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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, Tory R Spindle, Renuka Surujunarain, Elise M Weerts, Sumit Bansal, Jashvant D Unadkat, Mary F Paine, Ryan Vandrey

JAMA Network Open February 1, 2023 DOI: 10.1001/jamanetworkopen.2022.54752 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Randomized clinical trial (within-participant, double-blind, crossover) Peer reviewed
Sample size 18
Population Healthy adults who had not used cannabis for at least 30 days prior to the study (mean 86 days since last use), mean age 30 years, 11 males and 7 females
Interventions Placebo brownie omeprazole losartan dextromethorphan
Dose 20 mg Δ9-THC (THC-dominant extract); 20 mg Δ9-THC + 640 mg CBD (CBD-dominant extract); CYP cocktail: 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, 2 mg midazolam
Duration 3 test sessions separated by at least 1 week; study conducted January 2021 to March 2022
Topics Cannabis CBD
Registration NCT04201197
Key findings A CBD-dominant cannabis extract (20 mg THC + 640 mg CBD) produced higher plasma levels of THC and its metabolites and stronger adverse effects (anxiety, sedation, memory difficulty, increased heart rate, cognitive and psychomotor impairment) than a THC-dominant extract with the same 20 mg THC dose. The authors argue this contradicts common claims that CBD attenuates THC's adverse effects, and suggest CBD inhibition of THC metabolism as the likely mechanism.

Abstract

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. 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). 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. 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. 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. 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. 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. clinicaltrials.gov Identifier: NCT04201197.

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Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life Healthy subjects aged 18 to 35 years 2017 Randomized controlled trial n = 60
Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers Healthy male subjects 2012 Randomized controlled trial n = 16
Modulation of Mediotemporal and Ventrostriatal Function in Humans by Δ9-Tetrahydrocannabinol Healthy, native English-speaking, right-handed men of white race/ethnicity who had used... 2009 Randomized controlled trial n = 15

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