Neuron
October 5, 2022
Can Cao, Ximena Barros-Álvarez, Shicheng Zhang et al.
158 citations
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.
Neuron
July 15, 2025
Manish K Jain, Ryan H Gumpper, Samuel T Slocum et al.
42 citations
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.
British journal of pharmacology
October 2, 2024
Ryan H Gumpper, David E Nichols
9 citations
Classic serotonergic psychedelics come in three main chemical families: phenethylamines, ergolines, and tryptamines. Each family has distinct structural features that determine its psychedelic activity in humans. The 5-HT2A receptor, a G-protein coupled receptor, is the primary target for these compounds. Recent X-ray and cryoEM structures showing various ligands bound to the receptor reveal the atomic-level details of how different psychedelic molecules interact with this receptor. These structural insights help explain known pharmacological observations about how psychedelic drugs work and may guide future drug development.