Study finds high doses of oral CBD can exacerbate THC’s effects by inhibiting THC metabolism

In a recent study published in JAMA Network Open, researchers compare the pharmacokinetics (PK) and pharmacodynamics (PD) of oral Δ9-tetrahydrocannabinol (Δ9-THC)-dominant and cannabidiol (CBD)-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg).

Background

Previous studies have reported that CBD can exacerbate or attenuate Δ9-THC effects and that CBD and Δ9-THC can interact with each other and other pharmaceutical drugs through cytochrome P450 (CYP) enzyme inhibition. Such inhibition could enhance the oral bioavailability and/or reduce the clearance of the drugs, prolonging tissue and systemic concentrations and increasing the risk of adverse effects. However, data on the PK and PD of oral cannabis extracts with varying CBD and Δ9-THC concentrations are limited.

About the study

In the present randomized clinical trial, researchers compared PD and PK, including vital signs, subjective effects of the drugs, and psychomotor and cognitive performance) of cannabis extract comprising high amounts of Δ9-THC (20.0 mg) without CBD, with extracts comprising high amounts of CBD and a similar dose of Δ9-THC, and a therapeutic value- CBD dose of 640.0 mg.

The double-blinded, within-participant, crossover trial was conducted on the premises of the Johns Hopkins University behavioral pharmacology research unit in Baltimore between January 2021 and March of the following year. Eighteen adults participated in three outpatient testing sessions, ≥7.0 days apart.

The study interventions were brownies comprising (i) no cannabis extracts (i.e, placebo); (ii) Δ9-tetrahydrocannabinol-dominant extracts (20.0 mg of Δ9-THC without cannabidiol); and (iii) CBD-dominant extracts (20.0 mg of Δ9-THC and 640.0 mg of cannabidiol) were provided to individuals half hour before administering a CYP cocktail, comprising 100.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, and 2.0 mg of caffeine, omeprazole, losartan, dextromethorphan, and midazolam, respectively.

The main study outcomes were changes in serological Δ9-tetrahydrocannabinol (or its metabolite) concentrations, subjective drug effect scores, vitals, and psychomotor and cognitive performance. The team determined the area under the curve (AUC) for plasma versus concentration versus time and the maximal serological concentration (C_max) value.

Individuals were enrolled through word-of-mouth communications and media advertisements. Only individuals aged between 18 and 50 years, with body mass index (BMI) ranging from 18 to 34, with prior experience of cannabis but no cannabis usage in the previous 30 days before study initiation, were included. The participants had negative urine test reports for common drugs of abuse before the study sessions and were healthy, according to physical examination, medical history, and hematological and serological investigations.

Pregnant or lactating women and individuals with allergies to cannabinoids or the study drugs were excluded from the analysis. Intravenous catheters were placed in the forearms of the participants for blood collection at d 0.30, 0.50, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 hours, and 24.0 hours post-drug cocktail administration. In addition, urine samples were obtained, and the participants filled out drug effect questionnaires (DEQ). Psychomotor and cognitive performance were evaluated using tasks such as the digit symbol substitution task (DSST), the divided attention task (DAT), and a modified version of the paced serial addition task (PASAT).

Results

Out of 22 participants, 18 individuals completed the study, among which 61{b574a629d83ad7698d9c0ca2d3a10ad895e8e51aa97c347fc42e9508f0e4325d} (n=11) were men and 67{b574a629d83ad7698d9c0ca2d3a10ad895e8e51aa97c347fc42e9508f0e4325d} (n=12) were non-Hispanics and Whites, with mean values for BMI and age (years) of 25 and 30, respectively. The average duration since the most recent cannabis usage was 86 days, and the drug cocktail with or without the placebo brownie showed no effects on the drug pharmacodynamics.

In relation to the drug cocktail + Δ9-tetrahydrocannabinol, the cocktail, Δ9-tetrahydrocannabinol, and CBD combination yielded greater AUC and C_max values for Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol, and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol. The cocktail, CBD, and Δ9-THC combination elevated sedation, memory difficulties, anxiety, and psychomotor and cognitive impairments, with tachycardia, in comparison to the cocktail and Δ9-THC combination, and the cocktail and placebo combination.

Plasma exposure to Δ9-THC-COOH, 11-OH-Δ9-THC, and Δ9-THC after consuming CBD + Δ9-THC was greater compared to that after consuming Δ9-THC + placebo. Therefore, individuals experienced greater increases in heart rate, with more pronounced subjective-type effects of the drug and psychomotor and cognitive impairments. Different chemical compositions, other than Δ9-THC, could significantly change the PD and PK of cannabis products. High-dose cannabidiol could inhibit Δ9-tetrahydrocannabinol metabolism, increasing the probability of acute adverse effects than with a similar dose of Δ9-THC without CBD.

Conclusions

Overall, the study findings showed more pronounced adverse effects from cannabidiol-dominant cannabis extracts than with Δ9-tetrahydrocannabinol-dominant extracts at similar Δ9-THC combinations, contradicting commonly observed claims of CBD attenuating Δ9-tetrahydrocannabinol’s side effects. Discrepancies in Δ9-THC and CBD interactions across studies might be due to different administration routes, CBD doses, or time courses used for assessments.

The study findings highlight the importance of dosage adjustments for individuals opting for cannabidiol-dominant versus Δ9-tetrahydrocannabinol-dominant products. CBD inhibition of 11-OH-Δ9-THC and Δ9-tetrahydrocannabinol metabolism was likely the mechanism responsible for the discrepancies. However, further research is required to further characterize cannabinoid interactions with drugs for informing regulatory and clinical decision-makers concerning cannabis usage for therapeutic and non-therapeutic applications.