Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospinal fluid.
Eduardo R Butelman, Thomas E Prisinzano, Haiteng Deng, Szymon Rus, Mary Jeanne Kreek
Journal of Pharmacology and Experimental Therapeutics February 1, 2009 DOI: 10.1124/jpet.108.145342 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Sample size | 5 |
| Population | Nonhuman primates |
| Interventions | Salvinorin A U69 593 nalmefene |
| Dose | 0.01-0.1 mg/kg i.v. |
| Topics | Salvia divinorum |
| Keywords | Hallucinogen Psychoactive substance Primate research Nonhuman primates Animal studies Preclinical research Rapid drug action Fast onset Cns penetration Quick effects Pharmacokinetics Behavioral effects Sedation Postural relaxation Drug effects Opioid antagonism |
| Citations | 67 |
| Key findings | Salvinorin A produces rapid sedation and postural relaxation in nonhuman primates within 1–2 minutes of injection, effects that are blocked by the opioid antagonist nalmefene. |
Abstract
Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high-efficacy kappa-agonist in vitro, with some unique pharmacodynamic properties. Descriptive reports show that salvinorin A-containing products produce robust behavioral effects in humans. However, these effects have not been systematically characterized in human or nonhuman primates to date. Therefore, the present studies focused on the characterization of overt effects of salvinorin A, such as sedation (operationally defined as unresponsiveness to environmental stimuli) and postural relaxation, previously observed with centrally penetrating kappa-agonists in nonhuman primates. Salvinorin A was active in these endpoints (dose range, 0.01-0.1 mg/kg i.v.) in nonhuman primates (n = 3-5), similar to the synthetic kappa-agonist U69,593 [(+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]-dec-8-yl]-benzeneacetamide], used for comparison herein. Salvinorin A effects could be prevented by a clinically available opioid antagonist, nalmefene (0.1 mg/kg), at doses known to block kappa-receptor-mediated effects in nonhuman primates. When injected intravenously, salvinorin A (0.032 mg/kg) could enter the central nervous system (as reflected in cisternal cerebrospinal fluid) within 1 min and reach concentrations that are in the reported range of the affinity (K(i)) of this ligand for brain kappa-receptors. Consistent with this finding, specific translationally viable behavioral effects (e.g., facial relaxation and ptosis) could also be detected within 1 to 2 min of injection of salvinorin A. These are the first studies documenting rapid unconditioned effects of salvinorin A in a primate species, consistent with descriptive reports of rapid and robust effects of this powerful hallucinogen in humans.
Comparable studies
Other preclinical and animal studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Mice | 2005 | Experimental study | |
| Potential anxiolytic‐ and antidepressant‐like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents Male Sprague-Dawley rats and male Albino Swiss mice | 2009 | Experimental study | |
| Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward. Wistar rats | 2008 | Experimental study | |
| Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Rats | 2010 | Experimental study | |
| The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Rhesus monkeys | 2004 | Experimental study | n = 3 |
Citations in the library
Cited by 30
- Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats. Pharmacology, Biochemistry, and Behavior December 1, 2009
- Use patterns and self-reported effects of Salvia divinorum: an internet-based survey. Drug and Alcohol Dependence October 1, 2010
- Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders Frontiers in Pharmacology September 8, 2015
- From local to global-fifty years of research on Salvia divinorum. Journal of Ethnopharmacology February 3, 2014
- Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents. Molecules October 11, 2018
and 25 more in the library
Cites 18
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Journal of Pharmacology and Experimental Therapeutics March 1, 2004
- Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Psychopharmacology May 1, 2005
- Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint, Salvia divinorum The Journal of Organic Chemistry November 1, 1984
- Pattern of use and subjective effects of Salvia divinorum among recreational users. Drug and Alcohol Dependence November 8, 2006
and 13 more in the library