2,4,5-Trimethoxyphenethylamine

2C-O at a dose of under 300 mg by injection was reported to produce similar psychedelic effects as mescaline by Max Jansen in 1931, albeit with more nausea and no euphoria.^[1][2] Conversely, in a subsequent report described by Alexander Shulgin, it was said to be indistinguishable from placebo at a dose of up to 300 mg orally.^{[1][3][7][6][9]} The drug was also combined with the monoamine oxidase inhibitor (MAOI) harmaline, which acts as a reversible inhibitor of monoamine oxidase A (RIMA).^[10] Even with a dose of 150 mg harmaline and 200 mg 2C-O orally however, there were no additional hallucinogenic effects that could not be explained by harmaline alone.^[10]

According to Shulgin, the present-day consensus is that 2C-O by itself is inactive.^[1][7][6][8] In PiHKAL (Phenethylamines I Have Known and Loved), its dose is listed as greater than 300 mg orally and its duration as unknown.^[1] Although 2C-O does not seem to produce effects by itself, the drug at a dose of 200 mg orally was reported to strongly potentiate the action of 100 mg mescaline when employed as pretreatment 45 minutes 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 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.^[5][1]

2C-O has been found to act as full agonist of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors.^[4] However, it showed more than two orders of magnitude lower potency in activating the serotonin 5-HT_2A receptor than 2C-B and 2C-I.^[4] On the other hand, 2C-O was similar in potency to mescaline as a serotonin 5-HT_2A receptor agonist, with EC₅₀Tooltip half-maximal effective concentration values of 195 nM and 646 nM in terms of G_q signaling, respectively.^[4] The drug also showed higher efficacy than mescaline as a serotonin 5-HT_2A receptor agonist (E_maxTooltip 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 strong metabolism or low affinity and/or efficacy at the serotonin 5-HT_2A receptor.^[7][6] 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 hour whereas mescaline was deaminated 60% alone and 0% with semicarbazide after 1 hour.^[11] These findings suggest that 2C-O may be less susceptible to metabolism by monoamine oxidase (MAO) than mescaline.^[11] Moreover, it is now known that 2C-O shows far lower potency as a serotonin 5-HT_2A receptor agonist than other 2C drugs.^[4]

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-HT_2A receptor agonism in vitro, and the amphetamine (α-methyl) analogue TMA-2, as well as derivatives like MEM, are potent psychedelics.^[6][1][8]

2C-O, also known as 2,4,5-trimethoxyphenethylamine (2,4,5-TMPEA), is a substituted phenethylamine and 2C derivative.^[1]

2C-O was first described by Max Jansen in 1931 and was reported by him to produce psychedelic effects similar to those of mescaline.^[12][2] 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.^{[12][1][3][9]}

• Trimethoxyphenethylamine
• 2C (psychedelics)
• Substituted methoxyphenethylamine
• 2,4,5-Trimethoxyamphetamine (2,4,5-TMA; TMA-2)