ReviewSynthetic cannabinoids: Epidemiology, pharmacodynamics, and clinical implications☆
Introduction
Synthetic cannabinoids (SC) interact with CB1 and CB2 cannabinoid receptors and elicit cannabimimetic effects similar to Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent in cannabis (Wiley et al., 2013b). SC were developed as research tools to explore the endocannabinoid system and as potential therapeutics (Pertwee, 2006). CB1 receptors are expressed in the central and peripheral nervous systems, bone, heart, liver, lung, vascular endothelium, and reproductive system (Howlett et al., 2002). CB2 receptors are primarily in the immune system, but also in the central nervous system at lower levels than CB1 (Ashton et al., 2006, Onaivi et al., 2008, Van Sickle et al., 2005). SC activate CB1 receptors, G-protein coupled receptors predominantly located at pre-synaptic terminals. CB1 receptor activation decreases cellular cyclic adenosine monophosphate (cAMP) levels and elicits cannabimimetic responses (Pertwee, 2010). SC agonists interact with voltage-gated ion channels and inhibit potassium, sodium, and N- and P/Q-type-calcium channels by reducing membrane potentials.
Cyclohexylphenols (CP) were synthesized between 1970 and 1980 with CP55,940 (2-[(1R,2R,5R)-5-Hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-5-(2-methyl-octan-2yl)-phenol), commonly utilized to localize cannabinoid receptors (Johnson and Melvin, 1986). Created in Dr. Raphael Mechoulam's laboratory at Hebrew University (HU), Jerusalem, HU-210 [(6aR)[-trans-3-(1,1-Dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6Hdibenzo[b,d]pyran-9-methanol]] is a dibenzoypyran, structurally similar to THC, and a highly potent CB1 and CB2 agonist (Mechoulam et al., 1990, Howlett et al., 1995, Ovadia et al., 1995, Rodriguez de Fonseca et al., 1995). In the 1990s, aminoalkylindoles such as WIN55,212 [(R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[(1,2,3.de)-1,4-benzoxazin-6-yl]-1-naphthalen-ylmethanone]] were investigated as potentially safer (non-psychotropic) pharmacotherapies (Bell et al., 1991). John W. Huffman (JWH) created the most extensive SC series with chemical structures different from the classical dibenzopyran, but eliciting cannabimimetic effects in animals (Huffman and Dai, 1994). Other SC developed in the last two decades were the AM-series (Alexandros Makriyannis) (Makriyannis and Deng, 2000) and indazole-carboxamide derivatives, e.g., AB-FUBINACA [N-[(2S)-1-Amino-3-methyl-1-oxo-2-butanyl]-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide] (Buchler et al., 2009). To date hundreds of SC were categorized into the following structural groups (Fig. 1): adamantoylindoles, aminoalkylindoles, benzoylindoles, cyclohexylphenols, dibenzopyrans, naphthoylindoles, naphthylmethylindoles, naphthylmethylindenes, naphthoylpyrroles, phenylacetylindoles, tetramethylcyclopropyl ketone indoles, quinolinyl ester indoles, and indazole carboxamide compounds.
SC, synthesized in clandestine laboratories and sprayed on dried plant materials, were first marketed as legal cannabis alternatives in Europe in the early 2000s (United Nations Office on Drugs and Crime, 2011). SC sold on the Internet, in head shops and convenience stores as Spice and K2 are labeled “not for human consumption.” Many SC are Schedule I drugs under the US Controlled Substance Act (US Drug Enforcement Administration, 2014, US Drug Enforcement Administration, 2013a, US Drug Enforcement Administration, 2013b). As new SC groups are scheduled, more structurally-diverse cannabimimetic compounds emerge, which may not be covered under current regulations.
SC popularity are attributed to intense psychoactive effects, lack of detectability in routine urine drug tests, and, until recently, legal status in most jurisdictions (Gunderson et al., 2012, Vandrey et al., 2012, Winstock and Barratt, 2013). Documented serious adverse effects and limited human pharmacology data make SC intake an important public health and safety concern. We present SC epidemiology, pharmacodynamic profiles, and clinical implications, based on a systematic and comprehensive electronic literature review.
Section snippets
Methods
We conducted a comprehensive literature search of 7 electronic bibliographic databases (PubMed®, Embase™, Web of Science™, Scopus™, Cochrane, Biological Abstracts, and Chemical Abstracts via STN® and SciFinder® platforms) up to December 31, 2013, except that Biological Abstracts (Biosis) and Chemical Abstracts searches ended November 30, 2011. In addition, we expanded our query employing Google and Google Scholar, and hand-searched reference lists of identified articles. We employed
Epidemiology
We identified 9 SC epidemiological studies, none population- or community-based. Two worldwide surveys of self-selected convenience samples were conducted between 2011 and 2012. The first, collecting data online between January 4th and February 7th, 2011 recruited participants primarily from Internet drug forums providing SC information (Vandrey et al., 2012). Of 391 participants, 168 met inclusion criteria (self-reported SC intake, English speaking, and ≥18 years), representing 13 countries
Summary
SC consumption has become widespread, despite law enforcement and regulatory control measures. Epidemiological data suggest that the majority of SC users are young adults who perceive SC as safer than non-cannabinoid illicit drugs and a favorable cannabis alternative eliciting cannabis-like “high” while avoiding detection by standard drug screens. However, data suggest that many SC users prefer cannabis over SC due to the drugs’ negative effects. SC are readily accessible, sold under several
Role of funding source
This work was funded by an interagency agreement between the Department of Defense Counter Narcotics Program and Chemistry and Drug Metabolism Section, IRP, National Institute on Drug Abuse, NIH.
Contributors
Marisol Castaneto, David Gorelick, Nathalie Desrosiers, and Rebecca Hartman reviewed and selected articles as part of the comprehensive literature review. Marisol Castaneto organized the data included in this review and wrote the first draft of the manuscript with the assistance of David Gorelick, Sandrine Pirard, and Marilyn Huestis. All authors contributed and approved the final manuscript.
Conflict of interest
No conflict declared.
Disclaimer
The opinions or assertions herein are those of the authors and do not necessarily reflect the views of the NIH or the Departments of the Army, Navy, or the Department of Defense.
Acknowledgment
We thank Ms. Anne White-Olson and Ms. Barbara Brandys, NIH Library, Bethesda, MD for their invaluable assistance with the electronic literature search.
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Supplementary material can be found by accessing the online version of this paper. Please see Appendix A.