Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus

Abstract

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug‐drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3‐fold increase in dose‐normalized tacrolimus concentrations while receiving 2000‐2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA‐approved CBD product. Larger studies are needed to better understand the impact of this drug‐drug interaction in solid organ transplant recipients.

Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex

“…Given the bidirectional drug-drug interaction between cannabidiol and clobazam, in which exposure of the active metabolite of each agent is increased, 24,25 it is important to understand the clobazam-independent efficacy of cannabidiol. This trial supports cannabidiol's independent efficacy, because most patients (73%) were not taking clobazam, and cannabidiol was significantly more efficacious than placebo.…”

Cannabidiol (CBD) Consumption and Perceived Impact on Extrahepatic Symptoms in Patients with Autoimmune Hepatitis

“…Data on drug interactions in human subjects taking CBD are scarce; however, we hypothesize that there is risk of altered pharmacokinetics in CBD or concurrently administered drugs undergoing metabolism via these CYP systems. The steroid drug class and calcineurin inhibitors [30], metabolized via CYP3A4, are of significant concern given 177 patients (47.7%) of study respondents reported current use of either prednisone or budesonide and 21 patients (5.7%) reported use of either tacrolimus or cyclosporine. The relative infrequency that patients did not report CBD use to their treating doctors (45.7%) and product variability across manufacturers [23,24], dose [21], and route [25] of administration could further expand this risk.…”

Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox–Gastaut Syndrome

“…The included studies were randomized placebo-controlled trials [ 13 , 43 , 47 ], open-label interventional studies and their subgroup analyses [ 14 , 15 , 17 , 18 , 20 – 24 , 26 – 30 , 32 , 34 – 38 , 41 , 42 , 48 – 52 ], retrospective chart reviews [ 39 , 44 , 46 ], clinical series [ 19 , 40 , 53 ], and case reports [ 16 , 25 , 31 , 33 , 45 , 54 ]. The participants of the studies included patients of pediatric age [ 14 – 17 , 19 , 28 , 30 , 31 , 40 , 41 , 45 , 46 , 50 , 52 , 53 ], adult age [ 25 , 32 , 33 , 36 , 47 , 48 , 51 , 54 ], and both pediatric and adult age [ 13 , 18 , 20 – 24 , 26 , 27 , 29 , 34 , 35 , 37 – 39 , 42 – 44 , 49 ]. Details of the characteristics of participants and outcomes of the included studies are provided in the ESM.…”

“…Most studies aimed to assess the efficacy and safety of CBD treatment, and study endpoints included seizure frequency reduction, seizure response rate, seizure freedom, change in seizure severity, treatment discontinuation, and occurrence of adverse events. Eight studies were primarily aimed to describe pharmacokinetic analyses or drug–drug interactions between CBD and antiseizure or non-antiseizure medications [ 17 , 23 , 25 , 33 , 39 , 43 , 47 , 54 ]. Seven studies included cognitive and/or quality-of-life measures [ 20 – 22 , 32 , 36 , 50 , 51 ], and three mainly focused on functional brain imaging assessment [ 35 , 49 , 51 ].…”