Peter H. Addy

Spicing things up: synthetic cannabinoids

RationaleRecently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally.ObjectivesThe availability, acute subjective effects—including self-reports posted on Erowid—laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed.ResultsSpice is sold under the guise of potpourri or incense. Unlike delta-9-tetrahydrocannabinol, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned.ConclusionsThere is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug detection tests for synthetic cannabinoids need to become clinically available.

Salvinorin-A Induces Intense Dissociative Effects, Blocking External Sensory Perception and Modulating Interoception and Sense of Body Ownership in Humans

Background: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception, but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profiles of subjective effects of increasing doses of salvinorin-A in healthy volunteers, with a special emphasis on interoception. Methods: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included, among others, the Hallucinogen Rating Scale, the Altered States of Consciousness, and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness. Results: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the highest dose led to a sense of a complete loss of contact with the body. Conclusions: Salvinorin-A induced intense psychotropic effects characterized by a dose-dependent gating of external audio-visual information and an inverted-U dose-response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception, and the sense of body ownership in humans.

Clinical applications of hallucinogens: A review.

Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value. (PsycINFO Database Record

The subjective experience of acute, experimentally-induced Salvia divinorum inebriation:

This study examined the overall psychological effects of inebriation facilitated by the naturally-occurring plant hallucinogen Salvia divinorum using a double-blind, randomized, placebo-controlled trial. Thirty healthy individuals self-administered Salvia divinorum via combustion and inhalation in a quiet, comfortable research setting. Experimental sessions, post-session interviews, and 8-week follow-up meetings were audio recorded and transcribed to provide the primary qualitative material analyzed here. Additionally, post-session responses to the Hallucinogen Rating Scale provided a quantitative groundwork for mixed-methods discussion. Qualitative data underwent thematic content analysis, being coded independently by three researchers before being collaboratively integrated to provide the final results. Three main themes and 10 subthemes of acute intoxication emerged, encompassing the qualities of the experience, perceptual alterations, and cognitive-affective shifts. The experience was described as having rapid onset and being intense and unique. Participants reported marked changes in auditory, visual, and interoceptive sensory input; losing normal awareness of themselves and their surroundings; and an assortment of delusional phenomena. Additionally, the abuse potential of Salvia divinorum was examined post hoc. These findings are discussed in light of previous research, and provide an initial framework for greater understanding of the subjective effects of Salvia divinorum, an emerging drug of abuse.

Cannabis, Cannabinoids, and the Association with Psychosis

Recent advances in knowledge about cannabinoid receptor function have renewed interest in the association between cannabis and psychosis. Converging lines of evidence suggest that cannabinoids can produce a full range of transient schizophrenia-like positive, negative and cognitive symptoms. Cannabinoids also produce some psychophysiological deficits that are known to be present in schizophrenia. Also clear is that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Increasing evidence suggests that early and heavy cannabis exposure may increase the risk of developing a psychotic disorder such as schizophrenia. The relationship between cannabis exposure and schizophrenia fulfills some, but not all, of the usual criteria for causality. However, most people who use cannabis do not develop schizophrenia, and many people diagnosed with schizophrenia have never used cannabis. Therefore, it is likely that cannabis exposure is a “component cause” that interacts with other factors to contribute to the development of schizophrenia or other psychotic disorders, but is neither necessary nor sufficient to do so alone. As direct causes of schizophrenia have not been identified, the implications for public health policy are such that the role of component causes such as cannabinoid exposure should remain a focus of further study. Finally, further work is necessary in order to identify the factors that underlie individual vulnerability to cannabinoid-related psychosis and to elucidate the biological mechanisms underlying this risk.

Naltrexone but Not Ketanserin Antagonizes the Subjective, Cardiovascular, and Neuroendocrine Effects of Salvinorin-A in Humans.

Background: Salvinorin-A is a terpene found in the leaves of the plant Salvia divinorum. When administered to humans, salvinorin-A induces an intense but short-lasting modified state of awareness, sharing features with those induced by the classical serotonin-2A receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor rather than at the serotonin-2A receptor. Here, we assessed the involvement of kappa-opioid receptor and serotonin-2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. Methods: We conducted a placebo-controlled, randomized, double-blind study with 2 groups of 12 healthy volunteers with experience with psychedelic drugs. There were 4 experimental sessions. In group 1, participants received the following treatment combinations: placebo+placebo, placebo+salvinorin-A, naltrexone+placebo, and naltrexone+salvinorin-A. Naltrexone, a nonspecific opioid receptor antagonist, was administered at a dose of 50mg orally. In group 2, participants received the treatment combinations: placebo+placebo, placebo+salvinorin-A, ketanserin+placebo, and ketanserin+salvinorin-A. Ketanserin, a selective serotonin-2A antagonist, was administered at a dose of 40mg orally. Results: Inhalation of 1mg of vaporized salvinorin-A led to maximum plasma concentrations at 1 and 2 minutes after dosing. When administered alone, salvinorin-A severely reduced external sensory perception and induced intense visual and auditory modifications, increased systolic blood pressure, and cortisol and prolactin release. These effects were effectively blocked by naltrexone, but not by ketanserin. Conclusions: Results support kappa opioid receptor agonism as the mechanism of action underlying the subjective and physiological effects of salvinorin-A in humans and rule out the involvement of a serotonin-2A-mediated mechanism.

Tetrahydrocannabinol (THC) impairs encoding but not retrieval of verbal information

INTRODUCTION Cannabis and agonists of the brain cannabinoid receptor (CB1R) produce acute memory impairments in humans. However, the extent to which cannabinoids impair the component processes of encoding and retrieval has not been established in humans. The objective of this analysis was to determine whether the administration of Δ9-Tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, impairs encoding and/or retrieval of verbal information. MATERIALS AND METHODS Healthy subjects were recruited from the community. Subjects were administered the Rey-Auditory Verbal Learning Test (RAVLT) either before administration of THC (experiment #1) (n=38) or while under the influence of THC (experiment #2) (n=57). Immediate and delayed recall on the RAVLT was compared. Subjects received intravenous THC, in a placebo-controlled, double-blind, randomized manner at doses known to produce behavioral and subjective effects consistent with cannabis intoxication. RESULTS Total immediate recall, short delayed recall, and long delayed recall were reduced in a statistically significant manner only when the RAVLT was administered to subjects while they were under the influence of THC (experiment #2) and not when the RAVLT was administered prior. CONCLUSIONS THC acutely interferes with encoding of verbal memory without interfering with retrieval. These data suggest that learning information prior to the use of cannabis or cannabinoids is not likely to disrupt recall of that information. Future studies will be necessary to determine whether THC impairs encoding of non-verbal information, to what extent THC impairs memory consolidation, and the role of other cannabinoids in the memory-impairing effects of cannabis. CLINICAL TRIAL INFORMATION Cannabinoids, Neural Synchrony, and Information Processing (THC-Gamma) http://clinicaltrials.gov/ct2/show/study/NCT00708994 NCT00708994 Pharmacogenetics of Cannabinoid Response http://clinicaltrials.gov/ct2/show/NCT00678730 NCT00678730.

Commentary on Hermanns-Clausen et al. (2013): Spicing things up – the emerging phenomenon of synthetic cannabinoid use

There is growing concern about the use and abuse of synthetic cannabinoids, referred to collectively as ‘Spice’. Even though the first reports of the recreational use of Spice emerged in 2006 [1,2], it was not until 2008 that the first synthetic cannabinoid, JWH-018, was identified as a component of Spice [3]. The existing information about Spice is limited to retrospective reports of acute intoxication [4–6]. At present clinicians, emergency responders, law-enforcement and legislators must rely completely on these uncontrolled data [6], while some fairly basic information about Spice is not known. For example, what is the dose–response? What is the temporal profile of effects? Who is more vulnerable to negative effects? What are the differences between the combinations of synthetic cannabinoids present in Spice? What is the relationship between blood or urine levels of these drugs and their effects? What are the effects of these drugs on physical and laboratory parameters? Hermanns-Clausen and colleagues [6] report on a retrospective study of 29 patients who were hospitalized for Spice-related toxicity. Individuals presented with agitation, hallucinations, acute psychosis, vomiting, tachycardia and hypertension and even seizures. These cases involved nine synthetic cannabinoids belonging to different classes. They observed that the cannabinoids present in Spice changed over time. While this paper adds to a growing body of retrospective reports, it also highlights the need for controlled studies with carefully characterized subjects using well-validated measures to keep abreast with the everchanging nature of Spice and other modern recreational drug use. Adolescents and young adults continue to expose themselves to unknown risks, while efforts to obtain controlled data on Spice remain stalled largely because regulatory requirements make such studies challenging to conduct in humans. The typical process of characterizing the effects of a drug in humans involves extensive toxicology testing in animals followed by slow, dose-escalation first-in-human studies. The promise of commercial viability usually underwrites the expense of toxicology testing. However, manufacturers of Spice have no incentive to conduct toxicology testing for products that they market as ‘not for human consumption’ [5], and neither do the young adult consumers. Whether governmental funding agencies are going to conduct toxicology testing for these drugs of abuse remains an open question. One alternative is to conduct quasi-experimental studies in which the effects of Spice can be characterized carefully in people who already use it, in the safety of a laboratory, attended by trained medical and psychiatric personnel. Studying the effects of synthetic cannabinoids in people who already use them recreationally does not expose them to any additional risk. In fact, conducting such studies in the safety of a medical facility with psychiatric and medical oversight will reduce the risks, as the individuals who would be smoking Spice anyway would do so in a safe environment instead of in their home or at a party. Another alternative might be to characterize the effects of synthetic cannabinoids in non-human primates. However, the active constituents of Spice change over time in response to legislation in a perpetual ‘cat-and-mouse game’ [6,7]. Thus, studying a specific synthetic cannabinoid present in Spice today may be irrelevant a year from now, when the active constituents have changed. The existence and evolution of Spice illustrates some unintended consequences of current drug policy. Manufacturers are replacing banned compounds with related compounds for which there is little safety information, and potentially more harm. As suggested by HermannsClausen and colleagues [6], these full-agonist highaffinity synthetic cannabinoids are potentially more harmful than the partial-agonist low-affinity naturally occurring delta-9-tetrahydrocannabinol (THC). One of the reasons for the growth in Spice use is because users are trying to avoid the legal consequences of using cannabis [3]. It remains to be seen whether the decriminalization/legalization of cannabis will be associated with a reduction in the use of Spice. Controlled data on the acute pharmacology and toxicology of Spice in animals and humans is needed so that evidence-based treatments of Spice-induced side effects can be developed. It would be incorrect to assume that knowledge about the effects of cannabis and/or THC can be extrapolated to understand the pharmacology of the highly potent, full agonist, synthetic cannabinoids present in Spice. The behavioral, subjective, cognitive and physiological effects of Spice need to be characterized under controlled conditions. The relationship between effects and the blood/urine levels of parent cannabinoids and their metabolites needs to be established. Urine drug tests for synthetic cannabinoids need to become more widely available. Epidemiological studies are necessary in order to track the long-term impact of legislation. Finally, the acute and long-term effects of Spice use need to be compared to cannabis use. Studying the consequences of Spice use also has the potential of shedding further light on the association between cannabinoids and psychosis, COMMENTARY bs_bs_banner