Identification of 5-HT 2A Receptor Signaling Pathways Responsible for Psychedelic Potential

Introduction

Wallach and colleagues frame the study in the context of renewed interest in serotonergic psychedelics for rapid and sustained therapeutic effects, alongside enduring uncertainty about which 5-HT2A receptor (5-HT2AR) signalling pathways mediate their hallucinogenic versus putative therapeutic actions. Classical psychedelics from diverse chemical scaffolds all activate 5-HT2AR, and human and preclinical work (including blockade of subjective effects by the antagonist ketanserin and use of the mouse head-twitch response (HTR) as a predictive behavioural assay) point to 5-HT2AR as central to psychedelic effects. However, prototypical psychedelics engage both Gq/11 proteins and β-arrestin2 via 5-HT2AR, leaving the relative contribution of these transducers unclear and complicating rational design of new ligands that might separate therapeutic benefit from hallucinogenic liability. To address this gap, the investigators used structure-guided medicinal chemistry to create a series of 5-HT2AR-selective ligands with graded Gq efficacies, including β-arrestin2-biased agonists, and then used a battery of in vitro signalling assays, structural modelling and in vivo behavioural tests (chiefly the HTR in male mice) to probe which 5-HT2AR-coupled pathways predict psychedelic potential. The study aims to identify whether Gq or β-arrestin2 efficacy at 5-HT2AR determines psychedelic-like effects and to define structural features that enable tuning of 5-HT2AR signalling for drug development.