Dose-related Effects of Salvinorin A in Humans : Dissociative, Hallucinogenic, and Memory Effects

MacLEAN K.A., JOHNSON M.W., REISSIG C.J., PRISINZANO T.E., GRIFFITHS R.R. :

Psychopharmacology (Berl), 2013, 226, (2), 381–392.

doi: 10.1007/s00213-012-2912-9

 

Abstract

Rationale—Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of
the plant Salvia divinorum, which has increased in popularity as a recreational drug over the past decade. Few human studies have examined salvinorin A.
Objective—This double-blind, placebo-controlled study evaluated the dose-related effects of
inhaled salvinorin A in individuals with histories of hallucinogen use.
Methods—Eight healthy hallucinogen-using adults inhaled up to 16 doses of salvinorin A (0.375
– 21 μg/kg) in ascending order. Physiological, behavioral, and subjective effects were assessed
every 2 min for 60 min after administration. Qualitative subjective effects were assessed
retrospectively via questionnaires at the end of sessions. Persisting effects were assessed 1 month
later.
Results—Orderly dose-related effects peaked at 2 min and then rapidly dissipated, replicating
previous findings. Subjective effects were intense, with maximal drug strength ratings or
unresponsiveness frequently observed at high doses. Questionnaires assessing qualitative effects
(Hallucinogen Rating Scale, Pharmacological Class Questionnaire) suggested some overlap with
serotonergically mediated classic hallucinogens. Salvinorin A also produced dose-related
dissociative effects and impairments in recall/recognition memory. At 1-month follow-up, there
was no evidence of persisting adverse effects. Participants reported salvinorin A effects were
qualitatively different from other drugs.
Conclusions—Salvinorin A produces a unique profile of subjective and cognitive effects,
including strong dissociative effects and memory impairment, which only partially overlap with
classic hallucinogen effects. Along with nonhuman studies of salvinorin A, these results are
important for understanding the neurobiology of the kappa opioid system and may ultimately have
important therapeutic applications.

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

 

INTRODUCTION

Salvinorin A is the principal psychoactive constituent of Salvia divinorum, a member of the mint family that has been used historically in ethnomedical practices in Mexico (Siebert 1994; Ott 1995; Ott 1996; Valdes et al. 2001) and has gained increased popularity as a recreational drug (Wu et al., 2011; Perron et al., 2012). Salvinorin A is a unique hallucinogenic compound: It is a nonnitrogenous selective kappa opioid agonist with no activity at the 5-HT2A serotonin receptor, the principal site of activity of classic hallucinogens (Roth et al. 2002; Prisinzano 2005; Cunningham et al. 2011). Nonhuman research studies have characterized the pharmacological, behavioral, and discriminative effects of S. divinorum and salvinorin A (Vortherms and Roth 2006; Cunningham et al. 2011), and there is interest in using salvinorin A and related compounds to study kappa opioid mechanisms in neurological disorders (e.g., Alzheimer’s disease), psychiatric disorders, pain, and drug dependence (Mello and Negus 2000; Sheffler and Roth 2003; Morani et al. 2009; Kivell and Prisinzano 2010; Cunningham et al. 2011; Tejeda et al.
2012). However, few human laboratory studies have demonstrated reliable effects (Johnson et al. 2011; Addy 2012; Ranganathan et al., 2012; cf, no effects of sublingual salvinorin A in Mendelson et al. 2011). In the present double-blind, placebo-controlled study (N = 8), we extend some preliminary observations in four volunteers (Johnson et al., 2011) and characterize the effects of salvinorin A on new outcome measures, including a 1-month follow-up assessment, with a focus on identifying the unique and overlapping effects of salvinorin A compared to classic hallucinogens and other pharmacological drug classes.

Most information about the effects of S. divinorum in humans has come from survey studies and qualitative interviews of S. divinorum users. Survey respondents are in general agreement that the effects of S. divinorum are “intense” and “unique” compared to other drugs or methods for inducing alterations in consciousness (Albertson and Grubbs 2009; Baggott et al. 2010; Kelly 2011; Sumnall et al. 2011). Elevations in scores on the Hallucinogen Rating Scale (HRS) (Gonzalez et al., 2006; Albertson and Grubbs 2009) suggest some overlap with the subjective effects of classic serotonergic hallucinogens
(Strassman et al. 1994; Griffiths et al. 2006; Griffiths et al. 2011), However, less than a quarter of respondents across studies report that S. divinorum is similar to classic hallucinogens (Albertson and Grubbs 2009; Baggott et al. 2010). Results are mixed regarding the similarity of S. divinorum to cannabis (6.5%, Baggott et al. 2010; 44%, Albertson and Grubbs 2009). There is little evidence of S. divinorum causing psychological dependence or psychiatric dysfunction beyond acute effects (Sumnall et al. 2011), with mixed reports of positive antidepressant-like effects (Hanes 2001; Baggott et al. 2010) and
negative effects such as “mental cloudiness” lasting 24 hours or more after use (Kelly 2011). Most respondents indicate that they use S. divinorum for recreation or entertainment (Albertson and Grubbs 2009; Kelly 2011), while some individuals indicate spiritual reasons for use (Baggott et al. 2010).

Results from a double-blind, placebo-controlled study of salvinorin A in hallucinogenexperienced adults (Addy 2012) are consistent with these survey findings. The active condition (1017 μg salvinorin A) vs. the placebo condition (100 μg salvinorin A) increased HRS ratings, including somatosensory, perceptual, affective and cognitive effects, indicating overlap with the subjective effects of serotonergic hallucinogens. However, participants were more likely to compare salvinorin A effects to dreaming (43%) than to classic hallucinogens (e.g., 13% LSD, 10% psilocybin), dissociative hallucinogens (7%) or marijuana (10%). Eight-week follow-up data indicated a mix of positive and negative effects lasting more than 24 hours after inhalation, including increases in positive mood, empathy, and aesthetic sensitivity as well as headache, fatigue, and difficulty concentrating.

A previous report from our laboratory (Johnson et al. 2011) provided an initial demonstration in 4 participants of the safety, tolerability, and time course of vaporized/ inhaled salvinorin A across multiple doses, from sub-threshold (0.375 μg/kg) to high (21 μg/kg). These preliminary results showed consistent time- and dose-related effects on participant ratings of overall drug strength, indicating the reliability of the vaporization/ inhalation procedure. Dose-related increases on the HRS and the Mysticism Scale (a measure of mystical-type subjective effects that has been shown sensitive to psilocybin; Griffiths et al. 2006; Griffiths et al. 2011) suggested phenomenological overlap with classic hallucinogens. However, participants uniformly reported that salvinorin A produced unique effects that were not typical of other hallucinogens they had used. The aim of the present report was twofold: 1) to extend our preliminary findings to the full study sample (N = 8) and, 2) to characterize the effects of salvinorin A on a range of outcome measures not previously reported, including monitor ratings of drug effects (e.g., dissociation), participant ratings of qualitative subjective effects, a test of recall and recognition memory, and a 1- month follow-up assessment of psychological function.

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