CBD Gummies And Warfarin

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WebMD provides information about interactions between Coumadin and antipsychotics-sibutramine. If you've been prescribed warfarin (an anticoagulant) and are wondering if you can also take CBD oil, read this post before proceeding to know the risks of this 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. 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.

Warfarin/Cannabinoids Interactions

This information is generalized and not intended as specific medical advice. Consult your healthcare professional before taking or discontinuing any drug or commencing any course of treatment.

Medical warning:

Moderate. These medicines may cause some risk when taken together. Contact your healthcare professional (e.g. doctor or pharmacist) for more information.

How the interaction occurs:

Products that contain active ingredients from cannabis such as THC or CBD may slow down how quickly your body processes warfarin.

What might happen:

You may experience an increased chance for bleeding including bleeding from your gums, nosebleeds, unusual bruising, or dark stools.

What you should do about this interaction:

Make sure your healthcare professionals (e.g. doctor or pharmacist) know that you are taking dronabinol, using cannabis products such as CBD oil, or using marijuana. You may need to have your bleeding tests (e.g. INR) checked more often, especially when you first start taking these products, if the dose changes, or if you increase or decrease use of cannabis products and marijuana. If you have any signs of bleeding, such as bleeding from your gums, nosebleeds, unusual bruising, or dark stools, contact your doctor right away.Your healthcare professionals may already be aware of this interaction and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.

CBD and Warfarin: Can You Safely Mix Them Together?

CBD oil is a natural remedy that contains the cannabinoid CBD extracted from the cannabis plant. It’s said to reduce inflammation, provide greater resistance to stress, and promote nerve health.

However, CBD oil may have an adverse drug interaction with anticoagulants such as warfarin.

Can you take CBD oil with warfarin? Read on to find out.

How Does CBD Affect Your Body?

Cannabidiol (CBD) is a compound that comes from the cannabis plant known for its health benefits. CBD oil can be extracted from hemp or marijuana plants. Hemp-based CBD oil is legal in all 50 states, while marijuana-derived CBD oil varies by state.

There are several ways in which CBD affects your body. To begin with, CBD is not addictive and does not cause any withdrawal symptoms. This means taking higher doses of CBD is okay as long as you don’t exceed your daily recommended amount or take too much at once.

Furthermore, CBD is non-psychoactive, meaning it doesn’t get you high, unlike tetrahydrocannabinol (THC), the other compound from the cannabis plant.

These are just some of the common reasons why people use CBD oil:

  • Pain relief
  • Anti-anxiety
  • Acne cure
  • Weight management
  • Brain health
  • Cardiovascular health

However, CBD is not for everyone. Some side effects have been reported in rare cases, which may include:

  • Dry mouth
  • Fatigue
  • Sedation
  • Appetite changes
  • Diarrhea

Additionally, using CBD alongside certain medications raises some questions.

How Does CBD Oil Affect Your Blood?

It has been shown that CBD itself has mild anticoagulating effects, meaning that it can act somewhat like a blood thinner. Nevertheless, more studies must be done to better understand how CBD affects your blood.

In clinical trials, case studies, and scientific research, CBD is shown to work well with the endocannabinoid system in the body.

Following the passage of the Farm Bill, scientists now have greater access to CBD and can finally study its potential as a healing agent. As a result, researchers are conducting more and more studies and clinical trials on CBD every day.

Does CBD Interact With Medications?

Various pharmaceuticals, herbal products, and health supplements can interact with CBD. As a result, the use of other drugs might need to be reduced or modified if CBD is introduced.

The main thing is to understand that some medications should not be taken together.

There are many other factors that can influence drug interactions, such as one’s health condition, the dose of a medication, and the dose of CBD. So if you’re starting a new medication, consult your doctor first before taking CBD oil.

Does CBD Interact With Warfarin?

Short answer: Yes.

Taking any kind of medication or substance requires your body to metabolize it. In the metabolic process, drugs are broken down so the body can absorb their effects.

The chemical structure of a drug determines how it’s broken down by the liver, thereby determining how quickly it leaves your system. The enzyme family called cytochrome P450 (CYP450) is responsible for converting foreign substances and making them easily excreted by the body.

The CYP450 enzyme may be slowed or accelerated by some medication or substance, including CBD.

Drug interactions occur because your body’s metabolism rate is altered during this time. This is referred to as the “grapefruit effect” due to the grapefruit’s ability to slow down the absorption of the drug by the body.

CYP450, CBD Oil, and Warfarin

CYP450 is predominantly responsible for the metabolism of warfarin. CBD inhibits this enzyme class. CBD competes with warfarin on the same metabolic pathway, according to a US National Library of Medicine study published in 2017.

CBD can cause warfarin to stay in the body for too long without being broken down when taken together. This can result in unwanted side effects such as excessive bleeding or overdose.

What Can Increase the Risk of Bleeding?

Warfarin treatment can increase your chances of bleeding during the first three months. The risk is even greater for older adults. You may also be at risk if you use other blood-thinning medications.

Genetic factors may also cause some people who take warfarin to be more prone to bleeding. Your doctor may recommend a genetic test to determine the best dose for you.

Other medical conditions that increase your risk of bleeding are:

  • Alcoholism
  • Cancer
  • History of stroke
  • Kidney problems
  • Liver disease
  • Ulcers, gastritis, and peptic disease
  • Uncontrolled blood pressure

Can You Take CBD Oil With Warfarin?

CBD oil and warfarin should not be taken together. Taking any form of CBD during your warfarin treatment should be avoided as well.

Warfarin is an anticoagulant (blood thinner) medication that prevents the formation of dangerous blood clots that could lead to heart attacks or strokes. Warfarin is available under several brand names, including Coumadin and Jantoven.

Severe bleeding, headaches, swelling, or sudden pain in the extremities are some of the risks associated with warfarin.

A 2017 study published in Epilepsy & Behavior Case Reports showed that CBD increased the effects of blood-thinning drugs like warfarin by slowing down how the body metabolizes the substance. CBD may potentially increase some of the risks of warfarin by extending its duration in the body.

If you’re currently taking warfarin and want to use CBD for another condition, be sure to speak with your healthcare provider first.

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Can You Take Other Blood Thinners With CBD Oil?

Drug interactions can be influenced by a number of factors, including your health, weight, and general tolerance. When CBD oil is combined with blood thinners, several considerations must be made.

Two of the remaining three oral anticoagulants approved by the FDA to treat irregular rapid heart rates are also metabolized by the CYP450 system. As a result, they will also be affected by CBD’s grapefruit effect.

Rivaroxaban and apixaban are the oral anticoagulants described.

Further, a study published in 2011 described how dabigatran (Pradaxa), another oral anticoagulant, doesn’t undergo CYP450 metabolism. A review of dabigatran suggests that the drug may have a few drug-food and drug-drug interactions. The use of dabigatran as an alternative to warfarin treatment is also being considered.

Once again, it’s advisable to consult your doctor before taking any anticoagulant together with CBD to determine safety and tolerance.

The FDA has authorized warfarin use for the following purposes:

  • Treatment of venous thrombosis, associated pulmonary embolisms, and pulmonary thrombosis.
  • Treatment of thromboembolic complications caused by cardiac valve replacement or irregular or rapid heartbeats (atrial fibrillation).
  • Identify and prevent deaths, recurrent heart attacks or myocardial infarctions (MI), and other thromboembolic events like strokes and systemic embolisms that may follow a cardiac arrest.

Can CBD Replace Warfarin?

The overall research on CBD is relatively young compared to traditional drugs. Currently, CBD has not been explicitly evaluated as a safe replacement for warfarin or any form of the anticoagulant.

Phytomedicine published a study written in 2007 that used an obese rat model to show that cannabis extracts may have anticoagulant effects. In this study, cannabinoids like cannabinol (CBN) and tetrahydrocannabinol (THC) exhibited anticoagulant properties.

According to the researchers, the cannabinoids THC and CBN from Cannabis sativa were possible treatments for thrombosis and diabetes, a condition that could lead to an irregular rise in blood clotting.

There have been limited studies to determine if CBD can act as an anticoagulant, and at this time, there is no evidence that CBD can act as an anticoagulant medication.

You should still consult a medical expert before taking CBD as a substitute for warfarin or any prescription medication. There are still many unknowns regarding CBD’s effects on the body.

What To Look For When Shopping for CBD Oil

The market for CBD oil has expanded a lot in recent years. It is available online and in stores across the country. However, not all CBD oils are created equal and there are certain things you should know before purchasing your first bottle.

CBD Concentration

Some people are not sure what CBD concentration means when buying CBD oil.

There are many different types, and some can be much stronger than others. The concentration will depend on what you’re looking to use the CBD oil for and how often you plan on using it. The higher the concentration, the stronger the effects are likely to be.

There is also a limit to the amount of THC that can be present in a product. The percentage of THC in CBD oil should be clear on its label.

CBD Dosage

The next thing you should look at is how much CBD is in each dosage (the number of milligrams). Taking a certain amount of CBD will vary depending on the concentration as well as other factors like age or medical needs.

CBD Vendor’s Certificate of Analysis (COA)

Before buying CBD oil, it’s important to check its COA. This will not only ensure that the product is of good quality but also tell you if the vendor has been trustworthy in providing accurate information about the product.

This certificate ensures that the product is safe, and you shouldn’t have any worries about what you’re putting into your body. It lets you know that this product has been tested and meets all safety standards mandated by law.

CBD Source

When shopping for CBD oil, check the CBD’s source. If you’re in the United States, it’s best to buy CBD that uses American-grown organic hemp.

Hemp is a bioaccumulator, which means it absorbs the nutrients and elements from the soil it’s planted. These nutrients are dissolved within the plant’s cell walls and then released throughout its life cycle.

Bioaccumulators are effective at absorbing either good or harmful elements. So you can also compromise the quality of the CBD plant if polluted soil is used.

Ideally, hemp should be grown in fertile soil with no harsh chemicals.

Additional Ingredients

CBD products may be formulated with beneficial ingredients like MCT oils or melatonin.

Unfortunately, CBD products can sometimes contain potentially hazardous ingredients, such as vegetable glycerin and propylene. So be aware of these substances and steer clear of CBD products containing them.

Other Products That May Interact With Warfarin

In addition to individual factors, there are several drug interactions that can change how your body reacts.

Warfarin interacts with vitamins, nutritional supplements, drugs, and food. These items may reduce the efficacy of warfarin or increase bleeding risks.

Here’s a list of common foods and drinks to avoid while taking warfarin:

  • Grapefruit or grapefruit juice
  • Cranberries or cranberry juice
  • Pomegranate or pomegranate juice
  • Garlic
  • Black licorice
  • Alcohol

Here’s a list of common drugs to avoid while taking warfarin:

  • Abnormal heart rhythm medications, such as amiodarone (Pacerone, Nexterone)
  • Antibiotics
  • Aspirin or products containing aspirin
  • Antacids or laxatives
  • Antifungal medications, including fluconazole (Diflucan)
  • Colds and allergy medications
  • Ibuprofen (Advil, Motrin IB, etc.)
  • Naproxen sodium (Aleve, Naprelan, etc.)
  • Product containing acetaminophen (Tylenol, etc.)

Here’s a list of common herbal or nutritional supplements to avoid while taking warfarin:

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

Key Takeaways on Interactions Between CBD and Warfarin

The body absorbs CBD through the CPY450 system, which also helps your body process warfarin. Therefore, combining CBD with warfarin is not advisable.

If you insist on taking CBD together with it, warfarin may stay in your body for longer than necessary. This can lead to severe side effects such as excessive bleeding and even death from overdose.

If you’re on warfarin or about to use this medicine, be mindful of the other foods, drugs, and supplements that you should avoid as well.

CBD oil is a legal and safe drug in the United States. However, there are laws different for every state and you should make sure we check the law first before you buy CBD oil.

There are many benefits of using CBD. However, there are many fake products out there that don’t meet quality standards. To maximize its benefits and prevent any harm to your body, be sure to buy from a trusted source. You should also make sure that the product has been third-party tested.

Most importantly, it’s highly recommended to seek medical advice before using CBD products as a replacement for a prescribed drug or a nutritional supplement.

Have you tried taking CBD and warfarin together? Share your experience in the comments below to help other readers!

References:

  1. 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. (1)
  2. 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. (2)
  3. Deaton, J. G., & Nappe, T. M. (n.d.). Warfarin Toxicity. StatPearls. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK431112/
  4. 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.
  5. 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.
  6. 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
  7. 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.
  8. Badjatiya A, Rao SV. Advances in Antiplatelet and Anticoagulant Therapies for NSTE-ACS. Curr Cardiol Rep. 2019 Jan 12;21(1):3.
  9. 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
  10. 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
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Nina Julia

Nina created CFAH.org following the birth of her second child. She was a science and math teacher for 6 years prior to becoming a parent — teaching in schools in White Plains, New York and later in Paterson, New Jersey.

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).

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:

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

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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