The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.
Neuron – July 15, 2025
Source: PubMed
Summary
Psychedelics, known for their hallucinogen properties, show surprising potential. Research explored 41 psychedelics, finding they broadly interact with G-protein-coupled receptors, including serotonin receptors and dopamine receptors. This comprehensive profiling revealed these compounds activate multiple targets, suggesting their effects, including therapeutic benefits, stem from complex interactions beyond a single receptor. This broad engagement highlights their diverse pharmacological actions.
Abstract
The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT2A serotonin receptor (5-HT2AR). Recent clinical studies have suggested that classical psychedelics may additionally have therapeutic potential for many neuropsychiatric conditions including depression, anxiety, migraine and cluster headaches, drug abuse, and post-traumatic stress disorder. In this study, we investigated the pharmacology of 41 classical psychedelics from the tryptamine, phenethylamine, and lysergamide chemical classes. We profiled these compounds against 318 human G-protein-coupled receptors (GPCRs) to elucidate their target profiles, and in the case of LSD, against more than 450 human kinases. We found that psychedelics have potent and efficacious actions at nearly every serotonin, dopamine, and adrenergic receptor. We quantified their activation for multiple transducers and found that psychedelics stimulate multiple 5-HT2AR transducers, each of which correlates with psychedelic drug-like actions in vivo. Our results suggest that multiple molecular targets likely contribute to the actions of psychedelics.