2B receptor and, to a much lesser extent, at the serotonin 5-HT2C receptor. In an earlier study, its affinities (Ki) were 1,650nM at the serotonin 5-HT2 receptor and 46,400nM at the serotonin 5-HT1 receptor. Glennon RA Central serotonin receptors as targets for drug research J Med Chem 30 1 1–12 January 1987 3543362 10.1021/jm00384a001 Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites Shannon M, Battaglia G, Glennon RA, Titeler M 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 June 1984 6479216 10.1016/0014-2999(84)90333-9 TMA-2 is inactive at the monoamine transporters. It was inactive at the mouse trace amine-associated receptor 1 (TAAR1), whereas it bound to the rat TAAR1 with an affinity (Ki) of 3,100nM and was not assessed at the human TAAR1. Pharmacokinetics In terms of metabolism, TMA-2 is known to be at least partially O-demethylated in animals in vivo. Iversen LL, Iversen SD, Snyder SH Shulgin Alexander T. Stimulants Psychotomimetic Drugs: Structure-Activity Relationships Springer US Boston, MA 1978 978-1-4757-0512-6 10.1007/978-1-4757-0510-2_6 243–333 https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261 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). It might produce 2,4,5-trihydroxyamphetamine (THA) as a metabolite. The pharmacokinetics and metabolism of TMA-2 in humans are unknown. Chemistry Properties The chemical properties of TMA-2 have been described. Synthesis The chemical synthesis of TMA-2 has been described. Analogues and derivatives 2,5-Dimethoxy-4-ethoxyamphetamine#Derivatives TMA-2 (2,4,5-trimethoxyamphetamine) is very similar in chemical structure to the monoaminergic neurotoxin 6-hydroxydopamine (2,4,5-trihydroxyphenethylamine). A variety of derivatives of TMA-2 (MMM) have been developed and studied, such as MEM among others. Trachsel D Fluorine in psychedelic phenethylamines Drug Test Anal 4 7–8 577–590 2012 22374819 10.1002/dta.413 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=c7b41be36b1f580a264a752521d151e6e2d9409d subscription History TMA-2 was first described in the scientific literature by Viktor Bruckner in 1933. Iversen LL, Iversen SD, Snyder SH Shulgin Alexander T. Stimulants Psychotomimetic Drugs: Structure-Activity Relationships Springer US Boston, MA 1978 978-1-4757-0512-6 10.1007/978-1-4757-0510-2_6 243–333 https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261 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.Bruckner Viktor Über das Pseudonitrosit des Asarons Journal für Praktische Chemie 138 9–10 24 October 1933 0021-8383 10.1002/prac.19331380907 268–274 Subsequently, Alexander Shulgin discovered the hallucinogenic effects of TMA-2 in 1962 and published them in 1964. Shulgin AT Psychotomimetic amphetamines: methoxy 3,4-dialkoxyamphetamines Experientia 20 7 366–367 July 1964 5855670 10.1007/BF02147960 Shulgin AT The six trimethoxyphenylisopropylamines (trimethoxyamphetamines) J Med Chem 9 3 445–446 May 1966 5960939 10.1021/jm00321a058 The drug was later described in further detail by Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). Society and culture Legal status Canada TMA-2 is a controlled substance in Canada.Controlled Drugs and Substances Act Department of Justice Canada https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html 19 January 2026 United States TMA-2 is not an explicitly controlled substance in the United States.https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf Controlled Substances www.deadiversion.usdoj.gov However, it is a positional isomer of 3,4,5-trimethoxyamphetamine (TMA), and thus may be considered a Schedule I controlled substance in this country similarly to TMA.Drug Enforcement Administration Definition of “Positional Isomer” as It Pertains to the Control of Schedule I Controlled Substances Federal Register 3 December 2007 https://www.federalregister.gov/documents/2007/12/03/E7-23413/definition-of-positional-isomer-as-it-pertains-to-the-control-of-schedule-i-controlled-substances See also Trimethoxyamphetamine Substituted methoxyphenethylamine 2,4,5-Trimethoxyphenethylamine (2,4,5-TMPEA; 2C-O) 2,5-Dimethoxyamphetamine (2,5-DMA; DMA-4; DOH) 2,4-Dimethoxyamphetamine (2,4-DMA; DMA-3) References External links TMA-2 - Isomer Design TMA-2 - PsychonautWiki TMA-2 - Erowid TMA-2 - PiHKAL - Erowid TMA-2 - PiHKAL - Isomer Design TMA-2: An Amphetamine Compound With Unique Sedative Properties - Tripsitter Category:5-HT2A agonists Category:5-HT2B agonists Category:Alexander Shulgin Category:DOx (psychedelics) Category:Methoxyphenethylamines Category:PiHKAL Category:Psychedelic phenethylamines Category:Serotonin receptor agonists Category:TAAR1 modulators Category:Trimethoxyphenyl compounds