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      Review of the many faces of synthetic cannabinoid toxicities

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          Abstract

          Introduction

          Synthetic cannabinoids (SCs) are psychoactive substances that are gaining popularity for their availability and lack of detection by standardized drug tests. Although some users may perceive SCs as safer alternatives to marijuana, some SCs are more potent and result in more severe toxicities.

          Methods

          A search of the literature was conducted in the PubMed and SciFinder databases. Results in PubMed were limited to human studies, and only articles in English were included.

          Results

          Review of the literature illustrates the hazards associated with SC use. A range of severe toxicities affecting numerous systems has been identified, such as arrhythmias, myocardial infarction, sudden cardiac death, psychosis, suicidal ideation, seizures, acute tubular necrosis, and intracranial hemorrhage. Additionally, a recent outbreak of coagulopathies and at least 4 associated deaths due to SCs tainted with brodifacoum have been reported.

          Discussion

          Synthetic cannabinoids may be perceived as a safer alternative to marijuana; however, SCs can be more potent at the cannabinoid receptors and in turn have greater toxicities. Limited information is available on the metabolism of SCs; however, cytochrome P450 pathways may be involved, which could result in drug interactions and unpredicted adverse effects. Toxicity with SC use is not just related to its effects, but also to additives that may taint these products and enhance their effects. Health care providers should be aware of the range of toxicities related to SC use, and tainted products such as these agents are not detected on routine drug screens.

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          Most cited references43

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          A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment

          Synthetic cannabinoids (SCs) such as "Spice", "K2", etc. are widely available via the internet despite increasing legal restrictions. Currently, the prevalence of use is typically low in the general community (<1%) although it is higher among students and some niche groups subject to drug testing. Early evidence suggests that adverse outcomes associated with the use of SCs may be more prevalent and severe than those arising from cannabis consumption.
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            Spicing things up: synthetic cannabinoids.

            Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. The availability, acute subjective effects-including self-reports posted on Erowid-laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Spice 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. There 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.
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              Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity?

              K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances.
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                Author and article information

                Journal
                Ment Health Clin
                Ment Health Clin
                mhcl
                The Mental Health Clinician
                College of Psychiatric & Neurologic Pharmacists
                2168-9709
                March 2019
                1 March 2019
                : 9
                : 2
                : 93-99
                Affiliations
                [2  ]Assistant Professor, Department of Pharmacy Practice, Marshall B. Ketchum University College of Pharmacy, Fullerton, California
                [3  ]PharmD Candidate, University of Illinois at Chicago, College of Pharmacy, Chicago, Illinois
                [4  ]Pharmacy Librarian, Marshall B. Ketchum University, MB Ketchum Memorial Library, Fullerton, California
                Author notes
                1  Assistant Professor, Department of Pharmacy Practice, Marshall B. Ketchum University, College of Pharmacy, Fullerton, California, aalipour@ 123456ketchum.edu

                Disclosures: The authors of this article have no conflicts of interest to disclose.

                Author information
                https://orcid.org/0000-0003-4455-0525
                https://orcid.org/0000-0002-1756-9135
                https://orcid.org/0000-0002-2068-7757
                https://orcid.org/0000-0001-9420-4466
                Article
                mhcl-09-02-09
                10.9740/mhc.2019.03.093
                6398358
                30842917
                0b6a4565-cb13-4363-8945-e751c965aeea
                © 2019 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Literature Review
                Custom metadata
                How to cite: Alipour A, Patel PB, Shabbir Z, Gabrielson S. Review of the many faces of synthetic cannabinoid toxicities. Ment Health Clin [Internet].

                synthetic marijuana,synthetic cannabis,synthetic cannabinoids,cannabinoids,designer drugs,street drugs,toxicity,hemorrhage,bleeding,k2,spice

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