1-Methylpsilocin

Chemical compound vanc 6 1-Methylpsilocin.svg skin-invert-image 180px 1-Methylpsilocin 3D.png bg-transparent 200px Serotonin receptor agonist; Serotonin 5-HT2C receptor agonist; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen correct CAS 1465-16-3 44404883 21686519 correct FDA 65MKC68UST 197664 CMY; CMY-16; CMY16; 1-Methyl-psilocin; 1-Methyl-4-hydroxy-N,N-dimethyltryptamine; 1-Methyl-4-HO-DMT; 1-Me-4-HO-DMT; 1-Me-4-OH-DMT 1-methyl-3-[2-(N,N-dimethylamino)ethyl]-4-hydroxyindole 13 18 2 1 CN(C)CCc(cn1C)c2c1cccc2O 1S/C13H18N2O/c1-14(2)8-7-10-9-15(3)11-5-4-6-12(16)13(10)11/h4-6,9,16H,7-8H2,1-3H3 MZZRFEIDRWKTKJ-UHFFFAOYSA-N 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. Nichols DE April 2016 Psychedelics Pharmacological Reviews 68 2 264–355 10.1124/pr.115.011478 4813425 26841800 A second example is work by Halberstadt et al. (2011a), who compared the effects of psilocin with those of 1-methypsilocin and 5-MeO-DMT in mice using the BPM and the mouse HTR. 1-Methylpsilocin is a derivative of psilocin that is reported to act as a selective 5-HT2C receptor agonist (Sard et al., 2005). Psilocin at doses of 0.6–2.4 mg/kg produced an inverted U-shaped dose-response curve for the HTR. In 5-HT2A KO mice, however, psilocin did not produce the HTR. The HTR also was produced by 1-methylpsilocin, which was only about one-fourth the potency of psilocin, and again, the HTR was absent for 1-methylpsilocin in 5-HT2A KO mice. [...] By contrast, 1-methylpsilocin had no effect on locomotor activity in the BPM, despite the fact that it produced the HTR. These findings are further evidence that the 5-HT1A receptor can play a role in the behavioral effects of indoleamine-type psychedelics. Sard H, Kumaran G, Morency C, Roth BL, Toth BA, He P, Shuster L October 2005 SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist Bioorganic & Medicinal Chemistry Letters 15 20 4555–4559 10.1016/j.bmcl.2005.06.104 16061378 Bryan Roth Halberstadt AL, Koedood L, Powell SB, Geyer MA November 2011 Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice Journal of Psychopharmacology 25 11 1548–1561 10.1177/0269881110388326 3531560 21148021 It is the 1-methyl derivative of psilocin. The drug shows much greater selectivity as a serotonin 5-HT2C 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. "One code that is not mine, but Sandoz’s, is CMY for 1-methyl-psilocin. I know it has been looked at in a clinical environment, but I have no not idea as to its activity. It is a simple thing to make. I would love to know what it does." Scigliano JA 1968 Psychotomimetic Agents Journal of the American Pharmaceutical Association (1961) 8 1 28–29 10.1016/S0003-0465(16)30471-2 Psychotomimetic agents available from NIMH include [...] CMY-16 ampuls; 3.0 mg/ml; 1 ml/ampul 1-methyl-psilocybin Usdin E, Efron DH 1972 Psychotropic Drugs and Related Compounds 2 123, 644 https://books.google.com/books?id=xzJtkRD3sk8C&pg=PA123 2 April 2026 373. CMY. 1-Methyl-psilocybin. [Structure] Action: [H (Hallucinogen)] (1314). [...] 1314. Scigliano, J.A. J. Am. Pharm. Assoc., NS8, 28-29 (1967). As such, its properties and effects in humans are unknown. Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Pharmacology Pharmacodynamics The affinities (Ki) of 1-methylpsilocin for serotonin receptors have been reported to be 900nM for the serotonin 5-HT2A receptor, 38nM for the serotonin 5-HT2B receptor, and 7.0nM for the serotonin 5-HT2C receptor (unedited/INI isoform). Its activational potencies and efficacies (EC50 half-maximal effective concentration (Emax maximal efficacy)) were 633nM (31%) at the serotonin 5-HT2A receptor, inverse agonism at the serotonin 5-HT2B receptor (values not given), and 12nM (45%) at the serotonin 5-HT2C receptor. As a result, it was concluded that 1-methylpsilocin is a selective serotonin 5-HT2C receptor agonist. In subsequent research however, 1-methylpsilocin has been reported to have activational potencies and efficacies in terms of Gq dissociation BRET assays of 86nM (73%) at the serotonin 5-HT2A receptor, 32nM (40%) at the serotonin 5-HT2B receptor, and 9.5nM at the serotonin 5-HT2C receptor (92%). 12 March 2021 3-(2-(aminoethyl)-indol-4-ol derivatives, methods of preparation thereof, and the use as 5-ht2 receptor modulators Google Patents https://patents.google.com/patent/WO2021179091A1/en 1 April 2026 It was about 10-fold less potent than psilocin at the serotonin 5-HT2A receptor and 30-fold less potent at the 5-HT2B receptor but had similar potency at the serotonin 5-HT2C receptor. Besides at the serotonin 5-HT2 receptors, 1-methylpsilocin has shown affinity for the serotonin 5-HT1A receptor (Ki = 358nM), albeit approximately 7-fold lower than that of psilocin. Despite showing much greater potency at the serotonin 5-HT2C receptor than at the 5-HT2A receptor, 1-methylpsilocin produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. Halberstadt AL, Geyer MA 2018 Effect of Hallucinogens on Unconditioned Behavior Behavioral Neurobiology of Psychedelic Drugs 36 159–199 978-3-662-55878-2 10.1007/7854_2016_466 5787039 28224459 Curr Top Behav Neurosci The HTR also occurs in mice after administration of 1-methylpsilocin (Halberstadt et al. 2011). As shown in Fig. 1, 1-methylpsilocin acts with an ED50 of 0.70 mg/kg (3.22 μmol/ kg). [...] Although the latter findings indicate that 5-HT2C activation augments the HTR, it is not clear why 5-HT2C blockade attenuates the HTR in some studies but has no effect in others (see above). Although it has been proposed that strain differences may underlie these differences (Fantegrossi et al. 2010), unpublished studies in our laboratory have confirmed that SB-242,084 does not significantly reduce the intensity of the HTR induced by 1-methylpsilocin in C57BL/6J mice (Fig. 1). Therefore, 5-HT2C antagonists do not appear to consistently attenuate the HTR in C57BL6J mice. Because 1-methylpsilocin has higher affinity for 5-HT2C versus 5-HT2A sites (Sard et al. 2005), we hypothesized that it was an excellent candidate to test whether crosstalk occurs between 5-HT2 subtypes. [...] Fig. 1. Effect of 1-methylpsilocin on the head twitch response (HTR) in mice. [...] This effect was absent in serotonin 5-HT2A 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-HT2C receptor agonism does not suppress the head-twitch response mediated by the serotonin 5-HT2A receptor. Canal CE, Morgan D 2012 Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model Drug Testing and Analysis 4 7–8 556–576 10.1002/dta.1333 3722587 22517680 It is also worth noting that 1-methylpsilocin is a 5-HT2C agonist, with more than 50 times greater affinity and potency for activating human 5-HT2C-INI compared to 5-HT2A receptors,[118] yet causes a dose-dependent increase in the HTR in C57Bl/6J mice,[47] suggesting that 5-HT2C receptor activation (if the pharmacology of 1-methylpsilocin at human receptors is recapitulated at mice receptors) does not suppress 5-HT2A receptor-mediated HTRs. Accordingly, the serotonin 5-HT2C 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. Canal CE, Booth RG, Morgan D July 2013 Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model Neuropharmacology 70 112–121 10.1016/j.neuropharm.2013.01.007 3754837 23353901 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-HT1A 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-HT1A 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. Lima da Cruz RV, Leão RN, Moulin TC December 2024 Effects of psychedelics on neurogenesis and broader neuroplasticity: a systematic review Molecular Medicine 30 1 244 10.1186/s10020-024-01013-4 11657683 39701927 free Wankhar et al. investigated the acute and sub-acute (7 days) effects of 0.7 mg/kg 1-Methylpsilocin, a psilocin tryptamine derivative. Their research aimed to assess the potential of 5-HT2CR exploitation in mitigating symptoms common to mood disorders. Following a Chronic Unpredictable Stress (CUS) protocol in rats, they employed OF, FST, and EPM behavioral tests in conjunction with tissue sample analysis. Their findings indicated that 1-Methylpsilocin alleviated behavioral signs of anxiety and anhedonic phenotype by the seventh day post-CUS. Furthermore, they demonstrated that this treatment could rescue subjects from CUS-induced mitochondrial damage and imbalanced 5-HT/5-HT2CR levels in the PFC and hippocampus. Remarkably, the treatment also mitigated hippocampal cell morphological abnormalities and the CUS-induced rise in corticosterone levels (Wankhar et al. 2020). Wankhar W, Syiem D, Pakyntein CL, Thabah D, Sunn SE September 2020 Effect of 5-HT2C receptor agonist and antagonist on chronic unpredictable stress (CUS) - Mediated anxiety and depression in adolescent Wistar albino rat: Implicating serotonin and mitochondrial ETC-I function in serotonergic neurotransmission Behavioural Brain Research 393 112780 10.1016/j.bbr.2020.112780 32579979 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-HT2C receptor and reduced activity at the serotonin 5-HT2A receptor. Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD April 2021 Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore ACS Pharmacology & Translational Science 4 2 488–502 10.1021/acsptsci.0c00063 8033619 33860179 5-HT2B and 5-HT2C Receptors Are Not Involved in the Effects of (R)-DOI. Because (R)-DOI, as well as all other psychedelic drugs tested, also has significant affinity for and are agonists at 5-HT2B and 5-HT2C receptors, we sought to determine any potential involvement in the therapeutic effects to normalize PenH. We tested 0.5 mg/kg of a selective 5-HT2C agonist and 5-HT2B inverse agonist (1-methyl psilocin) (Figure 9A), and two mixed 5-HT2B/2C agonists (Ro 60−0175 fumarate and BW 723C86) (Figure 9B,C). There were no significant effects on PenH hyperresponsiveness to MeCh in the OVA treated animals for any of these three drugs. These results indicate that activity at 5-HT2B/2C receptors is not involved in the therapeutic effects of (R)-DOI to prevent allergic asthma in our model. Although these results are highly indicative of activity at the 5-HT2A receptor being necessary and sufficient for antiinflammatory/asthma activity, [...] 1-Methylpsilocin was shown to be a substantially biased agonist of the serotonin 5-HT2C receptor at different downstream signaling pathways similarly to many other psychedelics in 2025. Bonniwell EM, Alabdali R, Hennessey JJ, McKee JL, Cavalco NG, Lammers JC, Moore EJ, Franchini L, Orlandi C, McCorvy JD October 2025 Serotonin 5-HT2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism ACS Chemical Neuroscience 16 19 3899–3914 10.1021/acschemneuro.5c00647 12629614 40944639 For instance, it was a high-efficacy agonist of the Gq and G11 pathways (89–95%), a moderate-efficacy agonist of the Gz pathway (66%), and a low-efficacy agonist or inactive at the G12, G13, GoA, GoB, Gi1, Gi2, Gi3, 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. Lacivita E, Leopoldo M 2006 Selective agents for serotonin2C (5-HT2C) receptor Current Topics in Medicinal Chemistry 6 18 1927–1970 10.2174/156802606778522168 17017967 Sard and coworkers from Organix Inc. have studied some derivatives of psilocine, a metabolite of psilocybin, an hallucinogen component of the Psilocybe Mexicana [40]. In particular, they performed structural modification of 1- methylpsilocin (compound 351, Table 38). This compound displayed selective binding at both the INI and VGI isoforms of the h5-HT2C receptor (Ki= 7. 0 and 33 nM, respectively) as compared to the h5-HT2A receptor (Ki= 900 nM). Functional assays revealed that 351 was an agonist at both receptor subtypes with considerable selectivity (EC50 at 5-HT2C= 12 nM, EC50 at 5-HT2A= 633 nM). Evaluation of the affinity of 351 for the 5-HT2B receptor was also carried out, because agonist activity at 5-HT2B is strongly associated with heart valve toxicity. Although high affinity for the 5-HT2B receptor was found (Ki= 38 nM), the functional assay revealed that 351 was an inverse agonist at this receptor subtype. Some structural modifications of compound 351 were performed but they did not led to any improvement in affinity and/or specificity for the 5-HT2C receptor (Table 38). [...] 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. Troxler F, Seemann F, Hofmann A 1959 Abwandlungsprodukte von Psilocybin und Psilocin. 2. Mitteilung über synthetische Indolverbindungen Helvetica Chimica Acta 42 6 2073–2103 10.1002/hlca.19590420638 0018-019X 1959HChAc..42.2073T 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. Bhandari K, Srivastava S 2007 Obesity: Overview & Management Current Bioactive Compounds 3 4 278–290 10.2174/157340707783220266 1-methylpsilocin [98] and 4 [105] are recently reported potent and selective agonist at the 5-HT2C receptor hence can have potential for the treatment of obesity Fig. (4). See also Substituted tryptamine References External links 1-Methylpsilocin - Isomer Design Category:5-HT2A agonists Category:5-HT2B agonists Category:5-HT2B antagonists Category:5-HT2C agonists Category:1-Alkyltryptamines Category:Biased ligands Category:N,N-Dialkyltryptamines Category:Dimethylamino compounds Category:4-Hydroxytryptamines Category:Psychedelic tryptamines Category:Serotonin receptor modulators