Cannabidiol Presents Conundrums
Recent federal legalization and increases sales of CBD underscore the importance of considering its pharmacologic impact.
Cannabidiol (CBD) has been gaining popularity over the past few years and is now found in many pharmacies, supermarkets, and gas stations throughout the United States.
Cannabidiol is a substance isolated from the cannabis plant, which is the same plant from which tetrahydrocannabinol (THC), the psychoactive component of marijuana, is derived. The major difference between CBD and THC is that the former does not produce the euphoric and mind-altering effects attributed to the latter. Cannabidiol is touted as helping with a number of different conditions, such as anxiety, pain, and seizures, and is available in a variety of different formulations including food products, oral tinctures, and topical creams. Nevertheless, the FDA has not approved them, nor does it advocate CBD’s efficacy for these conditions.1 A majority of OTC formulations found in stores are not regulated by the FDA and may not contain the amount of CBD that they claim to contain.2
As none of these CBD natural supplements are regulated and as there are no long-term studies to endorse efficacy and safety, these products should be used cautiously. Like other OTC products, CBD can interact with medications, yet many people do not tell their health care providers about their use of CBD products. CBD undergoes hepatic metabolism via the cytochrome P450 enzymes. Specific CYP enzymes found to be responsible for CBD metabolism include CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5. Upon further evaluation, it was shown that CYP3A4 and CYP2C19 are the 2 major enzymes responsible for the metabolism of CBD; they are also responsible for the metabolism of many different drugs.3
CYP3A4 is a major cytochrome P450 enzyme that is abundantly expressed in the liver and is responsible for the metabolism of more than 50% of all commonly prescribed drugs.4 CBD is included as 1 of those drugs and is a known CYP3A4 substrate, which carries the risk of many drug interactions. CYP3A4 inducers, such as carbamazepine, phenytoin, and rifampin, may diminish the effects of CBD,5 whereas CYP3A4 inhibitors, such as amiodarone, azithromycin, diltiazem, erythromycin, and grapefruit juice, may increase the concentration of CBD and increase the risk of adverse effects.6 The interactions with CYP3A4 inducers and inhibitors are theoretical, based on the pharmacology of CBD, and have yet to be proven in human studies, but caution should be used if combining these medications.7
Animal studies have shown that CBD is also a CYP3A4 inhibitor, but this effect is still being evaluated in human studies. In past case reports and studies, CBD has been found to increase the plasma levels of everolimus, tacrolimus, and zonisamide, which are all CYP3A4 substrates.7 Theoretically, it could increase the concentrations of other CYP3A4 substrates, such as alprazolam and triazolam, which could be dangerous. The use of CBD with CYP3A4 substrates should be done cautiously with close monitoring and should be evaluated by a pharmacist whenever the opportunity is available.
Although CYP2C19 is not as ubiquitous an enzyme in the liver, nor as commonplace a metabolic-drug pathway as CYP3A4, it is responsible for the metabolism of many commonly prescribed medications. Of particular interest are those with overlapping indications to CBD, such as are used in the treatment of anxiety, depression, and epilepsy. A few of the more common CYP2C19 substrates include carisoprodol, citalopram, clobazam, fluoxetine, and phenytoin.7 Cannabidiol is both a minor substrate and a moderate inhibitor of CYP2C19. With enzyme inhibition, patients taking the aforementioned medications are at risk of increased adverse effects and may require lower doses and/or more frequent monitoring.
Cilostazol and clopidogrel are also metabolized by CYP2C19, and it is important to consider the patient’s bleeding or clotting risk before combining the use of these medications with CBD products.2 Cilostazol and clopidogrel act to prevent platelet aggregation but are mechanistically different from each other. Cilostazol is active upon administration and requires CYP2C19 metabolism into inactive compounds. Clopidogrel, on the other hand, is a prodrug dependent on CYP2C19 for conversion to the active form. This means the inhibition of CYP2C19 by CBD may increase the risk of bleeding in patients taking cilostazol and may increase the risk of clotting in patients taking clopidogrel. Additionally, the oral anticoagulant warfarin is a minor substrate of CYP2C19, which means bleeding risk may be increased with concomitant CBD use, as described in a 2018 case report that showed a nonlinear increase in international normalized ratio with an increased dose of CBD.8
With the growing popularity of CBD products, it is important to ensure that patients are aware of the risks associated with its use in combination with other drugs. Patients should talk to their providers before starting any CBD, OTC, or prescription medications. Upon dispensing, pharmacists should routinely ask patients about new or regular use of any natural-food products or nutraceuticals, with specific mention of CBD. Prospective in vivo studies are needed to assess the true clinical impact of these potential drug interactions. Until then, CBD’s benefits must be weighed against the risks for drug interactions, with appropriate cautionary dose adjustments for concomitant therapies where indicated.
Courtney Skriptshak, PharmD, and Jenel Clement, PharmD, are PGY-1 pharmacy residents at the Albany Stratton VA Medical Center in Albany, New York.Amy T. Murdico, PharmD, BCPS, is the associate chief of pharmacy services, the PGY-1 pharmacy residency director, and the PGY-2 pain and palliative care pharmacy residency coordinator at Albany Stratton VA Medical Center. She coordinates are precepts in the VALOR intern program and is an adjunct advanced pharmacy practice experience preceptor for Albany College of Pharmacy and Health Sciences and Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts.Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB, is CEO and founder of Remitigate LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.
- FDA. FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). www.fda.gov/newsevents/public-health-focus/fda-regulation-cannabis-andcannabis-derived-products-including-cannabidiol-cbd. Updated January 15, 2019. Accessed February 10, 2019.
- FDA. What you need to know (and what we’re working to find out) about products containing cannabis or cannabis-derived compounds, including CBD. www.fda.gov/consumers/consumerupdates/what-you-need-knowand-what-were-working-find-out-about-products-containingcannabis-or-cannabis. Updated November 25, 2019. Accessed February 10, 2020.
- Brown JD, Winterstein AG. Potential adverse drug events and drug—drug interactions with medical and consumer cannabidiol (CBD) use. J Clin Med. 2019;8(7). pii: E989. doi:10.3390/jcm8070989.
- Pharmacokinetics. In: Rollins DE, Blumenthal DK, eds. Workbook and Casebook for Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill; 2016.
- Epidiolex [prescribing information]. Carlsbad, CA: Greenwich Biosciences, Inc; 2018. accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed February 6, 2020.
- Marinol [prescribing information]. North Chicago, IL: AbbVie; 2017. accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf. Updated August 2017. Accessed February 10, 2020.
- Cannabidiol. Natural medicines. naturalmedicines.therapeuticresearch.com. Updated November 13, 2019. Accessed November 25, 2019.
- Grayson L, Vines B, Nichol K, Szaflarski JP; UAB CBD Program. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep. 2017;9:10-11. doi:10.1016/j.ebcr.2017.10.001.