CBD and Warfarin

Rationale

Warfarin is a widely used anticoagulant to prevent thromboembolism for patients with non-valvular atrial fibrillation, post-operative thromboembolism, cardiac valve replacement, and prevention of thromboembolism in patients with a prior history of thromboembolism.1,2 Warfarin is metabolized by cytochrome P450 (CYP450) metabolism and additionally has a narrow therapeutic window, with relatively slight changes in warfarin concentration significantly affecting the risk of bleeding.3 Due to cannabis’ ability to affect metabolism and increasing widespread use of cannabis, it is important to understand potential interactions cannabinoids may have with concurrent medication use.4,5,6

Algorithm

Explanation

Warfarin metabolism, specifically the more potent S-enantiomer, is mainly dependent on CYP2C9 metabolism. As a result, inhibitors of CYP2C9 have the potential to increase the pharmacological effects of warfarin, including increased risk of bleeding.7 Due to this pharmacokinetic property, the American Heart Association recommends considering a decrease in warfarin dose if necessary and monitoring warfarin within 3 days of concurrent use with CYP2C9 inhibitors.8

CBD containing substances’ interaction with warfarin is primarily dependent on the inhibition of CYP2C9 by cannabinoids.9 In-vitro assays have been conducted to show cannabidiols’ concentration dependent inhibition of CYP2C9 or warfarin. Yamaori et al. demonstrated a concentration dependent inhibition of S-warfarin from 3 major constituents of cannabis – THC, cannabinol (CBN), CBD – with inhibitory potentials (K­I) of 0.937 – 1.50 uM, 0.882 – 1.29 uM, and 0.954 – 9.88 uM respectively.10 Treyer et al. also found similar results for cannabinoids interacting with warfarin in vitro, where CBD and THC significantly inhibited warfarin through CYP2C9.11 Other in-vitro analysis have shown cannabinoids ability to inhibit CYP2C9 mediated metabolism with Ki values of 0.2 – 3.2 uM and Ki,u values of 0.90 ± 0.54 uM.12,13

In addition to in-vitro studies, five case studies have been reported showing increased risk of bleeding associated with warfarin either through bleeding events or increase in INR as the result of a potential interaction. In three of the case reports, the warfarin was withheld to allow the INR to return to therapeutic range. One case report presented the use of smoked cannabis with warfarin. The case report details a 56-year-old receiving warfarin therapy for 11 years. Within two weeks of each other, the patient had been hospitalized twice, once for an upper GI bleed and second for constant nosebleeds and bruising. On both visits, his INR was supratherapeutic at a level above 10 requiring warfarin to be withheld and medical treatment with vitamin K solely or in combination with fresh frozen plasma. This patient was revealed to have smoked more frequently before both of his hospitalization periods.14

Two more case reports with patients taking sublingual or oral and inhaled cannabis also reported supratherapeutic INR with no apparent signs of bleeding events.One individual was consuming oral and inhaled cannabis and his INR was supratherapeutic at 7.2 after starting daily edibles and occasional smoking for anxiety and ADHD. The patient was advised to hold warfarin to allow INR to return to normal and discontinue cannabis use.15 The other patient, who reported using sublingual CBD oil, had an INR of 5.2 on an at-home self-test device after increasing his CBD oil dose. To control his INR with continued use, warfarin is held for 1-2 days anytime his INR is found to be above 3, which happens about once per month.16 In the last two case reports, a different approach was taken from previous reports. Instead of holding the warfarin dose, the warfarin dose was adjusted to allow for concurrent use of CBD and warfarin. The first involved a 44-year-old epileptic patient using CBD oil for epilepsy while on chronic warfarin therapy. The patient was enrolled in a study for use of cannabidiol for treatment resistant epilepsy. The CBD dose was started at 5 mg/kg/day bid and increased by 5 mg/kg/day in increments every two weeks. In order to keep INR within range, warfarin dose was adjusted leading to a reduction of about 30% of the patient’s warfarin dose with no bleeding events. The INR was above the range six times during treatment with INRs of 6.86, 4.40, 3.27, 4.07, 3.93, and 3.49. A non-linear increase in INR concentration was noted with titration of CBD.17 The second case involved a 46-year-old patient taking warfarin was initiated on Epidiolex for epilepsy at a dose of 5 mg/kg/day. Epidiolex was to be titrated up to 20 mg/kg/day. As doses were titrated, the patient experienced supratherapeutic INR levels of 3.4 and 3.5 above the goal 2 – 3 during CBD treatment. This resulted in an approximately 20% reduction in warfarin dose to keep INR within range.18 Based on the above case studies and in-vitro studies, concurrent use of CBD containing substances with warfarin should be used with caution as shown by the algorithm above.

Artifacts for implementers

Reference

  1. Dong YH, Bykov K, Choudhry NK, Donneyong MM, Huybrechts KF, Levin R, et al. Clinical Outcomes of Concomitant Use of Warfarin and Selective Serotonin Reuptake Inhibitors: A Multidatabase Observational Cohort Study. J Clin Psychopharmacol. 2017;37(2):200-9. PMID: 28129313
  2. Cochran KA, Cavallari LH, Shapiro NL, Bishop JR. Bleeding incidence with concomitant use of antidepressants and warfarin. Ther Drug Monit. 2011;33(4):433-8. PMID: 21743381
  3. Johnson JA. Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation. 2012 Apr 24;125(16):1964-6. doi: 10.1161/CIRCULATIONAHA.112.100628. Epub 2012 Mar 19. PMID: 22431866; PMCID: PMC3337679.
  4. Bose J, Hedden SL, Lipari RN, and Park-LeeKey E (2016) Substance Use and Mental Health Indicators in the United States: Results from the 2015 National Survey on Drug Use and Health. https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2015/NSDUH-FFR1-2015/ NSDUH-FFR1-2015.pdf
  5. 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.
  6. Schauer Gillian L., King Brian A., Bunnell Rebecca E., Promoff Gabbi, and McAfee Timothy A. (2016) Toking, Vaping, and Eating for Health or Fun. American Journal of Preventive Medicine. 50 (1):1–8.
  7. Coumadin (warfarin) [prescribing information]. Princeton, NJ: Bristol-Meyers Squibb Company; December 2019.
  8. Page RL 2nd, Allen LA, Kloner RA, et al. Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association. Circulation. 2020;142(10):e131-e152. doi:10.1161/CIR.0000000000000883
  9. Brown, P. (rep.). Application Number: 210365Orig1s000, Non-Clinical Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000PharmR.pdf
  10. Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet. 2012;27(3):294-300. doi:10.2133/dmpk.dmpk-11-rg-107
  11. Treyer A, Reinhardt JK, Eigenmann DE, Oufir M, Hamburger M. Phytochemical Comparison of Medicinal Cannabis Extracts and Study of Their CYP-Mediated Interactions with Coumarinic Oral Anticoagulants. Med Cannabis Cannabinoids. 2023;6(1):21-31. Published 2023 Feb 8. doi:10.1159/000528465
  12. Doohan PT, Oldfield LD, Arnold JC, Anderson LL. Cannabinoid Interactions with Cytochrome P450 Drug Metabolism: a Full-Spectrum Characterization. AAPS J. 2021;23(4):91. Published 2021 Jun 28. doi:10.1208/s12248-021-00616-7
  13. Nasrin S, Watson CJW, Perez-Paramo YX, Lazarus P. Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions. Drug Metab Dispos. 2021;49(12):1070-1080. doi:10.1124/dmd.121.000442
  14. Yamreudeewong W, Wong HK, Brausch LM, Pulley KR. Probable interaction between warfarin and marijuana smoking. Ann Pharmacother. 2009;43(7):1347-1353. doi:10.1345/aph.1M064
  15. Hsu A, Painter NA. Probable Interaction Between Warfarin and Inhaled and Oral Administration of Cannabis. J Pharm Pract. 2020;33(6):915-918. doi:10.1177/0897190019854958
  16. Brown GW, Bellnier TJ, Janda M, Miskowitz K. Δ-9-tetrahydrocannabinol dose increase leads to warfarin drug interaction and elevated INR. J Am Pharm Assoc (2003). 2021;61(1):e57-e60. doi:10.1016/j.japh.2020.07.028
  17. 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. Published 2017 Oct 12. doi:10.1016/j.ebcr.2017.10.001
  18. Cortopassi J. Warfarin dose adjustment required after cannabidiol initiation and titration. Am J Health Syst Pharm. 2020 Oct 30;77(22):1846-1851. doi: 10.1093/ajhp/zxaa268. PMID: 33016308.

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