CBD and Clopidogrel

Rationale

Clopidogrel is an antiplatelet agent commonly used for ST-elevation myocardial infarction stenting and conditions and disease states such as stroke prevention and unstable angina. As an inactive prodrug, clopidogrel requires enzyme activation via CYP2C19 to become biologically active and prevent platelet aggregation. Variation between patients with respect to metabolism, either through genetic polymorphisms or medication dependent CYP inhibition, will cause fluctuations and unpredictable effects in clopidogrel treatment.1

Cannabis, a potent inhibitor of enzyme CYP2C19, is one of the most widely utilized illicit substances in the US. Although cannabis is illegal at the federal level, 12 states have legalized its use for recreational purposes and 34 states have allowed for medicinal use as of 2020, leading to about 52.5 marijuana users in 2021.2,3 Cannabis has been promoted to treat a variety of ailments, including pain, nausea, loss of appetite, and childhood epilepsy.4 Due to the increase in cannabis legalization and new medicinal indications, it is important to understand the potential interactions cannabinoids may have with concurrent medication use, such as with clopidogrel.

Algorithm

Explanation

CYP2C19 is an important enzyme for the effectiveness of clopidogrel. A boxed warning for Plavix (clopidogrel) states “Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.” In addition, poor metabolizers (patients with poor functionality of CYP2C19) have been shown to have higher cardiovascular event rates following ACS or PCI than patients with normal CYP2C19 functionality. As a result, CYP2C19 inhibition of clopidogrel metabolism can cause significant issues for any patients using clopidogrel as a part of their treatment regimen.5 According to the product labeling for CBD, cannabidiol is a potent inhibitor of CYP2C19.6,7 One in-vivo study supports the effect on CYP2C19 activity by using substrate concentrations of 60 μM (S)-mephenytoin, 2 μM omeprazole, and 4 μM 3-O-Methylfluorescein. CBD showed concentration dependent inhibition with IC50 values of 8.70 μM, 1.55 μM, and 1.79 μM respectively. 8 In another study that examined the interaction between CBD and clobazam in 13 children with refractory epilepsy, CBD was found to increase levels of clobazam, a CYP2C19 and CYP3A4 substrate. In that study, the clobazam dose was reduced when side effects were observed in 10 subjects. In addition, levels of clobazam were found to be increased 60 ± 80% and levels of nCLB, an active metabolite of clobazam, were found to be increased 500 ± 300%. Similarly, to clobazam, nCLB is also metabolized by CYP3A4 and CYP2C19. Although it is possible the nCLB levels could be caused by CYP3A4 inhibition, the study reports that poor metabolizers of CYP2C19 see a fivefold higher plasma level than extensive metabolizers in nCLB levels, supporting previous studies concerning CBD’s ability to inhibit CYP2C19.9 Due to the ability of cannabinoids to potently inhibit CYP2C19, concurrent use with clopidogrel should be done with caution.

Artifacts for implementers

References

  1. Beavers CJ, Naqvi IA. Clopidogrel. [Updated 2022 Jul 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470539/
  2. Paduch M, Thomason AR. Potential Drug Interactions Between Cannabinoids and Its Derivatives and Oral Anticoagulants. Hosp Pharm. 2022 Feb;57(1):188-192. doi: 10.1177/0018578720985438. Epub 2021 Jan 9. PMID: 35521023; PMCID: PMC9065521.
  3. Substance Abuse and Mental Health Services Administration. (2022). Key substance use and mental health indicators in the United States: Results from the 2021 National Survey on Drug Use and Health (HHS Publication No. PEP22-07-01-005, NSDUH Series H-57). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report
  4. Cox EJ, Maharao N, Patilea-Vrana G, Unadkat JD, Rettie AE, McCune JS, and Paine MF (2019) A marijuana-drug interaction primer: precipitants, pharmacology, and pharmacokinetics. Pharmacol Ther. 201:25–38.
  5. Plavix (clopidogrel) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis US LLC; September 2022.
  6. Epidiolex (cannabidiol) [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals Inc; January 2023.
  7. Brown, P. (rep.). Application Number: 210365Orig1s000, Non-Clinical Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000PharmR.pdf
  8. Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28(4):332-338. doi:10.2133/dmpk.dmpk-12-rg-129
  9. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246-1251. doi:10.1111/epi.13060

Authorship

Author: Dr. Kojo Abanyie with input from Dr. Daniel Malone, Dr. Lorenzo Villa-Zapata, Dr. Xiaotong Li

Email: koa27@pitt.edu

Date: September 17, 2023