Synthetic cannabinoids: Analysis and metabolites

Abstract

Cannabimimetics (commonly referred to as synthetic cannabinoids), a group of compounds encompassing a wide range of chemical structures, have been developed by scientists with the hope of achieving selectivity toward one or the other of the cannabinoid receptors CB1 and CB2. The goal was to have compounds that could possess high therapeutic activity without many side effects. However, underground laboratories have used the information generated by the scientific community to develop these compounds for illicit use as marijuana substitutes. This chapter reviews the different classes of these “synthetic cannabinoids” with particular emphasis on the methods used for their identification in the herbal products with which they are mixed and identification of their metabolites in biological specimens.

Introduction

Synthetic cannabinoids, better referred to as cannabimimetic compounds, are compounds prepared by scientists around the world targeting an interaction with the endocannabinoid system, namely CB1 and CB2 receptors. Although many of these compounds have been described in the literature for many years, their illicit use appeared only in the last few years. They appeared in the United States market in late 2008. They were mixed with herbal products and sold as incense or potpourri on the internet, gas stations and tobacco shops under many brand names (Spice, Spice gold, Aroma, K2, Spike 99, etc.) with labels stating “not for human consumption”. These products are claimed to contain only natural non-illegal compounds and consequently have no limitations in their commercial distribution (Carroll et al., 2012). The consumption of these products has become a popular alternative to marijuana, as they are of high-potency and high efficacy as cannabinoid receptor full agonists.

The number of patients presented to the emergency department with problems associated with these drugs has dramatically increased. In March, 2011 the US Drug Enforcement Administration (DEA) scheduled five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologue) as schedule 1 controlled substances. Many of these products especially Spice and K2 have been banned in many European countries (ElSohly et al., 2011, Wells and Ott, 2011) and in May 2013, three synthetic cannabinoids (UR-144, XLR-11 and AKB-48) were also placed in schedule 1.

Moreover, compared to THC, some synthetic cannabinoids possess a 4–5 times improved binding affinity to the cannabinoid CB1 receptor and many toxicity symptoms were reported including anxiety, paranoia, tachycardia, irritability, hallucination, numbness, seizures, high blood pressure, drowsiness, and slurred speech (Seely et al., 2012). Over the past few years a great effort has been exerted to identify and quantify synthetic cannabinoids in herbal products, and detect their metabolites in body fluids (urine, serum, and saliva) and also in hair specimens. These methods include liquid chromatography tandem mass spectroscopy (LC–MS/MS) (Teske et al., 2010), high mass resolution techniques like matrix-assisted laser desorption/ionization time of flight mass spectroscopy (MALDI-TOF) (Gottardo et al., 2012), direct analysis in real time mass spectrometry (DART-MS) (Musah et al., 2012), nuclear magnetic resonance (NMR) (Rollins et al., 2013), gas chromatography/mass spectrometry (GC/MS) (Sobolevskii et al., 2011), and immunoassays (Arntson et al., 2013).

Recently, many reviews on the chemistry, toxicity, and pharmacology of synthetic cannabinoids have been published (Carroll et al., 2012, Favretto et al., 2013, Seely et al., 2012, Spaderna et al., 2013, Wells and Ott, 2011). In this chapter, the focus will be on the analysis of the different classes of synthetic cannabinoids in herbal mixtures and the identification/analysis of their metabolites in biological fluids.

Synthetic cannabinoids can be chemically classified into naphthoylindoles, benzoylindoles, phenylacetylindoles, adamantylindoles, cyclophenols and a miscellaneous group. Different analytical techniques have been applied to the detection and quantitation of different members of each of these classes. Details are outlined below.