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

This double-blind, placebo-controlled study (n=4) documents the subjective effects of salvinorin A (26mg up to 1.47g). Dose-related increases were observed in measures of mystical-type experience and subjective effects associated with classic serotonergic (5-HT2A) hallucinogens, with recurring themes such as revisiting childhood memories, cartoon-like imagery, and contact with entities.

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-HT2A) 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.”

Authors: Matthew W. Johnson, Katherine A. MacLean, Chad J. Reissig, Thomas E. Prisinzano & Roland R. Griffiths

Summary

Introduction

A social worker conducted a clinical interview with participants and evaluated their medical history, including a complete blood count, ECG, and chemistry panel. Participants agreed to refrain from using S. divinorum or illicit drugs during the course of the study. Four participants (two males and two females) passed screening and completed all drug sessions and data collection. They had a high school education and reported using S. divinorum at least once in the past five years.

Methods

Participants received a dose of salvinorin A ranging from 0.375 g/kg of bodyweight to 21 g/kg, and a placebo was given on each subsequent block of 5 sessions. A butane microtorch was used to heat salvinorin A on the interior of a round-bottom flask to its boiling point, without substantial combustion of salvinorin A. Inhalation of un-volatilized drug was unlikely because the residue left upon evaporation of acetone appeared strongly attached to the interior of the flask. A participant inhaled slowly while the flask was heated, followed by a verbally cued exhale. The participant’s ratings of the drug strength were collected after the session. Participants completed 20 drug sessions across several weeks, and provided expired air samples and abstinence from opioids, cocaine, and benzodiazepines.

Participants were tested for drug use before each session, and were required to provide a negative urine pregnancy test. A non-invasive patient monitor was used to collect data at baseline and every 2min for 60min following drug administration.

Participants were asked to rate their drug liking and disliking, and good and bad effects using the same 11-point scale used to assess the time course of drug effects. We hypothesized that salvinorin A would have a time course profile more similar to intravenous dimethyltryptamine than orally administered psilocybin and LSD, and might elicit subject-rated mystical-type effects. We used two questionnaires to assess the effects of psilocybin: the Hallucinogen Rating Scale (HRS), which consists of six subscales assessing various aspects of hallucinogen effects, and the Mysticism Scale, which consists of 32 items assessing primary mystical or spiritual experiences.

Subjects factor of dose was used to examine doserelated changes in the subject-rated measures and physiology. Tukey’s HSD tests were conducted to compare dose levels.

All measures were administered at the end of each session; bold typeface indicates significantly different than placebo.

Salvinorin A, a plant-derived hallucinogen, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys, depressive-like effects in rats, and kappa-opioid receptor-mediated effects on inverted screen performance in the mouse. Salvia divinorum has been found to cause mystical-type experiences having substantial and sustained personal meaning and spiritual significance, and has been found to be a kappa opioid receptor agonist. Mello, N.K., Negus, S.S., Mowry, M., Mosher, W., Briner, W., 2003. Acute physiologic and chronic histologic changes in rats and mice exposed to the unique hallucinogen salvinorin A. Salvia divinorum is a hallucinogenic sage that contains salvinorin A, a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Salvinorin A is a unique diterpene hallucinogen that causes psychosis in some users. Salvia divinorum is a plant-derived hallucinogen that has been shown to have effects on dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice.

Authors

Authors associated with this publication with profiles on Blossom

Roland Griffiths
Roland R. Griffiths is one of the strongest voices in psychedelics research. With over 400 journal articles under his belt and as one of the first researchers in the psychedelics renaissance, he has been a vital part of the research community.

Matthew Johnson
Matthew Johnson is an Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University. His research is concerned with addiction medicine, drug abuse, and drug dependence.

Institutes

Institutes associated with this publication

Johns Hopkins University
Johns Hopkins University (Medicine) is host to the Center for Psychedelic and Consciousness Research, which is one of the leading research institutes into psychedelics. The center is led by Roland Griffiths and Matthew Johnson.

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