2,4,5-Trimethoxyphenethylamine

412502874 2C-O 2C-O.svg skin-invert-image 225px 2C-O ball-and-stick structure.png bg-transparent 200px Oral, injection Serotonin receptor agonist; Serotonin 5-HT2 receptor agonist None Schedule III Class A Schedule I (isomer of mescaline) Unknown correct CAS 15394-83-9 151954 correct chemspider 133931 correct FDA S27QYQ708U correct EBI 354924 2,4,5-TMPEA; TMPEA-2; TMPEA; 4-Methoxy-2,5-dimethoxyphenethylamine; 2,5-Dimethoxy-4-methoxyphenethylamine; 2C-O; 2C-OMe; 2C-MeO; 2C-TMA-2; 25O 2-(2,4,5-trimethoxyphenyl)ethan-1-amine 11 17 1 3 O(c1cc(c(OC)cc1OC)CCN)C correct chemspider 1S/C11H17NO3/c1-13-9-7-11(15-3)10(14-2)6-8(9)4-5-12/h6-7H,4-5,12H2,1-3H3 correct chemspider GKATTZLSNLYADI-UHFFFAOYSA-N 187 188 2C-O, also known as 2,4,5-trimethoxyphenethylamine (2,4,5-TMPEA) or TMPEA-2, is a serotonin receptor modulator of the phenethylamine and 2C families. Shulgin A, Manning T, Daley PF #124. TMPEA-2 307–309 https://archive.org/details/shulgin-index-vol-1/page/307/mode/1up The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds Transform Press Berkeley, CA 1 2011 978-0-9630096-3-0 709667010 Jansen, MPJM 1931 β-2: 4: 5-Trimethoxyphenylethylamine, an isomer of mescaline https://onlinelibrary.wiley.com/doi/10.1002/recl.19310500403 Recueil des Travaux Chimiques des Pays-Bas 50 4 291–312 10.1002/recl.19310500403 22 November 2022 subscription It is a positional isomer of the natural entheogen mescaline (3,4,5-trimethoxyphenethylamine) and is the α-desmethyl analogue of 2,4,5-trimethoxyamphetamine (TMA-2). The drug is the parent compound of the 2C-O series of drugs. 2C-O appears to be inactive in terms of psychoactive effects in humans, at least at doses that have been assessed. In any case, it is a low-potency full agonist of the serotonin 5-HT2 receptors in vitro, including of the serotonin 5-HT2A receptor. 2C-O was first described by Max Jansen in 1931 and was further described by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). Use and effects 2C-O at a dose of under 300mg by injection was reported to produce similar psychedelic effects as mescaline by Max Jansen in 1931, albeit with more nausea and no euphoria. Conversely, in a subsequent report described by Alexander Shulgin, it was said to be indistinguishable from placebo at a dose of up to 300mg orally. Trachsel D Fluorine in psychedelic phenethylamines Drug Test Anal 4 7–8 577–590 2012 22374819 10.1002/dta.413 Within the group of the 2,4,5-trisubstituted phenethylamines, a few 4-alkoxy analogs have been described before (Figure 3, B).[3] Both 2C-O (43; >300 mg) and 2C-O-4 (44; >60 mg) proved to be inactive in humans, at least at the levels tested.[3] Whether they underlie a strong metabolism[70] or show low affinities towards the serotonin 5-HT2A receptor[36] remains to be established. In humans, the α-methylated 3C analogs TMA-2 (45; 20–40 mg, 8–12 h) and MEM (46; 20– 50 mg, 10–14 h) are fairly active compounds,[3] probably resulting from increased metabolic resistance, higher lipophilicity and pronounced receptor activation. [...] Similar to 2C-O (43: >300 mg[3]), Ψ-2C-O (2,4,6-TMPEA, 61: >300 mg) did not show any human activity (P. Rausch, personal communication in 2009) and interestingly, the 3,4,5-trimethoxy isomer mescaline (22: 180–360 mg) does.[3] The drug was also combined with the monoamine oxidase inhibitor (MAOI) harmaline, which acts as a reversible inhibitor of monoamine oxidase A (RIMA). Even with a dose of 150mg harmaline and 200mg 2C-O orally however, there were no additional hallucinogenic effects that could not be explained by harmaline alone.Erowid Online Books : "TIHKAL" - #13 HARMALINE www.erowid.org http://www.erowid.org/library/books_online/tihkal/tihkal13.shtml 11 April 2025 According to Shulgin, the present-day consensus is that 2C-O by itself is inactive. Nichols DE, Glennon RA 1984 Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens Jacobs BL Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives 95–142 Raven Press New York 978-0-89004-990-7 10324237 https://books.google.com/books?id=EdpsAAAAMAAJ&pg=PA95 https://bitnest.netfirms.com/external/Books/HallucinogensNBCP95 The simplest modification is to remove the α-methyl group completely, since mescaline lacks an α-methyl group and is active. On the other hand, 2,4,5-trimethoxyphenethylamine is completely inactive whereas its α-methylated analog 2,4,5 trimethoxyamphetamine (TMA-2; Table I) is quite potent (Shulgin, 1978). Many of the non-α-methylated analogs of hallucinogenic amphetamines retain potency within about one order of magnitude of their amphetamine congeners (e.g., Shulgin and Caner, 1975). Although a decrease of this magnitude may seem dramatic from the perspective of structure-activity relationships, these compounds still remain active in humans with relatively small acute oral dosages. For example, 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 2,5-dimethoxy-4-iodophenethylamine (2C-I) possess only about one-tenth the potency of their amphetamine counterparts DOB and DOI, respectively. DOI are two of the most potent hallucinogenic amphetamines known. Therefore, oral human dosages of 2C-B and 2C-I are in the 5-20 mg range. In PiHKAL (Phenethylamines I Have Known and Loved), its dose is listed as greater than 300mg orally and its duration as unknown. Although 2C-O does not seem to produce effects by itself, the drug at a dose of 200mg orally was reported to strongly potentiate the action of 100mg mescaline when employed as pretreatment 45minutes prior to the administration of mescaline. https://erowid.org/library/books_online/pihkal/pihkal168.shtml Dittrich A Alteration of behavioural changes induced by 3,4,5-trimethoxyphenylethylamine (mescaline) by pretreatment with 2,4,5-trimethoxyphenylethylamine. A self-experiment Psychopharmacologia 21 3 229–237 1971 5095413 10.1007/BF00403861 In this self-experiment, conducted under double-blind conditions using several psychological tests to assess drug effects, it was found that the pretreatment with 2,4,5-trimethoxyphenylethylamine potentiates the effects of mescaline (3,4,5-trimethoxyphenylethylamine). 2,4,5-trimethoxyphenylethylamine alone proved to have no psychotomimetic properties. [...] The subject reported no changes indicating a psychotomimetic property of 2,4,5-MPEA. He guessed that he had had placebo when actually 300 mg of 2,4,5-MPEA had been administered. Correspondingly no behavioural changes were observed. [...] In this self-experiment, which was carried out under doubleblind conditions, 2,4,5-trimethoxyphenylethylamine in dosages up to 300 mg induced no changes described after the ingestion of psychotomimetic drugs. [...] the pretreatment with 2,4,5-trimethoxyphenylethylamine potentiated the effects of mescaline. [...] In one of several psychological tests used in this study, it was found (p < 0.01), that 2,4,5-trimethoxyphenylethylamine might have psychostimulant properties. If this could be confirmed, it would explain the potentiating effect of 2,4,5-trimethoxyphenylethylamine on the behavioural level, as psychostimulants are known to intensify the mescaline response (e.g. Balestrieri, 1961). The apparent inactivity of 2C-O (2,4,5-trimethoxyphenethylamine) in humans has been described as enigmatic because 2C-O's amphetamine (α-methyl) counterpart 2,4,5-trimethoxyamphetamine (TMA-2) is active, and because the drug's positional isomer mescaline (3,4,5-trimethoxyphenethylamine) is also active. Shulgin AT Basic Pharmacology and Effects 67–137 Laing RR Hallucinogens: A Forensic Drug Handbook Elsevier Science Forensic Drug Handbook Series 2003 978-0-12-433951-4 https://books.google.com/books?id=l1DrqgobbcwC https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6 1 February 2025 An exceptionally rich family of compounds has come from the substitution of groups at the 4-position of 2C-D which are not simple alkyl homologues. [...] An enigma is 2,4,5-trimethoxyphenethylamine, a positional isomer of mescaline (the 3,4,5-counterpart). It is devoid of activity even at doses that with mescaline would be fully effective. (See Table 3.8.) And yet, the addition of an alpha-methyl group to mescaline (a move that presumably protects it from oxidative deamination) only doubles the potency, whereas the same protective modification of this "inactive" isomer (to give the compound TMA-2), there is an increase of more than an order of magnitude. Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Pharmacology 2C-O has been found to act as full agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential Nat Commun 14 1 8221 December 2023 38102107 10724237 10.1038/s41467-023-44016-1 free 2023NatCo..14.8221W However, it showed more than two orders of magnitude lower potency in activating the serotonin 5-HT2A receptor than 2C-B and 2C-I. On the other hand, 2C-O was similar in potency to mescaline as a serotonin 5-HT2A receptor agonist, with EC50 half-maximal effective concentration values of 195nM and 646nM in terms of Gq signaling, respectively. The drug also showed higher efficacy than mescaline as a serotonin 5-HT2A receptor agonist (Emax maximal efficacy = 96–100% vs. 33–74%, respectively). It has been said in the past that it is unclear whether the apparent inactivity of 2C-O is due to strong metabolism or low affinity and/or efficacy at the serotonin 5-HT2A receptor. However, an in-vitro study using rabbit liver tissue found that 2C-O was deaminated 25% alone and 25% with the monoamine oxidase inhibitor (MAOI) semicarbazide after 1hour whereas mescaline was deaminated 60% alone and 0% with semicarbazide after 1hour. Clark LC, Benington F, Morin RD The Effects of Ring-Methoxyl Groups on Biological Deamination of Phenethylamines J Med Chem 8 3 353–355 May 1965 14323146 10.1021/jm00327a016 These findings suggest that 2C-O may be less susceptible to metabolism by monoamine oxidase (MAO) than mescaline. Moreover, it is now known that 2C-O shows far lower potency as a serotonin 5-HT2A receptor agonist than other 2C drugs. Although 2C-O and certain derivatives such as 2C-O-4 appear to be inactive or of low potency in humans, 2C-O derivatives show potent serotonin 5-HT2A receptor agonism in vitro, and the amphetamine (α-methyl) analogue TMA-2, as well as derivatives like MEM, are potent psychedelics. Chemistry 2C-O, also known as 2,4,5-trimethoxyphenethylamine (2,4,5-TMPEA), is a substituted phenethylamine and 2C derivative. Synthesis The chemical synthesis of 2C-O has been described. Analogues Notable positional isomers of 2C-O (2,4,5-TMPEA) include mescaline (3,4,5-TMPEA) and Ψ-2C-O (2,4,6-TMPEA). Derivatives A variety of derivatives of 2C-O, named 2C-O-2 (4-ethoxy-2,5-dimethoxyphenethylamine) through 2C-O-27, have been developed and studied. 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 Although the 2C-O derivatives initially examined by Shulgin were shown to be fairly inactive in humans (2C-O-1; 21 and 2C-O-4; 22, Figure 3 ) some derivatives such as 19 [(TMA-2)] and 2,5-dimethoxy-4-ethoxyamphetamie (MEM) (24) displayed psychedelic activity ( Figure 3 ) (Shulgin and Shulgin, 1991). However, upon further increasing chain length to a 4-propyloxy (MPM; 26) or 4-butyloxy (MBM; structure not shown) substituent, again no psychoactive effects could be observed on comparable doses as used for 19 and 24. The rather mixed results of low human potency and inactivity was one of the reasons Shulgin did not further evaluate the structure-activity relationship (SAR) of the 2C-O and 3C-O derivatives. Up-to-date, it remains unclear whether the early observations are due to pharmacokinetic properties such as a difference in metabolism or pharmacodynamic properties like differences in 5-HT receptor target interaction potency. [...] Compounds 2C-O-1 (21) and 2C-O-4 (22), two members of the 2C-O family, were not psychoactive in humans, at least at the doses tested so far (Shulgin and Shulgin, 1991). It has been suggested that this may be due to a rapid metabolism or low binding affinity to the 5-HT2A receptor (Clark et al., 1965; Nelson et al., 1999; Trachsel, 2012). The 5-HT2A activation mediates psychedelic effects (Glennon et al., 1992; Chambers et al., 2002; Kraehenmann et al., 2017) and receptor binding affinity has been shown to be a good predictor of the dose needed (clinical potency) to induce a psychedelic effect (Luethi and Liechti, 2018). A couple of notable derivatives are 2C-O-4 (4-isopropoxy-2,5-dimethoxyphenethylamine) and 2C-O-22 (4-ethoxy-2,5-dimethoxyphenethylamine). 25O-NBOMe is the N-(2-methoxybenzyl)- (NBOMe) derivative of 2C-O. It is far more potent as a serotonin 5-HT2 receptor agonist than 2C-O. The tetramethoxyphenethylamines TeMPEA-1 (2,3,4,5-TeMPEA) and TeMPEA-3 (2,3,5,6-TeMPEA) as well as pentamethoxyphenethylamine (PeMPEA) are derivatives of 2C-O. History 2C-O was first described by Max Jansen in 1931 and was reported by him to produce psychedelic effects similar to those of mescaline. 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 However, subsequent tests in the 1960s and 1970s, for instance by A. Dittrich and Alexander Shulgin, suggested that 2C-O is actually inactive as a psychedelic in animals and humans. Society and culture Legal status Canada As of October 31, 2016, 2C-O is a controlled substance (Schedule III) in Canada.http://gazette.gc.ca/rp-pr/p2/2016/2016-05-04/html/sor-dors72-eng.html Canada Gazette – Regulations Amending the Food and Drug Regulations (Part J — 2C-phenethylamines) Public Works and Government Services Canada Government of Canada May 4, 2016 gazette.gc.ca United Kingdom 2C-O and all other compounds featured in PiHKAL are Class A drugs in the United Kingdom. United States 2C-O is a Schedule I substance, as a positional isomer of mescaline. Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026) January 2026 U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division United States https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf See also Trimethoxyphenethylamine 2C (psychedelics) Substituted methoxyphenethylamine 2,4,5-Trimethoxyamphetamine (2,4,5-TMA; TMA-2) References External links TMPEA (2C-O) - Isomer Design TMPEA - PiHKAL - Erowid TMPEA - PiHKAL - Isomer Design Category:5-HT2A agonists Category:5-HT2B agonists Category:5-HT2C agonists Category:2C (psychedelics) Category:Trimethoxyphenyl compounds Category:PiHKAL Category:Psychedelic phenethylamines