https://www.nature.com/articles/s41586-025-10061-7

https://www.cas.cn/syky/202601/t20260129_5099021.shtml

Clinical studies have shown that classic hallucinogens such as lysergic acid diethylamide (LSD) and psilocybin are efficient in treating major depressive disorder, treatment-resistant depression, and anxiety-related disorders. However, their hallucinogenic side effects have consistently been a major obstacle to their clinical translation. Traditional theory considers the overactivation of the Gq signaling pathway following 5-HT2A receptor activation as the primary cause of hallucinations, but this viewpoint cannot fully explain the complex pharmacological properties of hallucinogens.

A collaborative study by the CAS Changchun Institute of Applied Chemistry and other institutions have now systematically characterized the downstream signaling cascade triggered by 5-HT2A receptor activation, confirming fthe key function of the Gi signaling pathway in the action of hallucinogens and revealing a new mechanism of action for classic hallucinogens. The research team developed a novel 5-HT2AR-selective Gq-biased agonist, DOI-NBOMe, through rational drug design. In preclinical models, DOI-NBOMe exhibited anxiolytic and antidepressant-like effects without inducing hallucinogenic-like effects, achieving an effective separation of the therapeutic benefits and hallucinogenic side effects of hallucinogens.

This research provides a new theoretical framework for understanding the mechanisms of action of hallucinogens, pioneers a new paradigm for precise drug design based on receptor signaling bias, and lays the foundation for developing next-generation non-hallucinogenic drugs for the treatment of mental illnesses.