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

Abstract

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.

Conjugation of Synthetic Cannabinoids JWH-018 and JWH-073, Metabolites by Human UDP-Glucuronosyltransferases

“…Analysis of human urine from individuals known to have ingested either JWH-018 or JWH-073 have identified several products of Phase I and II metabolism (Moller et al, 2010;Sobolevsky et al, 2010;Beuck et al, 2011;Grigoryev et al, 2011;Moran et al, 2011;Schneir et al, 2011). Many of these hydroxylated metabolites have been shown to be monohydroxy derivatives of the naphthalene, indole, or side-chain moieties (Sobolevsky et al, 2010) that are excreted in urine primarily as glucuronic acid conjugates (Sobolevsky et al, 2010;Wintermeyer et al, 2010;Moran et al, 2011), thus implicating the involvement of UGTs in this process.…”

“…These products are typically vegetative material laced with these potent CB-receptor agonists, and recent clinical data provide evidence of development of anxiety (Schneir et al, 2011), tolerance (Zimmermann et al, 2009), and enhancement of psychoses (Every-Palmer, 2010) in individuals using these products. There is also an evolving body of information available on the metabolism of synthetic cannabinoids, JWH-018 and JWH-073, in body fluids (Moller et al, 2010;Sobolevsky et al, 2010;Beuck et al, 2011;Grigoryev et al, 2011;Moran et al, 2011) and in vitro . Continued characterization of these metabolic pathways is important because recent studies have shown that oxidized products of JWH-018 retain significant in vitro and in vivo activity (L. K. Brents, E. E. Reichard, S. M. Zimmerman, J. H. Moran, W. E. Fantegrossi, and P. L. Prather, unpublished data).…”

First Characterization of AKB-48 Metabolism, a Novel Synthetic Cannabinoid, Using Human Hepatocytes and High-Resolution Mass Spectrometry

“…Most synthetic cannabinoids are eliminated via CYP metabolism, with further glucuronidation by UDPGT (phase II enzymes). Oxidative metabolites and glucuronide conjugates predominate with negligible parent compound present in human urine (16)(17)(18). Thus, it is essential to characterize metabolic profiles of synthetic cannabinoids to identify target analytes that effectively document their consumption during clinical and forensic urine testing.…”

Synthetic Cannabinoid ‘Bonzai’ Intoxication: Six Case Series

“…Tarım ilaçları, floresan tozu, yavşan otu, sanayi kimyasalları gibi birçok madde sentetik kannabinoid ile karıştırılabildiği medyaya yansımıştır. Kan ve idrar düzey-leri tespit edilemediği için, hangi olguda hangi etkiyi yaptı-ğının bilinmemesi de tanı ve tedavide yaşanacak bir başka ciddi olumsuzluktur (6,8,9). Yapılan bir çalışmada lipofilik kimyasal yapılarından ötürü intravenöz lipit tedavisinin etkili olduğu belirtilse de (10), yukarda aktarmaya çalıştığımız semptomatik tedaviler haricinde bilinen spesifik bir antidot veya tedavisi yoktur.…”