TY - JOUR
T1 - Naltrexone but Not Ketanserin Antagonizes the Subjective, Cardiovascular, and Neuroendocrine Effects of Salvinorin-A in Humans
AU - Maqueda, Ana Elda
AU - Valle, Marta
AU - Addy, Peter H.
AU - Antonijoan, Rosa Maria
AU - Puntes, Montserrat
AU - Coimbra, Jimena
AU - Ballester, Maria Rosa
AU - Garrido, Maite
AU - González, Mireia
AU - Claramunt, Judit
AU - Barker, Steven
AU - Lomnicka, Izabela
AU - Waguespack, Marian
AU - Johnson, Matthew W.
AU - Griffiths, Roland R.
AU - Riba, Jordi
N1 - Publisher Copyright:
© The Author 2016. Published by Oxford University Press on behalf of CINP.
PY - 2016
Y1 - 2016
N2 - 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 receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor rather than at the serotonin-2A receptor. Here, we assessed the involvement of kappa-opioid receptor and serotonin-2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. Methods: We conducted a placebo-controlled, randomized, double-blind study with 2 groups of 12 healthy volunteers with experience with psychedelic drugs. There were 4 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 serotonin-2A 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 serotonin-2A-mediated mechanism.
AB - 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 receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor rather than at the serotonin-2A receptor. Here, we assessed the involvement of kappa-opioid receptor and serotonin-2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. Methods: We conducted a placebo-controlled, randomized, double-blind study with 2 groups of 12 healthy volunteers with experience with psychedelic drugs. There were 4 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 serotonin-2A 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 serotonin-2A-mediated mechanism.
KW - Salvinorin-A
KW - human pharmacology
KW - kappa opioid receptor antagonism
KW - ketanserin
KW - naltrexone
KW - serotonin-2A antagonism
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U2 - 10.1093/ijnp/pyw016
DO - 10.1093/ijnp/pyw016
M3 - Article
C2 - 26874330
AN - SCOPUS:85039777151
SN - 1461-1457
VL - 19
SP - 1
EP - 13
JO - International Journal of Neuropsychopharmacology
JF - International Journal of Neuropsychopharmacology
IS - 7
ER -