ACS Chemical Neuroscience
January 8, 2024
Alexander M. Sherwood, Elise K. Burkhartzmeyer, Samuel E. Williamson et al.
18 citations
Psilocin, a metabolite of psilocybin, produces psychedelic effects in vivo, while norpsilocin, which differs by a single N-methyl group, does not. To explore this, eight norpsilocin derivatives with varied secondary amine groups were synthesized to increase lipophilicity and brain permeability. In mouse head-twitch response (HTR) studies, extending norpsilocin's N-methyl group to an N-ethyl group (4-HO-NET) produced psilocin-like activity (ED50 = 1.4 mg/kg). N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced HTRs (ED50 = 1.1–3.2 mg/kg), with variable maximum effects (26–77 total HTR events). Bulky tert-butyl or cyclohexyl groups did not elicit psilocin-like HTRs. In vitro, these tryptamines interacted with multiple serotonin receptor subtypes and other CNS proteins.
ChemRxiv
June 2, 2023
Samuel E. Williamson, Alexander M. Sherwood
1 citation
The Church of Psilomethoxin claims its sacrament is a novel tryptamine, psilomethoxin, produced by adding 5-MeO-DMT to the substrate of cultivated Psilocybe mushrooms. Using ultra-performance liquid chromatography with high-resolution mass spectrometry (UPLC-HRMS) and authentic reference standards, this analysis found no evidence of psilomethoxin in samples of the material sold to members online. Instead, the samples unambiguously contained psilocybin, baeocystin, and psilocin. The findings indicate that the church's claims about biosynthesis of psilomethoxin are likely misguided, with implications for public health and safety.
ACS Chemical Neuroscience
March 3, 2026
Samuel E. Williamson, Elise K. Burkhartzmeyer, Michael T. Faley et al.
To support ongoing clinical trials, the major human metabolites of psilocybin—psilocin-O-glucuronide and 4-hydroxyindole-3-acetic acid (4-HIAA)—along with putative minor metabolites and several deuterium-labeled derivatives, were synthesized on a preparative scale. When assayed for engagement at seven serotonin receptor subtypes using a BRET-based binding assay, only psilocin exhibited any discernible binding. Given the high cost and challenging preparation of these compounds, the work provides a comprehensive guide for researchers to access these resources, advancing both basic and clinical research with psilocybin and its metabolites.