Potential Adverse Drug Events and Drug–Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use

Abstract

Cannabidiol (CBD) is ubiquitous in state-based medical cannabis programs and consumer products for complementary health or recreational use. CBD has intrinsic pharmacologic effects and associated adverse drug events (ADEs) along with the potential for pharmacokinetic and pharmacodynamic drug–drug interactions (DDIs). Given CBD use among patients with complex conditions and treatment regimens, as well as its expanded consumer use, awareness of potential safety issues with CBD is needed. Prescribing information for federally approved products containing CBD were reviewed. Data on ADEs and DDIs were extracted and summarized. Nearly one-half of CBD users experienced ADEs, which displayed a general dose-response relationship. Common ADEs include transaminase elevations, sedation, sleep disturbances, infection, and anemia. Given CBD effects on common biological targets implicated in drug metabolism (e.g., CYP3A4/2C19) and excretion (e.g., P-glycoprotein), the potential for DDIs with commonly used medication is high. General clinical recommendations of reducing substrate doses, monitoring for ADEs, and finding alternative therapy should be considered, especially in medically complex patients. CBD is implicated as both a victim and perpetrator of DDIs and has its own ADE profile. These effects should be considered in the risk-benefit assessment of CBD therapy and patients and consumers made aware of potential safety issues with CBD use.

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

“…CBD can have opposed effects on CB1 receptors, given that it can act as an indirect agonist (De Petrocellis et al, 2011) and as a biased negative allosteric modulator (Tham et al, 2019). The complex pharmacology of this phytocannabinoid possess interesting properties for the management of different neuropsychiatric conditions but can also lead to some undesirable effects that are especially hard to predict (Brown and Winterstein, 2019). In conclusion, the complex pharmacology of CBD over CB1 receptor is still poorly understood and, as we show here, unexpected consequences can arise in specific situations leading to cocaine seeking reinstatement in rodent models of operant drug seeking.…”

Medical cannabis use among individuals with cancer: An unresolved and timely issue

“…These impacts are potentially more deleterious among the elderly and patients with concomitant renal and hepatic disease . Cannabinoids interact with other cytochrome P450 3A4 substrates, and many chemotherapeutics fall into this category (eg, tamoxifen and bosutinib) . Therefore, for these medications, there is an increased risk of side effects .…”

“…Cannabinoids interact with other cytochrome P450 3A4 substrates, and many chemotherapeutics fall into this category (eg, tamoxifen and bosutinib) . Therefore, for these medications, there is an increased risk of side effects . Furthermore, cannabinoids can inhibit phase 2 hepatic metabolism (eg, glucuronidation), thereby decreasing excretion of chemotherapeutics that are metabolized through these enzymes (eg, sorafenib, regorafenib, methotrexate, and imatinib) .…”

“…Furthermore, cannabinoids can inhibit phase 2 hepatic metabolism (eg, glucuronidation), thereby decreasing excretion of chemotherapeutics that are metabolized through these enzymes (eg, sorafenib, regorafenib, methotrexate, and imatinib) . One cannabinoid metabolite, 7‐COOH‐CBD, inhibits the breast cancer resistance protein and bile salt export pump, leading to increased tissue distribution and decreased excretion of the chemotherapeutics that use these pathways (eg, paclitaxel) . The coadministration of cannabinoids and chemotherapeutics with the potential for drug‐drug interactions via any of these pathways is discouraged.…”

“…If such medications and cannabinoids must be administered together, increased monitoring for side effects is recommended and/or a dose reduction of chemotherapeutics should be considered. Cannabidiol itself has an overlapping side effect profile with chemotherapeutics, and can in itself cause worsening of nausea, somnolence, appetite suppression, infection risk, weight loss, sleep disturbance, and diarrhea …”