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

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Abstract

A potent synthetic cannabinoid receptor agonist, JHW-018, was recently detected as one of the most prominent active agents in abusively used incenses such as Spice and other herbal blends. The high pharmacological and addictive potency of JWH-018 highlights the importance of elucidating the metabolism of JWH-018, without which a meaningful insight into its pharmacokinetics and its toxicity would not be possible. In the present study, the cytochrome P450 phase I metabolites of JWH-018 were investigated, after in vitro incubation of the drug with human liver microsomes, followed by liquid chromatography–tandem mass spectrometry analysis. This revealed monohydroxylation of the naphthalene ring system, the indole moiety, and the alkyl side chain. In addition, observations were made of dihydroxylation of the naphthalene ring system, and the indole moiety, or as result of a combination of monohydroxylations of both the naphthalene ring system and the indole moiety or the alkyl side chain, or a combination of monohydroxylations of both the indole ring system and the alkyl side chain. There is also evidence of trihydroxylation at different locations of the hydroxyl groups in the molecule. Furthermore, dehydration of the alkyl side chain, in combination with both monohydroxylation and dihydroxylation as well as arene oxidation of the naphthalene ring system, combined with both monohydroxylation and dihydroxylation at different sites of oxidation were found. N-dealkylation also in combination with both monohydroxylation and dihydrodiol formation of the N-dealkylated metabolite was detected. Finally, a metabolite was found carboxylated at the alkyl side chain.

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Abbreviations

ESI:

Electrospray ionization

HLM:

Human liver microsome

HPLC:

High-performance liquid chromatography

LC:

Liquid chromatography

MRM:

Multiple reaction monitoring

MS:

Mass spectrometry

MS/MS:

Tandem mass spectrometry

SPE:

Solid-phase extraction

Δ9-THC:

Δ9-tetrahydrocannabinol

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Acknowledgements

The authors thank J.W. Huffmann, Clemson University, USA, for providing samples of JWH-018, Daniel Lenz for his scientific support, and June Mercer-Chalmers for proofreading this manuscript and fruitful discussions.

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Authors and Affiliations

  1. Institute of Legal Medicine, Medical Faculty, University of Cologne, Melatengürtel 60–62, 50823, Cologne, Germany

    Annette Wintermeyer, Martin Jübner, Justus Beike, Markus A. Rothschild & Katja Bender

  2. Center for Preventive Doping Research, Institute of Biochemistry, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933, Cologne, Germany

    Ines Möller & Mario Thevis

Authors
  1. Annette Wintermeyer
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  2. Ines Möller
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  3. Mario Thevis
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  4. Martin Jübner
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  5. Justus Beike
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  6. Markus A. Rothschild
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  7. Katja Bender
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Correspondence to Katja Bender.

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Wintermeyer, A., Möller, I., Thevis, M. et al. In vitro phase I metabolism of the synthetic cannabimimetic JWH-018. Anal Bioanal Chem 398, 2141–2153 (2010). https://doi.org/10.1007/s00216-010-4171-0

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  • DOI: https://doi.org/10.1007/s00216-010-4171-0

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