Lysergic acid diethylamide (LSD) acts through serotonin 5-HT2-family receptors, primarily 5-HT2A, but the closely related 5-HT2B receptor serves as a model due to its high expression. Cryo-electron microscopy structures of LSD-bound 5-HT2B in three states—transducer-free, coupled with Gq protein, and coupled with β-arrestin-1—reveal distinct signaling snapshots from a partially active to fully active states. These findings provide comprehensive molecular insights into LSD's signaling mechanisms and may accelerate the discovery of novel psychedelic drugs.
Classical psychedelics like LSD, psilocybin, and mescaline produce their mind-altering effects by activating the 5-HT2A serotonin receptor. Recent clinical studies indicate they may also help treat depression, anxiety, migraines, cluster headaches, drug abuse, and PTSD. This work examined 41 psychedelics from three chemical classes, testing them against 318 human G-protein-coupled receptors and, for LSD, over 450 human kinases. The compounds potently activated nearly every serotonin, dopamine, and adrenergic receptor. They also stimulated multiple signaling pathways through the 5-HT2A receptor, each linked to psychedelic-like effects in animals. The findings suggest that many molecular targets contribute to the overall actions of psychedelics.
Ketamine, used for treatment-resistant depression and severe pain, acts primarily by blocking the N-methyl-D-aspartate receptor, but its therapeutic and abuse-related effects may involve additional targets. Structural evidence shows that ketamine and its analog phencyclidine (PCP) can directly bind to and activate human opioid receptors. The study identifies key molecular motifs involved in this binding and efficacy modulation, and also reveals the structure of the ligand-free state of the κ opioid receptor. Ketamine exhibits more dynamic binding than PCP at the orthosteric site, which may explain its distinct pharmacology. These findings indicate that opioid receptors are important for understanding ketamine's clinical versatility.