The polypharmacology of psychedelics reveals multiple targets for potential therapeutics

Introduction

Classical psychedelics (tryptamines, phenethylamines, lysergamides) are known to produce profound subjective effects and have renewed interest for therapeutic use in several neuropsychiatric conditions. Earlier work has established 5-HT2A receptor (5-HT2AR) activation as central to psychedelic effects, but other targets including various serotonin subtypes, dopamine receptors, trace amine receptors, σ receptors and even TrkB kinase have been proposed to contribute to either therapeutic or side-effect profiles. The precise molecular pharmacology across the broader chemotype diversity of psychedelics therefore remains incompletely defined. Jain and colleagues set out to characterise, in an unbiased and systematic way, the polypharmacology of a representative library of psychedelics. They selected 41 compounds spanning tryptamines, phenethylamines and lysergamides and profiled them against a large GPCR panel (318 non-sensory GPCRs), performed radioligand and functional characterisation across serotonin, dopamine and adrenergic receptors using TRUPATH and BRET platforms, screened LSD across >450 human kinases, and determined an active-state cryo-EM structure of LSD bound to the D2 dopamine receptor. The stated aim was to reveal the receptor and signalling pathways engaged by psychedelics and to clarify candidate mechanisms for both therapeutic actions and safety liabilities.