Assessing the influence of CYP2C9 and CYP2C19 genotypes on the metabolism of CBD-cannabis after controlled single and repetitive consumption

The availability of cannabis for recreational and medical purposes has increased substantially, making it the most widely used drug globally and the most frequently detected substance in road traffic controls. Genetic variations in cannabinoid-metabolizing enzymes are relevant but still understudied, and their effects on whole blood concentrations of tetrahydrocannabinol (THC), cannabidiol (CBD), and their metabolites remain unclear. In this retrospective analysis of blood samples from 27 individuals, we investigated whether genotype-predicted CYP2C9 and CYP2C19 phenotypes influenced blood concentrations of THC, THC-OH, THC-COOH, and CBD after single and repetitive high CBD/low THC cannabis vaporization under controlled conditions. Approximately 44% of participants carried function-impairing CYP2C9 alleles and about 52% function-impairing CYP2C19 alleles, with the observed genotype-predicted phenotypes consistent with European population frequencies. No statistical differences were observed in blood concentrations or metabolic ratios across predicted phenotypes. However, slight trends that align with the findings of previous studies were observed for CYP2C9 predicted phenotypes. Given the retrospective design and limited sample size, the results are indicative but not generalizable. For this, further prospective studies with larger cohorts and consideration of external factors are needed. Nevertheless, this is the first study to investigate genetic variations in relation to blood cannabinoid concentrations after controlled inhalative consumption of low-THC/high-CBD cannabis, providing a foundation for future pharmacogenetic investigations and offering valuable insights into the debate surrounding cannabis legalization.