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Naltrexone but not ketanserin antagonizes the subjective, cardiovascular and neuroendocrine effects of salvinorin-A in humans

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Background: Salvinorin-A is a terpene found in the leaves of the plant Salvia divinorum. When administered to humans, salvinorin-A induces an intense but short-lasting modified state of awareness, sharing features with those induced by the classical serotonin-2A (5-HT2A) receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor (KOR) rather than at the 5-HT2A receptor. Here we assessed the involvement of KOR- and 5-HT2A-agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans.

Methods: We conducted a placebo-controlled, randomized, double-blind study with two groups of 12 healthy volunteers with experience with psychedelic drugs. There were four experimental sessions. In Group-1 participants received the following treatment combinations: placebo+placebo, placebo+salvinorin-A, naltrexone+placebo and naltrexone+salvinorin-A. Naltrexone, a nonspecific opioid receptor antagonist, was administered at a dose of 50 mg orally. In Group-2 participants received the treatment combinations: placebo+placebo, placebo+salvinorin-A, ketanserin+placebo and ketanserin+salvinorin-A. Ketanserin, a selective 5-HT2A antagonist, was administered at a dose of 40 mg orally.

Results: Inhalation of 1 mg of vaporized salvinorin-A led to maximum plasma concentrations at 1 and 2 minutes after dosing. When administered alone, salvinorin-A severely reduced external sensory perception and induced intense visual and auditory modifications, increased systolic blood pressure, and cortisol and prolactin release. These effects were effectively blocked by naltrexone, but not by ketanserin.

Conclusions: Results support kappa opioid receptor agonism as the mechanism of action underlying the subjective and physiological effects of salvinorin-A in humans, and rule out the involvement of a 5-HT2A-mediated mechanism.

Maqueda, A. E., Valle, M., Addy, P. H., Antonijoan, R. M., Puntes, M., Coimbra, J., … & Barker, S. (2016). Naltrexone but not ketanserin antagonizes the subjective, cardiovascular and neuroendocrine effects of salvinorin-A in humans. International Journal of Neuropsychopharmacology, pyw016.
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