This double-blind, randomised controlled trial (n=10) assessed the behavioural, subjective, cognitive, psychophysiological and endocrine effects of Salvia divinorum (0, 8 and 12 mg) in healthy participants. Salvia produced psychotomimetic effects and perceptual alterations, including dissociative and somaesthetic effects, increased plasma cortisol and prolactin and reduced resting EEG spectral power, but did not produce euphoria, cognitive deficits or changes in vital signs. Overall, Salvia was well tolerated.
Background
Salvia divinorum (Salvia) is an increasingly popular recreational drug amongst adolescents and young adults. Its primary active ingredient, Salvinorin A (SA), a highly selective agonist at the kappa opiate receptor (KOR), is believed to be one of the most potent naturally occurring hallucinogens. However, there is little experimental data on the effects of SA in humans.
Methods
In a 3-day, double-blind, randomized, crossover, counterbalanced study, the behavioural, subjective, cognitive, psychophysiological and endocrine effects of 0 mg, 8 mg and 12 mg of inhaled SA were characterized in 10 healthy individuals who had previously used Salvia.
Results
SA produced psychotomimetic effects and perceptual alterations including dissociative and somaesthetic effects, increased plasma cortisol and prolactin and reduced resting EEG spectral power. SA administration was associated with a rapid increase of its levels in the blood. SA did not produce euphoria, cognitive deficits or changes in vital signs. The effects were transient and not dose-related. SA administration was very well tolerated without acute or delayed adverse effects.
Conclusions
SA produced a wide range of transient effects in healthy subjects. The perceptual altering effects and lack of euphoric effects would explain its intermittent use pattern. Such a profile would also suggest a low addictive potential similar to other hallucinogens and consistent with KOR agonism. Further work is warranted to carefully characterize a full spectrum of its effects in humans, elucidate the underlying mechanisms involved and explore the basis for individual variability in its effects.
Papers cited by this study that are also in Blossom
Johnson, M. W., Maclean, K. A., Reissig, C. J. et al. · Drug and Alcohol Dependence (2011)
Salvia divinorum and its principal psychoactive constituent, salvinorin A (SA), have become increasingly used recreationally, particularly by adolescents and young adults. SA is a highly potent, selective kappa opioid receptor (KOR) agonist and, unlike many classical hallucinogens, lacks activity at dopaminergic, serotonergic or NMDA receptor systems. The human literature up to the time of this study consisted mainly of anecdotal reports and a small number of experimental investigations that were limited by uncontrolled designs, sublingual administration with poor bioavailability, small samples, or use of Salvia leaf preparations rather than defined doses of pure SA. Important gaps remained regarding SA’s pharmacokinetics in humans and its objective behavioural, subjective, cognitive, endocrine and psychophysiological effects under controlled conditions. B. and colleagues set out to characterise comprehensively the acute effects and safety of inhaled SA in healthy human volunteers with prior Salvia exposure. The study aimed to measure dose-related subjective and behavioural effects, cognitive performance, resting EEG, plasma SA and its major metabolite salvinorin B (SB), and neuroendocrine responses (cortisol and prolactin) using a double-blind, randomised, placebo-controlled, counterbalanced crossover design. The authors framed the work as addressing prior methodological limitations by using pure SA, objective biological measures and standardised delivery in the laboratory.
The study used a double-blind, randomised, placebo-controlled, counterbalanced crossover design with three test days per subject at a specialised clinical research unit. Ten medically and psychiatrically healthy adults who had previously used Salvia were recruited after a rigorous screening process (details referenced to a Supplement). The extracted text reports inclusion of subjects aged 18–55 years with prior Salvia exposure; because recreational users commonly use other drugs, participants with other drug exposure were allowed to enhance representativeness. Subjects were asked to refrain from alcohol, illicit or prescription drugs for one week before the first test day through study completion. On each test day participants inhaled one of three conditions administered via a commercially available vapouriser: placebo (an empty aluminium container), low-dose SA (8 mg) or high-dose SA (12 mg). SA was prepared by research pharmacists on the morning of each test day; subjects and raters were blinded to dose. Procedures included urine toxicology and pregnancy testing, IV line placement and baseline ratings. Safety assessments were performed the day after the first and last test days and at follow-ups 1 and 3 months after completion. Outcome measures combined subjective, behavioural, cognitive, endocrine, pharmacokinetic and psychophysiological assessments. Subjective states were measured with visual analogue scales (VAS), psychotomimetic symptoms with the PANSS and the Psychotomimetic States Inventory (PSI), and perceptual/dissociative effects with the Clinician Administered Dissociative Symptoms Scale (CADSS) and the Hallucinogen Rating Scale (HRS). Cognitive performance used a brief WAIS-R derived battery (Digits Forward/Backward, Letter Number Sequence). Plasma cortisol and prolactin were assayed at multiple time points. SA and SB plasma and urine levels were quantified by LC-APCI-tandem mass spectrometry with limits of quantitation of 0.5 ng/ml. Resting-state EEG (three minutes, eyes closed) was recorded immediately following inhalation; analyses reported spectral power at midline electrodes (Cz, Pz, Oz). Statistical analyses used descriptive summaries and tests for normality. Approximately normally distributed outcomes (PANSS, PSI, HRS, cognitive measures) were analysed with linear mixed models including within-subject factors of dose (placebo, 8 mg, 12 mg) and time (pre- vs post-inhalation) and random subject effects. Non-normally distributed CADSS and VAS outcomes were analysed using a nonparametric ranked mixed-effects approach with ANOVA-type statistics (ATS). Hormone and SA/SB level trajectories and physiological measures were also compared using similar mixed models. EEG power was analysed with mixed models including dose and electrode as within-subject factors. Analyses were performed in SAS v9.2.
Ten subjects were enrolled (mean age 23.8 ± 3.2 years; 90% male; mean education 15.3 ± 1.2 years; mean IQ 117.2 ± 7.1). Nine completed all three test days and one dropped out after two sessions; all 10 were included in analyses. None met criteria for substance dependence; all had prior SA and other illicit drug exposure. No serious adverse events occurred; no test days were terminated early. Follow-up at 1, 3 and 6 months detected no new psychiatric symptoms or increased Salvia consumption. Subjective and behavioural effects: Participants reported somaesthetic changes, dissociative experiences and perceptual alterations, illustrated by brief subject quotations (e.g. cold prickling, detachment, heightened pattern perception). On VAS measures, SA produced a main effect on ‘‘drowsy’’ such that both 8 mg and 12 mg doses produced less drowsiness than placebo (ATS statistics reported: overall ATS=4.55, p=0.01; low dose ATS=4.9, p=0.03; high dose ATS=3.99, p<0.05). SA did not increase ratings of feeling ‘‘high’’, ‘‘calm’’, ‘‘sad’’, ‘‘irritable’’ or ‘‘anxious’’. On psychotomimetic scales the PANSS positive subscale increased by 3.5 points and the PSI by approximately 10 points, magnitudes the authors compared to effects seen with delta-9-THC and ketamine. Pharmacokinetics: Plasma SA levels rose rapidly after inhalation and peaked at about +15 minutes post-administration. Mixed-model comparisons showed a significant increase in SA levels after active dosing compared with pre-administration [F(3,38)=29.4, p<0.0001], without significant differences between the two active doses. SB levels also increased after SA administration [F(3,38)=8.66, p=0.0002]. Neuroendocrine effects: Low-dose SA significantly elevated plasma cortisol [F(2,120)=3.11, p<0.05], with cortisol returning to baseline by 60 minutes post-inhalation [F(4,120)=18.69, p<0.0001]. Both SA doses significantly elevated plasma prolactin [F(8,120)=4.07, p=0.0003], with prolactin also returning to baseline by 60 minutes. Physiology and cognition: Neither SA dose produced significant changes in heart rate or systolic/diastolic blood pressure. The extracted text reports no euphoria or persistent cognitive deficits; cognitive battery outcomes are not detailed numerically in the extracted text. EEG: Resting-state EEG spectral power decreased across frequencies examined, with statistically significant reductions in beta power (13–29 Hz) at both active doses versus placebo [F(68,2)=5.47, p<0.006]. Theta band power showed a trend toward reduction [F(68,2)=2.44, p=0.09]. Effects on delta, alpha and gamma bands were not statistically significant. Safety and tolerability: SA was well tolerated acutely and in follow-up. One subject dropped out after reporting no effects; no rescue medications were required and no serious adverse events were recorded. The subjective and objective effects were transient, peaking within about 10 minutes and generally returning to baseline within 30–60 minutes.
B. and colleagues interpret their findings as demonstrating that inhaled SA produces very rapid, short-lasting psychoactive effects in healthy humans characterised by somaesthetic changes, dissociation and perceptual alterations. The onset was within seconds to minutes, with peak intensity typically within 10 minutes and return toward baseline by 30 minutes; no lingering effects were reported at discharge (90 minutes) or during follow-ups. The magnitude of psychotomimetic effects on PANSS and PSI was described as comparable to those produced by delta-9-THC and ketamine on the same measures, although peak intensities reported by subjects in the laboratory were estimated at only 20–30% of their recalled recreational peak effects. The authors highlight objective biological corroboration of central KOR activity: rapid rises in plasma SA and SB, elevations in prolactin and cortisol consistent with KOR agonism, and reductions in resting-state EEG beta power. They note that the prolactin and cortisol responses align with preclinical and human data for other KOR agonists and suggest hypothalamic–pituitary–adrenal (HPA) activation. The decrease in beta-band EEG power differs from patterns observed with some other hallucinogens (which produce increases or no change in beta), supporting the view that SA has a distinct psychophysiological profile linked to its unique KOR mechanism. Regarding abuse liability, the authors argue that SA’s lack of euphoria and its putative KOR-mediated reductions in mesolimbic dopamine are consistent with lower addictive potential relative to drugs that increase accumbal dopamine. They caution that recreational use is variable and can range up to presentations prompting emergency care; they also note that SA exposure could be especially harmful in people vulnerable to psychotic illness. The discussion extends to potential relevance for understanding psychosis: SA produces psychosis-like effects despite decreasing dopamine, raising questions about KOR involvement in psychotic phenomena and suggesting that KOR antagonists warrant further investigation as possible antipsychotic agents. Strengths cited include the randomised double-blind crossover design, use of multiple doses and pure SA, measurement of blood levels and inclusion of both subjective and objective measures (hormones, EEG, pharmacokinetics). Limitations acknowledged by the authors include limited generalisability to recreational use because of standardised setting and method of delivery, and the inability to characterise a dose–response relationship since plasma levels and responses did not differ between the two active doses. The authors recommend future studies to examine a wider dose range, to test whether SA’s effects are blocked by KOR antagonists, and to use receptor imaging to clarify mechanisms.
The human literature on SA effects is limited by a preponderance of anecdotal reports. Salvia produces a rapid onset of transient mood alterations, dissociative symptoms and psychotomimetic effects. The anecdotal literature is difficult to interpret because of the use of variable doses and routes of administration, the use of other drugs before, with or after SA use, variable set and setting and a lack of characterization of the subject samples. Experimental data with Salvia/SA in humans include one study that developed a method of to detect SA in biological fluids after smoking Salviaand four on the effects of SA. Seibert (1994) described subjective effects of oral, sublingual, and inhaled Salvia and SA administration in an open-label, uncontrolled study in twenty subjects. Mendelson et al reported no effects and undetectable SA blood levels with SA administered sublingually at doses up to 4 mg in eight subjects. The lack of effects in this study was likely due to low bioavailability of sublingual SA. Johnson et al administered 16 doses of inhaled SA in a fixed-order, ascending-dose, placebo-controlled, single-blind study of four subjects. Subjects experienced a rapid onset of transient hallucinogenic effects without any physiological changes. Finally, Addy (2011), studied 30 healthy subjects who selfadministered 1017 µg of inhaled SA on dried Salvia leaves or placebo (unenhanced dried Salvia leaves) in a partially blinded manner (blinded only to the first dose). The latter two studies, while demonstrating the hallucinatory effects of SA, were also limited in the lack of randomization or objective outcomes, the use of fixed ascending order of dosesand the use of Salvia leaves as the vehicle and control. SA has been reported to produce behavioral effects, cognitive impairments and prolactin elevations in animals. Other KOR agonists have been reported to increase prolactin and cortisol levels in rodentsand humans, and to reduce resting EEG power in rats. Resting EEG is a potentially informative as it is sensitive to drug-induced changes in consciousnessand is altered in psychotic. Finally, the pharmacokinetics of SA have not been studied in humans. SA is rapidly metabolized to Salvinorin B (SB), which is a much less potent KOR agonist. However, these outcomes have not been studied thus far in humans. The behavioral, subjective, cognitive, endocrine and psychophysiological effects of SA and it's pharmacokinetic profile in humans were characterized in a controlled study to address the limitations and gaps in the existing literature.
This study was approved by the IRBs at Yale University and the VA Connecticut Healthcare System and the FDA, and was carried out in accordance with the Helsinki Declaration of 1975.
This double blind, randomized, placebo controlled, counterbalanced, cross over, 3-day study was conducted at the Neurobiological Studies Unit (VA Connecticut Healthcare System, West Haven, CT). Subjects-As detailed in the Supplement, a rigorous screening was conducted to include medically and psychiatrically healthy subjects, aged between 18 and 55 years with previous exposure to Salvia. Since Salvia users characteristically use other drugs, subjects with exposure to other drugs were included in order that the sample be representative. History provided by subjects was corroborated with an outside informant nominated by the subject. Subjects were instructed to refrain from alcohol, illicit drugs or prescription drugs from a week before the first test day until study completion. Subjects were paid $225 per test day for their participation.
Subjects presented to the research unit, about 1 hour prior to the scheduled time of administration of drug during which they underwent a urine toxicology exam and pregnancy test (in women), had an intravenous (IV) line placed and underwent baseline ratings. Instudy safety procedures were in place as described previously. Prospective safety assessments were performed the day after the first and last test days and 1 and 3 months after study completion. Drugs-Subjects on each test day inhaled one of 2 doses of active SA or placebo (in an aluminum container) administered through a commercially available vaporizer (see Supplement for details). SA was obtained from the laboratory of Dr. Bruce M. Cohen, McLean Hospital, Belmont, MA and stored in the research pharmacy at VA Connecticut Healthcare System, West Haven, CT. On the morning of each test day, the SA dose was prepared in the designated container by the research pharmacists. Placebo consisted of the container devoid of any SA. Subjects and raters were blinded to the dose administered.
Subjective and behavioral effects-Subjective feeling states such as "high", "anxious", "drowsy", "irritable", and "nervous" were measured using a self-reported visual analog scale (VAS). Psychotomimetic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS)and the Psychotomimetic States Inventory (PSI). Perceptual alterations were measured using the Clinician Administered Dissociative Symptoms Scale (CADSS)and the Hallucinogen Rating Scale (HRS). Cognitive effects-Phonological processing, working memory and attention were assessed using a simple cognitive battery comprising of the Digits Forward and Backward and Letter Number Sequence tasks of the WAIS-R. Neuroendocrine effects-Plasma cortisol and prolactin were assayed at various time points before and after SA inhalation. Levels were analyzed in duplicate by the Yale Center for Clinical Investigation, Yale University, New Haven, CT. SA and SB levels-Both SA and SB levels were analyzed by Dr. E. Thomas Everhart at the Drug Dependence Research Center (Langley Porter Psychiatric Institute, University of California) using a slightly modified liquid-chromatographic-atmospheric pressure chemical ionization-tandem mass spectrometric method(see Supplement for details). The limits of quantitation were 0.5 ng/ml for both SA and SB in plasma and urine. Psychophysiological effects-Three minutes of resting state EEG was obtained as subjects sat still with their eyes closed immediately following SA inhalation.
Initially, data were examined descriptively using means, standard deviations and graphs. Each outcome was tested for normality using Kolmogorov-Smirnov test statistics and normal probability plots. All PANSS, PSI, HRS and cognitive battery outcomes were approximately normally distributed. These outcomes were analyzed using linear mixed models, which included SA dose (placebo, low (8mg), and high (12mg)) and time (pre-vs. post-inhalation) as within-subjects explanatory factors and random subject effects. The bestfitting variance-covariance structure was chosen based on information criteria. Significant interactions between dose and time were interpreted by appropriate post-hoc tests. Similar models were used to compare physiological measures and serum SA and hormone (log) levels across time. All CADSS and VAS outcomes were highly skewed. Thus, these nonnormal outcomes were analyzed using the nonparametric approach for repeated measures data, in which data are ranked and then fitted using a mixed-effects model with an unstructured variance-covariance matrix and p-values adjusted for ANOVA-type statistics (ATS). In these models, SA (placebo, low dose, high dose and time (pre-vs. posttreatment)) were included as within-subjects explanatory factors. EEG power frequencies were compared using linear mixed models with dose and electrode (Cz, Pz, Oz) as withinsubjects factors. All data were analyzed using SAS, version 9.2 (Cary, NC).
Subjects were young (23.8 ± 3.2 years), predominantly male (90%), with 15.3(± 1.2) years of education, intelligence quotient scores of 117.2 (± 7.1) and low (2.8 ± 2.8) psychosis proneness scores on the Schizotypal Personality Questionnaire (Tablein the Supplement). Nine subjects completed all three test days and one dropped out after his second test day. All 10 subjects were included in the analyses. None of the subjects met criteria for alcohol or substance dependence. All subjects had previous exposure to SA) and other illicit substances (Tablein the Supplement). For parsimony, only positive results are reported in detail here. Subjective reports: Listed below are quotations from subjects describing SA-induced changes. Somaesthetic changes: "I felt a cold prickling feeling on my legs" "…tingling in my fingers" "…felt a pattern sweep over me like a wave… I felt as well as saw the waves…"
Feelings of detachment: "I could see you and hear you, but I felt separated and distant from you…" Heightened awareness of visual and/or auditory stimuli: "the patterns on the curtain appeared more prominent…the contrast was more vivid", "the air-conditioner seemed louder…" Withdrawal into Self: "…I wished I didn't have to answer questions…", "‥wished I was left alone…" Changes in concentration/increased distractibility: "‥felt distracted by background sounds" "I felt mesmerized by the pattern on the door"
There was a main effect of SA administration on feeling "drowsy" [ATS=4.55, num df=1.91, p=0.01] such that both low [ATS=4.9, num df=1, p=0.03] and high [ATS=3.99, num df=1, p<0.05] doses of SA produced less drowsiness compared to placebo. SA administration did not produce any changes on the VAS for feeling "high", "calm", "sad", "irritable" or "anxious".Plasma SA and SB levels (Figure)
Only samples from active dose conditions were analyzed for SA and SB levels; the main comparison was between blood levels before and after drug administration. Both doses of SA produced a rapid increase in SA levels compared to pre-administration levels [F (3,38)= 29.4, p< 0.0001] but without significant differences between the two active doses. The levels of SA peaked at + 15 minutes post administration. Both doses of SA also produced an increase in SB levels compared to pre-administration levels [F(3,38)= 8.66, p= 0.0002].
Cortisol Levels (Figure): Low dose SA significantly elevated plasma cortisol levels [F(2,120)= 3.11, p< 0.05], which returned to baseline 60 minutes after SA inhalation [F(4,120)=18.69, p<0.0001]. Prolactin Levels (Figure): Both doses of SA significantly elevated plasma prolactin levels [F(8,120)=4.07, p= 0.0003], which also returned to baseline by 60 minutes after administration.
Neither dose of SA produced any significant changes in heart rate, systolic or diastolic blood pressure in any subject.
SA administration decreased resting state EEG spectral power across all frequencies examined (although not all frequency bands reached significance). Compared to placebo, SA was associated with lower beta power at both doses [F(68,2) = 5.47, p < 0.006]. SA also lowered theta power with a trend toward significance [F(68,2) = 2.44, p = 0.09]. The effects of SA on delta, alpha, and gamma frequencies were not statistically significant.
No serious adverse events (death, hospitalization, or emergency room visit) occurred during or after the study. One subject dropped out for unspecified reasons after reporting no effects on either of the test days in which he participated. No test days were terminated prematurely nor were rescue medications necessary. Exit interviews conducted in a subsample of subjects revealed that subjects felt they had been adequately informed about the risks of the study. Follow-up assessments at 1, 3, and 6 months revealed no new psychiatric symptoms or increased Salvia consumption.
This is the first report to our knowledge on a wide range of dose-related subjective, behavioral, cognitive, cardiovascular, psychophysiological and neuroendocrine effects and safety of inhaled SA in a randomized, double-blind, placebo-controlled, crossover, counterbalanced study in healthy humans.
As expected, SA produced very short lasting psychoactive effects with some psychotomimetic features, most notably somaesthetic changes, dissociative effects and perceptual alterations. Consistent with anecdotal data and experimental reports, the onset of SA effects was very rapid (within seconds to minutes) as captured on the HRS "Intensity" subscale, with a peak within 10 minutes and a return to baseline within 30 minutes. No subjects reported any lingering effects at the time of discharge (90 minutes after inhalation) or any persistent or recurrent effects during the safety follow-ups.
The magnitude of psychotomimetic effects induced by SA as measured by the PANSS positive subscale (3.5 point increase) and PSI (10 point increase) was comparable to the effects of delta-9-tetrahydrocannabinol and ketamine on those measures.
Peak effects in this study were rated as only 20% to 30% of the peak effects experienced with recreational SA use. A number of factors might account for the differences, the most obvious being that the drug was delivered in this study more slowly and at lower doses than characteristic of recreational use. While a vaporizer reaches the target temperature within minutes, the typical recreational method of delivery (in which subjects apply direct heat to a glass pipe or aluminum foil containing Salvia) attains this temperature instantaneously. This factor should also be taken into consideration while comparing these data with other studies of inhaled SA. Secondly, in this study subjects received pure SA, whereas with recreational use either salvia leaves or extract-enhanced leaves are used. The contribution of other psychoactive compounds present in these preparations may alter subjective effects. Finally, the combination of variable strength of Salvia products and variability in the amount used recreationally makes accurate estimation of recreational dose near impossible. This limits the ability to accurately compare the doses in this study with recreational doses. These considerations notwithstanding, subjects were asked to compare effects in this laboratory study to those associated with recreational use in order to infer how doses used in this study compared to doses used recreationally.
Elevations in serum prolactin are a well-recognized biomarker of KOR agonism in rodent and non-human primates. This study is the first to demonstrate endocrine effects of SA in humans and thus, provides clear objective evidence of the centrally-mediated effects of SA. KORs are abundantly distributed in the hypothalamusand KOR agonists are known to increase prolactin levels, but the exact mechanism remains unclear. One possibility is that SA via KOR agonism may lower dopamine levels in the tuberoinfundibular pathway similar to the effects of KOR agonism on dopamine in other brain regions. This is the first report to our knowledge on the cortisol elevating effects of SA in humans; this effect is consistent with the cortisol elevating effects of other KOR agonists observed in animals and humans. The cortisol stimulatory effect in nonhuman primates was shown to be specific to KOR agonism, not produced by Mu or Delta opioid agonists and was blocked by a selective KOR antagonist. Collectively, the results of the current study and previous studies demonstrate that similar to other KOR agonists, SA stimulates the hypothalamic-pituitary axis (HPA) activity in humans.
No previous study has examined the psychophysiological effects of SA in humans. While all doses of SA decreased broadband resting-state EEG spectral power, the reductions were significant in the beta-band (13 to 29 Hz), and trended toward significance in the theta band (4 to 7 Hz). These effects are consistent with a previous human study showing that the KOR agonist pentazocine decreased resting EEG power in the theta, alpha, and beta frequency bands. However, the pattern of SA effects on resting EEG are different from that of other hallucinogens such as mescaline, ketamine and ayahuascawhich are associated with increases or no change in beta power. These differences serve to highlight the fact that SA produces its effects via a unique mechanism and thus may have a distinct psychophysiological profile. While the neurochemical mechanisms of these changes, as well as their functional implications remain unclear, the current findings suggest that resting EEG may provide an objective, behaviorally-independent index of KOR agonist effects on brain function. Thus the inclusion of outcomes such as resting EEG, hormonal levels and SA and SB levels in this study provide objective biological correlates of SA effects in humans. The method of delivery, doses of SA and overall study design are validated by effects detected on subjective as well as objective outcomes. This is particularly crucial, given the wide variability in subjective effects that may be reported in such a study.
SA is now recognized as a potential drug of abuse with increasing use especially amongst youth. However, several lines of evidence suggest that in contrast to other drugs of abuse with addictive liability, SA is less likely to be used compulsively, repetitively or persistently. In this study SA did not produce euphoria, an effect that is common to most addictive drugs. Furthermore, the findings from surveys of SA usersand reports from our subjects suggest that recreational Salvia use is sporadic, in contrast to the compulsive, repetitive use and persistent use pattern of addictive drugs. Addictive drugs share in common the capacity to increase dopamine in the nucleus accumbens (NAcc). SA and synthetic kappa opioid agonists (U-69593, U-50488 and R-84760) decrease dopamine levels in the nucleus accumbens of rodents. Synthetic KOR agonists and SA induce conditioned place aversion. KOR agonists reduce cocaine self-administration, cocaine-induced hyperlocomotion, cocaine-induced reinstatement of drug self-administration, and cocaine-induced behavioral sensitization. However, one study did show intracerebroventricular SA self-administration and conditioned place preference in mice at relatively low doses. KOR agonists also reduce intracranial self-stimulation (ICSS)consistent with a profile of aversive effects. Collectively the evidence suggests that SA and other KOR agonists are likely to have low addiction liability. In fact, KOR agonists have been studied as potential treatment for addictions, but further development has been hampered by adverse effects. Most likely, SA is used for its perceptual altering effects. Since the concept of drug "abuse" includes "use for nontherapeutic effects," SA may be considered an agent with recreational abuse liability similar to Lysergic Acid Diethylamide (LSD). The intensity of SA effects reported by recreational users is highly variable ranging from mild perceptual alterations to frank psychosis prompting contact with poison control or necessitating emergency care and hospitalization. In the current study too, the intensity of SA effects showed significant inter-individual variability. Finally, in individuals who may be vulnerable to psychotic illnesses or with an established psychotic disorder, SA exposure may have particularly devastating consequences.
The results of this study are also relevant to understanding the pathophysiology of psychosis and to drug development. According to the dominant DA hypothesis, increased mesolimbic dopamine is implicated in the pathophysiology of the positive symptoms of psychosis. SA induces psychosis-like effects but decreases dopamine in several brain regions; which arguably was indirectly reflected in the increased prolactin levels observed in this study. Furthermore, the DA D2 receptor antagonist haloperidol does not attenuate the deficits in prepulse inhibition produced by KOR activation. SA's only known mechanism of action is KOR agonism. It does not have affinity for serotonin (5-HT2), dopamine (DA), cannabinoid (CB1R) or N-Methyl-D-Aspartate (NMDA) receptor systems that have been implicated in the mechanism of other drugs that produce psychotomimetic effects. Therefore, KOR agonism may be relevant to the pathophysiology of psychosis and the study of the KOR system using a probe such as SA may shed more light on the involvement of this system in the pathophysiology of psychosis. Further studies are necessary to investigate the precise mechanism/s underlying the psychotomimetic effects of SA. Finally, while admittedly simplistic and speculative, the association between KOR agonism and psychosis raises the possibility that KOR antagonists might have antipsychotic potential.
Important strengths of this study include the double-blind, randomized, placebo-controlled, crossover design, the use of multiple doses, the estimation of blood levels, and the use of a range of objective and subjective measures. While the standardized set, setting and validation of method of delivery using objective measures and blood levels are strengths of this experimental approach, they limit generalizability of these findings to recreational use. Finally, the lack of differences in both plasma levels and responses between the two doses did not permit characterization of the dose-response profile of SA.
Future studies should focus on characterizing the safety, tolerability and effects of a wider dose range of SA in humans. Further, although preclinical data suggest that SA acts solely via the KOR, whether this is indeed the case in humans is unclear. Studies examining the effects of KOR blockade on the effects of SA, and receptor-imaging studies will help answer these questions. Salvinorin A (SA) administration induced reductions in resting beta-band EEG power. Figuredepicts the grand-averaged resting EEG spectral power in the beta range (13-29 Hz) at midline electrode sites. Error bars represent S.E.M. Figuredepicts the topographic maps indicating grand-averaged beta power across the placebo and the two active SA doses.
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Riba, J., Anderer, P., Morte, A. et al. · British Journal of Clinical Pharmacology (2002)
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