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July/August 2023
Medication Monitor: Cannabis and Warfarin: A Dangerous Combination People taking warfarin and using medical cannabis are at risk for drug-drug interaction. The well-known anticoagulant drug Coumadin was first approved by the FDA in 1954.1 The generic warfarin sodium—previously sold as Coumadin, now with the brand name Jantoven in the United States and Canada—is prescribed to prevent blood clots, thus lowering the risk of heart attack, pulmonary embolism, or deep vein thrombosis.2 Blood clots can also travel in the circulatory system, enter the brain, and cause a stroke.2 Warfarin, sometimes called a blood thinner even though it doesn’t thin the blood, slows the body’s process of making clots by decreasing the clotting factors in the blood, keeping clots from increasing in size and moving to other areas.3 Surgery may increase the risk for clots, and an anticoagulant prescription may be given to patients after they’ve had hip or knee surgery.3 People with clotting disorders, recipients of a mechanical heart valve, or those with other heart problems may be given warfarin.2 Older adults have the most significant risk for the primary side effect, which is bleeding, either externally, for example, from a cut that won’t stop bleeding, or internally, with signs that may include severe pain in the head, stomach, or joints; unexplained bruising; coughing blood or passing blood in the stool; changes in vision; dizziness; or weakness.4 Common Interactions Now, health practitioners have added cannabis to the list of drugs that may interact with warfarin. According to Philip Lazarus, PhD, a professor and researcher at Washington State University and author of more than 200 peer-reviewed papers, lab data and case studies suggest a drug-drug interaction. For older people who take medications, he says, adding cannabinoids increases the possibility of toxicity or a lack of response to treatment. In a case study of a patient taking both warfarin and increased use of cannabis, the patient experienced bleeding episodes.5 “This is consistent with lab data indicating that cannabinoids inhibit the enzyme CYP2C9, which is the enzyme that metabolizes warfarin,” Lazarus says.6,7 “It appears that THC [tetrahydrocannabinol] and other cannabinoids reduce the enzyme’s activity by direct binding to the enzyme in a competitive fashion.”6,7 Lazarus explains that the suppression of action of this enzyme could potentially increase the levels of warfarin in a patient, possibly leading to too great an effect from the anticoagulant, resulting in increased bleeding episodes. As cannabinoids block enzymes, the enzymes may fall behind in metabolizing or processing prescription drugs, such as warfarin, causing an excess of these drugs to still be in the person’s system. Research also sheds light on the use of cannabidiol (CBD) and warfarin together. “It’s consistent with other case data suggesting an association between CBD use and elevated international normalized ratio (commonly called INR, a measure of blood clot formation) values in patients taking warfarin,” Lazarus says.8 “Laboratory data from my group and others indicate that the enzyme inhibited by warfarin, CYP2C9, is inhibited by several cannabinoids, including THC and CBD.”6,7,9 “This includes studies showing that the hydroxylation of warfarin by CYP2C9 was directly inhibited by both THC and CBD,” he adds.9 It’s widely accepted that medical cannabis products can vary widely depending on their formulation, type of strain, and strength. Could other anticoagulants have lesser potential risks when used with medical cannabis than warfarin? “Yes and no,” says Andrew M. Peterson, PharmD, PhD, FCPP, John Wyeth Dean Emeritus and a professor of pharmacy at the Philadelphia College of Pharmacy at Saint Joseph’s University. People using oral anticoagulants, such as warfarin or other FDA-approved medications, are likely to be high-risk patients with cardiac conditions, he says. Additionally, patients who are using cannabis may increase their risk for a heart attack or stroke. “I’m cautious about using cannabis in patients who take oral anticoagulants,” Peterson says. “Because these people may be at risk for a cardiac event, cannabis should really be avoided as much as possible.” Peterson adds that data show that the components in medical cannabis have the potential to negatively interact with at least two other FDA-approved oral anticoagulants, rivaroxaban and apixaban—and possibly other types of anticoagulants as well. It should be noted that INR measurements are inappropriate for measuring the anticoagulant activity of rivaroxaban and apixaban. So, based on what’s suggested by studies, Peterson says, “You either manage patients on warfarin because you can monitor their INR, or you choose something other than rivaroxaban and apixaban. But these patients should be monitored,” he adds, “because we still don’t know enough about the interactions.” Older Adults May Have Greater Risk Peterson explains that older adults react differently to medical cannabis because of changes in the body. “As people age, their body composition changes. Their muscle mass and the amount of fat in their bodies change,” he says. “THC is typically stored in fat, so if you have lower fat, you may have less muscle and more water around, then it may increase the concentration of THC that is circulating in the body, which may also increase the potential for side effects. Also, as people age, metabolism slows down, which also decreases the body’s ability to handle the drug and increases the risk of toxicity.” Together, Peterson says, these combined effects may further exacerbate drug interactions between warfarin or other oral anticoagulants and medical cannabis in this population. As the legalization of cannabis continues and older populations are combining cannabis with prescription medications, clinicians must be diligent in asking about and recording cannabis use and determining drug-to-drug interactions. The amounts of THC and CBD in the products, how the cannabis is administered, and how often are all important factors.10 Since early 2022, 37 states, three territories, and the District of Columbia have allowed patients to be eligible to receive a recommendation for medical cannabis.11 According to a study published in 2020, cannabis use in older adults had already risen from 2.4% to 4.2% (a 75% increase), and it seems likely those statistics will continue to rise.12 Based on the potential risk, Lazarus and Peterson are both wary of combining cannabis use with warfarin. “For me, because of the cardiac risk, the first question is to consider is if cannabis is necessary,” Peterson says. “Secondly, there’s the risk of a potential drug interaction between cannabis and oral anticoagulants. Weigh the pros and cons, but these risks should really make clinicians think twice about giving patients this combination, particularly for older patients.” — Michele Deppe is a freelance writer based in South Carolina.
References 2. Hull RD, Garcia DA, Vazquez SR. Patient education: warfarin (beyond the basics). UpToDate website. https://www.uptodate.com/contents/warfarin-beyond-the-basics. Updated June 16, 2021. Accessed August 14, 2022. 3. Warfarin sodium — uses, side effects, and more. WebMD website. https://www.webmd.com/drugs/2/drug-3949/warfarin-oral/details. Accessed August 14, 2022. 4. Warfarin side effects: watch for interactions. Mayo Clinic website. https://www.mayoclinic.org/diseases-conditions/deep-vein-thrombosis/in-depth/warfarin-side-effects/art-20047592. Updated February 22, 2022. Accessed August 14, 2022. 5. Yamreudeewong W, Wong HK, Brausch LM, Pulley KR. Probable interaction between warfarin and marijuana smoking. Ann Pharmacother. 2009;43(7):1347-1353. 6. 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. 7. Bansal S, Paine MF, Unadkat JD. Comprehensive predictions of cytochrome P450 (P450)-mediated in vivo cannabinoid-drug interactions based on reversible and time-dependent P450 inhibition in human liver microsomes. Drug Metab Dispos. 2022;50(4):351-360. 8. Grayson L, Vines B, Nichol K, Szaflarski JP, UAB CBD Program. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep. 2018;9:10-11. 9. 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. 10. Thomas TF, Metaxas ES, Nguyen T, et al. Case report: medical cannabis—warfarin drug-drug interaction. J Cannabis Res. 2022;4(1):6. 11. State medical cannabis laws. National Conference of State Legislatures website. https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx. Updated September 12, 2022. Accessed July 26, 2022. 12. Han BH, Palamar JJ. Trends in cannabis use among older adults in the United States, 2015-2018. JAMA Intern Med. 2020;180(4):609-611. |
