Two drugs that alter perception and cognition in humans—salvinorin A (a kappa-opioid receptor agonist) and ketamine (an NMDA receptor antagonist)—produced similar disruptions in attention and motivation in rats tested on a food-motivated attention task. Both drugs increased omission errors (signs of reduced motivation) and slowed correct response latencies (processing deficits). Pre-feeding before testing produced a subtly different pattern, suggesting the drug effects were not purely motivational. A kappa-opioid receptor blocker (JDTic) prevented all effects of salvinorin A and some effects of ketamine. Binding studies showed ketamine also activates kappa-opioid receptors, though less potently than salvinorin A. These findings suggest kappa-opioid receptors may contribute to cognitive disruptions seen in conditions like schizophrenia.
Salvinorin A, the active compound in the hallucinogenic herb Salvia divinorum, does not directly interact with the endocannabinoid system. Although some earlier studies suggested a link, this work shows that salvinorin A does not bind to or activate CB1 cannabinoid receptors. In laboratory tests, it caused reduced movement and pain relief, effects blocked by a kappa-opioid receptor antagonist but not by a CB1 antagonist. Salvinorin A also did not substitute for THC in drug discrimination tests. The results indicate that similarities between salvinorin A and cannabinoid effects stem from its activation of kappa-opioid receptors, and previous findings of CB1 antagonist reversal may be due to that antagonist also dampening kappa-opioid receptor activation.