Psychedelics elicit their effects by 5-HT_2A receptor-mediated G_i signalling

Psychedelics are undergoing a renaissance as potential therapy for psychiatric disorders, with more than 200 clinical trials being studied across several countries^1-3. However, the precise mechanisms by which these drugs bring about benefits and the potential clinical risks are not yet fully understood. The serotonin 2A receptor (5-HT_2AR) was reported to be a G_q-coupled receptor and the primary interoceptive target of psychedelics^4,5. Here we compared psychedelics and their non-hallucinogenic analogues (nHAs) using in vitro and in vivo approaches, finding that 5-HT_2AR-mediated non-canonical G_i signalling is essential for hallucinogenic effect. We further presented five cryo-electron microscopy structures of 5-HT_2AR-G_i/G_q in complex with psychedelics or nHAs. Structural analysis and pharmacological investigation revealed that a special contact between nHAs with 5-HT_2AR mediated the signalling bias. Building on this insight, we identified a 2,5-dimethoxy-4-iodoamphetamine derivative, DOI-NBOMe, which exhibits potent and selective G_q-biased activity, and demonstrates promising therapeutic effects in mouse models without hallucinogenic effect. Our finding uncovers the functional mechanisms underlying the G_i signalling mediated by 5-HT_2AR and provides valuable insights for designing psychedelic-based drugs with minimized risk from hallucinogenic effects.