Randomized, Double-Blind, Placebo-Controlled Study About the Effects of Cannabidiol (CBD) on the Pharmacokinetics of D-Tetrahydrocannabinol (THC) After Oral Application of THC Verses Standardized Cannabis Extract

Cannabidiol (CBD) is known to modify the effects of D-tetrahydrocannabinol (THC) by decreasing anxiety and antagonizing other THC-effects. As a reason, pharmacodynamic as well as pharmacokinetic mechanisms were suggested. In context of the use of cannabis-based medicine extracts for therapeutic purposes, a study was performed in a double-blind and placebo-controlled cross-over design in which each of 24 volunteers (12 male and 12 female, age 18-45 years) obtained soft-gelatin capsules with 10 mg THC (THCset), cannabis extract containing 10 mg THC +5.4 mg CBD (CANset) or placebo in weekly intervals. Blood samples were taken 30 minutes before and 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours and 24 hours after the intake. The concentrations of THC, of its metabolites 11-OH-THC, THC-COOH and of CBD in the plasma samples were determined by automatic solid phase extraction, derivatization with N,O-bis(trimethylsilyl)triflouroacetamide and gas chromatography–mass spectrometry. The concentration versus time curves (maximum concentrations Cmax, corresponding time tmax and areas under the curves AUC) were evaluated by statistical methods with respect to equivalence or differences between the CAN-set and the THC-set. Furthermore, the intra-individual ratios of Cmax and AUC for 11-OH-THC/THC, THC-COOH/THC and THC-COOH/11-OH-THC were compared between the THC-set and the CAN-set. Despite the large variation of the data, evidence emerged from the total of the results that CBD partially inhibits the CYP 2C catalyzed hydroxylation of THC to 11-OH-THC. The probability for this inhibition is particularly high for oral intake because THC and CBD attain relatively high concentrations in the liver and because of the high first-pass metabolism of THC. However, the effect of CBD is small in comparison to the variability caused by other factors. Therefore, a pharmacokinetic reason for the differences determined between pure THC and cannabis extract is improbable at the doses chosen in this study. Significantly higher AUC and Cmax and shorter tmax were found for females as compared with males.