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2022: Clinical Drug Interaction Assessment of Cannabidiol and Methylphenidate

John S. Markowitz
University of Florida

Co-authors: Brandon Klee1, Ludmila De Faria1, Qingchen Zhang1, Philip W. Melchert1, Reginald Frye1, Yuli Qian1
1University of Florida

Medical cannabis (MC) refers to cannabis or cannabis-based products recommended to alleviate or reduce symptoms of a medical condition or a disease. The two primary cannabinoids utilized for their therapeutic properties are cannabidiol (CBD) and Δ9tetrahydrocannabinol (THC). MC may consist of purified single agents (e.g. CBD or THC), or complex mixtures within multiple which may be administered via a range of dosing routes. Drug-drug interactions (DDIs) are a significant cause of ED visits, hospital admissions and increased morbidity and mortality. Importantly, MC is frequently used by complex medical patients taking conventional prescription medications and the DDI potential of MC remains only partially understood. In vitro data indicate that THC and CBD can potently inhibit the drug metabolizing enzyme, carboxylesterase (CES1). This finding may be significant since functional CES1 is required for both detoxification and metabolic activation of prodrugs.

Objective: An open-label, placebocontrolled, crossover study in healthy subjects (n=12) assessed the influence of 4-days of either 750 mg CBD oral solution (Epidiolex®) twice daily vs placebo on a 10 mg dose of the CES1 substrate methylphenidate (MPH; Ritalin®).

Methods: Following a run-in of CBD or placebo, an additional dose of CBD or placebo, and 10 mg of MPH was administered. Serial blood samples were collected over 8 hrs and concentrations of MPH and CBD were measured by LCMS/MS. Pharmacokinetic parameters were summarized by noncompartmental analyses.

Results: The MPH maximum plasma concentration (Cmax) was reached within 0.5-3 h and CBD (1-6 hours). Co-administration of CBD led to a numerical increase in the exposure to MPH. The ratio (90% CI) of AUCinf and Cmax central values when MPH was administered with CBD versus alone were 1.09 (0.98, 1.22) and 1.08 (0.87, 1.35), respectively. The geometric mean AUC0-8 and Cmax of CBD were 1470 ng∙hr/mL and 360 ng/mL, respectively. There was a trend of increased MPH exposure with CBD co-administration.

Conclusion: CBD at the dose evaluated, produced only weak and clinically insignificant effects on MPH exposure. However, given the positive trend observed between MPH and CBD exposure, some vigilance is warranted when CBD is administered at higher doses or with CES1 substrate medications.

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