In silico, in vitro, and in vivo human metabolism of a new semi-synthetic cannabinoid: Hexahydrocannabinol (HHC) and its stereoisomers

Since 2021, there was an overall increase in reports of herbal material where natural cannabinoids were found alongside synthetic cannabinoids in at least 13 European countries. It results in a growing concern that consumers of cannabis may be at risk of inadvertent exposure to synthetic cannabinoids. New regulatory challenges have emerged about the commercialisation of cannabis derivatives and about the recreational drug market. In 2022, the appearance of new semi-synthetic cannabinoids reflected these concerns. Hexahydrocannabinol (HHC) was identified in May 2022 and had been reported by 20 EU Member States by March 2023. The effects of HHC in humans have not been studied, but consumers and reports suggest they may be subjectively similar to those of cannabis. Some of the products are available in forms that may deliver high doses, raising concerns about the possible implications for public health. The purpose of this thesis was to identify the main metabolites of HHC through in silico and in vitro studies. Subsequently, a method using UHPLC-MS/MS was developed and fully validated for their detection in biological matrices. Finally, the identification and quantification of HHC stereoisomers and metabolites were carried out on real samples of oral fluid, blood, and urine from individuals who had smoked a known quantity of HHC.