Targeted metabolomic approach for assessing human synthetic cannabinoid exposure and pharmacology

Anal Chem. 2013 Oct 1;85(19):9390-9. doi: 10.1021/ac4024704. Epub 2013 Sep 12.


Designer synthetic cannabinoids like JWH-018 and AM2201 have unique clinical toxicity. Cytochrome-P450-mediated metabolism of each leads to the generation of pharmacologically active (ω)- and (ω-1)-monohydroxyl metabolites that retain high affinity for cannabinoid type-1 receptors, exhibit Δ(9)-THC-like effects in rodents, and are conjugated with glucuronic acid prior to excretion in human urine. Previous studies have not measured the contribution of the specific (ω-1)-monohydroxyl enantiomers in human metabolism and toxicity. This study uses a chiral liquid chromatography-tandem mass spectroscopy approach (LC-MS/MS) to quantify each specific enantiomer and other nonchiral, human metabolites of JWH-018 and AM2201 in human urine. The accuracy (average % RE = 18.6) and reproducibility (average CV = 15.8%) of the method resulted in low-level quantification (average LLQ = 0.99 ng/mL) of each metabolite. Comparisons with a previously validated nonchiral method showed strong correlation between the two approaches (average r(2) = 0.89). Pilot data from human urine samples demonstrate enantiospecific excretion patterns. The (S)-isomer of the JWH-018-(ω-1)-monohydroxyl metabolite was predominantly excreted (>87%) in human urine as the glucuronic acid conjugate, whereas the relative abundance of the corresponding AM2201-(ω-1)-metabolite was low (<5%) and did not demonstrate enantiospecificity (approximate 50:50 ratio of each enantiomer). The new chiral method provides a comprehensive, targeted metabolomic approach for studying the human metabolism of JWH-018 and AM2201. Preliminary evaluations of specific enantiomeric contributions support the use of this approach in future studies designed to understand the pharmacokinetic properties of JWH-018 and/or AM2201.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chromatography, Liquid
  • Humans
  • Indoles / metabolism*
  • Indoles / pharmacokinetics
  • Indoles / urine
  • Metabolomics*
  • Molecular Structure
  • Naphthalenes / metabolism*
  • Naphthalenes / pharmacokinetics
  • Naphthalenes / urine
  • Solid Phase Extraction
  • Tandem Mass Spectrometry
  • Tissue Distribution


  • 1-(5-fluoropentyl)-3-(1-naphthoyl)indole
  • Indoles
  • Naphthalenes
  • 1-pentyl-3-(1-naphthoyl)indole