Synthetic cannabinoid triggers severe organ damage in cautionary case

Following the recent amendments in international legislations on cannabis, semi-synthetic cannabinoid derivatives have become increasingly available worldwide. These new psychoactive substances are obtained through chemical modifications of cannabidiol (CBD), a widely available legal compound, or through chemical synthesis from fitting precursors. Compared to Δ9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent of Cannabis sativa, they usually display more potent effects and threatening toxicities, raising safety concerns thus requiring strengthened vigilance and monitoring. In the present study, we investigated a reported case of hexahydrocannabinol (HHC) poisoning, using a comprehensive toxicokinetic and metabolomic approach. A 35-year-old chronic tobacco and HHC male user experienced after smoking products a tonic-clonic seizure followed by a coma. His clinical course was marked by severe rhabdomyolysis, leading to acute kidney injury. The patient recovered without dialysis and was discharged after an 15-day stay in the hospital, including 11 days in the ICU. Toxicological monitoring was conducted through serial plasma sampling throughout his hospitalization. Xenometabolome and endometabolome were determined using untargeted metabolomic analysis combined to molecular networking. The assay was based on ultra-high performance liquid chromatography hyphenated to high resolution mass spectrometry data acquisition. Thirty-five HHC metabolites including hydroxylated, carboxylated and glucuronoconjugated forms were identified in plasma and urine, similarly to Δ9-THC metabolites. A correlation of HHC concentration with phenylalanine level and of creatine kinase and creatinine concentrations with carnitine and dicarboxylic acids were observed. This case report of HHC intoxication provides a detailed clinical description. The toxicological exploration of biological matrices enabled the identification of HHC metabolites. Based on metabolomic analysis, physiological perturbations of biochemical pathways, such as phenylalanine metabolism, carnitine pathway, β-oxidation and ω-oxidation were highlighted. They corroborate recent findings from in vitro and in vivo studies, and provide new insights into the consequences of cannabinoid intoxication.