CBD Gummies And Warfarin

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WebMD provides information about interactions between Coumadin and antipsychotics-sibutramine. CBD & warfarin (Coumadin) carry a moderate to high risk of interaction. Speak to your doctor about CBD if you’ve been prescribed blood thinners. 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.

Does CBD Interact With Warfarin (Coumadin)?

CBD & warfarin (Coumadin) carry a moderate to high risk of interaction. Speak to your doctor about CBD if you’ve been prescribed blood thinners.

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Warfarin (Coumadin) is an anticoagulant. It’s used to prevent clot formation in conditions such as deep vein thrombosis, pulmonary embolism, to prevent stroke, and as an adjunct treatment for angina and myocardial infarction.

Cannabidiol (CBD), a cannabinoid from hemp and marijuana plants, is a popular alternative treatment for pain, inflammation, anxiety, insomnia, and as a general health supplement.

Is it safe to mix blood thinners like warfarin with CBD or other cannabinoids?

Table of Contents

Does CBD Interact With Warfarin (Coumadin)?

Yes. CBD may interact with warfarin (Coumadin). This combination is considered moderate to high risk of interaction and should be avoided unless otherwise specified by your doctor.

This combination may slow the breakdown and elimination of warfarin, leading to increased serum levels of both substances over time. If serum concentrations become too high, side effects will result — some of which are severe and require medical attention (such as internal bleeding).

There are two main ways by which CBD can interact with warfarin:

A) Slowed Elimination (Metabolic Inhibitor)

Metabolic inhibition occurs when two drugs need the same enzymes to get metabolized. Hence, they end up competing against each other for the said enzymes. This action could result in slowing down the metabolism of one or both drugs.

Warfarin is metabolized by the CYP450 enzymes, mainly by CYP3A4 and CYP2C19, and less commonly by CYP1A22, CYP2D6, and CYP3A5.

These same enzymes metabolize CBD as well. Besides this, CBD is also capable of inhibiting these enzymes. So taking warfarin and CBD together could slow down the former’s metabolism.

This action could also lead to an excess accumulation of warfarin in the body, causing severe side effects such as bleeding, bruising, severe headaches, etc.

B) Increased Effect (Agonistic Interaction)

Agonistic interaction occurs when two drugs have similar effects on the body. When used together, both these drugs push on the same receptors or cause some effects in the same direction.

CBD can cause excess accumulation of warfarin in the body. It can also make it sustain for a longer time. It means warfarin would stay in the body for longer and become more potent. Hence, CBD could work as an agonist for warfarin as well. But this could also lead to heightened abilities of warfarin and cause more side effects as well.

Is It Safe to Take CBD & Warfarin (Coumadin) Together?

CBD and warfarin (Coumadin) are unlikely to result in serious side effects — however, this combination isn’t considered safe because of the severity of potential side effects should there be an interaction.

This combination could lead to an increase in the side effects of warfarin. Some recent studies have explored the potential interaction of these compounds [1]. Studies have shown high chances of a rise in the international normalized ratio (INR) of the users who are on long-term warfarin.

This means the blood may clot more slowly in users taking both these drugs, causing a tendency to bleed more easily. This could result in serious internal bleeding, bruising, or hemorrhage from relatively small injuries.

It is not recommended to take these two medicines together. Always consult your physician first before you decide to start CBD while on warfarin or any other blood thinner medications.

Your doctor may want to modify your dose of warfarin or CBD and may suggest taking both substances at least 2 hours apart.

If necessary, take only a minimal dose of CBD and always be wary of any abnormal side effects. In patients who are taking warfarin and have started CBD, it’s suggested to do regular laboratory tests, especially the INR test. If you experience any side effects, contact your medical practitioner at once.

Similar Medications: CBD & Blood Thinners

Warfarin is classified as an anticoagulant. CBD and most blood thinners share a similar risk of interaction and side effects.

Here’s a list of similar medications that share a similar level of risk when combined with CBD:

Is CBD A Viable Alternative to Warfarin (Coumadin)?

CBD is not a viable alternative to warfarin. These medications work through entirely different mechanisms and are used to treat different conditions altogether.

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Some studies show that cannabis, the base ingredient of CBD, may have some anticoagulant properties [2]. A study performed on obese rats demonstrated that cannabis displays some anticoagulant activity.

It also showed that the cannabinoids cannabinol (CBN) and delta 9 tetrahydrocannabinol (THC) might also have anticoagulant abilities.

However, these effects are substantially weaker than the anticoagulant effects of warfarin and are therefore not suitable as a substitute for this prescription medication.

What is Warfarin (Coumadin)?

Warfarin, the generic name of the drug Coumadin, is a type of anticoagulant or blood thinners.

It’s a vitamin K antagonist that can decrease the rate of clotting of blood in the body.

Warfarin is used to treat and prevent blood clots in several conditions such as deep vein thrombosis, pulmonary embolism, etc. It’s used as a preventative for patients at risk of a stroke (such as those diagnosed with atrial fibrillation, valvular heart disease, or artificial heart valves).

Warfarin is also used to reduce the risk of death in patients with recurrent myocardial infarction (heart attack), stroke, and systemic embolism.

Coumadin is a prescription drug approved for use by the FDA in 2007.

Warfarin Specs:

Drug Name Warfarin
Trade Names Coumadin, Jantoven, Warf, Warfin, Farin, Fargem, Warco
Classification Anticoagulant
CYP Metabolism Major: CYP3A4 & CYP2C19. Minor: CYP1A22, CYP2D6, & CYP3A5
Interaction With CBD Metabolic inhibitor, agonistic
Risk of Interaction High

What Does Warfarin Do?

Warfarin is an anticoagulant. It was originally produced as rat poison, but its anticoagulant ability proved to be a valuable asset in treating hypercoagulable conditions. It was formally approved for human use in 1954 to treat blood clots.

Warfarin can disrupt the coagulation cascade and stop clot formations. It is a vitamin K antagonist that inhibits the production of vitamin K by using an enzyme called vitamin K epoxide reductase.

Warfarin blocks the liver from using vitamin k to make clotting factors. It can thin out the blood so that clotting time increases. It takes about three days for its abilities to take full effect. After this, however, it can take a few weeks to get a stable level of warfarin in the blood and get the body to settle on the correct dosage.

Warfarin stops the synthesis of biologically active forms of clotting factors II, VII, IX, and X. It also inhibits the synthesis of regulatory factors protein C, protein S, and protein Z. It does this by competitively inhibiting the vitamin K epoxide reductase complex 1 (VKORC1), an enzyme essential for activating the vitamin K in the body.

The precursors of these factors need their glutamic acid residues to undergo gamma-carboxylation. Gamma carboxylation is required so that the coagulation factors can bind to phospholipid surfaces inside blood vessels. The enzyme that allows the carboxylation of glutamic acid is gamma-glutamyl carboxylase.

Carboxylation reaction is possible only if the carboxylase enzyme converts vitamin k hydroquinone (a reduced form of vitamin k) to vitamin k epoxide. The vitamin k epoxide gets recycled back to vitamin K and vitamin k hydroquinone by another enzyme called vitamin k epoxide reductase.

Warfarin inhibits vitamin k epoxide reductase. This action leads to the diminishing of the available vitamin K and vitamin K hydroquinone in the tissues, which decreases the carboxylation activity of the glutamyl carboxylase. The drug works by inhibiting the formation of Vitamin K and making coagulation factors unable to work.

When this occurs, the coagulation factors are no longer carboxylated at some glutamic acid residues and are incapable of binding to the endothelial surface of blood vessels. This makes them biologically inactive. Hence, the coagulation factors are still being produced but have decreased ability to work.

Warfarin needs to be adjusted according to individual needs, and the dosage may be increased or decreased depending on the response of the treatment. Dosing and adjusting warfarin can be complicated as it is known to interact with many medications. Regular laboratory tests, including international normalized ratio (INR), are mandatory after starting warfarin to monitor the coagulation levels in the body.

The risk factors of excess bleeding on using warfarin can be found in patients with high intensity of anticoagulation or high INR, age of over 65 years, highly variable INR, patients with a history of gastrointestinal bleeding, high blood pressure, serious heart disease, anemia, and renal insufficiency.

Warfarin is contraindicated in some conditions such as pregnancy, recent major surgery, thrombocytopenia, coagulation defects, decompensated liver disease, known hypersensitivity, and hemorrhagic tendencies.

Side Effects of Warfarin

  • Severe bleeding such as heavy menstrual bleeding and internal hemorrhage
  • Bleeding from gums, nosebleeds
  • Easy bruising
  • Red or brown urine
  • Black or bloody stool
  • Severe headache
  • Stomach pain
  • Joint pain
  • Joint swelling or discomfort
  • Vomiting blood or coffee-ground like materials
  • Coughing up blood
  • Abnormal bruising
  • Dizziness
  • Blood dyscrasias
  • Hepatitis
  • Weakness
  • Vision changes
  • Intracranial hemorrhage
  • Lethargy
  • Hypersensitivity
  • Purple toe syndrome
  • Renal injury
  • Taste disturbance
  • Flatulence
  • Hair loss
  • Intraocular hemorrhage
  • Warfarin necrosis
  • Osteoporosis
  • Valvular and vascular calcification

Other Names For Warfarin (Coumadin)

Warfarin is sold under many different names. All share the same risk and potential interactions.

Other names for warfarin include:

Key Takeaways: Is it Safe to Take Warfarin With CBD?

CBD carries a moderate to high risk of interaction with warfarin. The severity of this interaction can be life-threatening.

It can decrease its rate of metabolism, make it more potent, have a longer duration of action, and increase the chances of experiencing side effects. Therefore, it’s not recommended to take them together unless advised by your prescribing medical practitioner.

If needed, use only a minimal amount of CBD and always be on the lookout for any side effects.

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.

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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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