934 hallucinations, and dissociation (Walsh et al. 2001). Although reported effects of SD appear brief and range from laughter to depersonalization (González et al. 2006), a few reports raise the question of possibly persisting neuropsychiatric effects (i.e. paranoia, psychosis) (Breton et al. 2010; Paulzen and Grunder 2008; Przekop and Lee 2009). One case report of paranoia and cognitive impairment sometimes attributed to SD appears to have been caused by marijuana, illustrating the difficulties of defining psychoac- tive effects without controlled trials (Singh 2007). Anecdotal reports suggest that SD produces strong effects when taken orally (Valdés 1983) or when held in the mouth (Siebert 1994), but there have been conflicting reports on sublingual absorption of pure SA. Psychoactivity has been reported from sublingual doses as low as 100 μg (Ott 1996), but in other reports, no consistent effects have been seen at doses up to 2 mg (Siebert 1994) or even 12 mg (Zhah 2009). Most SA users smoke the drug (Baggott et al. 2010; González et al. 2006); however, due to individual differ- ences in smoking technique, peculiarities of smoking apparatuses, and losses of drug to combustion, determin- ing the delivered dose of a smoked drug can be difficult or impossible. In addition, maximal psychoactive effects can occur almost immediately after smoked drug delivery, decreasing the ability to assess and document effects on the ascending limb of the dose–response function. In contrast to the typical smoked administration, which produces rapid, brief, and intense effects, we sought to produce effects that would be less intense, better con- trolled, and more easily measurable (by virtue of their increased duration: an estimated 45–60 min (Baggott et al. 2010). We therefore administered SA sublingually to attain a slower onset (relative to smoking) and standardize dose delivery. This study reports on the first laboratory- based, dose-controlled study on the effects of SA in humans. Methods Study design An ascending-dose (0–4,000 μg SA, sublingual), placebo-controlled design in eight SD-experienced sub- jects was used. To be included, subjects had to be between the ages of 21 and 45; healthy as determined by medical history, mental status, and physical examina- tions, laboratory tests of renal and hepatic function; and have at least three self-reported SD experiences with and no adverse reactions to SD or hallucinogen use. Subjects were excluded for dependence on any illicit drug or alcohol. Psychopharmacology (2011) 214:933–939 Sublingual doses ranged from 0 to 4,000 μg. This dose range was selected based on a review of likely doses taken recreationally (Ott 1995; 1996; Siebert 1994) and with the goal of producing (at most) modest pharmacological effects in humans. Dosing sessions were separated by at least 24 h. The first two doses (placebo and 100 μg) were double- blind; the remaining five doses (250, 500, 1,000, 2,000, and 4,000 μg) were single-blind. The predetermined stopping criteria for dose escalation were a Visual Analog Scale (VAS) “Intoxication” rating above 50%, a self-report indication that the previous dose was not tolerable, or clinically significant cardiovascular, neurological, or psy- chiatric symptoms as determined by the study physician. The study was approved by the California Pacific Medical Center Institutional Review Board, and an Investigational New Drug Exemption was obtained from the US Food and Drug Administration. Dose preparation SA was isolated from dried commercial SD leaves (Bouncing Bear Botanicals, Lawrence, KS) as previously described (Munro and Rizzacasa 2003). Proton nuclear magnetic resonance (300 MHz) and liquid chromatography (LC)–mass spectrometry (MS) was consistent with past results (Munro and Rizzacasa 2003) and showed no detectable impurities. SA was soluble in 25% dimethyl sulfoxide (DMSO)/75% polyethylene glycol 400 (PEG-400) at 4,000 μg/mL and was stable for 6 days, as determined by LC-MS/MS, with only trace amounts of the hydrolysis product salvinorin B (SB) forming. Doses were prepared by a research pharmacist. A 500-μg/mL SA solution was made in ethyl acetate; appropriate doses were pipetted into scintillation vials, then evaporated to dryness, and stored in a cool, dry location. Doses were prepared by redissolving the SA in 1 mL of a slightly viscous mixture of 25% DMSO/75% PEG-400; both were USP grade (Coyerly et al. 1998). Sublingual dosing procedure SA in the DMSO/PEG-400 vehicle or the DMSO/PEG-400 placebo was administered sublingually with a needle-less syringe. Subjects were instructed to hold the liquid without swallowing for 5 min and were monitored for adherence. After 5 min, subjects expectorated mouth contents into a container for disposal then rinsed with 60 mL water before swallowing. Safety monitoring and outcome measures Subjects were continually monitored for signs and symp- toms of toxicity until 4 h post-dose. Heart rate, blood