Science
March 21, 2013
Daniel Wacker, Chong Wang, Vsevolod Katritch et al.
689 citations
Serotonin receptors are targets for drugs treating depression, obesity, and migraine headaches. Crystal structures of two serotonin receptor subtypes bound to antimigraine medications or a precursor of LSD reveal how subtle differences in ligand binding cause substantial differences in receptor signaling and biological responses. The structures show that the same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which receptor it binds.
Science
March 22, 2013
Chong Wang, Yi Jiang, Jinming Ma et al.
522 citations
Two research teams independently determined the crystal structures of two serotonin receptors bound to antimigraine drugs or a precursor of LSD. The structures show that subtle differences in how ligands bind to these receptors lead to substantial differences in the signals generated and the resulting biological responses. The same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which specific receptor it binds to.
Journal of Neuroscience
December 15, 2001
Raúl Martín‐Ruiz, M. Victoria Puig, Pau Celada et al.
335 citations
The hallucinogen DOI suppresses the firing rate of most serotonergic neurons in the dorsal raphe nucleus and reduces serotonin release in the medial prefrontal cortex to 33% of baseline, effects mediated by 5-HT2A receptors and reversed by a GABA-A antagonist. However, locally applied DOI in the medial prefrontal cortex increases serotonin release to 164% of baseline through AMPA receptors, not NMDA receptors. DOI also increases the firing rate of a subgroup of serotonergic neurons, indicating enhanced output of pyramidal neurons. Pyramidal neurons coexpress 5-HT1A and 5-HT2A receptors, and DOI disrupts the balance between excitatory and inhibitory inputs, leading to increased activity that may mediate its hallucinogenic action.
Nat Neurosci
October 24, 2022
Alex C. Kwan, David E. Olson, Katrin H. Preller et al.
291 citations
This review synthesizes the neurobiology of psychedelic drugs, which are serotonin 2A receptor agonists that alter perception, cognition, and mood. It covers the chemistry of diverse psychoactive molecules, their potency and pharmacokinetics, and the roles of serotonin receptors and downstream signaling pathways. The review describes effects on neuronal spiking in cortical and subcortical regions, transcriptional changes, and structural plasticity. Neuroimaging findings highlight impacts on association cortices and thalamocortical connectivity, informing theories of psychedelic action. The authors integrate knowledge across chemical, molecular, neuronal, and network levels to explain acute and enduring behavioral effects.
Proceedings of the National Academy of Sciences
November 4, 2009
Kelly A. Jones, Deepak P. Srivastava, John Allen et al.
215 citations
The 5-HT(2A) serotonin receptor, abundant in cortical pyramidal neurons and targeted by hallucinogens and psychiatric medications, is present in a subset of dendritic spines and colocalizes with PSD-95 and MUPP1. Activation by the agonist DOI transiently increases spine size and phosphorylates PAK, a downstream target of kalirin-7. Peptide interference preventing kalirin-7 localization to the postsynaptic density disrupts DOI-induced PAK phosphorylation and spine morphogenesis. These findings suggest serotonin signaling may modulate dendritic spine morphology through kalirin-7 at cortical synapses.
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.
Journal of Neuroscience
June 3, 2009
Atheir I. Abbas, Prem N. Yadav, Wei-Dong Yao et al.
131 citations
The scaffolding protein PSD-95, known for organizing glutamate receptors at synapses, also critically regulates serotonin 5-HT2A and 5-HT2C receptors. In mice lacking PSD-95, these serotonin receptors show reduced expression, abnormal distribution in dendrites, and impaired signaling. Hallucinogen-induced behaviors and the effects of atypical antipsychotics that target these receptors are disrupted. PSD-95 is essential for normal serotonergic receptor function, expanding its role beyond glutamate signaling.
Scientific Reports
September 5, 2021
Ramona M. Rodriguiz, Vineet Nadkarni, Christopher R. Means et al.
92 citations
Lysergic acid diethylamide (LSD) produces psychedelic effects through the 5-HT2A serotonin receptor, which activates both Gq and β-arrestin signaling pathways. Using mice lacking either β-arrestin1 or β-arrestin2, researchers found that LSD stimulated motor activities and psychedelic-like behaviors—including head twitches, grooming, retrograde walking, and nose-poking—in normal mice and those missing β-arrestin1, but not in mice missing β-arrestin2. The 5-HT2A antagonist MDL100907 blocked these effects. LSD also disrupted prepulse inhibition in normal and β-arrestin1-knockout mice, but not in β-arrestin2-knockouts. These findings indicate that LSD's psychedelic actions require β-arrestin2 signaling.
Bioorganic & Medicinal Chemistry Letters
August 3, 2005
Howard Sard, Govindaraj Kumaran, Cynthia Morency et al.
78 citations
A structure-activity relationship study of psilocybin and psilocin derivatives found that 1-methylpsilocin acts as a selective agonist at the human 5-HT(2C) receptor. Its phosphate derivative, 1-methylpsilocybin, and 4-fluoro-N,N-dimethyltryptamine each showed efficacy in an animal model of obsessive-compulsive disorder. These findings point to a new avenue for developing novel 5-HT(2C) receptor agonists with potential applications in drug discovery.
Journal of Neurochemistry
November 19, 2021
Samuel T. Slocum, Jeffrey F. Diberto, Bryan L. Roth
59 citations
Psychedelic drugs like LSD, mescaline, and psilocybin are gaining renewed scientific and clinical interest due to the need for new mental health treatments, progress in research, and changing drug policies. The FDA's designation of psilocybin as a "Breakthrough Therapy" for treatment-resistant depression has opened a path for these drugs to be used in clinical settings. However, a clearer understanding of how these drugs work at the molecular level is essential for developing such applications. This review examines current knowledge about the molecular details of psychedelic drug actions and suggests that these discoveries can provide new insights into their hallucinogenic and therapeutic mechanisms.
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.
Proceedings of the National Academy of Sciences
January 30, 2012
Hyeong-Min Lee, Bryan L. Roth
47 citations
The authors argue that it is time to reconsider long-standing hypotheses about how hallucinogens like psilocybin, found in Psilocybe cubensis, act in the human brain.
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.
Beilstein Journal of Organic Chemistry
October 8, 2012
Adam Pigott, Stewart Frescas, John D. Mccorvy et al.
19 citations
Replacing the ethylamine side chain of two psychedelic amphetamine derivatives, DOI and DOB, with a cyclopropylamine moiety produced compounds with high affinity for the 5-HT(2) family of serotonin receptors. The more potent stereoisomer of these cyclopropane analogues had the expected (-)-(1R,2S)-configuration. However, the cyclopropane congeners also showed increased affinity at several other serotonin receptor subtypes beyond 5-HT(2A) and 5-HT(2B). While at appropriate doses the compounds may serve as tools to probe 5-HT(2) receptor function, their selectivity for 5-HT(2A) receptors is somewhat less than that of DOI itself.
bioRxiv (Cold Spring Harbor Laboratory)
September 26, 2023
Yi-Ting Chiu, Wei Wang, Pierre Llorach et al.
15 citations
preprint
Psychedelic drugs such as LSD and psilocybin show promise as treatments for depression, anxiety, PTSD, migraine, and cluster headaches by activating the 5-HT2A receptor (HTR2A). Researchers engineered several new mouse lines to study the role of HTR2A and the neurons that express it. One line allows visualization of the receptor and identification of HTR2A-containing cells, providing a detailed anatomical map. Another line has a humanized version of the receptor, and a third enables targeted genetic manipulation. The mice exhibited expected behavioral responses to psychedelics, confirming their usefulness. Electrophysiology showed that serotonin increases firing of specific pyramidal neurons through HTR2A, consistent with the receptor's location on the cell surface. These tools will help clarify how psychedelics work at molecular, cellular, and behavioral levels.
bioRxiv (Cold Spring Harbor Laboratory)
November 15, 2022
Gavin P. Schmitz, Yi-Ting Chiu, Gabriele M. König et al.
15 citations
preprint
Psilocin, the active compound in psilocybin mushrooms, activates serotonin 2A receptors (5-HT2ARs) in the prefrontal cortex (PFC), but its specific effects on PFC neurons were unclear. Using slice electrophysiology in mice, researchers found that psilocin application onto layer 5 pyramidal neurons in the prelimbic PFC produced variable firing changes (increase, decrease, or no change) in unspecific neurons. However, in neurons identified as expressing 5-HT2ARs, psilocin consistently increased firing without altering synaptic transmission. The results demonstrate that psilocin evokes strong, 5-HT2AR- and Gαq-dependent firing changes in the PFC, offering insights into how psychedelics affect a brain region key to their therapeutic actions.
Translational Psychiatry
October 6, 2025
Gavin P. Schmitz, Yi-Ting Chiu, Mia L. Foglesong et al.
13 citations
Psilocybin's active metabolite psilocin increases activity in the medial prefrontal cortex (mPFC), a brain region rich in 5-HT2A receptors. A specific population of neurons in the prelimbic/anterior cingulate mPFC that express these receptors becomes more excitable and fires more in response to psilocin and a selective 5-HT2A receptor compound, effects dependent on both the receptor and Gα q signaling. A novel non-hallucinogenic psychedelic compound produced similar effects. These results point to membrane-bound 5-HT2A receptors and intracellular Gα q signaling as potential therapeutic targets for psychedelic-associated plasticity.
bioRxiv Preprint Server
June 13, 2022
Isha Singh, Anubha Seth, Christian B. Billesbølle et al.
8 citations
preprint
The serotonin transporter (SERT) adopts three conformations, and most antidepressants target its outward-open state. Ibogaine, which targets the inward-open state, has an unusual antidepressant profile but is cardiotoxic. Computational docking of over 200 million small molecules against the ibogaine-stabilized inward-open SERT identified 36 top compounds; 13 inhibited SERT with potencies from 29 to 5000 nM. Optimization yielded two inhibitors with Ki values as low as 3 nM that stabilized an outward-closed state and showed little off-target activity. A cryo-EM structure confirmed the predicted binding geometry. In mice, both compounds showed anxiolytic and antidepressant activity with potencies up to 200 times greater than fluoxetine.
bioRxiv Preprint Server
February 4, 2021
Ramona M. Rodriguiz, Vineet Nadkarni, Christopher R. Means et al.
7 citations
preprint
Lysergic acid diethylamide (LSD) produces its psychedelic effects through the 5-HT2A serotonin receptor, which activates two signaling pathways: Gq and β-arrestin. Using mice lacking either β-arrestin1 or β-arrestin2, the authors show that LSD's psychedelic-like behaviors—head twitches, retrograde walking, nose poking, and disrupted prepulse inhibition—require β-arrestin2, not β-arrestin1. LSD also affects motor activity and body temperature in a β-arrestin-dependent manner. The 5-HT2A antagonist MDL100907 blocks these effects in wild-type mice, but in β-arrestin1-knockouts, haloperidol is needed to restore prepulse inhibition. These findings indicate that LSD's diverse behavioral actions are mediated through distinct β-arrestin subtypes, with β-arrestin2 necessary for its psychedelic-like effects.
bioRxiv (Cold Spring Harbor Laboratory)
June 30, 2026
Blake A Fordyce, Yi-Ting Chiu, Nicholas A. Wright et al.
Activation of mGluR2, the primary presynaptic autoreceptor for glutamate in the brain, attenuates the behavioral and electrophysiological effects of psychedelics. The mechanisms behind this are debated, with two competing hypotheses: direct actions via mGluR2/5-HT2A heterodimers, or presynaptic inhibition of glutamate release. In mice expressing tagged receptors, mGluR2 agonist pretreatment reduced the head twitch response induced by the psychedelic DOI. Multiple orthogonal in vivo and in vitro approaches found no evidence for receptor colocalization or oligomerization under basal or agonist-exposed conditions, nor for mGluR2-mediated modulation of 5-HT2A ligand binding. The findings support models where mGluR2 signaling modulates 5-HT2A receptor activity in layer V pyramidal neurons rather than requiring mGluR2/5-HT2A multimers.
bioRxiv Preprint Server
December 9, 2021
Gavin P. Schmitz, Manish K. Jain, Samuel T. Slocum et al.
preprint
Random genetic variations in the serotonin 2A receptor can modestly alter how four commonly used psychedelic drugs activate this receptor, with effects that differ depending on the specific drug. Seven naturally occurring receptor variants were tested in the lab; each showed small but statistically significant changes in drug potency and efficacy. These findings suggest that individual genetic differences may influence responses to psychedelic medications.
UNC Libraries
October 31, 2020
Adam Pigott, Bryan L. Roth, Xi‐ping Huang et al.
Replacing the ethylamine side chain of the psychedelic compounds DOI and DOB with a cyclopropylamine group produced new molecules that bind strongly to 5-HT2 family serotonin receptors. The most potent version had the (−)-(1R,2S)-configuration. However, these cyclopropane analogs also showed increased affinity for other serotonin receptor subtypes beyond 5-HT2A and 5-HT2B, making them less selective than the original compounds. At appropriate doses, they may serve as research tools for studying 5-HT2 receptor function, but their reduced selectivity for 5-HT2A receptors must be considered.
ChemInform
December 13, 2005
Howard Sard, Govindaraj Kumaran, Cynthia Morency et al.
The abstract indicates that the full text contains a ChemInform Abstract, which is a secondary source summarizing a previously published chemical synthesis or study. No original finding, argument, or data is provided in the abstract itself.
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.