Psychopharmacology
May 1, 2005
Yong Zhang, Eduardo R Butelman, Stefan D Schlussman et al.
198 citations
Salvinorin A, a hallucinogen from Salvia divinorum, is a potent kappa opioid receptor agonist. In mice, higher doses (1.0 and 3.2 mg/kg) significantly decreased dopamine levels in the caudate putamen but not in the nucleus accumbens, an effect blocked by a kappa opioid receptor antagonist. These same doses caused conditioned place aversion and reduced locomotor activity. The findings suggest that salvinorin A's reduction of striatal dopamine may contribute to its aversive and motor-suppressing effects, consistent with its in vitro characterization as a kappa opioid receptor agonist.
Psychopharmacology
March 1, 2004
Eduardo R Butelman, Todd J Harris, Mary Jeanne Kreek
102 citations
Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, produces effects in rhesus monkeys that closely resemble those of a high-efficacy kappa-opioid receptor agonist. In monkeys trained to discriminate the kappa-agonist U69,593 from a placebo, salvinorin A dose-dependently produced full generalization to U69,593 at doses of 0.001 to 0.032 mg/kg. These effects began within 5 to 15 minutes after injection and faded by 120 minutes. The opioid antagonist quadazocine fully blocked salvinorin A's effects, while the kappa-selective antagonist GNTI only partially blocked them. The NMDA antagonist ketamine did not produce similar effects, suggesting that not all hallucinogens act through the same mechanism.
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.
Frontiers in Pharmacology
September 8, 2015
Mary Jeanne Kreek, Eduardo R. Butelman
77 citations
Salvinorin A, a hallucinogen from the plant Salvia divinorum, selectively activates kappa-opioid receptors (KOPr) in the brain, which are normally stimulated by endogenous dynorphins. This activation counterbalances dopamine-driven reward and mood systems, producing aversion and anhedonia in animal models. Unlike other opioid ligands, salvinorin A is a non-nitrogenous neoclerodane, offering a novel chemical scaffold for drug development. Ongoing research aims to create semi-synthetic analogs with partial or biased KOPr agonism to achieve therapeutic effects—such as for pain or mood disorders—while reducing the undesirable effects seen with salvinorin A itself.
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.
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.
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.
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.
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.
Frontiers in pharmacology
January 1, 2015
Eduardo R. Butelman, Mary Jeanne Kreek
3 citations
correction
No Summary