Consider discontinaution of CBD product or use of a minimally interacting anticoagulant such as apixaban. Monitor patient for adverse events.
Warfarin has a narrow therapeutic range and is metabolized mainly by cytochrome P450 2C9 (CYP2C9). Concurrent use of warfarin and CYP2C9 inhibitors, such as cannabidiol (CBD), may potentially lead to significant increases in warfarin levels which can lead to severe warfarin-related adverse events.
Preferred managment options can include discontinuation of the CYP2C9 inhibitor(s) or use of another anticoagulant drug such as apixaban (see the "Alternative Options" box). Patients should also be monitored for signs of bleeding such as fatigue and somnolence.
Warfarin metabolism, specifically the more potent S-enantiomer, is mainly dependent on CYP2C9 metabolism. As a result, inhibitors of CYP2C9 have the potential to increase the pharmacological effects of warfarin, including increased risk of bleeding.1 Due to this pharmacokinetic property, the American Heart Association recommends considering a decrease in warfarin dose if necessary and monitoring warfarin within 3 days of concurrent use with CYP2C9 inhibitors.2
CBD containing substances’ interaction with warfarin is primarily dependent on the inhibition of CYP2C9 by cannabinoids.3 In-vitro assays have been conducted to show cannabidiols’ concentration dependent inhibition of CYP2C9 or warfarin. Yamaori et al. demonstrated a concentration dependent inhibition of S-warfarin from 3 major constituents of cannabis – THC, cannabinol (CBN), CBD – with inhibitory potentials (K¬I) of 0.937 – 1.50 uM, 0.882 – 1.29 uM, and 0.954 – 9.88 uM respectively.4 Treyer et al. also found similar results for cannabinoids interacting with warfarin in vitro, where CBD and THC significantly inhibited warfarin through CYP2C9.5 Other in-vitro analysis have shown cannabinoids ability to inhibit CYP2C9 mediated metabolism with Ki values of 0.2 – 3.2 uM and Ki,u values of 0.90 ± 0.54 uM.6,7
In addition to in-vitro studies, five case studies have been reported showing increased risk of bleeding associated with warfarin either through bleeding events or increase in INR as the result of a potential interaction. In three of the case reports, the warfarin was withheld to allow the INR to return to therapeutic range. One case report presented the use of smoked cannabis with warfarin. The case report details a 56-year-old receiving warfarin therapy for 11 years. Within two weeks of each other, the patient had been hospitalized twice, once for an upper GI bleed and second for constant nosebleeds and bruising. On both visits, his INR was supratherapeutic at a level above 10 requiring warfarin to be withheld and medical treatment with vitamin K solely or in combination with fresh frozen plasma. This patient was revealed to have smoked more frequently before both of his hospitalization periods.8
Two more case reports with patients taking sublingual or oral and inhaled cannabis also reported supratherapeutic INR with no apparent signs of bleeding events. One individual was consuming oral and inhaled cannabis and his INR was supratherapeutic at 7.2 after starting daily edibles and occasional smoking for anxiety and ADHD. The patient was advised to hold warfarin to allow INR to return to normal and discontinue cannabis use.9 The other patient, who reported using sublingual CBD oil, had an INR of 5.2 on an at-home self-test device after increasing his CBD oil dose. To control his INR while continuing use of CBD, warfarin is held for 1-2 days anytime his INR is found to be above 3, which happens about once per month.10
In the last two case reports, a different approach was taken from previous reports. Instead of holding the warfarin dose, the warfarin dose was adjusted to allow for concurrent use of CBD and warfarin. The first involved a 44-year-old epileptic patient using CBD oil for epilepsy while on chronic warfarin therapy. The patient was enrolled in a study for use of cannabidiol for treatment resistant epilepsy. The CBD dose was started at 5 mg/kg/day bid and increased by 5 mg/kg/day in increments every two weeks. In order to keep INR within range, the warfarin dose was adjusted leading to a reduction of about 30% of the patient’s warfarin dose with no bleeding events. The INR was above the range six times during treatment with INRs of 6.86, 4.40, 3.27, 4.07, 3.93, and 3.49. A non-linear increase in INR concentration was noted with titration of CBD.11 The second case involved a 46-year-old patient taking warfarin. The patient was initiated on Epidiolex for epilepsy at a dose of 5 mg/kg/day, and the Epidiolex was to be titrated up to 20 mg/kg/day. As doses were titrated, the patient experienced supratherapeutic INR levels of 3.4 and 3.5 above the goal 2 – 3 during CBD treatment. This resulted in an approximately 20% reduction in warfarin dose to keep INR within range.12 Based on the above case studies and in-vitro studies, concurrent use of CBD containing substances with warfarin should be used with caution.
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