Psychopharmacology (2011) 214:933–939 DOI 10.1007/s00213-010-2103-5 ORIGINAL INVESTIGATION Lack of effect of sublingual salvinorin A, a naturally occurring kappa opioid, in humans: a placebo-controlled trial John E. Mendelson & Jeremy R. Coyle & Juan Carlos Lopez & Matthew J. Baggott & Keith Flower & E. Thomas Everhart & Thomas A. Munro & Gantt P. Galloway & Bruce M. Cohen Received: 13 August 2010 / Accepted: 12 November 2010 / Published online: 8 December 2010 # The Author(s) 2010 This article is published with open access at Springerlink.com Abstract Rationale Salvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant. Objectives The objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels. Methods Sublingual SA doses up to 4 mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design. Results No dose of SA produced significantly greater physiological or subjective effects than placebo. Further- more, effects did not resemble reported “typical” effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5 ng/mL). J. E. Mendelson : J. R. Coyle : J. C. Lopez (*) : M. J. Baggott : K. Flower : G. P. Galloway Addiction and Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, San Francisco, CA, USA e-mail: lopez.juan.c@gmail.com E. T. Everhart Department of Psychiatry, UCSF, San Francisco, CA, USA T. A. Munro : B. M. Cohen Department of Psychiatry, Harvard Medical School, Cambridge, MA, USA T. A. Munro : B. M. Cohen McLean Hospital, Belmont, MA, USA Conclusions Our results suggest that the sublingual bio- availability of SA is low. Higher doses, alternate formula- tions, or alternate routes of administration will be necessary to study the effects of SA in humans. Keywords Salvia divinorum . Salvinorin A . Kappa opioid receptor . Sublingual administration Introduction An estimated 1.8 million Americans have tried Salvia divinorum (SD), a psychoactive mint that traditionally had been used for divination and healing in the Mazatec region of Mexico (Substance Abuse and Mental Health Services Administration 2006). SD use is also occurring in Europe (Pavarin 2006) and Japan (Tsujikawa et al. 2008), and SD is sold in smoke shops and over the web in preparations with often inaccurately labeled and varying strength (Wolowich et al. 2006). The psychoactive agent in S. divinorum is believed to be salvinorin A (SA), a trans-neoclerodane diterpenoid (Ortega et al. 1982; Valdés et al. 1984). Siebert reported that when administered to humans by vaporization and inhalation, SA is psychoactive with effects substantial- ly similar to those of the whole leaf (Siebert 1994). A recent placebo-controlled trial confirmed this, reporting intense self-rated and observer-rated effects from a smoked dose of 1 mg SA (Addy 2010). Several animal studies have also confirmed the psychoactivity of SA (Butelman et al. 2004; Carlezon et al. 2006; Fantegrossi et al. 2005; Valdés et al. 1987). SA is the first known naturally occurring selective kappa opioid and may be the most potent naturally occurring hallucinogen (Roth et al. 2002). Limited clinical studies suggest kappa opioids induce effects, including dysphoria,