Psychedelics elicit their effects by 5-HT2A receptor-mediated Gi signalling.
Nature January 28, 2026 Zheng Xu, Hongshuang Wang, Jingjing Yu et al. 5 citations
Psychedelics are being tested in over 200 clinical trials as potential treatments for psychiatric disorders, but how they work and their risks are not fully understood. The serotonin 2A receptor (5-HT2AR) is the main target of psychedelics. This study compared psychedelics with non-hallucinogenic analogues using cell and animal experiments, finding that 5-HT2AR signaling through a non-canonical Gi pathway is essential for hallucinogenic effects. Five cryo-electron microscopy structures of 5-HT2AR bound to these drugs were solved. A special contact between non-hallucinogenic analogues and the receptor biased signaling away from Gi. A derivative called DOI-NBOMe showed potent Gq-biased activity and therapeutic effects in mice without causing hallucinations. These findings reveal mechanisms of 5-HT2AR Gi signaling and guide the design of safer psychedelic-based drugs.