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

Abstract

ImportanceControlled 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.ObjectiveTo 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 ParticipantsThis 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.InterventionsBrownies 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 MeasuresChange-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.ResultsThe 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 RelevanceIn 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 Registrationclinicaltrials.gov Identifier: NCT04201197

Evaluation of Cytochrome P450‐Mediated Cannabinoid‐Drug Interactions in Healthy Adult Participants

“…Indeed, except for CYP1A2, our oral CBD PBPK model successfully predicted the magnitude of CBD‐CYP probe drug interactions. CBD increased the AUC 0‐t of Δ9‐THC and the active metabolite 11‐OH Δ9‐THC, resulting in enhanced pharmacological effects of Δ9‐THC 22 . After completing our Δ9‐THC PBPK model (in progress), the CBD and Δ9‐THC models can be applied to predict CBD‐Δ9‐THC interactions, as well as CYP‐ or UGT‐mediated CBD and/or Δ9‐THC interactions for different combinations of Δ9‐THC and CBD present in cannabis products.…”

“…The study was conducted in cannabis-experienced healthy participants who signed the Johns Hopkins Medicine Institutional Review Boardapproved informed consent document (see Zamarripa et al 22 for details of inclusion and exclusion criteria as well as the CONSORT checklist; Table S1). The study is registered with the Clini calTr ials.gov database (NCT04201197).…”

“…Cannabis brownies. CBD-dominant (59% CBD; 2% Δ9-THC) and Δ9-THC-dominant (70% Δ9-THC; no CBD) whole plant cannabis extracts were obtained from the National Institute on Drug Abuse (NIDA) Drug Supply Program (see Zamarripa et al 22 for additional details). Unfortunately, a CBD-dominant extract devoid of Δ9-THC was not available.…”

Cannabis recreativo: Perfil de los cannabinoides presentes en muestras de marihuana suministradas por población consumidora

“…Lo anterior presume un uso recreacional de variedades fitomejoradas ricas en CBD lo cual podría ser un indicio de cambio en las dinámicas de consumo dentro de la ciudad, que favorecen los cuadros tóxicologicos cuando solo se consume cannabis con altos contenidos de THC sin CBD. El CBD al no poseer actividad psicotrópica tiene efectos neuroprotectores, antiinflamatorios y ansiolíticos, de igual manera existen estudios que indican que podría atenuar algunos de los efectos neurocognitivos y conductuales del THC (44,45,46) ; y aunque la evidencia de interacción entre ambos componentes no es concluyente por la existencia de estudios contradictorios (47,48) , la presencia de CBD en cannabis de uso recreativo se perfila como un posible factor a controlar, con el propósito de reducir los riesgos toxicológicos asociados al consumo (41,49) . Siguiendo esta línea, se observa que, en ensayos clínicos realizados para personas consumidoras de cannabis, las farmacoterapias basadas en CBD (cannabis con 0,4% de THC y 9% de CBD) han reducido la frecuencia de consumo de cannabis, las ansias y los síntomas de abstinencia (50) .…”

Potential, Limitations and Risks of Cannabis-Derived Products in Cancer Treatment

“…It has been reported that CBD can either attenuate or increase the effects of THC and that a pharmacokinetic interaction may occur through cytochrome P450 inhibition. Findings from a recent randomised clinical trial (RCT) with 18 healthy adults, in which the effects of oral 20 mg THC plus oral 640 mg CBD were compared to 20 mg THC alone and placebo, suggest that high doses of CBD can inhibit the metabolism of THC, resulting in stronger drug effects (greater impairment of cognitive and psychomotor activity, greater increase in heart rate) [ 78 ].…”