Jain Manish K, Gumpper Ryan H, Slocum Samuel T, Schmitz Gavin P, Madsen Jakob S, Tummino Tia A, Suomivuori Carl-Mikael, Huang Xi-Ping, Shub Laura, DiBerto Jeffrey F, Kim Kuglae, DeLeon Chelsea, Krumm Brain E, Fay Jonathan F, Keiser Michael, Hauser Alexander S, Dror Ron O, Shoichet Brian, Gloriam David E, Nichols David E, Roth Bryan L
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark.
Neuron. 2025 Jul 15. doi: 10.1016/j.neuron.2025.06.012.
The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT serotonin receptor (5-HTR). Recent clinical studies have suggested that classical psychedelics may additionally have therapeutic potential for many neuropsychiatric conditions including depression, anxiety, migraine and cluster headaches, drug abuse, and post-traumatic stress disorder. In this study, we investigated the pharmacology of 41 classical psychedelics from the tryptamine, phenethylamine, and lysergamide chemical classes. We profiled these compounds against 318 human G-protein-coupled receptors (GPCRs) to elucidate their target profiles, and in the case of LSD, against more than 450 human kinases. We found that psychedelics have potent and efficacious actions at nearly every serotonin, dopamine, and adrenergic receptor. We quantified their activation for multiple transducers and found that psychedelics stimulate multiple 5-HTR transducers, each of which correlates with psychedelic drug-like actions in vivo. Our results suggest that multiple molecular targets likely contribute to the actions of psychedelics.
经典致幻剂（+）-麦角酸二乙酰胺（LSD）、裸盖菇素和三甲氧苯乙胺通过激活5-羟色胺受体（5-HTR）发挥其致幻作用。最近的临床研究表明，经典致幻剂可能还对包括抑郁症、焦虑症、偏头痛和丛集性头痛、药物滥用以及创伤后应激障碍在内的多种神经精神疾病具有治疗潜力。在本研究中，我们研究了来自色胺、苯乙胺和麦角酰胺化学类别的41种经典致幻剂的药理学。我们针对318种人类G蛋白偶联受体（GPCR）对这些化合物进行了分析，以阐明它们的靶点谱，对于LSD，则针对450多种人类激酶进行了分析。我们发现致幻剂对几乎每一种5-羟色胺、多巴胺和肾上腺素能受体都有强效且有效的作用。我们对它们对多种转导器的激活进行了量化，发现致幻剂会刺激多种5-HTR转导器，其中每一种都与体内致幻药物样作用相关。我们的结果表明，多个分子靶点可能共同促成了致幻剂的作用。
