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J. Coimbra

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

February 12, 2016 / Neuroscience, Papers, Publications, Salvia / Salvinorin A / By / , , , , , ,

Abstract

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. http://dx.doi.org/10.1093/ijnp/pyw016
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Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans

June 5, 2015 / Neuroscience, Papers, Psychology, Publications, Salvia / Salvinorin A / By / , , , , , ,

Abstract

Background: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profile of subjective effects of increasing doses of salvinorin-A in healthy volunteers with special emphasis on interoception.

Methods: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1 mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included among others: the Hallucinogen Rating Scale (HRS), the Altered States of Consciousness (APZ), and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness (MAIA).

Results: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the high dose led to a sense of a complete loss of contact with the body.

Conclusions: Salvinorin-A induced intense psychotropic effects characterized by a dose-dependent gating of external audio-visual information and an inverted-U dose-response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception and the sense of body ownership in humans.

Maqueda, A. E., Valle, M., Addy, P. H., Antonijoan, R. M., Puntes, M., Coimbra, J., … & Riba, J. (2015). Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans. International Journal of Neuropsychopharmacology, pyv065. http://dx.doi.org/10.1093/ijnp/pyv065
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