Metabolism and toxicological analysis of synthetic cannabinoids in biological fluids and tissues.

Synthetic cannabinoids, which began proliferating in the United States in 2009, have gone through numerous iterations of modification to their chemical structures. More recent generations of compounds have been associated with significant adverse outcomes following use, including cognitive and psychomotor impairment, seizures, psychosis, tissue injury and death. These effects increase the urgency for forensic and public health laboratories to develop methods for the detection and identification of novel substances, and apply these to the determination of their metabolism and disposition in biological samples. This comprehensive review describes the history of the appearance of the drugs in the United States, discusses the naming conventions emerging to designate new structures, and describes the most prominent new compounds linked to the adverse effects now associated with their use. We review in depth the metabolic pathways that have been elucidated for the major members of each of the prevalent synthetic cannabinoid drug subclasses, the enzyme systems responsible for their metabolism, and the use of in silico approaches to assist in predicting and identifying the metabolites of novel compounds and drug subclasses that will continue to appear. Finally, we review and critique analytical methods applied to the detection of the drugs and their metabolites, including immunoassay screening, and liquid chromatography mass spectrometry confirmatory techniques applied to urine, serum, whole blood, oral fluid, hair, and tissues.

Pharmacology, Toxicology, and Adverse Effects of Synthetic Cannabinoid Drugs.

Synthetic cannabinoid drugs have become an established part of the recreational drug landscape in the United States and internationally. These drugs are manufactured in clandestine laboratories internationally and distributed in the United States in smoking mixtures, use of which produces effects very similar to use of marijuana. The adverse-effect profile of the drugs has not been studied in humans and infrequently in animal models, so much of the information about their toxicity comes from emergency department and treatment reports and forensic case studies. This review considers the discovery and characterization of the endocannabinoid system, approaches to receptor-binding studies of various synthetic cannabinoids from the first wave of naphthoylindoles (e.g., JWH-018) to the emerging adamantoylindole drugs (e.g., AKB-48), and their analogs, to evaluate the potential activity of drugs in this class. Currently employed approaches to assessing functional activity of the drugs using in vitro and in vivo models is also described, and comparisons made to the effects of THC. The physiological effects of activation of the endocannabinoid system in humans are reviewed, and the physiological effects of cannabinoid use are described. Case reports of adverse events including emergency department admissions, mental health admissions, and clinical and forensic case reports are presented in detail and discussed to summarize the current state of knowledge of adverse effects, both clinical and forensic in humans, including effects on driving ability, and tissue injury and death. The greatest weight is accorded to those reports that include toxicological confirmation of use. Finally, we discuss the current status of attempts to schedule and control the distribution of synthetic cannabinoids and the relevance of receptor binding and functional activity in this context. There is growing toxicological and pharmacological evidence of impairment, psychosis, tissue injury, and isolated deaths attributable to this emerging class of drugs.

Analysis of Synthetic Cannabinoids in Botanical Material: A Review of Analytical Methods and Findings.

Synthetic cannabinoid analogs have gained a great deal of attention from the forensic community within the last four years. The compounds found to be of most interest to forensic practitioners include those of the following series: JWH, CP, HU, AM, WIN, RCS, and most recently, XLR and UR. Structurally the HU compounds are most similar in structure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. The novel compounds include cyclohexylphenols, naphthoylindoles, naphthylmethylindoles, naphthylmethylindenes, benzoylindoles, naphthoylpyrroles, phenylacetylindoles, adamantoylindoles, and tetramethylcyclopropylindoles. Many of these compounds are cannabinoid receptor agonists and were originally synthesized for medical research purposes but have recently been appropriated into the illicit drug market. Their psychoactive effects, mimicking those of marijuana, as well as their indeterminate legal status, have made them popular for recreational use. Solutions of the compounds dissolved in organic solvents are sprayed onto botanical material and sold as "herbal incense" products via the Internet, and in smoke shops, convenience stores, and gas stations around the world. Many of the products are labeled "Not for human consumption" in an attempt to circumvent legislation that bans the sale and manufacture of certain compounds and their analogs for human use. The compounds that were first detected following forensic analysis of botanical materials included JWH-018, JWH-073, and CP 47,497 (C7 and C8 homologs). However, in the four years since their appearance the number of compounds has grown, and additional diverse classes of compounds have been detected. Governments worldwide have taken action in an attempt to control those compounds that have become widespread in their regions. This article discusses the history of synthetic cannabinoids and how they have been detected in the illicit drug market. It also discusses the analytical methods and techniques used by forensic scientists to analyze botanical products obtained via the Internet or from law enforcement investigations and arrests.