Assessment of Orally Administered?9-Tetrahydrocannabinol When Coadministered With Cannabidiol on?9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial

IMPORTANCE Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of ?9-tetrahydrocannabinol (?9-THC). No studies have evaluated differences in pharmacokinetics (PK) of ?9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to ?9-THC and CBD concentrations.OBJECTIVE To compare the PK and PD of orally administered ?9-THC-dominant and CBD-dominant cannabis extracts that contained the same ?9-THC dose (20 mg).DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week.INTERVENTIONS Brownies containing (1) no cannabis extract (ie, placebo); (2) A9-THC-dominant extract (20 mg ?9-THC with no CBD); and (3) CBD-dominant extract (20 mg ?9-THC + 640 mg CBD) were administered to participants 30 minutes prior to administering a cytochrome P450 (CYP) probe drug cocktail, which consisted of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam.MAIN OUTCOMES AND MEASURES Change-from-baseline plasma concentrations for ?9-THC or ?9-THC metabolites and scores for subjective drug effects, cognitive and psychomotor performance, and vital signs. The area under the plasma vs concentration vs time curve (AUC) and maximum plasma concentration (C-max) were determined.RESULTS The participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean [SD] day since last cannabis use, 86 [66] days). The CYP cocktail + placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail + ?9-THC, CYP cocktail + ?9-THC + CBD produced a higher C-max and area under the plasma concentration vs time curve for ?9-THC, 11-OH-?9-THC, and ?9-THC-COOH. The CYP cocktail + A9-THC + CBD increased self-reported anxiety, sedation, and memory difficulty, increased heart rate, and produced a more pronounced impairment of cognitive and psychomotor performance compared with both CYP cocktail + ?9-THC and CYP cocktail + placebo.CONCLUSIONS AND RELEVANCE In this randomized clinical trial of oral ?9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a ?9-THCdominant cannabis extract at the same ?9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of ?9-THC. CBD inhibition of ?9-THC and 11-OH-?9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoidcannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision making regarding the therapeutic and nontherapeutic use of cannabis products.