Salvinorin A and derivatives: protection from metabolism does not prolong short-term, whole-brain residence.
Jacob M Hooker, Thomas A Munro, Cécile Béguin, David Alexoff, Colleen Shea, Youwen Xu, Bruce M Cohen
Neuropharmacology September 2009 DOI: 10.1016/j.neuropharm.2009.06.044 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical imaging study Peer reviewed |
|---|---|
| Population | Baboons and rodents |
| Interventions | Salvinorin A EOM-SB |
| Topics | Salvia divinorum |
| Key points | Metabolically stable salvinorin A derivatives showed similar rapid brain pharmacokinetics to salvinorin A in baboons, indicating metabolism is not solely responsible for its brief brain residence time. In rodents, EOM-SB declined more slowly than SA after intraperitoneal administration, suggesting metabolic protection prolongs action only with slow absorption. |
Abstract
Salvinorin A (SA) is a potent kappa opioid agonist with a brief duration of action. Consistent with this, our previous positron emission tomography (PET) studies of carbon-11 labeled SA showed that brain levels decrease rapidly after intravenous administration. SA is rapidly metabolized, giving the much less potent salvinorin B (SB), which is presumed to be responsible in part for SA's brief duration of action. To test this, we labeled the metabolically stable methyl ester of SA and SB with carbon-11 and compared their pharmacokinetics by PET imaging after intravenous administration to baboons. Labeling of salvinorin B ethoxymethyl ether (EOM-SB), a derivative with greater potency and resistance to metabolism, provided an additional test of the role of metabolism in brain efflux. Plasma analysis confirmed that SB and EOM-SB exhibited greater metabolic stability than SA. However, the three compounds exhibited very similar pharmacokinetics in brain, entering and exiting rapidly. This suggests that metabolism is not solely responsible for the brief brain residence time of SA. We determined that whole-brain concentrations of EOM-SB declined more slowly than SA after intraperitoneal administration in rodents. This is likely due to a combination in EOM-SB's increased metabolic stability and its decreased plasma protein affinity. Our results suggest that protecting salvinorin A derivatives from metabolism will prolong duration of action, but only when administered by routes giving slow absorption.
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 17
- Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the κ opioid agonist Salvinorin A in humans. Biological Psychiatry November 15, 2012
- Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A. Pharmacological Reviews June 1, 2011
- New psychoactive substances of natural origin: A brief review Journal of Food and Drug Analysis April 18, 2017
- The discriminative effects of the kappa-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects. Psychopharmacology June 1, 2010
- Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A. Journal of Natural Products April 25, 2011
and 12 more in the library
Cites 16
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum(Labiatae) Journal of the Chemical Society Perkin Transactions 1 1982
- 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
- Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans. Neuroimage July 1, 2008
and 11 more in the library