Psychopharmacology
March 1, 2013
Katherine A Maclean, Matthew W Johnson, Chad J Reissig et al.
134 citations
Inhaled salvinorin A, the active compound in Salvia divinorum, produces intense, dose-related subjective and cognitive effects that peak within 2 minutes and rapidly dissipate. In eight healthy adults with hallucinogen experience, high doses frequently caused maximal drug strength ratings or unresponsiveness. The compound induced dissociative effects and impaired recall and recognition memory, with some overlap with classic hallucinogens but a qualitatively distinct profile. No persisting adverse effects were observed at one-month follow-up. These findings contribute to understanding the kappa opioid system and may inform future therapeutic applications.
Drug and alcohol dependence
May 1, 2011
Matthew W Johnson, Katherine A Maclean, Chad J Reissig et al.
134 citations
Salvinorin A, the psychoactive compound in Salvia divinorum, produces rapid, dose-dependent subjective effects that peak at 2 minutes and subside within 20 minutes after inhalation. In a double-blind, placebo-controlled study with 4 healthy hallucinogen-using adults, doses from 0.375 to 21 μg/kg increased ratings of mystical-type experiences and effects similar to classic hallucinogens. Salvinorin A did not significantly raise heart rate or blood pressure. Participants reported intense experiences involving altered spatial orientation, pressure on the body, childhood memories, cartoon-like imagery, and contact with entities. The findings suggest salvinorin A has a unique profile that includes mystical-type effects.
Life sciences
December 22, 2005
Thomas E Prisinzano
128 citations
The Mexican mint Salvia divinorum is currently an unregulated hallucinogen, leading online botanical companies to market it as a legal alternative to other controlled plant hallucinogens, and its misuse is predicted to increase rapidly. The active ingredient, salvinorin A, acts as a kappa opioid receptor agonist in both laboratory and animal studies. This review covers the current state of research into the psychopharmacology of S. divinorum.
Journal of medicinal chemistry
December 26, 2014
Andrew P Riley, Chad E Groer, David Young et al.
115 citations
Salvinorin A, a compound from the leaves of Salvia divinorum, activates κ-opioid receptors and could be a basis for treating substance abuse. Researchers synthesized several derivatives with modified furan rings to better understand how this part of the molecule binds to the receptor. Functional assays showed that smaller substitutions are preferred, indicating the furan ring fits into a tight part of the binding pocket. The most potent analogue reduced drug-seeking behavior in an animal model of relapse without causing sedation, a common side effect of other κ-opioid agonists.
Pharmacological reviews
June 1, 2011
Christopher W Cunningham, Richard B Rothman, Thomas E Prisinzano
109 citations
Salvinorin A, the psychoactive compound in the Salvia divinorum plant, activates kappa-opioid receptors (KOP) to produce its intense hallucinogenic effects, making it the first known non-nitrogenous opioid receptor agonist. Unlike classic hallucinogens such as LSD and mescaline, its effects do not involve the 5-HT(2A) receptor. Research into its structure has yielded receptor probes and tools to study its psychological effects. Salvinorin A shows therapeutic potential for treating pain, mood disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloid compounds can serve as scaffolds for developing drugs targeting aminergic G-protein coupled receptors.
Synapse (New York, N.Y.)
December 1, 2005
Matthew D Schmidt, Mark S Schmidt, Eduardo R Butelman et al.
85 citations
Salvinorin A, a potent hallucinogen from Salvia divinorum, is rapidly eliminated from the body after intravenous administration in rhesus monkeys, with an average elimination half-life of about 57 minutes. Pharmacokinetic differences in distribution half-life, elimination half-life, and area under the curve were observed between males and females, suggesting potential sex differences in the drug's effects. The presumed major metabolite, salvinorin B, was not detected in the study, though it is known to accumulate outside the body.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
June 1, 2009
Zeynep S Teksin, Insong J Lee, Noble N Nemieboka et al.
76 citations
Salvinorin A, a potent hallucinogen from Salvia divinorum, is rapidly eliminated after intraperitoneal dosing in rats, with a half-life of 75 minutes and a clearance of 26 L/h/kg. Its distribution is extensive (47.1 L/kg), but brain levels are low (brain-to-plasma ratio 0.050) and the brain half-life is only 36 minutes. In cell studies, salvinorin A is transported by P-glycoprotein and metabolized by several enzymes, including CYP2D6, CYP1A1, CYP2C18, CYP2E1, and UGT2B7. These findings align with the compound's fast onset and short duration of action.
The Journal of pharmacology and experimental therapeutics
February 1, 2007
Richard B Rothman, Daniel L Murphy, Heng Xu et al.
75 citations
Salvinorin A, a hallucinogenic compound that activates kappa-opioid receptors, also partially inhibits mu-opioid receptor binding through an allosteric mechanism. In cells expressing human mu-opioid receptors, salvinorin A reduced binding of two different radioligands (DAMGO and diprenorphine) in a dose-dependent, nonlinear way, altering both the number of binding sites and their affinity. It also slowed the dissociation of these ligands from the receptor and acted as an uncompetitive inhibitor of receptor signaling. Similar effects were observed in rat brain tissue. Together, these findings indicate that salvinorin A modulates the mu-opioid receptor allosterically, not by binding at the same site as typical opioids.
Bioorganic & medicinal chemistry letters
October 18, 2004
Kevin Tidgewell, Wayne W Harding, Mark Schmidt et al.
68 citations
Salvinorin A, a hallucinogen from Salvia divinorum, may serve as a therapeutic for stimulant abuse, but no methods exist to detect it or its metabolites in biological fluids. This work describes a straightforward synthesis of a deuterium-labeled analog of salvinorin A and its use as an internal standard for detecting salvinorin A and its metabolites in biological fluids using LC-MS, providing a tool for studying its metabolism and potential therapeutic development.
The Journal of pharmacology and experimental therapeutics
February 1, 2009
Eduardo R Butelman, Thomas E Prisinzano, Haiteng Deng et al.
67 citations
Salvinorin A, the main active component of the hallucinogenic plant Salvia divinorum, produces rapid behavioral effects in nonhuman primates, including sedation and postural relaxation, similar to synthetic kappa-agonists. These effects occur within 1 to 2 minutes of intravenous injection and can be blocked by the opioid antagonist nalmefene. The drug enters the central nervous system within 1 minute at concentrations matching its affinity for brain kappa-receptors. This is the first systematic documentation of such rapid unconditioned effects in a primate species, consistent with human reports of the drug's fast and powerful effects.
The Journal of pharmacology and experimental therapeutics
January 1, 2007
Eduardo R Butelman, Marek Mandau, Kevin Tidgewell et al.
64 citations
The hallucinogen salvinorin A, derived from the plant Salvia divinorum, acts as a high-efficacy kappa-opioid agonist in nonhuman primates. In a neuroendocrine biomarker assay measuring the anterior pituitary hormone prolactin, salvinorin A produced dose- and time-dependent effects in adult male and female rhesus monkeys (n = 4 each). It was approximately equipotent to the synthetic kappa-agonist U69,593 (ED50 0.015 mg/kg vs. 0.0098 mg/kg) but had a shorter duration. The effects were blocked by a high dose of the opioid antagonist nalmefene (0.1 mg/kg) but not by a low dose (0.01 mg/kg) or by the 5HT2 receptor antagonist ketanserin. Effects were more robust in females. Cloning of the rhesus monkey kappa-opioid receptor gene showed high homology with the human gene.
Journal of natural products
January 1, 2006
Wayne W Harding, Matthew Schmidt, Kevin Tidgewell et al.
59 citations
Salvinorin A, a hallucinogen from the plant Salvia divinorum, is unique as the first non-nitrogenous compound known to bind to opioid receptors. To understand why it selectively targets kappa opioid receptors, researchers systematically altered its structure and tested the effects on receptor binding and activity. This work describes chemical transformations of salvinorin A, including a semisynthesis of salvinicins A and B. It also identifies compound 10a as the first neoclerodane diterpene with delta opioid antagonist activity, providing new tools for studying opioid receptor interactions.
Molecules (Basel, Switzerland)
October 11, 2018
Bronwyn M Kivell, Kelly F Paton, Nitin Kumar et al.
45 citations
A potent and selective kappa opioid receptor (KOPr) analogue of Salvinorin A, Mesyl Sal B, reduces cocaine-induced hyperactivity and behavioral sensitization to cocaine in male rats without causing aversion, sedation, anxiety, or learning and memory deficits. It does not alter sucrose self-administration. However, it increases immobility in the forced swim test, indicating pro-depressive effects. In male mice, Mesyl Sal B is less potent than Salvinorin A at reducing pain in antinociceptive assays. The compound has fewer side effects and longer in vivo action than Salvinorin A, but its pain-relieving effects are limited.
Psychopharmacology
June 1, 2010
Eduardo R Butelman, Szymon Rus, Thomas E Prisinzano et al.
43 citations
Salvinorin A, a plant-derived hallucinogen, selectively activates kappa-opioid receptors and produces effects distinct from classic hallucinogens like psilocybin or dissociatives like ketamine. In adult rhesus monkeys trained to discriminate salvinorin A from vehicle, the compound's discriminative cue generalized to other kappa-opioid agonists (bremazocine, U69,593, U50,488) but not to mu- or delta-opioid agonists, psilocybin, or ketamine. The opioid antagonist quadazocine blocked these effects, while the serotonin antagonist ketanserin did not. Unconditioned behavioral measures (facial relaxation, ptosis) confirmed kappa-receptor mediation. These results demonstrate that salvinorin A's interoceptive effects are mediated specifically by kappa-opioid receptor agonism, mechanistically distinct from serotonergic hallucinogens.
Journal of natural products
April 25, 2011
Anthony Lozama, Christopher W Cunningham, Michael J Caspers et al.
40 citations
New chemical methods using microwave heating enabled the first successful Diels-Alder cycloaddition reactions on the furan ring of salvinorin A, a neoclerodane diterpene natural product. This approach introduced electron-withdrawing groups and bulky aromatic rings at the C-12 position. Some of the resulting cycloadducts, specifically dimethyl- and diethylcarboxylate analogues, retained affinity and selectivity for kappa opioid receptors and acted as full agonists. However, converting these cycloadducts into planar phenyl ring systems reduced their receptor affinity. The work provides a novel strategy for rapidly exploring structure-activity relationships of furan-containing natural products.
Bioorganic & medicinal chemistry
May 1, 2012
Kimberly M Lovell, Tamara Vasiljevik, Juan J Araya et al.
35 citations
A palladium-catalyzed cross-coupling reaction (Liebeskind-Srogl) applied to a modified natural product scaffold produces ketone analogs of salvinorin A at neutral pH and room temperature, expanding synthetic access to this class. A one-step microwave method converts salvinorin A to its 12-epimer, previously requiring multiple steps. Several new analogs (alkene 9 and aromatic compounds 12, 19, 23, 25, 26) retain affinity and selectivity for kappa opioid receptors (KOP), and the furan-2-yl analog (31) shows similar affinity to the parent compound. These results indicate that diverse aromatic groups attached to the decalin core may be tolerated by KOP receptors, potentially yielding additional ligands.
Tetrahedron
December 20, 2008
Gianfranco Fontana, Giuseppe Savona, Benjamín Rodríguez et al.
32 citations
Salvinorin A, a compound from the hallucinogenic mint Salvia divinorum, is the only known non-nitrogenous and specific kappa-opioid agonist. Several related compounds from Salvia splendens and a series of semisynthetic derivatives, including some with a pyrazoline structural moiety, were tested for their ability to bind to human mu, delta, and kappa opioid receptors. None of these compounds showed high-affinity binding to these receptors. However, one compound (10) showed modest affinity for kappa receptors, suggesting that other naturally occurring neoclerodanes from different Salvia species may have opioid affinity.
The Journal of pharmacology and experimental therapeutics
June 1, 2012
Eduardo R Butelman, Michael Caspers, Kimberly M Lovell et al.
27 citations
The major efflux transporter P-glycoprotein at the blood-brain barrier modulates the central nervous system effects of the hallucinogen salvinorin A. Pretreatment with either the competing substrate loperamide (0.032-0.32 mg/kg) or the selective blocker tariquidar (0.32-3.2 mg/kg) dose-dependently enhanced salvinorin A-induced ptosis, but not facial relaxation, in nonhuman primates. Neither agent affected the effects of U69,593, a κ-agonist that is a poor P-glycoprotein substrate. Tariquidar (3.2 mg/kg) also increased peak levels of salvinorin A in cerebrospinal fluid after intravenous administration. These findings demonstrate that P-glycoprotein activity can influence salvinorin A's behavioral effects and CNS entry.
Journal of medicinal chemistry
May 9, 2013
Thomas E Prisinzano
22 citations
Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, activates opioid receptors—the same targets as morphine—despite being non-nitrogenous, a first for opioid receptor agonists. Its effects also do not involve previously studied psychotomimetic targets. This Perspective describes a research program aimed at developing tools to understand drug tolerance and dependence, with the goal of designing new treatments for pain, drug abuse, and other central nervous system disorders.
Tetrahedron
February 21, 2009
Gianfranco Fontana, Giuseppe Savona, Benjamín Rodríguez et al.
12 citations
Salvinorin A is a unique naturally occurring compound that activates κ-opioid receptors without containing nitrogen. Researchers modified the A ring of salvinorin A and related compounds from Salvia splendens and a non-natural derivative, producing new molecules. When tested for opioid receptor activity, none of these derivatives were active. The absence of activity may be due to the presence of a lactone group at specific positions in the molecular structure.
Journal of psychopharmacology (Oxford, England)
April 1, 2016
Matthew W Johnson, Katherine A Maclean, Michael J Caspers et al.
11 citations
After inhaling a high dose of vaporized salvinorin A (18–21 mcg/kg), plasma levels of the compound peak at 2 minutes and then rapidly decline. Higher drug levels are strongly linked to stronger subjective and observer-rated drug effects. Prolactin rises significantly from 5 minutes onward, peaking at 15 minutes, while cortisol increases are inconsistent across participants. Hormonal changes do not closely track drug levels. This work demonstrates a direct relationship between salvinorin A plasma concentrations and drug effects in humans, validating an efficient inhalation method.
Analytical methods : advancing methods and applications
December 21, 2013
Michael J Caspers, Todd D Williams, Kimberly M Lovell et al.
6 citations
A method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) measures the hallucinogen salvinorin A in non-human primate cerebrospinal fluid (CSF) and human plasma. For CSF, simple dilution with acetonitrile and formic acid replaces solid phase extraction. Human plasma requires centrifugation, then loading onto a C18 SPE column. A shallow acetonitrile/water gradient elutes the compound. Limits of quantification are 0.0125 ng/mL for CSF and 0.05 ng/mL for plasma. Interday precision and accuracy are below 1.7% and 9.42% for CSF and 3.47% and 12.37% for plasma. The method determined salvinorin A concentrations in a Rhesus monkey study and a human trial using behaviorally active doses.