Received for publication September 4, 2008.
Revised November 7, 2008.
Accepted for publication November 7, 2008.

Unconditioned behavioral effects of the powerful -opioid hallucinogen, salvinorin A: Fast onset and entry into cerebrospinal fluid

Abstract

Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high efficacy -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 non-human primates to date. The present studies therefore 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 -agonists in non-human primates. Salvinorin A was active in these endpoints (dose range: 0.01-0.1 mg/kg, i.v.) in non-human primates (n=3-5), similarly to the synthetic -agonist U69,593, 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 -receptor mediated effects in non-human primates. When injected i.v., salvinorin A (0.032 mg/kg) could enter the CNS (as reflected in cisternal CSF) within 1 minute, and reach concentrations that are in the reported range of the affinity (K_i) of this ligand for brain -receptors. Consistent with this finding, specific translationally viable behavioral effects (e.g., facial relaxation and ptosis) could also be detected within 1-2 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.

Key words: CSF, Salvia divinorum, kappa opioid, nalmefene, salvinorin A, sedation