1-Methylpsilocin

1-Methylpsilocin (developmental code name CMY or CMY-16), also known as 1-methyl-4-hydroxy-N,N-dimethyltryptamine (1-Me-4-HO-DMT), is a serotonin receptor agonist and putative psychedelic drug of the tryptamine and 4-hydroxytryptamine families related to psilocin. It is the 1-methyl derivative of psilocin. The drug shows much greater selectivity as a serotonin 5-HT_2C receptor agonist than psilocin, but still robustly induces psychedelic-like effects in animals, albeit with lower potency.

Use and effects

According to Alexander Shulgin in his book TiHKAL (Tryptamines I Have Known and Loved), 1-methylpsilocin is known to have been assessed in clinical studies by Sandoz (code name CMY or CMY-16) but its activity has not been reported. As such, its properties and effects in humans are unknown.

Interactions

Pharmacology

Pharmacodynamics

The affinities (K_i) of 1-methylpsilocin for serotonin receptors have been reported to be 900nM for the serotonin 5-HT_2A receptor, 38nM for the serotonin 5-HT_2B receptor, and 7.0nM for the serotonin 5-HT_2C receptor (unedited/INI isoform). Its activational potencies and efficacies ( ()) were 633nM (31%) at the serotonin 5-HT_2A receptor, inverse agonism at the serotonin 5-HT_2B receptor (values not given), and 12nM (45%) at the serotonin 5-HT_2C receptor. As a result, it was concluded that 1-methylpsilocin is a selective serotonin 5-HT_2C receptor agonist.

In subsequent research however, 1-methylpsilocin has been reported to have activational potencies and efficacies in terms of G_q dissociation BRET assays of 86nM (73%) at the serotonin 5-HT_2A receptor, 32nM (40%) at the serotonin 5-HT_2B receptor, and 9.5nM at the serotonin 5-HT_2C receptor (92%). It was about 10-fold less potent than psilocin at the serotonin 5-HT_2A receptor and 30-fold less potent at the 5-HT_2B receptor but had similar potency at the serotonin 5-HT_2C receptor. Besides at the serotonin 5-HT₂ receptors, 1-methylpsilocin has shown affinity for the serotonin 5-HT_1A receptor (K_i = 358nM), albeit approximately 7-fold lower than that of psilocin.

Despite showing much greater potency at the serotonin 5-HT_2C receptor than at the 5-HT_2A receptor, 1-methylpsilocin produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. This effect was absent in serotonin 5-HT_2A receptor knockout mice. The median effective dose (ED₅₀) of 1-methylpsilocin for induction of the head-twitch response was about 2.3-fold lower than that of psilocin (0.3mg/kg and 0.7mg/kg, respectively), and hence 1-methylpsilocin was somewhat less potent than psilocin. The two drugs showed similar maximal responses in terms of head twitch counts. Due to its induction of the head-twitch response, it is very likely that 1-methylpsilocin would produce hallucinogenic effects in humans, but may have reduced potency in comparison.

The fact that 1-methylpsilocin is able to robustly induce the head-twitch response similarly to psilocin suggests that serotonin 5-HT_2C receptor agonism does not suppress the head-twitch response mediated by the serotonin 5-HT_2A receptor. Accordingly, the serotonin 5-HT_2C receptor antagonist SB-242084 did not significantly reduce the head-twitch response induced by 1-methylpsilocin in rodents. On the other hand, 1-methylpsilocin was found to strongly suppress the head-twitch response induced by the phenethylamine psychedelic DOI (by up to 82%) in rodents. It was hypothesized that these paradoxical findings might be accounted for by differences in functional selectivity between the drugs and/or by 1-methylpsilocin possibly additionally activating certain serotonin 5-HT₁ receptors.

Unlike psilocin, which produced hypolocomotion mediated by serotonin 5-HT_1A receptor activation, 1-methylpsilocin showed no effects in locomotor activity in rodents. These findings suggest that 1-methylpsilocin may be inactive as a serotonin 5-HT_1A receptor agonist. 1-Methylpsilocin has shown anti-obsessional-like effects in rodents. In addition, it has shown antidepressant-, antianhedonic-, and anxiolytic-like effects in rodents. In contrast to psilocin and DOI, 1-methylpsilocin did not show anti-inflammatory effects in preclinical research, which was attributed to its selectivity for the serotonin 5-HT_2C receptor and reduced activity at the serotonin 5-HT_2A receptor.

1-Methylpsilocin was shown to be a substantially biased agonist of the serotonin 5-HT_2C receptor at different downstream signaling pathways similarly to many other psychedelics in 2025. For instance, it was a high-efficacy agonist of the G_q and G₁₁ pathways (89–95%), a moderate-efficacy agonist of the G_z pathway (66%), and a low-efficacy agonist or inactive at the G₁₂, G₁₃, G_oA, G_oB, G_i1, G_i2, G_i3, β-arrestin1, and β-arrestin2 pathways (0–28%).

Chemistry

Synthesis

The chemical synthesis of 1-methylpsilocin has been described.

Analogues

Various analogues and derivatives of 1-methylpsilocin, including prodrugs, have been studied and described.

Some notable analogues of 1-methylpsilocin include 1-methyltryptamine, 1-methyl-DMT, lespedamine (1-methoxy-DMT), 1-propyl-5-MeO-AMT, O-4310 (1-isopropyl-6-fluoropsilocin), and CP-132,484 (4,5-dihydropyrano-1-methyltryptamine), among others. In addition, 1-methyl lysergamides like MLD-41 (1-methyl-LSD) and methysergide (1-methylmethylergometrine) are cyclized tryptamines and hence have some structural similarity to 1-methylpsilocin.

History

1-Methylpsilocin was originally developed by Albert Hofmann and colleagues at Sandoz in the late 1950s. Subsequently, it was studied by Sard and colleagues at Organix in the mid-2000s and by other researchers such as Adam Halberstadt and colleagues in the 2010s and thereafter.

1-Methylpsilocin has been investigated for potential medical applications such as treatment of glaucoma, obsessive–compulsive disorder (OCD), cluster headaches, and obesity, as these conditions are amenable to treatment with psychedelic drugs but are not generally treated with such agents due to the hallucinogenic side effects they produce, which are considered undesirable. 1-Methylpsilocin therefore represents a potential alternative treatment to psilocin that may be less likely to produce hallucinogenic effects.

See also

• Substituted tryptamine

References

External links

• 1-Methylpsilocin - Isomer Design