2,4,5-Trimethoxyphenethylamine

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. 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.

According to Shulgin, the present-day consensus is that 2C-O by itself is inactive. 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.

The apparent inactivity of 2C-O (2,4,5-trimethoxyphenethylamine) in humans has been described as enigmatic for several reasons. 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.

Interactions

Pharmacology

2C-O has been found to act as full agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. 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 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 ( = 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. 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. 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. 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.

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.

References

References

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2. (1931). "β-2: 4: 5-Trimethoxyphenylethylamine, an isomer of mescaline". Recueil des Travaux Chimiques des Pays-Bas.
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7. (1971). "Alteration of behavioural changes induced by 3,4,5-trimethoxyphenylethylamine (mescaline) by pretreatment with 2,4,5-trimethoxyphenylethylamine. A self-experiment". Psychopharmacologia.
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9. (December 2023). "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nat Commun.
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11. (2019). "Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines". Front Pharmacol.
12. Shulgin, Alexander T.. (1978). "Stimulants". Springer US.
13. Government of Canada, Public Works and Government Services Canada. (May 4, 2016). "Canada Gazette – Regulations Amending the Food and Drug Regulations (Part J — 2C-phenethylamines)".
14. (January 2026). "Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026)". U.S. [[Department of Justice]]: [[Drug Enforcement Administration]] (DEA): Diversion Control Division.