Dose-related effects of salvinorin A in humans: Dissociative, hallucinogenic, and memory effects

Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD, 21224-6823, USA, .
Psychopharmacology (Impact Factor: 3.88). 11/2012; 226(2). DOI: 10.1007/s00213-012-2912-9
Source: PubMed


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 that 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.

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Available from: Matthew W Johnson, Aug 11, 2014
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    • "Using Salvia profoundly disturbs subjective experience, supporting the idea of Crick and Koch that the claustrum is important for consciousness. The analysis of the subjective reports presented here is in agreement with several studies which report significant hallucinogenic effects of S. divinorum, and effects different from those of serotroninergic hallucinogens (Johnson et al., 2011; Addy, 2012; Ranganathan et al., 2012; MacLean et al., 2013). The fact that besides the differences a considerable overlap exists between the effects of different hallucinogens is, in our opinion, evidence of the complexity and unified nature of the human psyche. "
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    ABSTRACT: THIS ARTICLE BRINGS TOGETHER THREE FINDINGS AND IDEAS RELEVANT FOR THE UNDERSTANDING OF HUMAN CONSCIOUSNESS: (I) Crick's and Koch's theory that the claustrum is a "conductor of consciousness" crucial for subjective conscious experience. (II) Subjective reports of the consciousness-altering effects the plant Salvia divinorum, whose primary active ingredient is salvinorin A, a κ-opioid receptor agonist. (III) The high density of κ-opioid receptors in the claustrum. Fact III suggests that the consciousness-altering effects of S. divinorum/salvinorin A (II) are due to a κ-opioid receptor mediated inhibition of primarily the claustrum and, additionally, the deep layers of the cortex, mainly in prefrontal areas. Consistent with Crick and Koch's theory that the claustrum plays a key role in consciousness (I), the subjective effects of S. divinorum indicate that salvia disrupts certain facets of consciousness much more than the largely serotonergic hallucinogen lysergic acid diethylamide (LSD). Based on this data and on the relevant literature, we suggest that the claustrum does indeed serve as a conductor for certain aspects of higher-order integration of brain activity, while integration of auditory and visual signals relies more on coordination by other areas including parietal cortex and the pulvinar.
    Frontiers in Integrative Neuroscience 02/2014; 8:20. DOI:10.3389/fnint.2014.00020
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    ABSTRACT: The neoclerodane diterpene salvinorin A is the major active component of the hallucinogenic mint plant Salvia divinorum Epling & Játiva (Lamiaceae). Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of opioid receptors, the site of action of morphine and related analogues, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because (1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and (2) its effects are not mediated through the previously investigated targets of psychotomimetics. This perspective outlines our research program, illustrating a new direction to the development of tools to further elucidate the biological mechanisms of drug tolerance and dependence. The information gained from these efforts is expected to facilitate the design of novel agents to treat pain, drug abuse, and other CNS disorders.
    Journal of Medicinal Chemistry 04/2013; DOI:10.1021/jm400388u · 5.45 Impact Factor
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    ABSTRACT: Background & objectives: Over the past decade, non-medical use of novel drugs has proliferated worldwide. In most cases these are synthetic drugs first synthesized in academic or pharmaceutical laboratories for research or drug development purposes, but also include naturally occurring substances that do not fit the typical pharmacological or behavioral profile of traditional illicit substances. Perhaps most unique to this generation of new drugs is that they are being sold over the counter and on the Internet as "legal highs" or substitutes for traditional illicit drugs such as cannabis, cocaine, amphetamines, MDMA, and LSD. The purpose of this review is to provide an overview of novel drugs in current use, including the epidemiology of use and toxicologic and pharmacological properties, and to offer some guidelines to clinicians who see patients experiencing adverse effects from these drugs. Method: We review the known scientific literature on recently introduced synthetic drug types, synthetic cannabinoids and synthetic cathinones, and the hallucinogen Salvia divinorum. Results: These substances comprise part of a rapidly evolving and controversial drug market that has challenged definitions of what is legal and illegal, has benefitted from open commercial sales without regulatory oversight, and is noteworthy for the pace at which new substances are introduced. Conclusions: This emerging trend in substance use presents significant and unique public health and criminal justice challenges. At this time, these substances are not detected in routine drug screens and substance-specific treatment for cases of use-related toxicity are not available. Clinicians are encouraged to learn characteristic signs associated with misuse of novel drugs to recognize cases in their practice, and are recommended to use a symptom-specific approach for treatment in each case.
    Adolescent psychiatry 05/2013; 3(2):123-134. DOI:10.2174/2210676611303020003
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