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Prediction of Pharmacokinetic Interactions between Methylphenidate and Cannabinoids

John Markowitz
University of Florida

Cannabis (Cannabis sativa L; marijuana) has been widely used for both recreational, ceremonial, and medical purposes. The increasing popularity of cannabis use recreationally, and increasingly as medical cannabis in the majority of US States, there is growing concern of potential drug-drug interactions (DDIs) with conventional medications.

We have previously demonstrated potent in vitro inhibition of cannabinoids on carboxylesterase 1 (CES1), the major esterase present in the liver. Methylphenidate ([MPH], Ritalin®, others), a known CES1 substrate, is indicated for treatment of attention-deficit/hyperactivity disorder (ADHD) in both pediatric and adult patients.

In this study, the inhibition mechanism and potency of the major cannabinoids ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) were assessed utilizing an in vitro system of human liver S9. THC and CBD inhibited the hydrolysis of MPH reversibly with mixed competitive-noncompetitive and mostly competitive characteristics, respectively.

Excessive nonspecific binding (>95%) of both cannabinoids to the protein and tube wall was noticed in the incubation mixture. After correcting for the fractions bound, the estimated unbound inhibition constants (Ki) for THC and CBD were 0.031 and 0.091 µM.

A static mechanistic model integrated with the estimated parameters predicted a mild pharmacokinetic interaction between MPH and THC from smoking a cannabis cigarette and a strong interaction between MPH and CBD from recommended doses of CBD solution (Epidiolex®).

A clinical study of DDIs sponsored by the Consortium for Medical Marijuana Clinical Outcomes Research is presently underway to verify these predictions.

Co-authors: Yuli Quian1
1University of Florida

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