Determination and identification of synthetic cannabinoids and their metabolites in different matrices by modern analytical techniques – a review

doi:10.1016/j.aca.2014.12.055

Analytica Chimica Acta

Volume 874, 18 May 2015, Pages 11-25

https://doi.org/10.1016/j.aca.2014.12.055 Get rights and content

Highlights

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Synthetic cannabinoids from analytical point of view.
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Determination and identification methods of synthetic cannabinoids in different matrices.
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Analytical techniques used from thin layer chromatography to high resolution mass spectrometry.
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Detailed survey of gas and liquid chromatography methods for synthetic cannabinoids analysis.

Abstract

Synthetic cannabinoids have gained popularity due to their easy accessibility and psychoactive effects. Furthermore, they cannot be detected in urine by routine drug monitoring. The wide range of active ingredients in analyzed matrices hinders the development of a standard analytical method for their determination. Moreover, their possible side effects are not well known which increases the danger.

This review is focused on the sample preparation and the determination of synthetic cannabinoids in different matrices (serum, urine, herbal blends, oral fluid, hair) published since 2004. The review includes separation and identification techniques, such as thin layer chromatography, gas and liquid chromatography and capillary electrophoresis, mostly coupled with mass spectrometry. The review also includes results by spectral methods like infrared spectroscopy, nuclear magnetic resonance or direct-injection mass spectrometry.

Graphical abstract

Introduction

The story about synthetic cannabinoids (SCs) is mainly connected to the fact, that they induce psychoactive effects and that they are readily available and highly attractive mainly for young abusers. SCs as new designer drugs were marketed as chemical powders or smoking blends (added artificially on the herbs surface) labeled: “for aromatherapy only”, “not for human consumption” or “incense”, to mask their intended purpose and to avoid regulatory oversight. This created a loophole for drug abusers who gained easy and legal access to the drugs. Moreover it is commonly known, that SCs and their metabolites are hard to detect in common drug-screening assays of human body fluids (urine, blood, oral fluid, etc.), which makes them even more attractive [1], [2].

Recent years’ experience shows clearly that SCs are a significant potential hazard to the human health and represent a new class of drugs abuse [1], [2], [3], [4]. The compounds found in the first generation of herbal blends (marketed as “Spice” label products) were C8 homologues of the nonclassical cannabinoid CP-47,497 and the aminoalkylindole JWH-018 [4], [5]. From that time the number of newly identified SCs has increased continuously, according to the report of the United Nations Office on Drugs and Crime (UNODC) [6] in 2012 sixty new SCs were identified whereas in 2013 the number was doubled. Most of countries’ authorities try to take countermeasures against the new psychoactive drugs, including SCs, by introducing new law regulations and by banning many of such substances. The UNODC organization and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) monitor the drug market situation and evaluate the need to update the list of banned cannabinoids.

Considering the significant growth in the manufacture, sale and use of products containing SCs it is necessary for forensic and toxicologic purposes to have selective, sensitive and high-throughput analytical methods to monitor the SCs in marketed products and in body fluids (urine, blood or oral fluid). Such methods are essential for the clinical care of abusers. Starting in 2004, the number of publications concerning the identification and quantification of SCs has continuously increased and is illustrated in Fig. 1.

The presented review sums up and comments on all available analytical procedures for separation and identification of SCs and their metabolites in different matrices. To get the full picture on SCs the manuscript is also supported with short information about metabolism, pharmacology and toxicity of the studied compounds. The review discusses advantages and limitations regarding the homogenization of samples, interferences, and data interpretation. It could be helpful for many analytical toxicologists in their practice for both ante- and post-mortem investigation and for development of new methods.

Section snippets

Classification and nomenclature of synthetic cannabinoids

The nomenclature and classification of SCs is quite complex and not fully systematized, as a result of ongoing development and broad differences in their chemical structure. The nomenclature contains abbreviations and numbering. Some of SCs have a prefix indicating the place where a substance was tested or analyzed for the first time or who synthesized it. There are also names that have probably been chosen to help market the products like AKB-48, the name origins form a popular Japanese girl

Pharmacology and toxicity of synthetic cannabinoids

SCs represent a wide group of compounds with different chemical structure and functional similarity to THC. These similarities allow binding to one of the known cannabinoids receptors, namely CB1 or CB2 or to both of them [9], [10], [11]. The health-related problems associated with the use of herbal blends have been reported to be similar to those of cannabinoids, e.g., panic attacks or cardiovascular problems like tachycardia, hypertension, and hypotension [12], [13], [14], [15], [16].

Metabolism of synthetic cannabinoids

From the analytical point of view, the knowledge about the probable metabolites of studied compounds is useful to recognize parent compounds taken by drug abuser. It was also found that SCs are rapidly metabolized [26], [27]. The metabolism studies of SCs are continuously developing and are based on in vitro experiments on the human or rat liver’s microsomes, which mimics the first phase metabolism [7], [26], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40] as well

Sample preparation

To conduct a reliable analysis, the stability of the samples and conditions for their optimal storage have to be known. Tests have already been carried out on urine [46], serum [53], [54], [55], hair [56], [57], [58] and oral fluid [59] as sample matrices. The stability studies combine the storage conditions at room temperature (RT), at 4 °C, at −20 °C and under freezing–thawing cycles. The serum, oral fluids and urine samples for testing of SCs content should be refrigerated. The analysis of

Conclusion

Concerning the threat of SCs for human health and their continuous expansion as well as a great popularity among users of different ages, there is a great need to develop reliable methods for their qualitative and quantitative analysis. The effort should be put on exploring low cost and less time consuming approaches for screening analysis such as Immunoassay tests. However, regarding the complexity and the broad range of drugs in the black drug market, it is obvious that the most often used

Acknowledgement

The financial support by the Grant Agency of the Ministry of Health of the Czech Republic (No. NT 13593-3/2012) is gratefully acknowledged.

Joanna Znaleziona is a Junior Researcher at the Department of Analytical Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University in Olomouc. Her research is concentrated on the separation of biologically active compounds, chiral separation by capillary electrophoresis as well as the development of new separation methods. Currently, she is involved in the project focused on the permanent and dynamic coatings of the capillary inner wall for

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Pavlina Ginterova is a postgraduate student at the Department of Analytical Chemistry, Faculty of Science, Palacky University in Olomouc. Her area of research includes the capillary electromigration separation techniques in the field of food and clinical analysis.

Jan Petr obtained his PhD in 2008. Now, he is an Associate Professor at the Department of Analytical Chemistry, Palacký University in Olomouc. His research is focused on capillary electrophoresis of biologically active compounds, characterization of nanoobjects and microobjects by various analytical techniques, and low-cost miniaturization. He published over 35 papers with more than 300 citations.

Peter Ondra is associate professor at the Department of Forensic Medicine and Medical Law, Faculty of Medicine, Palacký University in Olomouc and Faculty Hospital in Olomouc. His research activities covers separation of toxicological interested compounds and drugs by gas chromatography and liquid chromatography hyphenated with mass spectrometry, development of new method for toxicological analysis.

Ivo Válka is assistant professor at Department of Forensic Medicine and Medical Law, Faculty of Medicine, Palacký University in Olomouc and Faculty Hospital in Olomouc. His research is focused on development of the new analytical methods for abused drugs by gas chromatography–mass spectrometry.

Juraj Sevcik is professor of Analytical Chemistry at the Faculty of Science, Palacky University in Olomouc. His research activities cover chiral separations, preconcentration techniques by capillary electrophoresis and development of new analytical methods. He published more than hundred papers on separation science.

Jan Chrastina is assistant professor at the Institute of Special Education Studies, Faculty of Education, Palacký University in Olomouc. His research is focused on somatopaedics and disability studies, qualitative research of impact of chronic illnesses, lifestyle research, content analysis of healthcare measurement tools, rare disease research and metabolic disorders and drug abuses.

Vítězslav Maier is associate professor at the Department of Analytical Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University in Olomouc. His research activities covers separation of enantiomers, capillary electrophoresis hyphenated with mass spectrometry, development of new on-line preconcentration methods and toxicological analysis. He published more than forty papers on capillary electrophoresis application and theoretical studies.

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ReviewDetermination and identification of synthetic cannabinoids and their metabolites in different matrices by modern analytical techniques – a review

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Classification and nomenclature of synthetic cannabinoids

Pharmacology and toxicity of synthetic cannabinoids

Metabolism of synthetic cannabinoids

Sample preparation

Conclusion

Acknowledgement

Lancet

Toxicol. Appl. Pharmacol.

Toxicol. Lett.

Drug Alcohol Depend.

Bioorg. Med. Chem.

J. Emerg. Med.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neuropharmacology

Fundam. Appl. Toxicol. Off. J. Soc. Toxicol.

J. Pharm. Biomed. Anal.

J. Chromatogr. B

J. Chromatogr. B

Forensic Sci. Int.

J. Chromatogr. B

J. Chromatogr. B Anal. Technol. Biomed. Life Sci.

J. Chromatogr. B

J. Chromatogr. B

Toxicol. Anal. Clin.

Forensic Sci. Int.

Clin. Biochem.

Forensic Sci. Int.

J. Pharm. Biomed. Anal.

J. Chromatogr. A

Forensic Sci. Int.

J. Chromatogr. B

J. Chromatogr. B

Forensic Sci. Int.

J. Chromatogr. B

J. Chromatogr. A

Spice and other herbal blends: harmless incense or cannabinoid designer drugs?

J. Mass Spectrom.

Identification of a cannabinoid analog as a new type of designer drug in a herbal product

Chem. Pharm. Bull. (Tokyo)

International Union of Pharmacology. XXVII. Classification of cannabinoid receptors

Pharmacol. Rev.

CB1 cannabinoid receptor ligands

Mini Rev. Med. Chem.

Blockade of effects of smoked marijuana by the cb1-selective cannabinoid receptor antagonist sr141716

Arch. Gen. Psychiatry

Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings

Addiction

The new marijuana

Ann. Pharmacother.

An overview on the biochemistry of the cannabinoid system

Mol. Neurobiol.

Cannabimimetic Indoles, Pyrroles, and Indenes: Structure–Activity Relationships and Receptor Interactions

Severe toxicity following synthetic cannabinoid ingestion

Clin. Toxicol.

Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A4

FASEB J.

A review of nabilone in the treatment of chemotherapy-induced nausea and vomiting

Ther. Clin. Risk Manag.

Metabolism of synthetic cannabinoids PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte incubation and high-resolution mass spectrometry

Anal. Bioanal. Chem.

Characteristics of the designer drug and synthetic cannabinoid receptor agonist AM-2201 regarding its chemistry and metabolism

J. Mass Spectrom.

In vitro metabolism of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate, a cannabinoid receptor agonist

Drug Metab. Dispos.

Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC–MS/MS

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In vitro phase I metabolism of the synthetic cannabimimetic JWH-018

Anal. Bioanal. Chem.

Review
Determination and identification of synthetic cannabinoids and their metabolites in different matrices by modern analytical techniques – a review