According to Shulgin, the present-day consensus is that 2C-O by itself is inactive.[1][7][6][8] InPiHKAL (Phenethylamines I Have Known and Loved), its dose is listed as greater than 300mg orally and itsduration as unknown.[1] 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.[1][9]
The apparent inactivity of 2C-O (2,4,5-trimethoxyphenethylamine) in humans has been described as enigmatic for several reasons.[5] This is because other2C drugs are active, because 2C-O'samphetamine (α-methyl) counterpart2,4,5-trimethoxyamphetamine (TMA-2) is active, and because the drug'spositional isomermescaline (3,4,5-trimethoxyphenethylamine) is active.[5][1]
2C-O has been found to act asfull agonist of theserotonin5-HT2A,5-HT2B, and5-HT2C receptors.[4] However, it showed more than two orders of magnitude lowerpotency in activating the serotonin 5-HT2A receptor than2C-B and2C-I.[4] On the other hand, 2C-O was similar in potency to mescaline as a serotonin 5-HT2A receptor agonist, withEC50Tooltip half-maximal effective concentration values of 195nM and 646nM in terms ofGqsignaling, respectively.[4] The drug also showed higherefficacy than mescaline as a serotonin 5-HT2A receptor agonist (EmaxTooltip maximal efficacy = 96–100% vs. 33–74%, respectively).[4]
It has been said in the past that it is unclear whether the apparent inactivity of 2C-O is due to strongmetabolism or lowaffinity and/orefficacy at the serotonin 5-HT2A receptor.[7][6] However, anin-vitro study usingrabbitlivertissue found that 2C-O wasdeaminated 25% alone and 25% with themonoamine oxidase inhibitor (MAOI)semicarbazide after 1hour whereasmescaline was deaminated 60% alone and 0% with semicarbazide after 1hour.[11] These findings suggest that 2C-O may be less susceptible to metabolism bymonoamine oxidase (MAO) than mescaline.[11] Moreover, it is now known that 2C-O shows far lower potency as a serotonin 5-HT2A receptor agonist than other2C drugs.[4]
Although 2C-O and certainderivatives such as2C-O-4 appear to be inactive or of low potency in humans, 2C-O derivatives show potent serotonin 5-HT2A receptoragonismin vitro, and theamphetamine (α-methyl)analogueTMA-2, as well as derivatives likeMEM, are potent psychedelics.[6][1][8]
A variety ofderivatives of 2C-O, named2C-O-2 (4-ethoxy-2,5-dimethoxyphenethylamine) through2C-O-27, have been developed and studied.[6] One notable derivative is2C-O-4 (4-isopropoxy-2,5-dimethoxyphenethylamine).[6]
2C-O was first described by Max Jansen in 1931 and was reported by him to produce psychedelic effects similar to those ofmescaline.[12][2] However, subsequent tests in the 1960s and 1970s, for instance by A. Dittrich andAlexander Shulgin, suggested that 2C-O is actually inactive as a psychedelic in animals and humans.[12][1][3][9]
^abcdShulgin AT (2003)."Basic Pharmacology and Effects". In Laing RR (ed.).Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137.ISBN978-0-12-433951-4. Retrieved1 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.
^abcdefghKolaczynska 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.PMC6893898.PMID31849671.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).
^abcdTrachsel D (2012). "Fluorine in psychedelic phenethylamines".Drug Test Anal.4 (7–8):577–590.doi:10.1002/dta.413.PMID22374819.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]
^abcNichols DE, Glennon RA (1984)."Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". In Jacobs BL (ed.).Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. pp. 95–142.ISBN978-0-89004-990-7.OCLC10324237.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.
^abcDittrich A (1971). "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.doi:10.1007/BF00403861.PMID5095413.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).
^abClark LC, Benington F, Morin RD (May 1965). "The Effects of Ring-Methoxyl Groups on Biological Deamination of Phenethylamines".J Med Chem.8 (3):353–355.doi:10.1021/jm00327a016.PMID14323146.
