2,4,5-Trimethoxyphenethylamine

{{Infobox drug | verifiedrevid = 412502874 | drug_name = 2C-O | image = 2C-O.svg | image_class = skin-invert-image | width = 225px | image2 = 2C-O ball-and-stick structure.png | image_class2 = bg-transparent | width2 = 200px

| legal_CA = Schedule III | legal_UK = Class A | legal_US = Schedule I (isomer of mescaline) | legal_status =

| CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 15394-83-9 | CAS_supplemental = | PubChem = 151954 | PubChemSubstance = | IUPHAR_ligand = | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 133931 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = S27QYQ708U | KEGG = | ChEBI = | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 354924 | NIAID_ChemDB = | PDB_ligand = | synonyms = 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

| IUPAC_name = 2-(2,4,5-trimethoxyphenyl)ethan-1-amine | C=11 | H=17 | N=1 | O=3 | SMILES = O(c1cc(c(OC)cc1OC)CCN)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = GKATTZLSNLYADI-UHFFFAOYSA-N

| melting_point = 187 | melting_high = 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 related to the psychedelic drug mescaline.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011">{{cite book | vauthors = Shulgin A, Manning T, Daley PF | chapter = #124. TMPEA-2 | pages = 307–309 | chapter-url = https://archive.org/details/shulgin-index-vol-1/page/307/mode/1up | title = The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher = Transform Press | location = Berkeley, CA | volume = 1 | year = 2011 | isbn = 978-0-9630096-3-0 | oclc = 709667010 }}</ref><ref name="Jansen1931">{{cite journal |vauthors=Jansen, MPJM |date=1931 |title=β-2: 4: 5-Trimethoxyphenylethylamine, an isomer of mescaline |url=https://onlinelibrary.wiley.com/doi/10.1002/recl.19310500403 |journal=Recueil des Travaux Chimiques des Pays-Bas |volume=50 |issue=4 |pages=291–312 |doi=10.1002/recl.19310500403 |access-date=22 November 2022|url-access=subscription }}</ref><ref name="WallachCaoCalkins2023" /> It is a positional isomer of mescaline (3,4,5-trimethoxyphenethylamine)<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /><ref name="Shulgin2003" /> and is the α-desmethyl analogue of 2,4,5-trimethoxyamphetamine (TMA-2).<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /><ref name="Shulgin2003" /> The drug is the parent compound of the 2C-O series of drugs.<ref name="KolaczynskaLuethiTrachsel2019" /> 2C-O appears to be inactive in terms of psychoactive effects in humans, at least at doses that have been assessed.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /><ref name="Trachsel2012" /><ref name="KolaczynskaLuethiTrachsel2019" /><ref name="NicholsGlennon1984" /> 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.<ref name="WallachCaoCalkins2023" /> 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'').<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /><ref name="Jansen1931" />

==Use and effects== 2C-O at a dose of under 300{{nbsp}}mg by injection was reported to produce similar psychedelic effects as mescaline by Max Jansen in 1931, albeit with more nausea and no euphoria.<ref name="PiHKAL" /><ref name="Jansen1931" /> Conversely, in a subsequent report described by Alexander Shulgin, it was said to be indistinguishable from placebo at a dose of up to 300{{nbsp}}mg orally.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /><ref name="Trachsel2012">{{cite journal | vauthors = Trachsel D | title = Fluorine in psychedelic phenethylamines | journal = Drug Test Anal | volume = 4 | issue = 7–8 | pages = 577–590 | date = 2012 | pmid = 22374819 | doi = 10.1002/dta.413 | url = | quote = 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]}}</ref><ref name="KolaczynskaLuethiTrachsel2019" /><ref name="Dittrich1971" /> The drug was also combined with the monoamine oxidase inhibitor (MAOI) harmaline, which acts as a reversible inhibitor of monoamine oxidase A (RIMA).<ref name="TiHKAL-Harmaline" /> Even with a dose of 150{{nbsp}}mg harmaline and 200{{nbsp}}mg 2C-O orally however, there were no additional hallucinogenic effects that could not be explained by harmaline alone.<ref name="TiHKAL-Harmaline">{{cite web | title=Erowid Online Books : "TIHKAL" - #13 HARMALINE | website=www.erowid.org | url=http://www.erowid.org/library/books_online/tihkal/tihkal13.shtml | access-date=11 April 2025}}</ref>

According to Shulgin, the present-day consensus is that 2C-O by itself is inactive.<ref name="PiHKAL" /><ref name="Trachsel2012" /><ref name="KolaczynskaLuethiTrachsel2019" /><ref name="NicholsGlennon1984">{{cite book | vauthors = Nichols DE, Glennon RA | date = 1984 | chapter = Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens | veditors = Jacobs BL | title = Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives | pages = 95–142 | publisher = Raven Press | location = New York | isbn = 978-0-89004-990-7 | oclc = 10324237 | url = https://books.google.com/books?id=EdpsAAAAMAAJ&pg=PA95 | chapter-url = https://bitnest.netfirms.com/external/Books/HallucinogensNBCP95 | quote = 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.}}</ref> In ''PiHKAL'' (''Phenethylamines I Have Known and Loved''), its dose is listed as greater than 300{{nbsp}}mg orally and its duration as unknown.<ref name="PiHKAL" /> Although 2C-O does not seem to produce effects by itself, the drug at a dose of 200{{nbsp}}mg orally was reported to strongly potentiate the action of 100{{nbsp}}mg mescaline when employed as pretreatment 45{{nbsp}}minutes prior to the administration of mescaline.<ref name="PiHKAL">{{CitePiHKAL}} https://erowid.org/library/books_online/pihkal/pihkal168.shtml</ref><ref name="Dittrich1971">{{cite journal | vauthors = Dittrich A | title = Alteration of behavioural changes induced by 3,4,5-trimethoxyphenylethylamine (mescaline) by pretreatment with 2,4,5-trimethoxyphenylethylamine. A self-experiment | journal = Psychopharmacologia | volume = 21 | issue = 3 | pages = 229–237 | date = 1971 | pmid = 5095413 | doi = 10.1007/BF00403861 | url = | quote = 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).}}</ref>

The apparent inactivity of 2C-O (2,4,5-trimethoxyphenethylamine) in humans has been described as enigmatic for several reasons.<ref name="Shulgin2003" /> This is because other 2C drugs are active, 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 active.<ref name="Shulgin2003">{{cite book | vauthors = Shulgin AT | chapter=Basic Pharmacology and Effects | pages=67–137 | veditors = Laing RR | title=Hallucinogens: A Forensic Drug Handbook | publisher=Elsevier Science | series=Forensic Drug Handbook Series | year=2003 | isbn=978-0-12-433951-4 | url=https://books.google.com/books?id=l1DrqgobbcwC | chapter-url=https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6 | access-date=1 February 2025 | quote = 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.}}</ref><ref name="PiHKAL" />

==Interactions== {{See also|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.<ref name="WallachCaoCalkins2023">{{cite journal | vauthors = 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 | title = Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential | journal = Nat Commun | volume = 14 | issue = 1 | article-number = 8221 | date = December 2023 | pmid = 38102107 | pmc = 10724237 | doi = 10.1038/s41467-023-44016-1 | bibcode = 2023NatCo..14.8221W }}</ref> However, it showed more than two orders of magnitude lower potency in activating the serotonin 5-HT2A receptor than 2C-B and 2C-I.<ref name="WallachCaoCalkins2023" /> On the other hand, 2C-O was similar in potency to mescaline as a serotonin 5-HT2A receptor agonist, with {{Abbrlink|EC50|half-maximal effective concentration}} values of 195{{nbsp}}nM and 646{{nbsp}}nM in terms of Gq signaling, respectively.<ref name="WallachCaoCalkins2023" /> The drug also showed higher efficacy than mescaline as a serotonin 5-HT2A receptor agonist ({{Abbrlink|Emax|maximal efficacy}} = 96–100% vs. 33–74%, respectively).<ref name="WallachCaoCalkins2023" />

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.<ref name="Trachsel2012" /><ref name="KolaczynskaLuethiTrachsel2019" /> 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 1{{nbsp}}hour whereas mescaline was deaminated 60% alone and 0% with semicarbazide after 1{{nbsp}}hour.<ref name="ClarkBeningtonMorin1965">{{cite journal | vauthors = Clark LC, Benington F, Morin RD | title = The Effects of Ring-Methoxyl Groups on Biological Deamination of Phenethylamines | journal = J Med Chem | volume = 8 | issue = 3| pages = 353–355 | date = May 1965 | pmid = 14323146 | doi = 10.1021/jm00327a016 | url = }}</ref> These findings suggest that 2C-O may be less susceptible to metabolism by monoamine oxidase (MAO) than mescaline.<ref name="ClarkBeningtonMorin1965" /> Moreover, it is now known that 2C-O shows far lower potency as a serotonin 5-HT2A receptor agonist than other 2C drugs.<ref name="WallachCaoCalkins2023" />

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.<ref name="KolaczynskaLuethiTrachsel2019" /><ref name="PiHKAL" /><ref name="NicholsGlennon1984" />

==Chemistry== 2C-O, also known as 2,4,5-trimethoxyphenethylamine (2,4,5-TMPEA), is a substituted phenethylamine and 2C derivative.<ref name="PiHKAL" />

===Synthesis=== The chemical synthesis of 2C-O has been described.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" />

===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).<ref name="PiHKAL" />

===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.<ref name="KolaczynskaLuethiTrachsel2019">{{cite journal | vauthors = Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, Liechti ME | title = Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines | journal = Front Pharmacol | volume = 10 | issue = | article-number = 1423 | date = 2019 | pmid = 31849671 | pmc = 6893898 | doi = 10.3389/fphar.2019.01423 | doi-access = free | url = | quote = 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).}}</ref> A couple of notable derivatives are 2C-O-4 (4-isopropoxy-2,5-dimethoxyphenethylamine) and 2C-O-22 (4-ethoxy-2,5-dimethoxyphenethylamine).<ref name="KolaczynskaLuethiTrachsel2019" />

25O-NBOMe is the ''N''-(2-methoxybenzyl)- (NBOMe) derivative of 2C-O.<ref name="WallachCaoCalkins2023" /> It is far more potent as a serotonin 5-HT2 receptor agonist than 2C-O.<ref name="WallachCaoCalkins2023" />

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.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" />

==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.<ref name="Shulgin1978">{{cite book | veditors = Iversen LL, Iversen SD, Snyder SH | last=Shulgin | first=Alexander T. | title=Stimulants | chapter=Psychotomimetic Drugs: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_6 | pages=243–333 | chapter-url=https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 | url=https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261 }}</ref><ref name="Jansen1931" /> 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.<ref name="Shulgin1978" /><ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /><ref name="Dittrich1971" />

==Society and culture== ===Legal status=== ====Canada==== As of October 31, 2016, 2C-O is a controlled substance (Schedule III) in Canada.<ref>{{Cite web|url=http://gazette.gc.ca/rp-pr/p2/2016/2016-05-04/html/sor-dors72-eng.html|title=Canada Gazette – Regulations Amending the Food and Drug Regulations (Part J — 2C-phenethylamines)|first=Public Works and Government Services Canada|last=Government of Canada|date=May 4, 2016|website=gazette.gc.ca}}</ref>

====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.<ref name="OrangeBook2026">{{citation | title = Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026) | date = January 2026 | publisher = U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division | location = United States | url = https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf}}</ref>

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/168 TMPEA (2C-O) - Isomer Design] * [http://www.erowid.org/library/books_online/pihkal/pihkal168.shtml TMPEA - PiHKAL - Erowid] * [http://pihkal.info/read.php?domain=pk&id=168 TMPEA - PiHKAL - Isomer Design]

Category:5-HT2A agonists Category:5-HT2B agonists Category:5-HT2C agonists Category:2C (psychedelics) Category:Methoxyphenethylamines Category:PiHKAL Category:Psychedelic phenethylamines