Analytical toxicology of the semi-synthetic cannabinoid hexahydrocannabinol studied in human samples, pooled human liver S9 fraction, rat samples, and drug product using HPLC-HRMS/MS.

Hexahydrocannabinol (HHC) is an emerging semi-synthetic cannabinoid, that is obtained from cyclization of cannabidiol and subsequent hydrogenation. As a potentially legal alternative of Δ9-tetrahydrocannabinol (Δ9-THC), it is increasingly seized in the United States and Europe. The aims of this study were to investigate the metabolism of HHC in pooled human liver S9 fraction (pHLS9), in rat, and human samples. Additionally, a locally obtained low-THC cannabis product was investigated that was advertised with elevated concentration of HHC. Overall, HHC formed an 11-HO metabolite, as well as a carboxy metabolite. While only the parent compound was detected in rat urine and feces, the hydroxy metabolite was additionally detected in pHLS9 and human plasma. The carboxy metabolite was only detectable in human plasma. The metabolism corresponded well to that of Δ9-THC, although glucuronidation and the formation of an 8-HO metabolite was not observed. Detectability of HHC and its carboxy metabolite in rat urine was investigated using GC-MS, but neither the parent compound, nor the metabolite were detectable. The investigated low-THC cannabis product appeared to be an actual cannabis product, since in addition to HHC, cannabinol, cannabidiol, and Δ9-THC were detected after qualitative analysis. Estimation of its content revealed 30.6 % HHC but also 4 % of Δ9-THC.