Chemical analysis of synthetic cannabinoids as designer drugs in herbal products

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Abstract

Several synthetic cannabinoids were found in 44 of 46 different kinds of herbal products that are currently distributed on the illegal drug market in Japan due to their expected narcotic effects. Gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) analyses indicated that most of the products contained two major synthetic cannabinoids: (1RS,3SR)-3-[2-hydroxy-4-(2-methylnonan-2-yl)phenyl]cyclohexan-1-ol, renamed cannabicyclohexanol with the agreement of Pfizer Inc., and/or 1-naphthalenyl(1-pentyl-1H-indol-3-yl)methanone, named JWH-018. Oleamide (cis-9,10-octadecenoamide), which is an endogenous cannabinoid, was also detected in 7 products. Additionally, two synthetic cannabinoids were identified as minor components in some products. One was (1RS,3SR)-3-[2-hydroxy-4-(2-methyloctan-2-yl)phenyl]cyclohexan-1-ol, which is named CP-47,497 and is a homolog of cannabicyclohexanol. The other was 1-naphthalenyl(1-butyl-1H-indol-3-yl)methanone, which is named JWH-073 and is a homolog of JWH-018. These compounds were reported as synthetic cannabinoids possessing pharmacological cannabimimetic activity. The concentrations of cannabicyclohexanol, JWH-018 and oleamide in the products ranged from 1.1 to 16.9 mg/g, 2.0 to 35.9 mg/g and 7.6 to 210.9 mg/g, respectively, and showed considerable variation. In this study, details of the analysis and identification of these synthetic cannabinoids in herbal products being sold on the Japanese drug market are described.

Introduction

Cannabis sativa L. (cannabis, marijuana) is widely abused throughout the world because it contains psychoactive cannabinoids such as Δ9-tetrahydrocannabinol. In Japan, the abuse of cannabis has recently increased, along with the abuse of a number of herbal products that are also distributed on the drug market for their cannabis-like effects when smoked. Although the active components of these herbal products were not identified, we recently found two synthetic cannabinoids as adulterants in herbal products that had been sold commercially as incense. One was (1RS,3SR)-3-[2-hydroxy-4-(2-methylnonan-2-yl)phenyl]cyclohexan-1-ol (cannabicyclohexanol, 1), which was detected together with its trans-diastereomer (2) [1]; the other was 1-naphthalenyl(1-pentyl-1H-indol-3-yl)methanone (JWH-018, 3) [2] (Fig. 1). Compound 1, which is a non-classical cannabinoid, was first synthesized by Pfizer Inc. in 1979 [3] and reported as a potent cannabinoid analog in the 1990s [4], [5], [6], [7], [8]. In consideration of its general properties, this compound was renamed cannabicyclohexanol with the agreement of Pfizer Inc. Compound 3, which is an aminoalkyl naphthoyl indole derivative, was first synthesized by Huffman et al. in 1998 and reported as a potent cannabinoid receptor agonist possessing in vivo pharmacological cannabinoid analog activity [9], [10], [11], [12]. Auwärter et al. also reported the identification of these compounds from some herbal products around the same time [13]. In January 2009, Germany's Health Minister announced that compounds 1 and 3 and their homologs had been identified as active components in a mislabeled mixture of herbs. Control of these compounds was begun in Germany immediately thereafter (on 22 January 2009) [14]; Austria, France and other countries initiated legal actions to ban or otherwise control these synthetic cannabinoids over the preceding months [15].

In this study, we report the analysis and identification of several synthetic cannabinoids as adulterants in herbal products using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS). In addition, the results of a survey of herbal products being sold on the Japanese market are described.

Section snippets

Chemicals and reagents

HPLC-grade acetonitrile, betamethasone valerate (internal standard, IS) and α-tocopherol were obtained from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Authentic cannabicyclohexanol (1) and JWH-018 (3) were isolated from herbal products and identified in our previous studies [1], [2]. Oleamide (4) was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). CP-47,497 (5) and JWH-073 (6) were purchased from Cayman Chemical (Ann Arbor, MI). All other common chemicals and solvents

Analyses of herbal products obtained from the Japanese market

Forty-six herbal products currently being sold in Japan for their expected cannabis-like effects were purchased via the Internet. These products appeared in primarily two forms i.e., as bits of dried leaves or as cigarettes (Table 1).

GC-MS and LC-MS analyses indicated that most of the products contained the two major compounds (1 and 3) (Fig. 1, Fig. 2a–p) and these compounds were reported in our previous studies [1], [2]. Oleamide (cis-9,10-octadecenoamide, 4), which shows cannabinoid-like

Discussion

Compound 1 has been reported as a cannabimimetic agent that produces more potent effects than those of typical cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC). Compton et al. reported that compound 1 showed an 8.5-fold more potent affinity for the CB receptor (Ki = 4.7 nM) and 5 had a 4.3-fold more potent affinity for the CB receptor (Ki = 9.5 nM) than did Δ9-THC (Ki = 40.7 nM) [4]. Additionally, they reported that compounds 1 and 5 were approximately 5-fold and 2-fold more potent than Δ9-THC,

Acknowledgment

Part of this work was supported by a Health and Labor Sciences Research Grant from the Ministry of Health, Labour, and Welfare, Japan.

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