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 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | In vitro and mouse models |
| Intervention | DOI-NBOMe |
| Topics | Serotonin |
| Citations | 5 |
| Key findings | 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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 12
- Psychoplastogens to Reduce Persistent Cognitive Symptoms for Traumatic Brain Injury as a Chronic Condition Journal of Neurotrauma October 19, 2026
- Multilevel Mechanisms and Clinical Efficacy of Psilocybin in Depression Treatment: A Systematic Review International Journal of Molecular Sciences September 10, 2026
- The Emergence of Isotryptamine Analogs as Novel Serotonergic Agents with Psychotherapeutic Potential ACS Pharmacology & Translational Science August 18, 2026
- Classic Psychedelics for Treating Chronic Pain: Mechanism and Clinical Translation Molecules July 27, 2026
- Modulating the Thermodynamics and Kinetics of Psychedelics at Serotonin Receptors via Terahertz Waves The Journal of Physical Chemistry B September 12, 2026
and 7 more in the library
Cites 22
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Psychedelics as Medicines: An Emerging New Paradigm Clinical Pharmacology & Therapeutics November 4, 2016
- Structure-based discovery of nonhallucinogenic psychedelic analogs Science January 27, 2022
- Psilocybin desynchronizes the human brain. Nature August 1, 2024
- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
and 17 more in the library