Human psychopharmacology and dose-effects of salvinorin A, a kappa-opioid agonist hallucinogen present in the plant Salvia divinorum, Matthew W. Johnson et al., 2011

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

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

Drug and Alcohol Dependence, 2011, 115, (1-2), 150–155.

doi: 10.1016/j.drugalcdep.2010.11.005



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. Salvia 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 minutes for 60 minutes after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2 minutes (first time point) and definite subjective effects were no longer present at approximately 20 minutes 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.

Keywords : salvinorin A; Salvia divinorum; kappa opioid agonist; hallucinogen; psychedelic; humans


1. Introduction

Shamans of the Mazatec people of Oaxaca, Mexico have used Salvia divinorum, a member of the mint family, for at least centuries in ethnomedical practices including divination and spiritual healing (Valdes, 1994; Ott, 1995, 1996; Siebert, 1994). S. divinorum contains the known psychoactive constituent salvinorin A, which is a neoclerodane diterpene and a potent nonnitrogenous kappa opioid agonist, with no activity at the 5-HT2A serotonin receptor, the principal site of activity of classic hallucinogens such as LSD, psilocybin, dimethyltryptamine, and mescaline (Roth et al., 2002; Prisinzano, 2005). Studies in monkeys show salvinorin A produces discriminative stimulus effects similar to other high efficacy kappa agonists (Butelman et al., 2004). A kappa-like profile of antinociceptive and behavioral effects has also been demonstrated in rodents (Fantegrossi et al., 2005; Wang et al., 2005; Zhang et al., 2005; McCurdy et al., 2006; Carlezon et al., 2006). Nonhuman research with salvinorin A has shown mixed results regarding abuse potential. Evidence suggestive of no or low abuse potential includes research showing salvinorin A to elevate thresholds for intracranial stimulation and decrease extracellular dopamine concentrations in the nucleus accumbens in rats (Carlezon et al., 2006), and produce conditioned place
aversion in mice (Zhang et al., 2005). Evidence suggestive of abuse potential are recent findings demonstrating intracerebroventricular salvinorin A self-administration and conditioned place preference in mice at relatively low doses (Braida et al., 2008).

Although the ethnomedical use of S. divinorum by shamans dates back at least for hundreds of years, an understanding of the psychoactive effects of salvinorin A by American and European drug users dates back only about 15 years (Siebert, 1994; Ott, 1995). In traditional Mexican use, the leaves of S. divinorum are chewed or made into an infusion and swallowed (Valdes, 1994; Siebert, 1994, Ott, 1995). Outside the Mazatec, drug users typically inhale the drug via smoking or, less frequently, via volatilization, although buccal administration also occurs (Baggott et al., 2010; González et al., 2006). Internet vendors and “head shops” sell S. divinorum plants, dried leaves, leaf extracts with increased salvinorin A concentrations (for smoking), and tinctures (for buccal administration). As of 2006 at least 1.8 million people age 12 or older have used the drug in the United States (Office of Applied Studies, 2007), and the prevalence is likely higher now. Survey research suggests that effects are brief and that users claim positive after-effects such as increased insight and improved mood (Baggott et al., 2010). One study found high scores on a measure of state anxiety when asking participants to retrospectively evaluate their last use (González et al., 2006). During a recent 10-year period, the California Poison Control System received 37 telephone calls concerning S. divinorum exposures with reported neurologic, cardiovascular, and gastrointestinal effects (Vohra et al, 2009). Three cases reported that S. divinorum use was associated with an extended psychotic-type reaction, although concurrent other drug use (Singh, 2007), suspected schizophrenic predisposition (Przekop and Lee, 2009), and injuries secondary to medical treatment (Paulzen and Grunder, 2008) have complicated interpretation of these cases. Possession or use of S. divinorum is currently illegal in 13 nations and 15 states within the United States, and additional nations and states have implemented lesser forms of control.

Given the wide availability, continued popular use, and legal controversy, information is needed regarding the human psychopharmacology of salvinorin A. In addition to providing information about this novel drug, studying the effects salvinorin A may assist in identifying new opioid receptor modulators that may have therapeutic applications in certain psychiatric disorders (e.g., Alzheimer’s disease, schizophrenia, bipolar disorder, cocaine abuse) and in the treatment of pain (Mello and Negus, 2000; Sheffler and Roth, 2003; Kivell and Prisinzano, 2010). This is a report of preliminary findings of basic physiological, behavioral and subjective effects of inhaled salvinorin A across a range of doses, from sub-threshold to high, delivered under comfortable and interpersonally supportive conditions to healthy participants who reported histories of hallucinogen use.