Psychedelics elicit their effects by 5-HT2A receptor-mediated Gi signalling.
Zheng Xu, Hongshuang Wang, Jingjing Yu, Yue Deng, Xiaowen Tian, Rongjun Ni, Fan Xia, Lingyi Yang, Chanjuan Xu, Liting Zhang, Renxuan Luo, Peipei Chen, Xiaoyu Zhang, Yuxuan Liu, Jingyu Hou, Miyuan Zhang, Shasha Chen, Lantian Su, Hui Sun, Yixiao He, Dandan Chen, Xiaoting Chen, Zhuang Miao, Jie Xie, Xinlei Liu, Jie Zhao, Bowen Ke, Xiaohe Tian, Linan Zeng, Lingli Zhang, Xiangdong Tang, Shengyong Yang, Jianfeng Liu, Xiaohui Wang, Wei Yan, Zhenhua Shao
Nature January 28, 2026 DOI: 10.1038/s41586-025-10061-7 via PubMed
Summary
AI-generated from the abstractPsychedelics 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.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | In vitro and mouse models |
| Intervention | DOI-NBOMe |
| Citations | 5 |
| Key finding | 5-HT2AR-mediated non-canonical Gi signaling is essential for hallucinogenic effects, and a Gq-biased derivative, DOI-NBOMe, shows therapeutic effects in mice without hallucinogenic effects. |
Abstract
Psychedelics are undergoing a renaissance as potential therapy for psychiatric disorders, with more than 200 clinical trials being studied across several countries1-3. 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-HT2AR) was reported to be a Gq-coupled receptor and the primary interoceptive target of psychedelics4,5. Here we compared psychedelics and their non-hallucinogenic analogues (nHAs) using in vitro and in vivo approaches, finding that 5-HT2AR-mediated non-canonical Gi signalling is essential for hallucinogenic effect. We further presented five cryo-electron microscopy structures of 5-HT2AR-Gi/Gq in complex with psychedelics or nHAs. Structural analysis and pharmacological investigation revealed that a special contact between nHAs with 5-HT2AR mediated the signalling bias. Building on this insight, we identified a 2,5-dimethoxy-4-iodoamphetamine derivative, DOI-NBOMe, which exhibits potent and selective Gq-biased activity, and demonstrates promising therapeutic effects in mouse models without hallucinogenic effect. Our finding uncovers the functional mechanisms underlying the Gi signalling mediated by 5-HT2AR and provides valuable insights for designing psychedelic-based drugs with minimized risk from hallucinogenic effects.