Cannabidiol Does Not Convert to Δ⁹-Tetrahydrocannabinol in an In Vivo Animal Model

Introduction: Cannabidiol (CBD) can convert to Δ⁹-tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo. Materials and Methods: Synthetic CBD (100 mg/mL) was administered orally in a sesame oil formulation twice daily to minipigs (N=3) in 15 mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 h after morning doses on Days 1 and 5. Six hours after the final dose on Day 5, the animals were euthanized, and samples of gastrointestinal (GI) tract contents were obtained. Liquid chromatography with tandem mass spectrometry analysis determined CBD, THC, and 11-hydroxy-THC (11-OH-THC) concentrations. Lower limits of quantification: plasma CBD=1 ng/mL, plasma THC and 11-OH-THC=0.5 ng/mL, GI tract CBD=2 ng/mL, and GI tract THC and 11-OH-THC=1 ng/mL. Results: THC and 11-OH-THC were undetectable in all plasma samples. Maximum plasma concentrations (C_max) of CBD were observed between 1 and 4 h on Days 1 and 5. CBD was present in plasma 6 h after administration on Days 1 (mean 33.6 ng/mL) and 5 (mean 98.8 ng/mL). Mean C_max CBD values, 328 ng/mL (Day 1) and 259 ng/mL (Day 5), were within range of those achieved in clinical studies. Mean CBD exposure over 6 h was similar on Days 1 (921 h·ng/mL) and 5 (881 h·ng/mL). THC and 11-OH-THC were not detected in all GI tract samples. Mean CBD concentrations reached 84,500 ng/mL in the stomach and 43,900 ng/mL in the small intestine. Conclusions: Findings of the present study show that orally dosed CBD, yielding clinically relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function.