CBD Gummies And Warfarin

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Taking warfarin with CBD can make warfarin stay in the body for too long without being broken down. This may have detrimental effects like overdose. Learn more. A case of an 85-year-old patient with concurrent use of warfarin and medical cannabis containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is described. Warfarin continues to be a cornerstone of anticoagulation treatment despite the recent addition of FDA-approved anticoagulant agents. It is well known that warfarin has numerous drug interactions; however, much remains unknown about its interaction with THC and CBD. A literature review was conducted to identify documented cases of possible interactions between cannabis and warfarin. The case reports we identified noted that cannabis may potentially increase warfarin’s effect. Therefore, we aimed to determine why an effect was not seen on our patient’s warfarin dose despite daily use of medical cannabis. This case report describes an 85-year-old patient who despite starting an oromucosal medical cannabis regimen of THC and CBD (which provided 0.3 mg of THC and 5.3 mg CBD once daily and an additional 0.625 mg of THC and 0.625 mg CBD once daily as needed) had minimal INR fluctuations from October 2018 to September 2019. Despite the introduction and use of medical cannabis therapy, with both THC and CBD components, an elderly patient with concurrent warfarin use did not see major INR fluctuations, in contrast to published literature. The potential for warfarin and THC/CBD interactions may be dependent on route of administration and dose of the cannabis product.

CBD and Warfarin – August 2022

Warfarin (brand names: Coumadin, Jantoven) is an oral anticoagulant or blood thinner that is primarily used to help prevent and treat blood clots. It can also be administered to treat blood clots arising from certain heart conditions, heart attack, or open-heart surgery (4 ) .

Warfarin is metabolized by Cytochrome P450, also known as CYP450. It is a class of liver enzymes that play an essential role in the metabolism of warfarin and other medications before the drugs are cleared through the renal system (5 ) .

CYP450 includes CYP3A4, CYP1A1, CYP2C8, CYP1A2, CYP2C18, CYP219, and CYP2C69, which predominantly metabolize warfarin (6 ) .

Consequently, medications, treatments, and other factors that affect the CYP269 enzyme can also alter the effects of warfarin in the body (7 ) .

Like warfarin, CBD is metabolized through the hepatic P450 enzyme system. Both CBD and warfarin share similar proteins during their respective metabolism processes.

CBD is metabolized by the body through CYP1A1, CYP1A2, CYP2C19, CYP3A4, CYP2D6, CYP269, and CYP3A5, five of which are active enzymes that act on warfarin.

A 2017 study facilitated by the U.S. National Library of Medicine National Institutes of Health explained that CBD competes in a similar metabolic pathway with that of warfarin (8 ) .

CBD also acted as a powerful inhibitor of CYP3A4 enzymes, which can diminish the degradation of warfarin (9 ) . This is also known as the “grapefruit effect” as the grapefruit juice can also slow down the body’s absorption of warfarin (10 ) .

As such, taking warfarin together with CBD can make warfarin stay in the body for too long without being broken down. This may have detrimental effects such as bleeding, or worse, overdose (11 ) .

This is why regular measurement of a user’s international normalized ratio (INR) is necessary, more so when warfarin is taken with CBD. It ensures that the blood levels remain within a narrow range to avoid the side effects brought by warfarin.

Mayo Clinic presented a number of warfarin side effects that require immediate medical attention (12 ) :

  • Excessive bleeding, including heavy menstrual bleeding, nosebleed, and internal hemorrhage
  • Bloody or black stool
  • Brown or red urine
  • Reduced urine output
  • Bruises that appear even without suffering from any injury
  • Chronic pain in the stomach
  • Vomiting of blood
  • Changes in the vision
  • Unusual weakness, tiredness, or dizziness
  • Joint pain, swelling or discomfort, especially after experiencing an injury
  • Stupor

Other less serious side effects of warfarin are:

  • Bleeding between menstruation period
  • Gum bleeding after brushing the teeth
  • Vomiting, diarrhea, or being unable to eat for 24 hours or more
  • Fever

In rare cases, warfarin can also cause necrosis or death of skin tissue. Any changes in skin temperature or color, as well as severe pain on the skin, warrant prompt medical care. Be on the lookout for blotchy, net-like spots on the skin, too.

Pain in the toes, especially when they turn dark or purple in color, signifies a severe health problem.

Patients who intend to use CBD with warfarin must seek the advice of a licensed medical professional first to ensure that the drug interactions will be beneficial to their health.

Can Another Oral Anticoagulant Be a Substitute for Warfarin so CBD Oil Can Be Taken?

Among the remaining three oral anticoagulants approved by the FDA to treat irregular rapid heart rate, two are also metabolized by the CYP450 system. Thus, they can also be subjected to the grapefruit effect of CBD (13 ) .

These oral anticoagulants are rivaroxaban and apixaban (14 ) .

Meanwhile, a 2011 review explained that another approved oral anticoagulant, dabigatran (Pradaxa), does not undergo metabolism through CYP450. According to the review, dabigatran has shown a few drug-food and drug-drug interactions. Medical professionals are also considering dabigatran as a substitute for warfarin therapy (15 ) .

However, it is still best to schedule a consultation with a health professional before taking any anticoagulant along with CBD to ascertain safety and body tolerance.

The U.S. Food and Drug Administration or FDA has authorized the use of warfarin for the following purposes:

  • Treat clots that form in the vein (venous thrombosis) and associated pulmonary embolisms or blood clot in the lungs (16 )
  • Treat thromboembolic complications caused by cardiac valve replacement or irregular or rapid heart rate (atrial fibrillation) (17 )
  • Reduce the risk of death, recurrent heart attack or myocardial infarction (MI) and other thromboembolic events such as stroke and systemic embolism that may occur after a cardiac arrest (18 )

Can CBD Replace Warfarin?

There is no specific study or case report that directly expounds on CBD as a safe substitute for warfarin or any anticoagulants.

One study used an obese rat model to describe how cannabis extract could possibly contain anticoagulant effects is that of a 2007 study written in the journal Phytomedicine (19 ) .

The study showed that cannabinoids such as cannabinol (CBN) and tetrahydrocannabinol (THC) demonstrated anticoagulant activity (20 ) .

Thus, the authors suggested that Cannabis sativa and the cannabinoids THC and CBN can be potentially used to treat thrombosis and type 2 diabetes, a kind of ailment which could cause an irregular increase of blood clotting (21 ) .

Since there are limited studies on whether CBD can act as an anticoagulant, it is still best to ask a medical expert before considering CBD as a replacement for a prescription drug, and there is currently no evidence to suggest that CBD could be anticoagulant medications.

What to Look for in a CBD Product

There are several things to keep in mind before purchasing CBD products, the first of which is seeking a doctor’s approval. Once it is done, consider these action steps prior to buying any CBD product.

  1. Check the laws in the area where the product will be bought and consumed. In the United States, there are jurisdictions that have specific restrictions regarding the allowable THC content in CBD products.
  2. Take time to read reviews before buying from an online store. When buying from a clinic or a physical store, make sure that it is an authorized CBD seller by the government. Remember to purchase from reliable and legitimate brands only.
  3. Examine the additional ingredients. Some products include beneficial ingredients like MCT oils or melatonin. However, there are also CBD products that contain potentially dangerous ingredients such as vegetable glycerin and propylene.
  4. Determine the right dosage. CBD intake may be low dose or higher depending on the user’s condition.

It is advisable to talk to a trusted and experienced medical professional who has deep knowledge about CBD to minimize probable risks and avoid side effects, especially because CBD has other verified drug interactions, too.

Studies show that aside from warfarin, CBD also inhibits the metabolism of other drugs, including clobazam, an anti-epileptic medicine (22 ) .

The grapefruit effect also applies to certain kinds of benzodiazepines, a class of prescribed medications for anxiety. Some of the benzodiazepines that are metabolized by the CYP450 system are alprazolam (Xanax), brotizolam, triazolam, and midazolam (23 ) .

An author and professor of medicine at Harvard Medical School, Peter Grinspoon, MD, warns the public through a Harvard Health article that CBD can cause nausea, irritability, and fatigue (24 ) .

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In addition, Brent A. Bauer, M.D., medical editor of Mayo Clinic Book of Alternative Medicine , also explained that other side effects of CBD include diarrhea, reduced appetite, dry mouth, fatigue, and drowsiness (25 ) .

What food, supplements, and drugs interact with warfarin?

Warfarin, like other medications, can interact with vitamins, nutritional supplements, drugs, and food. The interaction might lessen the efficacy of warfarin or increase the risk of bleeding.

Aside from grapefruit, some of the typical food and drinks that can interact with warfarin are:

  • Garlic
  • Alcohol
  • Cranberry juice or cranberries
  • Pomegranate
  • Black licorice

Common herbal or nutritional supplements that might interact with warfarin include:

  • Dong Quai
  • Ginseng
  • Coenzyme Q10 (ubiquinone)
  • Green tea
  • St. John’s wort
  • Vitamin E

Some of the common drugs that have been identified to have warfarin interaction include:

  • Laxatives or antacids
  • Aspirin or any product that has aspirin
  • Antifungal medications like fluconazole (Diflucan)
  • Acetaminophen or any product that has acetaminophen
  • Several antibiotics
  • Allergy or cold medicines
  • Naproxen sodium (Naprelan, Aleve) or ibuprofen (Motrin IB, Advil)
  • Medications used to treat abnormal heart rhythms (Nexterone, Pacerone)

Some of the medical conditions that can also increase the risk of bleeding are:

  • Uncontrolled blood pressure
  • Stomach ulcer, peptic disease or gastritis
  • Cancer
  • Alcoholism
  • Kidney ailments
  • Liver disease
  • Increased risk of falling
  • Stroke history

The presence of the following ailments may affect the usage of warfarin:

  • Catheter insertion
  • Congestive heart failure
  • Anemia
  • Diabetes
  • Kidney disease
  • Blood disease called Polycythemia vera
  • Deficiency in Protein C
  • Thrombocytopenia (heparin-induced)
  • Bowel problems or stomach ache including bleeding
  • Inflammation of blood vessel (vasculitis)
  • Spinal anesthesia
  • Intestinal or stomach ulcer
  • Threatened miscarriage (patients who have this condition are strictly discouraged from taking warfarin)
  • Deficiency in Vitamin K
  • Malnutrition
  • Fats in the stool or steatorrhea
  • Diarrhea
  • Trauma

How to Minimize the Risk of Bleeding while Taking Warfarin

There are action steps that can be taken to lower the risk of bleeding while undergoing warfarin treatment:

  • Inform the attending physician of all the medications and supplements that a patient is taking. Doing so can help the doctor evaluate if further testing or dosage adjustment is needed, or if a new drug might alter the effect of the warfarin treatment.
  • Be cautious of injury, especially from falling. As much as possible, abstain from participating in contact sports that may cause bruising or physical damage. Report any chronic pain in case an injury occurred.
  • Keep away from sharp objects to avoid being cut.
  • Refrain from nose-picking and, if needed, gently blow the nose.
  • If a patient who is having warfarin treatment undergo surgeries or even minor procedures like dental cleanings or vaccinations, tell the assigned health care provider about it to ensure proper and safe medical attention.
  • Use a soft-bristled toothbrush, electric razor, and waxed dental floss for hygiene and grooming. Ask the physician for a safer way to clean the gums and teeth.
  • In case of emergency, it will be helpful if a patient has a card or note that says he is having warfarin treatment (and other medications, if any) so the medical providers can take the right course of action.

Understanding the Role of Vitamin K with Warfarin Treatment

Vitamin K is a nutrient that can lessen the effectiveness of warfarin. However, it is vital for the heart and bones. Consistency in Vitamin K intake is necessary when taking warfarin. A sudden increase in Vitamin K consumption can significantly increase clotting risk.

The recommended Vitamin K intake level for adult men and women is 120 micrograms (mcg) and 90 mcg, respectively.

Food and drinks that are rich in Vitamin K include:

  • Spinach
  • Kale
  • Collards
  • Chard
  • Mustard greens
  • Turnip greens
  • Broccoli
  • Asparagus
  • Plums
  • Asparagus
  • Rhubarb
  • Green tea
  • Brussels sprouts
  • Certain oils extracted from vegetables such as soybean oil and canola oil

Before making any changes in the diet, it is encouraged to consult a physician for proper guidance.

Conclusion

Cannabidiol or CBD is one of the chemical compounds found in the cannabis plant. It is a non-psychoactive substance, which means it will not make a person “high”. The body reacts to cannabinoids through the receptors in the endocannabinoid system.

Since CBD is absorbed by the body through the CPY450 system, which is also responsible for the metabolism of warfarin in the body, it is not recommended to take CBD and warfarin together. Doing so may cause the warfarin to stay longer in the body than necessary and may lead to harmful effects such as excessive bleeding and overdose.

Expert medical advice is highly encouraged before consuming CBD products either as a replacement for a prescribed drug or a nutritional supplement.

Yamaori S., Ebisawa J., Okushima Y., Yamamoto I., Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci. 2011;88(15–16):730–736
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.
Deaton, J. G., & Nappe, T. M. (n.d.). Warfarin Toxicity. StatPearls. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK431112/
Mayo Clinic. (2020, February 1) Warfarin (Oral Route) Retrieved from: https://www.mayoclinic.org/drugs-supplements/warfarin-oral-route/description/drg-20070945
Lynch T, Price A. The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects. Am Fam Physician. 2007 Aug 1;76(3):391-396. Retrieved from https://www.aafp.org/afp/2007/0801/p391.html
Coumadin Product Data- FDA. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789126/
Johnson J.A. Clinical pharmacogenetics implementation consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther. 2017 (n/a-n/a); Whirl-Carrillo M., EMM, Hebert J.M., Gong L., Sangkuhl K., Thorn C.F. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414–417; Wadelius M., Chen L.Y., Downes K., Ghori J., Hunt S., Eriksson N. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. J Pharm. 2005;5(4):262–270. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789126/
Yamaori and Koeda, op. cit.
Yamaori and Okushima, op. cit.
Grinspoon, P. (2019, Aug 27). Cannabidiol (CBD) — what we know and what we don’t. Retrieved from https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476 .
Deaton, J. G., & Nappe, T. M. (n.d.). Warfarin Toxicity. StatPearls. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK431112/
Mayo Clinic. Warfarin Side Effects: Watch for Interactions. Retrieved from https://www.mayoclinic.org/diseases-conditions/deep-vein-thrombosis/in-depth/warfarin-side-effects/art-20047592
Doliner B, Jaller JA, Lopez AJ, Lev-Tov H. Treatments to prevent primary venous ulceration after deep venous thrombosis. J Vasc Surg Venous Lymphat Disord. 2019 Mar;7(2):260-271.e1.
W., M., D., K., & M., B. (2013). Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. doi: 10.1111/bcp.12075.
Ganetsky, M., Babu, K. M., Salhanick, S. D., Brown, R. S., & Boyer, E. W. (2011). Dabigatran: Review of Pharmacology and Management of Bleeding Complications of This Novel Oral Anticoagulant, 7(4). doi: 10.1007/s13181-011-0178-y
Sharp CR, deLaforcade AM, Koenigshof AM, Lynch AM, Thomason JM. Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 4-Refining and monitoring antithrombotic therapies. J Vet Emerg Crit Care (San Antonio). 2019 Jan;29(1):75-87.
Badjatiya A, Rao SV. Advances in Antiplatelet and Anticoagulant Therapies for NSTE-ACS. Curr Cardiol Rep. 2019 Jan 12;21(1):3.
Unger, E. F. (2015, October 16). Atrial fibrillation and new oral anticoagulant drugs. Retrieved from https://www.fda.gov/drugs/news-events-human-drugs/atrial-fibrillation-and-new-oral-anticoagulant-drugs
Coetzee, C., Levendal, R. A., van de Venter, M., & Frost, C. L. (2007). Anticoagulant effects of a Cannabis extract in an obese rat model. Phytomedicine , 14 (5). doi: 10.1016/j.phymed.2006.02.004
Anderson, L. L., Absalom, N. L., Abelev, S. V., Low, I. K., Doohan, P. T., Martin, L. J., … Arnold, J. C. (2019). Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions. Epilepsia, 60(11). doi: 10.1111/epi.16355.
Otani, K. Cytochrome P450 3A4 and Benzodiazepines. Seishin Shinkeigaku Zasshi. 2003;105(5):631-42. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12875231
Grinspoon, P. (2019, Aug 27). Cannabidiol (CBD) — what we know and what we don’t. Retrieved from https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476 .
Bauer, B. A. (n.d.). What are the benefits of CBD — and is it safe to use? Retrieved from https://www.mayoclinic.org/healthy-lifestyle/consumer-health/expert-answers/is-cbd-safe-and-effective/faq-20446700

Table of Contents

  • Does CBD interact with warfarin?
  • Can CBD Be Taken with Warfarin?
  • Can Another Oral Anticoagulant Be a Substitute for Warfarin so CBD Oil Can Be Taken?
  • Can CBD Replace Warfarin?
  • What to Look for in a CBD Product
  • What food, supplements, and drugs interact with warfarin?
  • How to Minimize the Risk of Bleeding while Taking Warfarin
  • Understanding the Role of Vitamin K with Warfarin Treatment
  • Conclusion

CBD Drug Interactions

Dr. Aaron Wiegmann, BS, FL, MD, MS

Aaron Wiegmann, BS, FL, MD, MS is a general surgeon and scientist currently training to become a plastic and reconstructive surgeon. He practices in Chicago, where he was born and raised. He has several peer-reviewed publications (mostly on surgical outcomes).

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Case report: Medical cannabis—warfarin drug-drug interaction

A case of an 85-year-old patient with concurrent use of warfarin and medical cannabis containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is described. Warfarin continues to be a cornerstone of anticoagulation treatment despite the recent addition of FDA-approved anticoagulant agents. It is well known that warfarin has numerous drug interactions; however, much remains unknown about its interaction with THC and CBD. A literature review was conducted to identify documented cases of possible interactions between cannabis and warfarin. The case reports we identified noted that cannabis may potentially increase warfarin’s effect. Therefore, we aimed to determine why an effect was not seen on our patient’s warfarin dose despite daily use of medical cannabis.

This case report describes an 85-year-old patient who despite starting an oromucosal medical cannabis regimen of THC and CBD (which provided 0.3 mg of THC and 5.3 mg CBD once daily and an additional 0.625 mg of THC and 0.625 mg CBD once daily as needed) had minimal INR fluctuations from October 2018 to September 2019.

Conclusion

Despite the introduction and use of medical cannabis therapy, with both THC and CBD components, an elderly patient with concurrent warfarin use did not see major INR fluctuations, in contrast to published literature. The potential for warfarin and THC/CBD interactions may be dependent on route of administration and dose of the cannabis product.

Introduction

Warfarin is a widely used agent in the USA for the prevention of thrombotic complications related to atrial fibrillation and venous thromboembolism (US Department of Health and Human Services, Office of Disease Prevention and Health Promotion 2014). Due to warfarin’s narrow therapeutic index, it is paramount that health care professionals are aware of agents that may interact with it. Legalization of cannabis for both medical and recreational purposes has greatly increased its use throughout the USA. The increased use in the older population is notable, as older people are likely to be on chronic medications which may interact with cannabis, including warfarin (Han et al. 2017; Lloyd and Striley 2018). Medical cannabis is commonly used to treat chronic pain of various origins. Evidence suggests receptors in the endocannabinoid system are heavily involved in pain regulation (Lloyd and Striley 2018; Health Canada 2018). Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) interact with cannabinoid receptor sub-type 1 (CB1) and cannabinoid receptor sub-type 2 (CB2) receptors to produce analgesia. THC is a partial agonist at CB1&2, while CBD acts indirectly on these receptors and modulates THC’s effects (MacCallum and Russo 2018). Based on THC and CBD’s ability to inhibit cytochrome P450 enzymes CYP3A4 and CYP2C9, medical cannabis is purported to inhibit the metabolism of warfarin, increasing its anticoagulant effects. This report describes the case of an older patient on warfarin who started medical cannabis for pain management. In contrast to published literature showing INR elevation with concomitant warfarin and cannabis product use, there was no change observed in his warfarin dosing requirement despite the patient’s consistent daily use of medical cannabis for nearly a year.

Patient case

This case report describes an older-adult patient who was maintained on warfarin therapy and later started treatment with medical cannabis for pain management. This patient, an 85-year-old, 82.55 kg male, was enrolled in our institution’s anticoagulation clinic for the management of warfarin for secondary stroke prevention in the setting of atrial fibrillation/flutter since 2012. The patient’s past medical history was significant for coronary artery disease, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, stroke, and chronic lower back pain. The patient reported to our anticoagulation clinic pharmacists that he began taking medical cannabis in November 2018 to help with his chronic lower back pain. In the preceding 2 years, prior to medical cannabis use, the patient had been on a stable dose of warfarin at 22.5 mg/week with minimal deviations. The patient’s weekly warfarin doses, INR levels, and medical cannabis use are described in Table 1. In addition to warfarin, his other home medications included albuterol, amiodarone, amlodipine, atorvastatin, docusate, finasteride, folic acid, gabapentin, isosorbide mononitrate, metoprolol tartrate, and sertraline. The patient reported no relevant medication or dietary changes over the course of his concomitant treatment with warfarin and medical cannabis.

The patient reported, and his medical cannabis dispensary confirmed that he was taking a combination of two oil cannabis products administered via the oromucosal route. One of these products he self-administered once daily, every day, the other product he used as needed. His once daily product was used for basal pain control and delivered 0.3 mg of THC and 5.3 mg of CBD once daily. His product for breakthrough pain was used once daily as needed and delivered 0.625 mg of THC and 0.625 mg of CBD. Despite daily use of medical cannabis for nearly a year, his warfarin requirements remained unchanged (see Table 1). The patient’s INRs were checked consistently while the patient was taking this medical cannabis product, at intervals according to our facility’s warfarin monitoring algorithm. Further inquiry with the patient’s dispensary revealed that the patient’s medical cannabis regimen was designed to provide him with “micro-doses” of CBD and THC. This practice is based on the theory that small doses may provide minor activation of cannabinoid 1 and 2 receptors and allow the user’s body to adapt to the drug. Micro-dosing appears to be a medical cannabis industry term, as we were unable to find any published, peer-reviewed references using this term.

Discussion

In our patient case, treatment with medical cannabis did not significantly impact warfarin therapy and INR levels remained stable. This observed effect is contrary to other reports that suggest cannabis may interact with warfarin therapy and lead to increased INR levels (Damkier et al. 2019; Yamreudeewong et al. 2009; Hsu and Painter 2019; Grayson et al. 2017; Brown et al. 2021). THC is the primary psychoactive compound present in cannabis. CBD, another major cannabinoid compound, is believed to contribute to cannabis’ therapeutic effects (Health Canada 2018; Pertwee 2014). Available dosage forms for cannabis include capsules, oils, tinctures, lozenges, edibles, topicals, rectal suppositories, and oromucosal spray (MacCallum and Russo 2018). Medical cannabis products may be prepared for oral, oromucosal, nasal, transdermal, and rectal administration (MacCallum and Russo 2018). Inhalation of the aerosols from vaporization (i.e., “vaping”) or combustion (i.e., “smoking”) are also common methods of administration (MacCallum and Russo 2018).

Our search revealed 5 relevant articles describing INR elevations in patients on warfarin who were also using cannabis products. Two case reports revealed INR elevation with smoked cannabis for recreational use (Damkier et al. 2019; Yamreudeewong et al. 2009). A third case report also showed INR elevation with primarily edible cannabis and occasional smoked cannabis use that was prescribed for anxiety and attention deficit hyperactivity disorder (Hsu and Painter 2019). A fourth case report describes INR elevation in a patient on warfarin receiving two medical cannabis sublingual oil products at a total daily dose of 14.7 mg THC and 10.3 mg CBD (Brown et al. 2021).

In addition to previously published case reports, information on the FDA-approved drug, CBD oral solution (Epidiolex®), may be helpful in predicting the effects medical cannabis may have on metabolism of concurrent drugs. The manufacturer recommends considering dose reductions of CYP2C9 substrates, such as warfarin, in patients treated with CBD oral solution. The fifth case report found that CBD oral solution, administered at a dose starting at 5 mg/kg/day and titrated up to 35 mg/kg/day, did impact warfarin therapy resulting in an elevated INR (Grayson et al. 2017).

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Our patient’s medical cannabis regimen delivered between 0.064 and 0.072 mg/kg/day of CBD and did not elevate his INR. In vitro studies suggest THC and CBD both are capable of inhibiting CYP2C9 and may increase warfarin’s effect in a dose-dependent manner (Health Canada 2018; Yamaori et al. 2012). We theorize that the THC and CBD amounts our patient was exposed to were lower than the amounts required to inhibit CYP2C9’s warfarin metabolism. Our theory is supported by the low ratios of the estimated maximum serum concentrations (Cmax) of CBD and THC and the in vitro inhibitory concentrations (Ki). According to Kiyomi et al., a Cmax/Ki ratio < 0.1 is considered to have a low risk of causing a clinically observed drug-drug interaction (Kiyomi et al. 2004). The Cmax/Ki ratios for CBD and THC for this patient were 4.9 × 10 −4 and 7.3 × 10 −4 , respectively. Because we did not have the patient’s serum CBD or THC levels, we estimated CBD and THC Cmax by using dosing data reported by Miller et al. to find the best-fit line and its equation for CBD (Miller et al. 2018). Table 2 shows the CBD doses, Cmax, and the equation and R 2 value for the best-fit trend line. Using the estimated Cmax, 0.87 ng/mL (by entering the patient’s daily CBD dose into the best-fit line equation), the Ki determined by Yamaori (5.6 μM), and CBD’s molecular weight (314.47 ng/nanomoles), we calculated the ratio as follows:

$$_>/_>=0.87;mathrm/mathrmdiv 5.6 upmu mathrm/mathrm=left(0.87;mathrm/mathrmtimes 1000;mathrmright)div 5.6 upmu mathrm=left(870;mathrmtimes 1 mathrmdiv 314.47;mathrmright)div 5.6 upmu mathrm=2.77 mathrmmathrmdiv 5.6 upmu mathrm=2.77times ^ upmu mathrmdiv 5.6 upmu mathrm=4.9times ^$$

Table 2 Cannabidiol (CBD) doses, maximum serum concentrations, and best-fit trend line to estimate our patient’s maximum serum concentration

To estimate our patient’s THC Cmax, we utilized the Cmax and THC dosing data reported by Poyatos et al. to find the best-fit line and its equation (Poyatos et al. 2020). Table 3 shows the THC doses, Cmax, and the equation and R 2 value for the best-fit trend line. Using the estimated Cmax, 0.35 ng/mL, the Ki determined by Yamaori (1.5 μM), and THC’s molecular weight (314.45 ng/nanomoles), we calculated the ratio as follows:

$$_>/_>=0.35;mathrm/mathrmdiv 1.5 upmu mathrm/mathrm=left(0.35;mathrm/mathrmtimes mathrm;mathrmright)div 1.5 upmu mathrm=left(350;mathrmtimes mathrmdiv 314.45;mathrmright)div 1.5 upmu mathrm=1.1 mathrmdiv 1.5 upmu mathrm=1.1times ^ upmu mathrmdiv 1.5 upmu mathrm=7.3times ^$$

Table 3 Tetrahydrocannabinol (THC) doses, maximum serum concentrations and best-fit trend line to estimate our patient’s maximum serum concentration

While our estimated Cmax/Ki ratios of CBD and THC were much lower than 0.1, we want to point out that the Cmax/Ki ratio of THC in the fourth case report by Brown et al. was 0.012, also less than 0.1, but 100 times closer to the 0.1 ratio. Despite achieving a Cmax/Ki ratio of less than 0.1, Brown and colleagues observed interaction between medical cannabis and warfarin (Brown et al. 2021). These conflicting findings confirm the need for additional study of the estimated plasma doses achieved with medical cannabis products and the mechanism by which medical cannabis interacts with other medications.

THC is metabolized by CYP3A4, CYP2C19, and CYP2C9, while CBD is metabolized by CYP3A4, CYP2C19, and potentially by CYP2C9 and CYP1A1/1A2 (Health Canada 2018).Though information about how THC and CBD interact with CYP enzymes varies in the literature, both THC and CBD appear to inhibit CYP3A4, CYP2C19, CYP2C9, and CYP1A1/1A2 (Health Canada 2018; Yamaori et al. 2012). Therefore, it is important that the health care professional monitors for a medical cannabis product’s potential to interact with drugs metabolized by these enzymes, which would include warfarin. Warfarin is comprised of a racemic mixture of S- and R-warfarin, and the S-enantiomer is the more potent of the two. CYP2C9 is responsible for metabolizing the more potent S-warfarin. Therefore, interactions affecting CYP2C9 metabolism are expected to have a greater effect on warfarin’s anticoagulant effects, as measured by INR levels, and the need for warfarin dosage adjustments to maintain therapeutic INR levels. Table 4 summarizes enzymes involved in warfarin, THC, and CBD metabolism.

Table 4 CBD and THC interactions with enzymes associated with warfarin metabolism (Health Canada 2018; Yamaori et al. 2012; Anderson and Chan 2016; Sachse-Seeboth et al. 2009)

Numerous variables affect the likelihood of cannabinoids, such as THC and CBD, to interact with CYP450 enzymes, including the route of administration, product formulation, pharmacogenetics, and dosage (Health Canada 2018). Cannabis products may be administered via multiple different routes, including smoking, vaping, and ingestion, and each mode of administration has a unique effect on CYP enzymes and consequently its potential to interact with drugs. For example, smoke from combustion of cannabis contains polyaromatic hydrocarbons which are capable of inducing CYP1A1/2. This could theoretically increase metabolism of R-warfarin leading to decreased INR levels. Sublingual and buccal routes are known to avoid first-pass metabolism by the liver and thus may have less potential for interactions with CYP enzymes. However, in the fourth case report, the authors describe a patient using oromucosal THC products which led to a supratherapeutic INR, suggesting that oromucosal routes do not completely avoid hepatic metabolic pathways (Brown et al. 2021). Despite the use of oromucosal medical cannabis products in our patient, we did not see any changes in INR levels that were suggestive of changes in warfarin metabolism. Therefore, we believe the THC and CBD doses consumed by our patient were below the threshold needed to produce meaningful inhibition of CYP2C9 (Health Canada 2018; MacCallum and Russo 2018; Kaminsky and Zhang 1997).

Finally, we considered the possibility of CYP activity decline as a factor for not observing an interaction between medical cannabis and warfarin. CYP-mediated phase I reactions have been shown to decline with advancing age, but phase II reactions appear to remain intact (Klotz 2009). We are unable to comment on the impact of reduced phase I metabolism on our observed findings. The link between declining CYP-mediated phase I reactions and the risk for medical cannabis-drug interactions may warrant additional investigation.

When evaluating the drug-drug interaction potential of cannabis products, one must take into consideration the route of administration and dosage of THC and/or CBD. Our report was strengthened by the frequent monitoring of the INR level and our ability to verify medical cannabis product information with the patient’s dispensary. Limitations to our clinical assessment include the following: limited information about the patient’s pain as this was primarily managed outside our facility, lack of THC and CBD serum concentrations (test unavailable at our facility, and the information was not needed to effectively manage the patient’s anticoagulation therapy), and the paucity of published data of dose thresholds of CBD and THC expected to interact with warfarin.

Conclusion

Based on the limited studies and information available, we believe that THC and CBD used by our patient did not impact his warfarin dosing requirements because his THC and CBD doses were too low to inhibit CYP enzymes responsible for warfarin metabolism. This case provides additional evidence that THC interacts with warfarin in a dose-dependent manner. In our patient case, 0.3–0.925 mg THC and 5.3–5.925 mg CBD administered via the oromucosal route daily for up to 8 months did not impact warfarin’s metabolism or result in any significant changes in INR levels.

As legalization of cannabis continues to expand, the number of people using cannabis products will increase. Healthcare professionals must be diligent in asking about cannabis use, which includes use of CBD-only products and cannabis products (which will contain both THC and CBD compounds). If the patient confirms use, the health care professional must also attempt to determine the THC and CBD amounts in the products, the frequency of use, and route of administration. All of these considerations will help the healthcare professional to make informed decisions about the potential for drug-drug interactions. Finally, we must note that the ability to determine the THC and CBD amounts in a medical cannabis product will vary by state, as wide variability exists in state reporting requirements of THC and CBD amounts.

Availability of data and materials

Not applicable; no author-generated data are described in this manuscript.

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