Acute and post-acute behavioral and psychological effects of salvinorin A in humans, Peter H. Addy, 2012

Acute and post-acute behavioral and psychological effects of salvinorin A in humans

Peter H. Addy

Psychopharmacology, 2012, 220, 195–204

DOI 10.1007/s00213-011-2470-6


Rationale : Salvia divinorum has been used for centuries, and nontraditional use in modern societies is increasing. Inebriation and aftereffects of use are poorly documented in the scientific literature.

Objectives : This double-blind, placebo-controlled, randomized study analyzed subjective experiences of salvinorin A (SA) inebriation and consequences of use after 8 weeks.

Methods : Thirty middle-aged, well-educated, hallucinogenexperienced participants smoked either 1,017 or 100μg SA 2 weeks apart in counterbalanced order. Vital signs were recorded before and after inhalation. A researcher rated participants’ behavior during sessions. Participants completed the Hallucinogen Rating Scale (HRS) assessing inebriation immediately after each session. Differences were analyzed between groups as functions of dose and time. After 8 weeks, participants were interviewed to determine reported consequences and aftereffects.

Results : Participants talked, laughed, and moved more often on an active dose. All six HRS clusters were significantly elevated on an active dose indicating hallucinogenic experiences. No significant adverse events were observed or reported by participants.

Conclusions : The present results indicate similarities as well as differences between the subjective effects of S. divinorum and other hallucinogens. As a selective kappa opioid receptor agonist, SA may be useful for expanding understanding of the psychopharmacology and psychology of hallucinogenic states beyond serotonergic mechanisms.

Keywords : Double-blind . Hallucinogen . Hallucinogen rating scale . Human . Kappa opioid . Placebo-controlled . Psychedelic . Randomized . Salvia divinorum . Salvinorin A



Salvinorin A (SA), a nonnitrogenous diterpenoid with potent and selective agonist activity at the kappa opioid receptor (KOR), is the principal psychoactive component of the Mexican mint Salvia divinorum (Roth et al. 2002). S. divinorum has been used for centuries within the Mazatec culture and others in structured manners for divinatory or religious purposes and for physical healing (Ott 1995). The psychological effects of S. divinorum include significant alterations in affect, behavior, and cognition (Siebert 1994) leading to “a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type experiences” (Johnson et al. 2010 p. 5). These hallucinations occur with no binding activity at the 5- HT2A receptor (Roth et al. 2002), which is the principal binding site of “classic” hallucinogens. Traditionally, the leaves of the plant are chewed or brewed into a tea (Ott 1995); however, nontraditional use usually involves smoking an extract of the leaves (Baggott et al. 2010).

Four clinical studies of SA with human participants have been published. Siebert (1994) administered S.
divinorum extracts and pure SA in an informal group setting of 20 participants without using double-blind randomized placebo-controlled methodology. Participants swallowed capsules of SA, absorbed an alcohol-based spray of SA on their oral mucosa, and inhaled SA vapors. Siebert determined that psychoactivity typically began at about 200 μg via vaporization. The highest dose administered via vaporization was 2,600 μg, and no acute or long-term negative effects were reported for that dose
(Siebert 1994). A phenomenological account of one of participant is presented in Turner (1996). Pichini et al. (2005) focused on detection and quantification of smoked S. divinorum in biological fluids of two users. These first two reports provide almost no information on demographics of participants and little information on administration procedures and either behavioral or subjective effects of SA. Mendelson et al. (2010) did not obtain any psychoactive effects in eight participants, presumably due to the unreliable nature of sublingual absorption of SA. Finally, Johnson et al. (2010) completed a placebocontrolled dose–response study of inhaled SA in four participants, focusing on vital signs and objective measurements, of inebriation and briefly describing some subjective effects.

Meanwhile, human use outside of the traditional context is increasing (Wu et al. 2011). The plant is legal to buy and sell in many states and countries. In response to increased visibility of use, S. divinorum and SA are now scheduled in some states and have received much negative attention in the popular press (Gonzalez et al. 2006). However, little scientific research has examined either the subjective experiences facilitated by S. divinorum or the aftereffects of use with human participants.

SA is a potent and selective KOR agonist in vitro (Roth et al. 2002). Discrimination trials demonstrate SA to generalize to synthetic KOR agonists with both rodents (Baker et al. 2009; Wilmore-Fordham et al. 2007) and primates (Butelman et al. 2004, 2010). These generalization effects were blocked by general opioid antagonist quadazocine (Butelman et al. 2004, 2010) and KOR agonist norbinaltorphimine dihydrochloride ( Wilmore-Fordham et al. 2007), were not blocked by 5-HT2 antagonist ketanserin (Butelman et al. 2010), and were partially blocked by KOR antagonist 5′-guanidinonaltrindole (effective in two of three monkeys; Butelman et al. 2004). Further, discrimination trials demonstrate that SA does not generalize to 5-HT2 agonists 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane ( Li et al. 2008), d-lysergic acid diethylamide (LSD; Killinger et al. 2010), or psilocybin (Butelman et al. 2010); CB1 agonist delta 9-tetrahydrocannabinol (Walentiny et al. 2010); delta opioid receptor agonist SNC80 (Butelman et al. 2010); mu opioid receptor agonist fentanyl (Butelman et al. 2010); or NMDA antagonist ketamine (Butelman et al. 2010; Killinger et al. 2010).

Little is known about KOR agonist activity in humans. Synthetic KOR agonists produce dysphoria and hallucinations. KOR agonist enadoline administration up to 2 μg/kg i.v. resulted in hallucinations (Walsh et al. 2001). KOR agonist MR 2034 administration of 3.8 μg/kg i.v. resulted in “somesthetic changes and disturbances in the perception of space and time….uncontrolled laughter….described their experiences as dreamlike” (Pfeiffer et al. 1986, p. 775). However, Johnson et al. (2010) noted a relative lack of dysphoric effects and significant positive effects as well as hallucinations with inhaled KOR agonist SA administered in ascending doses up to 21 μg/kg. The differences in affect between study participants may be related to any number of factors, including Johnson et al. having more stringent inclusion and exclusion criteria for participants, focusing on establishing trust and rapport with participants, and emphasizing a safe and supportive physical environment (see also Johnson et al. 2008 for a discussion of these factors).

In the present study, we used a double-blind, placebocontrolled, randomized methodology to evaluate acute (up to approximately 70 min post-inhalation) differences in observer-rated behavioral and participant-rated psychological effects of enhanced smoked S. divinorum leaf containing approximately 1,017 μg SA per 25 mg dried leaf relative to a placebo compound containing a presumed non-psychoactive dose (Johnson et al. 2010; Siebert 1994) of approximately 100 μg SA per 25 mg dried leaf. Participant-reported postacute (mean, 56 days) effects were recorded as well. In contrast to the previous report of Johnson et al. (2010), the present study included 30 participants instead of four and recorded participant behavior during SA inebriation.