Short communicationHuman psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum
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, Ott, 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., 2004; 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 Gründer, 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.
Section snippets
Participants
Participants were recruited from the Baltimore, MD area through flyers and ads in local newspapers. After a phone screen confirmed basic inclusion criteria (age, high-school-level education, and prior hallucinogen use), volunteers came to the laboratory for in-person screening. A social worker (who was trained by psychometricians and had a psychiatrist and clinical psychologist available for consultation) conducted a structured clinical interview to exclude individuals with a current or past
Time course of acute drug effects
Orderly time- and dose-related effects were observed. Subject-rated drug strength peaked at 2 min (first time point) and then progressively decreased toward pre-inhalation levels. By 20 min after inhalation, mean ratings indicated only a “possible mild” effect (see Fig. 1A). Two participants (1 male, 1 female) provided the maximal rating of 10 at one or more time points during at least one session. Both male participants were unresponsive (scores imputed as 10) on at least one time point for at
Discussion
Consistent with results from nonhuman animal research (Mowry et al., 2003), the present results suggest a safe physiological profile for salvinorin A at the studied doses, under controlled conditions, and in psychologically and physically healthy hallucinogen-experienced participants. Salvinorin A produced no significant changes in heart rate or blood pressure; no tremor was observed; and no adverse events were reported. Participants tolerated all doses. However, because of the small sample and
Role of the funding source
Conduct of the study was supported by National Institute on Drug Abuse (NIDA) grant R01DA003889. Support for Dr. Prisinzano was provide by NIDA grant R01DA018151.
Contributors
Drs. Johnson and Griffiths designed the study and wrote the protocol. Drs. Johnson, MacLean, and Reissig conducted experimental sessions and collected data. Dr. Prisinzano provided expertise on the chemistry and pharmacology of salvinorin A. Drs. Johnson, MacLean, and Griffiths contributed to interpretation of results. Dr. Johnson conducted statistical analyses. Drs. Johnson and MacLean wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgment
The authors would like to thank Annie Umbricht, M.D. and the medical staff at the Behavioral Pharmacology Research Unit for medical screening and medical coverage, Janna Bonesteel, Crystal Barnhouser, Eric Richter, and Jenna Cohen for assistance in conducting sessions and collecting and organizing the data, Mary Cosimano, M.S.W., for conducting psychological screenings, and Ronald W. Wood, Ph.D. for helpful discussions on drug volatilization.
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