Proceedings of the National Academy of Sciences of the United States of America
September 3, 2002
Bryan L. Roth, Karen Baner, Richard B Westkaemper et al.
782 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, potently and selectively activates kappa opioid receptors while having no effect on the serotonin 5-HT(2A) receptor targeted by classical hallucinogens like LSD. This makes it the first known naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A produces perceptual distortions, the findings suggest that kappa opioid receptors play a key role in modulating human perception and that kappa opioid-selective antagonists could be developed as novel treatments for disorders involving perceptual distortions, such as schizophrenia, dementia, and bipolar disorders.
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.
The Journal of pharmacology and experimental therapeutics
March 1, 2004
Charles Chavkin, Sumit Sud, Wenzhen Jin et al.
212 citations
Salvinorin A, a diterpene from Salvia divinorum, is a high-affinity and selective full agonist at human kappa-opioid receptors. In human embryonic kidney-293 cells, salvinorin A fully inhibited forskolin-stimulated cAMP production, while derivatives like 2-propionate and 2-heptanoate were partial agonists. Further tests using chimeric G proteins confirmed its potency and efficacy. In Xenopus oocytes with minimal receptor reserve, salvinorin A acted as a full agonist, more efficacious than standard agonists U50488 and U69593, and similar to dynorphin A. The 2-position substituent is critical for receptor binding and activation. Salvinorin A is the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors.
Nature reviews. Drug discovery
June 1, 2022
Tristan D Mcclure-Begley, Bryan L. Roth
195 citations
Psychedelic drugs like psilocybin, DMT, and LSD are being reconsidered as treatments for neuropsychiatric diseases, with phase II trials showing that one or two doses of psilocybin can produce significant clinical effects for depression and anxiety. This has sparked commercial interest, with nearly 60 companies formed to explore psychedelic therapeutics. Despite strong evidence that the 5-HT2A receptor mediates the behavioral effects of psychedelics, it remains unclear which aspects of its activity in the central nervous system underlie therapeutic effects and whether these can be isolated with novel chemical probes. The review discusses controversies and consensus in this emerging field, highlighting how basic science can guide development of improved psychedelic-inspired medications without hallucinogenic or rewarding effects.
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.
PLoS One
June 14, 2016
Bryan L. Roth, Simon Gibbons, Warunya Arunotayanun et al.
153 citations
Novel ketamine and phencyclidine analogues sold as designer drugs bind with high affinity to the same NMDA receptor site as the parent compounds, based on radioligand binding assays conducted through a national screening program. Methoxetamine and 3-MeO-PCE, along with the 3- and 4-methoxy analogues of phencyclidine, all showed strong affinity for the PCP-site on the glutamate NMDA receptor. Methoxetamine and phencyclidine and its analogues also bound appreciably to the serotonin transporter, while the PCP analogues had high affinity for sigma receptors. NMDA receptor antagonism likely explains their dissociative and psychotomimetic effects in humans; additional receptor actions may contribute to side effects.
Trends in Pharmacological Sciences
March 1, 2003
Douglas J Sheffler, Bryan L. Roth
151 citations
Salvinorin A, a naturally occurring hallucinogen as potent as LSD, works by selectively activating the kappa opioid receptor (KOR). It is unique among KOR agonists because it contains no nitrogen. This selectivity suggests the KOR could be a target for developing drugs to treat perception-related disorders such as schizophrenia, Alzheimer's disease, and bipolar disorder.
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.
Psychopharmacology
June 1, 2010
Christina L Nemeth, Tracie A Paine, Joseph E Rittiner et al.
102 citations
Two drugs that alter perception and cognition in humans—salvinorin A (a kappa-opioid receptor agonist) and ketamine (an NMDA receptor antagonist)—produced similar disruptions in attention and motivation in rats tested on a food-motivated attention task. Both drugs increased omission errors (signs of reduced motivation) and slowed correct response latencies (processing deficits). Pre-feeding before testing produced a subtly different pattern, suggesting the drug effects were not purely motivational. A kappa-opioid receptor blocker (JDTic) prevented all effects of salvinorin A and some effects of ketamine. Binding studies showed ketamine also activates kappa-opioid receptors, though less potently than salvinorin A. These findings suggest kappa-opioid receptors may contribute to cognitive disruptions seen in conditions like schizophrenia.
The Journal of pharmacology and experimental therapeutics
August 1, 2006
Michael Ansonoff, Jiwen Zhang, Traci Czyzyk et al.
101 citations
Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, produces pain relief (antinociception) and lowers body temperature in mice by activating the kappa-opioid receptor. These effects were observed after injection of salvinorin A or a similar compound, salvinorinyl-2-propionate, into the brain of normal mice, but not in mice genetically lacking the kappa-opioid receptor. Salvinorin A showed high affinity specifically for the kappa-1 subclass of opioid receptors. In contrast, salvinorin B, an inactive derivative, had no effect on pain or body temperature. The findings confirm that salvinorin A acts through the kappa-opioid receptor to produce its behavioral effects.
Pharmacology & Therapeutics
May 1, 2004
Bryan L. Roth, Estela Lopez, Scott Beischel et al.
98 citations
Psychoactive plants alter perception, emotion, and cognition, and understanding their molecular mechanisms may reveal the biological basis of consciousness and provide validated targets for central nervous system drug discovery. This review describes an unbiased, discovery-based approach that screens the main active ingredients of psychoactive plants against the 'receptorome'—the portion of the proteome encoding receptors. It overviews the receptorome, describes public-domain in silico resources, and details new tools for mining data from the National Institute of Mental Health Psychoactive Drug Screening Program's K(i) Database. Three case studies on Hypericum perforatum, Salvia divinorum, and Ephedra sinica illustrate the approach, and recommendations for future studies are offered.
Cell
May 11, 2023
Isha Singh, Anubha Seth, Christian B. Billesbølle et al.
97 citations
Docking over 200 million small molecules against the inward-open state of the serotonin transporter (SERT) identified two potent, low-nanomolar inhibitors that stabilize an outward-closed conformation. These compounds showed little activity against common off-targets, and a cryo-EM structure confirmed the predicted binding geometry. In mouse behavioral assays, both compounds exhibited anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold greater than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects. The work suggests a promising path toward new treatments for depression, anxiety, and addiction with improved safety.
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.
Molecular interventions
October 1, 2006
Timothy A Vortherms, Bryan L. Roth
91 citations
The hallucinogenic plant Salvia divinorum, used traditionally by the Mazatecs for divination and shamanism, has seen increased recreational use in the past decade. Its active component, the neoclerodane diterpene salvinorin A, has been identified as acting through the kappa opioid receptor (KOR) in both in vitro and in vivo studies. This discovery creates opportunities for drug discovery and development targeting a range of psychiatric and non-psychiatric disorders.
Biochemistry
June 21, 2005
Feng Yan, Philip D Mosier, Richard B Westkaemper et al.
91 citations
Salvinorin A, a hallucinogenic compound from the plant Salvia divinorum, selectively and potently activates kappa-opioid receptors (KORs), making it the only known lipid-like molecule to do so and the only non-nitrogenous opioid receptor agonist. Key residues in KORs responsible for its high binding affinity and agonist efficacy were identified: interactions with tyrosine residues in helix 7 (Tyr313 and Tyr320) and helix 2 (Tyr119) stabilize salvinorin A in the binding pocket, while activation requires interactions with helix 7 tyrosines Tyr312, Tyr313, and Tyr320 and with Tyr139 in helix 3.
Biochemistry
July 28, 2009
Feng Yan, Ruslan V Bikbulatov, Viorel Mocanu et al.
81 citations
Salvinorin A, the most potent naturally occurring hallucinogen, targets the kappa-opioid receptor (KOR). Researchers designed and synthesized novel irreversible salvinorin A-derived ligands, RB-64 and RB-48, as active state probes of KOR. Based on molecular modeling, they targeted cysteine residue C315(7.38) for covalent binding. Both compounds were extraordinarily potent and selective KOR agonists in vitro and in vivo. RB-64 showed wash-resistant inhibition of binding requiring a free cysteine near the binding pocket. Mass spectrometry confirmed C315(7.38) as the anchoring residue and suggested a biochemical mechanism for covalent binding. These findings provide direct evidence of a free cysteine in the agonist-bound KOR state and insights into salvinorin A's binding and activation mechanism.
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.
Life Sciences
October 15, 2004
Feng Yan, Bryan L. Roth
68 citations
Salvinorin A, a natural hallucinogen, acts as a highly selective agonist at kappa-opioid receptors (KORs), which are the main site for dynorphin and related neuropeptides. This review summarizes the chemistry, pharmacology, and biology of salvinorin A. Because it profoundly alters consciousness and perception, studying how salvinorin A interacts with KORs may reveal new insights into the molecular and cellular basis of higher human cortical functions.
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.