Oxidation of abused synthetic cannabinoids in K2/Spice by human cytochromes P450

K2 is an emerging drug of abuse sold as plant materials laced with synthetic cannabinoids, which possess psychoactive properties similar to those of Δ9‐tetrahydrocannabinol (Δ9‐THC). Here, we identify CYP2C9, CYP2C19, and CYP1A2 as major cytochrome P450s involved in the oxidation of the two most commonly observed K2 compounds, JWH‐018 [naphthalen‐1‐yl‐(1‐pentylindol‐3‐yl)methanone] and JWH‐073 [naphthalen‐1‐yl‐(1‐butylindol‐3‐yl)methanone]. Interestingly, though active toward Δ9‐THC, CYP3A4 did not metabolize either of these compounds. Unique product profiles were seen for each active enzyme. Retention time comparisons and mass spectral analysis showed monohydroxy and carboxy derivatives as the primary P450 metabolites. Kinetic constants were similar to values previously reported for ∆9‐THC and show a higher affinity (K m and IC 50 values) for JWH‐018 than for JWH‐073. The high inhibitory potency suggests the potential for adverse drug‐drug reactions in humans. This is the first report on the specific P450 isoforms involved in the metabolism of K2 compounds. Identification of the mechanism of K2 oxidation and the CYPs involved is essential for future pharmaco‐kinetic and ‐genetic studies as well as understanding the clinical pharmacology of these compounds in man. (NIH‐GM075893 to AR‐P; APHL Innovation Award to JM)