(018) Interaction Between Cannabis And Cytochromes P450 Substrates: Potential Safety Signals from a Disproportionality Analysis Using the US Food And Drug Administration Adverse Event Reporting System Database
PhD student University of Pittsburgh Pittsburgh, United States
Background: The annual prevalence of cannabis use in North America was estimated to be approximately 16.6% in 2020. Previous in vitro studies have demonstrated that the major active components of cannabis and their metabolites competitively inhibit multiple major hepatic cytochrome P450 enzymes (CYPs). Due to this natural product-drug interaction (NPDI), adverse drug reactions (ADRs) have been described in case reports, but no study has quantified the association.
Objectives: The aim of this study is to identify potential safety signals of NPDIs between cannabis and substrates of CYPs in pharmacovigilance data.
Methods: This study employed a disproportionality analysis using data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Three CYP2C19 substrates, three CYP2D6 substrates, and six CYP3A4 substrates commonly used in clinical practice were selected by a physician and a pharmacovigilance expert. They also went through the list of Standardized Medical Dictionary for Regulatory Activities Query (SMQ) for ADRs considered either possible or unlikely (serving as negative controls) to be induced by the NPDIs between CYP substrates and cannabis. ADRs reported to FAERS from January 2004 to September 2021 were queried. Natural products (reported with Latin binomials and common names) and drugs were mapped to RxNorm terminology, allowing for variations. All ADRs were deduplicated using a probabilistic method that was developed based on vigiMatch, while reports related to combinations of interest were further deduplicated by visual inspection. The conservative observed-to-expected ratios with shrinkage (OES) was estimated to assess whether there were excess numbers of reports concurrently related to cannabis, CYP substrates and the ADR of interest. A safety signal was defined as an OES with a lower limit of the 95% confidence interval (CI) greater than zero and a minimum of five cases.
Results: Of the 264 CYP substrates-cannabis-ADR combinations investigated, seventeen disproportionate reporting signals were identified. The numbers of NPDI signals related to CYP3A4, CYP2C19 and CYP2D6 substrates were 8, 6 and 3 respectively. The largest OES was for the NPDI between cannabis and aripiprazole-related Parkinson-like events (OES 2.32, 95% CI 1.38-2.96). Citalopram was associated with four signals, making it the medication associated with the most NPDI signals. The SMQ with the largest number of signals was anticholinergic syndrome.
Conclusions: This study identified significant disproportionate reporting signals about the NPDI of cannabis with substrates of CYP3A4, CYP2D6, and CYP2C19, indicating that caution should be exercised when using these CYP substrates concurrently with cannabis.
