The Changchun Institute of Applied Chemistry, Chinese Academy of Sciences (CIAC, CAS) has achieved a breakthrough in research on the mechanism of action of hallucinogens. The research team led by Wang Xiaohui, in collaboration with Sichuan University (Professors Shao Zhenhua, Yan Wei, and Yang Shengyong) and Huazhong University of Science and Technology (Professor Liu Jianfeng), discovered that the non-classical G_i signaling pathway of the 5-hydroxytryptamine 2A (5-HT_2A) receptor is critical for its hallucinogenic effects. The findings were published in the journal Nature on January 28, 2026 (January 29, Beijing time), under the title "Psychedelics elicit their effects by 5-HT_2Areceptor-mediated G_isignalling."

Figure 1. Pharmacological profiles of hallucinogens and non-hallucinogenic analogues targeting the 5-HT_2Areceptor.

For a long time, classic hallucinogens such as lysergic acid diethylamide (LSD) and psilocybin have attracted considerable attention due to the contradiction between their significant psychoactive properties and therapeutic potential. Although clinical studies have shown that these substances exhibit remarkable efficacy in treating major depressive disorder, treatment-resistant depression, and anxiety-related disorders, their intense hallucinogenic side effects have remained a major obstacle to their clinical translation. Traditional theories have attributed hallucinogenesis primarily to excessive activation of the G_q signaling pathway following 5-HT_2Areceptor activation, yet this view has been insufficient to fully explain the complex pharmacological properties of these substances. By integrating multidimensional signaling pathway analysis with cutting-edge structural biology techniques, this study has successfully revealed a new mechanism underlying the action of classic hallucinogens.

The research team systematically characterized the downstream signaling cascade triggered by 5-HT_2Areceptor activation (Figure 1), and for the first time confirmed the critical function of the G_i signaling pathway in the action of hallucinogens, overturning conventional understanding. Using single-particle cryo-electron microscopy (cryo-EM), the team successfully resolved high-resolution structures of five distinct ligand–receptor–G protein complexes, including the DOI- and psilocin-bound 5-HT_2AR–G_qcomplexes, as well as the DOI-, ariadne-, and DOI-NBOMe-bound 5-HT_2AR–G_icomplexes. These detailed structures revealed that ligand-specific receptor conformations are the key determinants of G protein selectivity, much like how different tooth shapes of a key open different locks.

Based on this molecular mechanism, the research team successfully developed a novel 5-HT_2AR-selective G_qbiased agonist, DOI-NBOMe (Figure 2), through rational drug design. In preclinical models, DOI-NBOMe exhibited anxiolytic-like and antidepressant-like efficacy without inducing hallucinogenic-like effects (Figure 3), achieving an effective separation of therapeutic benefits from hallucinogenic side effects. This compound has been jointly patented by CIAC and Sichuan University (Patent No. CN120204186A).

Figure 2. Structure-based design of a novel 5-HT_2AR–G_q-selective agonist.

Figure 3. The G_q-selective agonist DOI-NBOMe exhibits anxiolytic-like and antidepressant-like effects in animal models without eliciting hallucinogenic-like effects.

CIAC is a leading force in hallucinogen research in China. In recent years, the team led by Researcher Wang Xiaohui has published more than 30 papers on hallucinogens — covering structural modification, receptor pharmacology, brain circuit mechanisms, and preclinical translation — in high-level journals including Nature, National Science Review, Molecular Psychiatry, and Brain, exerting broad international influence.

Based on these research accumulations and the formation of an academic community, and with support from the National Natural Science Foundation of China, the 1st Workshop on Hallucinogens was successfully held in Changchun on August 27–29, 2023. With support from the Jilin Provincial Association for Science and Technology and the Jilin Provincial Academicians and Experts Association, the 2nd workshop was held in Changchun on November 19–21, 2025. In addition, the project "Hallucinogen-Induced Neural Plasticity Regulation for Reversing Cognitive Impairment in Late-Stage Alzheimer's Disease" was recently funded under the 2025 Expert-Recommended Original Exploration Program of the National Natural Science Foundation of China, further consolidating CIAC's position as an academic highland in basic and translational hallucinogen research in China.

The research findings are published in Nature: https://www.nature.com/articles/s41586-025-10061-7