Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum

Abstract

Salvinorin A is a potent, selective nonnitrogenous kappa opioid agonist and the known psychoactive constituent of Salvia divinorum, a member of the mint family that has been used for centuries by Mazatec shamans of Mexico for divination and spiritual healing. S. divinorum has over the last several years gained increased popularity as a recreational drug. This is a double-blind, placebo controlled study of salvinorin A in 4 psychologically and physically healthy hallucinogen-using adults. Across sessions, participants inhaled 16 ascending doses of salvinorin A and 4 intermixed placebo doses under comfortable and supportive conditions. Doses ranged from 0.375 μg/kg to 21 μg/kg. Subject-rated drug strength was assessed every 2 min for 60 min after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2 min (first time point) and definite subjective effects were no longer present at approximately 20 min after inhalation. Dose-related increases were observed on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects associated with classic serotonergic (5-HT2(A)) hallucinogens (Hallucinogen Rating Scale). Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities. Under these prepared and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects.

Figure 1. Time- and dose-related changes in drug effects

(A) Subject-rated drug strength (reported at 2-minute intervals) as a function of time (pre-drug baseline to 60 minutes following inhalation). Data points show mean ratings (N=4). For graphical clarity, alternating doses in the dose sequence were deleted. (B) Subject-rated peak drug strength from the end-of-session ratings as a function of dose (logarithmic abscissa). Data points show mean ratings (N=4); brackets show + and −1 SEM. Filled symbols indicate that the data point was significantly different from placebo (Tukey’s HSD test, p<.05). (C) Peak heart rate (beats per minute) and blood pressure (mm of Hg) as a function of dose (logarithmic abscissa). Data points show means (N=4); brackets show + and − 1 SEM.