Synthesis and Characterization of Psilocybin Metabolites and Deuterated Analogs

To support ongoing clinical trials, the major human metabolites of psilocybin were synthesized on a preparative scale, specifically psilocin-O-glucuronide and 4-hydroxyindole-3-acetic acid (4-HIAA), along with putative minor metabolites and several deuterium-labeled derivatives. Psilocybin, psilocin, psilocin-O-glucuronide, and 4-HIAA were assayed for engagement at seven serotonin receptor subtypes using a BRET-based binding assay, which showed that only psilocin exhibited any discernible binding across the subtypes investigated. Given the high cost and challenging preparation of these compounds, our work offers a comprehensive guide for researchers to access these resources, advancing both basic and clinical research with psilocybin and its metabolites.