National Center for Mental Disorders, Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
2 papers in the library · 5 citations · publishing 2026
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.
Psilocybin, a psychedelic compound, rapidly inhibited mouse locomotor activity, with effects resolving within about one hour. In the nucleus accumbens, a brain region involved in reward and emotion, psilocybin increased expression of the immediate early gene c-Fos in neurons around six hours after treatment and in non-neuronal cells around 1.5 hours. Blocking serotonin 2A receptors reduced psilocybin-induced c-Fos only in neurons, while blocking serotonin 2B receptors reduced it in both neurons and non-neuronal cells. These findings suggest that serotonin 2B receptors and non-neuronal cells may play important roles in the neural circuits underlying mood disorders.