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.
Science
May 16, 2024
Jiankun Lyu, Nicholas J. Kapolka, Ryan H. Gumpper et al.
145 citations
Docking large libraries of molecules against unrefined AlphaFold2 (AF2) models of the σ2 and serotonin 2A (5-HT2A) receptors produced hit rates and affinities as high as those obtained by docking against experimental structures. These results were achieved despite differences in orthosteric residue conformations between the AF2 models and the experimental structures. A cryo–electron microscopy structure of one potent 5-HT2A ligand identified from AF2 docking showed residue accommodations similar to the AF2 prediction. AF2 models may sample low-energy conformations that differ from experimental structures but remain useful for ligand discovery, extending the reach of structure-based drug design.
The American journal of psychiatry
May 1, 2023
Bryan L. Roth, Ryan H. Gumpper
55 citations
Psychedelic compounds show promise as treatments for several neuropsychiatric conditions such as depression, cluster headaches, migraines, anxiety, and obsessive-compulsive disorder. Historically, basic science has used these compounds to study neurotransmitter systems, primarily the serotonin 5-HT2A receptor. This review covers recent advances in understanding the biological mechanisms of psychedelics, new drug discovery efforts, and potential pitfalls in their widespread therapeutic use. Understanding the pharmacology behind their therapeutic mechanisms is crucial for their safe and effective application.
Cell Reports
August 1, 2022
Ryan H. Gumpper, Jonathan F. Fay, Bryan L. Roth
49 citations
The serotonin 2C receptor, a G protein-coupled receptor (GPCR) targeted by drugs like the weight-loss medication lorcaserin and the psychedelic psilocin, exists in many protein isoforms due to RNA editing. This study presents the structures of three representative isoforms bound to each drug and analyzes agonist activation and constitutive activity across all 24 isoforms. A unique hydrogen-bonding network on intracellular loop 2, which is altered by RNA editing, differentially affects the receptor's constitutive and agonist signaling activities.
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.
Nat Commun
March 19, 2025
Ryan H. Gumpper, Manish K. Jain, Kuglae Kim et al.
31 citations
Classical psychedelics are being studied for treating depression, addiction, anxiety, and cluster headaches. Their therapeutic effects are thought to involve the 5-HT2A serotonin receptor. Seven cryo-EM structures were determined, covering major classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound. These structures reveal both common and distinct molecular interactions between different psychedelics and the receptor. The findings provide a mechanistic understanding of 5-HT2A activation that could aid development of new drugs with fewer side effects.
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.
Neuropsychopharmacology
January 1, 2024
Ryan H. Gumpper, Bryan L. Roth
Psychedelics show promise as treatments for neuropsychiatric disorders, though their clinical potential is not fully understood. This review explores current knowledge of their basic biology, pharmacology, and structural biology, highlighting both established facts and unanswered questions as these compounds gain popularity in therapeutic and recreational settings.