Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol. Pharmacokinetics and Pharmacodynamics in Healthy Adults : A Randomized Clinical Trial, C. Austin Zamarripa et al., 2023

Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol. Pharmacokinetics and Pharmacodynamics in Healthy Adults : A Randomized Clinical Trial

C. Austin Zamarripa, PhD; Tory R. Spindle, PhD; Renuka Surujunarain; Elise M. Weerts, PhD; Sumit Bansal, PhD; Jashvant D. Unadkat, PhD; Mary F. Paine, PhD; Ryan Vandrey, PhD

Jama Network Open, 2023, 6, (2), e2254752, 1-15.

doi : 10.1001/jamanetworkopen.2022.54752

Key Points

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

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

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



IMPORTANCE : Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations.

OBJECTIVE : To compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-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) Δ9-THC-dominant extract (20 mg Δ9-THC with no CBD); and (3) CBD-dominant extract (20 mg Δ9-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 Δ9-THC or Δ9-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 (Cmax) 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 + Δ9-THC, CYP cocktail + Δ9-THC + CBD produced a higher Cmax and area under the plasma concentration vs time curve for Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH. The CYP cocktail + Δ9-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 + Δ9-THC and CYP cocktail + placebo.

CONCLUSIONS AND RELEVANCE : In this randomized clinical trial of oral Δ9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a Δ9-THC- dominant cannabis extract at the same Δ9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of Δ9-THC. CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoid- cannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision- making regarding the therapeutic and nontherapeutic use of cannabis products.

TRIAL REGISTRATION :  Identifier : NCT04201197


Globally, the reform of laws regulating cannabis products and their constituent chemical components has increased access to these products and decreased the stigma associated with their use. As of this writing, 37 US states and Washington, DC, have legalized the use of cannabis for recreational and/or medicinal purposes. Collectively, more than 5 million individuals in the US have registered as medicinal cannabis users, and approximately 50 million people in the US reported using cannabis in 2020.1

Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the 2 primary cannabinoids contained in cannabis products and are the most commonly purported constituents to have therapeutic benefits.2 Additionally, many users believe that CBD mitigates some of the adverse effects of Δ9-THC (eg, anxiogenic effects).3 However, results of controlled clinical laboratory research on the interactive effects of Δ9-THC and CBD were equivocal. For example, some studies have shown that CBD reduces certain acute effects associated with Δ9-THC,4,5 while others have shown that CBD potentiates the pharmacodynamics (PD) of Δ9-THC, resulting in stronger drug effects compared with Δ9-THC alone.6,7 Compounding these observations is that some studies suggest CBD alters neither the PD8-10 nor the pharmacokinetics (PK)11,12 of Δ9-THC.

Prior controlled Δ9-THC and CBD studies have predominantly used inhaled routes of administration, meaning much of the extant data regarding acute interactions between Δ9-THC and CBD may not translate to oral cannabis products (ie, edibles), which undergo first-pass metabolism in the intestine and liver before reaching the systemic circulation.13 Moreover, some prior studies have used synthetically manufactured Δ9-THC and/or CBD, limiting generality to retail oral cannabis products, which are often manufactured with whole-plant cannabis extracts. Edibles are among the most popular cannabis products and contain a large range of Δ9-THC and CBD doses that are often mislabeled.14,15 Additionally, evidence from the few published clinical studies suggests that Δ9-THC and CBD interact with pharmaceutical drugs, as well as with each other, via inhibition of cytochrome P450 (CYP) enzymes.16-19 Such inhibition can increase drug oral bioavailability and/or reduce drug clearance, which can prolong drug systemic and/or tissue concentrations and increase the risk of adverse effects.20

The primary goal of this study was to evaluate potential cannabinoid-drug interactions with 5 established CYP probe drugs (ie, caffeine, losartan, omeprazole, dextromethorphan, and midazolam) administered as an oral CYP cocktail, and the secondary goal (and focus of the present manuscript) was to compare the PK and PD (ie, subjective drug effects, cognitive and psychomotor performance, and vital signs) of a cannabis extract high in Δ9-THC (20 mg) and containing no CBD with an extract high in CBD containing the same dose of Δ9-THC and a therapeutically-relevant dose of CBD (640 mg).21-23 Subsequent manuscripts will describe the PK interactions between the cannabis extracts and the oral CYP cocktail probe drugs and physiologically based PK modeling and simulations resulting from this study, as those outcomes are beyond the scope of a single manuscript.