Psychedelics elicit their effects by 5-HT2A receptor-mediated Gi signalling

Psychedelics produce hallucinogenic effects through 5-HT2A receptor signaling that depends on non-canonical G(i) pathways rather than only the traditionally assumed G(q) coupling. The study compares psychedelics with non-hallucinogenic analogues (nHAs) using in vitro and in vivo experiments, then uses cryo-electron microscopy to visualize five 5-HT2A receptor complexes (5-HT2A-Gi/Gq) bound to psychedelics or nHAs. Structural and pharmacological analyses identify a specific interaction that drives signaling bias toward G(i) in hallucinogens. Based on the mechanism, the researchers design and test a 2,5-dimethoxy-4-iodoamphetamine derivative, DOI-NBOMe, which shows potent selective G(q)-biased activity and demonstrates promising therapeutic effects in mouse models without hallucinogenic effect, suggesting a route to psychedelic-based drugs with reduced risk.