Proceedings of the National Academy of Sciences of the United States of America
September 3, 2002
Bryan L Roth, Karen Baner, Richard 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.
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.
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 A 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.
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.
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.
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.
Bioorganic & medicinal chemistry letters
June 1, 2013
Warunya Arunotayanun, Jeffrey W Dalley, Xi-Ping Huang et al.
41 citations
Two widely marketed novel psychoactive drugs, alpha-methyl-tryptamine and 5-methoxy-N,N-diallyl-tryptamine, were analyzed for their chemical structure and binding to serotonin receptor subtypes. These tryptamine-derived compounds, sold without restriction, can cause psychosis and hallucinations that may lead to injury or death. The study elucidates their structures and receptor binding profiles, providing insight into their pharmacological actions.
The Journal of biological chemistry
February 2, 2007
Timothy A Vortherms, Philip D Mosier, Richard B Westkaemper et al.
40 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, binds selectively and potently to the kappa-opioid receptor (KOR). Unlike most ligands for peptide-binding receptors, it is non-nitrogenous and lipid-like. Using chimeric receptors, mutagenesis, accessibility methods, and modeling, the study found that helix 2 of KOR is essential for binding, with two valine residues (Val-108 and Val-118) conferring selectivity. Modeling suggested these residues indirectly affect binding by rotating helix 2. Accessibility experiments comparing KOR and the delta-opioid receptor, which does not bind salvinorin A, showed differential water accessibility of key residues, indicating that differences in helix 2 orientation are critical for salvinorin A's selective binding to KOR.
European journal of medicinal chemistry
October 6, 2014
Prabhakar R Polepally, Krzysztof Huben, Eyal Vardy et al.
28 citations
Salvinorin A, a compound from the plant Salvia divinorum, binds strongly and selectively to the κ-opioid receptor (KOR). A new series of salvinorin A derivatives with reactive Michael acceptor groups at C-2 was created to explore how the compound interacts with the receptor. Most of these derivatives retained high affinity for KOR, and some also bound to the μ-opioid receptor (MOR). None showed wash-resistant irreversible binding. Using the KOR crystal structure, mutagenesis data, and other methods, the researchers identified possible ways the new compounds interact with both KOR and MOR.
Frontiers in molecular biosciences
January 1, 2023
Vladimir M Pogorelov, Ramona M Rodriguiz, Bryan L Roth et al.
26 citations
Lisuride, a drug that activates the serotonin 2A receptor but preferentially stimulates G protein over β-arrestin signaling, produced few hallucinogenic-like behaviors (head twitches) in mice, unlike LSD. In wild-type and β-arrestin knockout mice, lisuride reduced locomotion and rearing, increased then decreased grooming in βArr2 knockouts, and decreased serotonin syndrome responses especially in βArr2 knockouts. Prepulse inhibition was disrupted only in βArr1 knockouts at 0.5 mg/kg, and this effect was not reversed by a 5-HT2A antagonist but was normalized by clozapine and other drugs. In vesicular monoamine transporter 2 mice, lisuride reduced immobility in the tail suspension test and promoted sucrose preference for up to two days, suggesting antidepressant-like effects without hallucinogenic actions.
Bioorganic & medicinal chemistry letters
May 15, 2013
Prabhakar R Polepally, Kate White, Eyal Vardy et al.
24 citations
Salvinorin A, the active ingredient in the hallucinogenic plant Salvia divinorum, is nature's most potent hallucinogen and selectively activates the κ-opioid receptor. To explore how these compounds bind to specific receptors, researchers synthesized a series of dicarboxylic ester derivatives of salvinorin A and tested their binding affinity at κ-, δ-, and μ-opioid receptors. Most of the new compounds showed high affinity for the κ-opioid receptor. The methyl malonyl derivative 4 had the strongest binding, with a Ki of 2 nM, while analogues 5, 7, and 14 also exhibited significant affinity, with Ki values of 21, 36, and 39 nM respectively. These findings provide insights into brain chemistry and ligand-receptor interactions.
Life sciences
December 22, 2005
Kerry Ann O'Connor, Bryan L Roth
22 citations
Psychoactive plants and their derivatives have long been used for spiritual, therapeutic, and recreational purposes, and they have also advanced understanding of neurochemical processes and central nervous system diseases. G-protein coupled receptors (GPCRs) are the most common molecular targets for psychoactive drugs, and the receptorome—the portion of the genome encoding ligand reception—comprises over 8% of the human genome, offering many possible targets. A systematic, comprehensive study is needed to identify novel active psychoactive plant-based compounds and their molecular targets. This work describes a high-throughput screening system for psychoactive compounds against the receptorome, using Salvia divinorum and Banisteriopsis caapi as examples where the system identified each compound's molecular target.
The International Journal of Neuropsychopharmacology
January 30, 2024
Blake A Fordyce, Bryan L Roth
4 citations
Psychedelic compounds from natural sources have been consumed for centuries. Modern scientists now use computational tools, cellular assays, and behavioral metrics to study how these compounds cause changes across molecular, cellular, circuit, and system levels. This paper reviews the history of psychedelics in science, medicine, and culture, outlines current pharmacological research techniques, and identifies gaps in knowledge about the physiological changes induced by psychedelics, the limits of their therapeutic potential, and how to improve treatments becoming accessible worldwide.
bioRxiv : the preprint server for biology
June 5, 2023
Vladimir M Pogorelov, Ramona M Rodriguiz, Bryan L Roth et al.
4 citations
preprint
Lisuride, a drug that activates the serotonin 2A receptor without causing hallucinations, reduced locomotion and rearing in mice but produced a U-shaped pattern of stereotypies. Head twitches and retrograde walking were rare. Grooming decreased in β-arrestin1 knockout mice but showed a biphasic response in β-arrestin2 knockouts. Prepulse inhibition was disrupted by lisuride only in β-arrestin1 knockouts, and this effect was not reversed by a serotonin 2A antagonist but was normalized by a dopamine D2/D3 antagonist in wild-type mice. Lisuride also reduced immobility in the tail suspension test and increased sucrose preference for up to two days, suggesting antidepressant-like effects without hallucinogenic activity.