Evaluation of orally administered Δ9-tetrahydrocannabinol when co-administered with cannabidiol

Study finds that high doses of oral CBD can exacerbate the effects of THC by inhibiting THC metabolism

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

Are there any acute pharmacokinetic or pharmacodynamic differences between the oral ingestion of a Δ9-tetrahydrocannabinol (Δ9-THC) dominant cannabis extract versus a cannabidiol (CBD) dominant extract at the same dose of Δ9- THC (20 mg) in healthy adults who rarely use cannabis?

In this randomized clinical trial including 18 adult participants, ingestion of 20 mg of Δ9-THC + 640 mg of CBD resulted in stronger subjective effects of the drug, greater impairment of cognitive and psychomotor abilities, and greater increase in heart rate compared to 20 mg of Δ9-THC. alone and placebo. These effects appear to be mediated by CBD's inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism.

These results suggest that high doses (>600 mg) of oral CBD can inhibit oral Δ9-THC metabolism, resulting in stronger drug effects compared to Δ9-THC in the absence of CBD.


Previous studies have reported that CBD can exacerbate or mitigate the effects of Δ9-THC and that CBD and Δ9-THC may interact with each other and with other pharmaceutical drugs through inhibition of cytochrome P450 (CYP) enzymes. This inhibition could improve oral bioavailability and/or reduce drug clearance, prolonging tissue and systemic concentrations and increasing the risk of adverse effects. However, data on the pharmacokinetics and pharmacodynamics of oral cannabis extracts with varying concentrations of CBD and Δ9-THC are limited.

About the study

In the present randomized clinical trial, researchers compared the pharmacodynamics and pharmacokinetics (including vital signs, subjective drug effects, and psychomotor and cognitive performance) of a cannabis extract comprising high amounts of Δ9-THC ( 20,0 mg) without CBD, extracts comprising high amounts of CBD and a similar dose of Δ9-THC, and a therapeutic dose of CBD of 640,0 mg.

The double-blind crossover trial was conducted at Johns Hopkins University's Behavioral Pharmacology Research Unit in Baltimore between January 2021 and March of the following year. Eighteen adults participated in three outpatient trial sessions, spaced ≥7,0 days apart.

The study interventions were brownies comprising (i) no cannabis extract (i.e., placebo); (ii) Δ9-tetrahydrocannabinol-dominant extracts (20,0 mg of Δ9-THC without cannabidiol); and (iii) CBD-dominant extracts (20,0 mg Δ9-THC and 640 mg cannabidiol) were provided to individuals half an hour prior to administration of a CYP cocktail, comprising 0 mg , 100,0 mg, 20,0 mg, 25,0 mg, and 30,0 mg of caffeine, omeprazole, losartan, dextromethorphan, and midazolam, respectively.

The primary study outcomes were changes in serological concentrations of Δ9-tetrahydrocannabinol (or its metabolite), subjective drug effect scores, constants, and psychomotor and cognitive performance. The team determined the area under the curve (AUC) of plasma concentration as a function of time and the value of the maximum serological concentration (Cmax).

Individuals were recruited through word of mouth communications and media advertisements. Only individuals between the ages of 18 and 50, with a body mass index (BMI) between 18 and 34, who had already used cannabis but had not used it in the 30 days preceding the start of the study, been included. Participants had negative urine test results for common drugs of abuse before the study sessions and were in good health, according to physical examination, medical history, and hematological and serological investigations.

Pregnant or breastfeeding women and people allergic to cannabinoids or study drugs were excluded from the analysis. Intravenous catheters were placed in the participants' forearms for blood collection at D 0,30, 0,50, 1,0, 2,0, 4,0, 6,0, 8,0, 12,0, 24,0 hours and XNUMX hours after drug cocktail administration. In addition, urine samples were collected and participants completed Drug Effect Questionnaires (DEQs). Psychomotor and cognitive performance were assessed using tasks such as the Numerical Symbol Substitution Task (DSST), the Divided Attention Task (DAT), and a modified version of the Paced Serial Addition Task (PASAT ).


Of the 22 participants, 18 people completed the study, of which 61% (n=11) were male and 67% (n=12) were non-Hispanic and white, with mean values ​​for BMI and age (years) of 25 and 30, respectively. The mean time since last cannabis use was 86 days, and the drug cocktail with or without the placebo brownie showed no effect on the pharmacodynamics of the drug.

Compared to the cocktail + Δ9-tetrahydrocannabinol, the combination cocktail, Δ9-tetrahydrocannabinol and CBD gave higher AUC and Cmax values ​​for Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol and 11-Nor -9-carboxy-Δ9-tetrahydrocannabinol. The cocktail, CBD and Δ9-THC association increased sedation, memory difficulties, anxiety and psychomotor and cognitive disorders, with tachycardia, compared to the cocktail and Δ9-THC association, and to combination cocktail and placebo.

Plasma exposure to Δ9-THC-COOH, 11-OH-Δ9-THC, and Δ9-THC after CBD + Δ9-THC consumption was greater than that after Δ9-THC + placebo consumption. Consequently, individuals experienced greater increases in heart rate, with more pronounced subjective-like drug effects and psychomotor and cognitive impairments. Different chemical compositions, other than Δ9-THC, could significantly alter the pharmacodynamics and pharmacokinetics of cannabis products. High-dose cannabidiol might inhibit Δ9-tetrahydrocannabinol metabolism, increasing the likelihood of acute adverse effects compared to a similar dose of Δ9-THC without CBD.

Overall, study results showed more pronounced adverse effects with cannabidiol-dominant cannabis extracts than with Δ9-tetrahydrocannabinol-dominant extracts for similar Δ9-THC combinations, contradicting commonly held claims. observed that CBD attenuates the side effects of Δ9-tetrahydrocannabinol. Discrepancies in the interactions between Δ9-THC and CBD across studies could be due to different routes of administration, doses of CBD, or time periods used for assessments.

The study results highlight the importance of dosage adjustments for people opting for cannabidiol-dominant products over Δ9-tetrahydrocannabinol-dominant products. CBD's inhibition of 11-OH-Δ9-THC and Δ9-tetrahydrocannabinol metabolism is likely the mechanism responsible for these discrepancies. However, further research is needed to further characterize cannabinoid-drug interactions to inform regulatory and clinical decision-makers regarding the use of cannabis for therapeutic and non-therapeutic applications.

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