Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls

Institute of Biochemistry-Center for Preventive Doping Research, German Sport University Cologne, Germany.
Drug Testing and Analysis (Impact Factor: 2.51). 09/2011; 3(9):609-20. DOI: 10.1002/dta.158
Source: PubMed


Referred to as 'spice', several new drugs, advertised as herbal blends, have appeared on the market in the last few years, in which the synthetic cannabinoids JWH-018 and a C(8) homologue of CP 47,497 were identified as major active ingredients. Due to their reported cannabis-like effects, many European countries have banned these substances. The World Anti-Doping Agency has also explicitly prohibited synthetic cannabinoids in elite sport in-competition. Since urine specimens have been the preferred doping control samples, the elucidation of the metabolic pathways of these substances is of particular importance to implement them in sports drug testing programmes. In a recent report, an in vitro phase-I metabolism study of JWH-018 was presented yielding mainly hydroxylated and N-dealkylated metabolites. Due to these findings, a urine sample of a healthy man declaring to have smoked a 'spice' product was screened for potential phase-I and -II metabolites by high-resolution/high-accuracy mass spectrometry in the present report. The majority of the phase-I metabolites observed in earlier in vitro studies of JWH-018 were detected in this urine specimen and furthermore most of their respective monoglucuronides. As no intact JWH-018 was detectable, the monohydroxylated metabolite being the most abundant one was chosen as a target analyte for sports drug testing purposes; a detection method was subsequently developed and validated in accordance to conventional screening protocols based on enzymatic hydrolysis, liquid-liquid extraction, and liquid chromatography/electrospray tandem mass spectrometry analysis. The method was applied to approximately 7500 urine doping control samples yielding two JWH-018 findings and demonstrated its capability for a sensitive and selective identification of JWH-018 and its metabolites in human urine.

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    • "Recently, novel immunoassay tests for the detection of the most commonly used synthetic cannabinoids have become available. The standard identification method is chromatography; however, until recently only limited databases existed for their identification (Möller et al., 2011). We present four cases of patients with synthetic cannabinoid intoxication, all of whom were hospitalized in our intensive psychiatric unit for treatment of paranoid schizophrenia. "
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    ABSTRACT: An increasing number of synthetic cannabinoids have become available on the black market in recent years, and health professionals have seen a corresponding increase in use of these compounds among patients with psychiatric disorders. Unfortunately, there is almost no research available in the literature on this topic, and what little exists is based on case reports of individuals without psychiatric disorders. Synthetic cannabinoids are functionally similar to, but structurally different from, delta-9-tetrahydrocannabinol, the active principle in cannabis, and are problematic for many reasons. The psychotropic action of synthetic cannabinoids in patients with schizophrenia is unpredictable, with very diverse clinical presentations. These drugs can be much more potent than delta-9-tetrahydrocannabinol, they are readily available and difficult to detect. The gold standard for identification of synthetic cannabinoids is gas chromatography with mass spectrometry, but even this is difficult because new formulations of these designer drugs are constantly emerging. In this manuscript, we provide an overview and discussion of synthetic cannabinoids and present four cases of patients with synthetic cannabinoid intoxication who were hospitalized in our intensive psychiatric unit at the time of intoxication. All patients had a history of schizophrenia and had been hospitalized several times previously. While hospitalized, they smoked an unknown substance brought in by a visitor, which was then confirmed using gas chromatography with mass spectrometry to be the synthetic cannabinoid AM-2201. Our patients experienced predominantly psychiatric adverse clinical effects. We observed the appearance of new psychotic phenomena, without exacerbation of their previously known psychotic symptoms, as well as the occurrence or marked worsening of mood and anxiety symptoms. Despite several similar reactions, and even though they ingested the same exact substance, the clinical picture differed markedly between individual patients. We assume that the acute effects of synthetic cannabinoids in patients with schizophrenia would be different from those in persons without psychotic disorders. The reasons for this difference could be the actual symptomatology of the presenting disorder, the impact of psychopharmacotherapy, individual patient differences and probably many, as yet unknown, factors. The long-term consequences of synthetic cannabinoid use on preexisting psychotic disorders are unclear.
    Full-text · Article · Aug 2014 · Journal of Dual Diagnosis
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    • "For the first time, it was reported that (1) the JWH-018 parent compound is not excreted in urine; (2) the two major urinary metabolites of JWH-018 in humans are monohydroxylations of either the indole moiety (Figure 5Bi) or of the alkyl chain (Figure 5Bii); (3) the minor urinary metabolites of JWH-018 include a carboxylated metabolite, dihydroxylated metabolites, reduced trihydroxylated metabolites , reduced dihydroxylated metabolites and N-dealkylated monohydroxylated metabolites; and (4) the major metabolites are almost completely glucuronidated, while some of the minor metabolites are excreted in their free forms (Sobolevsky et al., 2010). Soon after this study, another group validated that JWH-018 monohydroxylated metabolites in urine are sensitive and selective biomarkers of JWH-018 abuse (Moller et al., 2011). The results of these studies prompted investigators at the Arkansas Department of Health, the Arkansas State Crime Lab and Cayman Chemical to develop authentic standards of the major urinary metabolites "
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    ABSTRACT: Abstract In 2008, the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) detected unregulated, psychoactive synthetic cannabinoids (SCBs) in purportedly all-natural herbal incense products (often known as K2 or Spice) that were being covertly abused as marijuana substitutes. These drugs, which include JWH-018, JWH-073 and CP-47,497, bind and activate the cannabinoid receptors CB1R and CB2R with remarkable potency and efficacy. Serious adverse effects that often require medical attention, including severe cardiovascular, gastrointestinal and psychiatric sequelae, are highly prevalent with SCB abuse. Consequently, progressively restrictive legislation in the US and Europe has banned the distribution, sale and use of prevalent SCBs, initiating cycles in which herbal incense manufacturers replace banned SCBs with newer unregulated SCBs. The contents of the numerous, diverse herbal incense products was unknown when SCB abuse first emerged. Furthermore, the pharmacology of the active components was largely uncharacterized, and confirmation of SCB use was hindered by a lack of known biomarkers. These knowledge gaps prompted scientists across multiple disciplines to rapidly (1) monitor, identify and quantify with chromatography/mass spectrometry the ever-changing contents of herbal incense products, (2) determine the metabolic pathways and major urinary metabolites of several commonly abused SCBs and (3) identify active metabolites that possibly contribute to the severe adverse effect profile of SCBs. This review comprehensively describes the emergence of SCB abuse and provides a historical account of the major case reports, legal decisions and scientific discoveries of the "K2/Spice Phenomenon". Hypotheses concerning potential mechanisms SCB adverse effects are proposed in this review.
    Full-text · Article · Sep 2013 · Drug Metabolism Reviews
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    • "Since first identified in late 2008, [1] [2] [3] the analysis of synthetic cannabinoids in biosamples has continuously gained importance in the field of drug testing. This has led to the development of sophisticated methods which proved suitable for the detection of these new drugs in various matrices such as whole blood, [4] [5] serum, [6] [7] [8] [9] urine, [10] [11] [12] [13] hair, [14] [15] or oral fluid. [16] [17] [18] While in clinical and forensic casework blood and urine are the matrices commonly used for proving synthetic cannabinoid use, oral fluid has been shown to be a well-suited alternative since sampling is non-invasive and parent compounds can be detected in this matrix. "
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    ABSTRACT: Although synthetic cannabinoids have been intensively investigated in recent years and oral fluid testing is becoming increasingly popular in suspected driving under the influence of drugs cases, only scarce data on their stability in authentic neat oral fluid (nOF) samples are yet available. However, especially for these new psychoactive drugs, investigations focusing on stability issues are necessary as inappropriate storage conditions may lead to considerable analytical problems. Since it has been shown for Δ(9) -tetrahydrocannabinol that adsorption to plastic surfaces may lead to considerable drug loss, we aimed to evaluate whether adsorption also has to be taken into account for synthetic cannabinoids in nOF samples. In this paper, the results of investigations on the recovery of 11 prevalent synthetic cannabinoids from authentic nOF samples stored over 72 h in RapidEASE (high quality borosilicate glass) and Sciteck Saliva Split Collector (polypropylene) tubes at 4 and 25 °C are presented. Our findings clearly demonstrate that lipophilic synthetic cannabinoids present in nOF samples adsorb to the surface of polypropylene containers when stored at room temperature, leading to considerable drug loss. Hence, when using polypropylene tubes, samples should be shipped cooled in order to avoid a substantial decrease of the analyte concentration during transportation. Copyright © 2013 John Wiley & Sons, Ltd.
    Full-text · Article · Jul 2013 · Drug Testing and Analysis
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