Δ-9-tetrahydrocannabinol dose increase leads to warfarin drug interaction and elevated INR

We have reported a case of a drug-drug interaction (DDI) involving warfarin and Δ-9-tetrahydrocannabinol (THC) that resulted in a supratherapeutic international normalized ratio (INR) level. The purpose of this case report is to highlight the possibility of a pharmacokinetic DDI between THC and warfarin.

A 67-year-old Caucasian man suffering from chronic pain presented to a dispensary in Buffalo, NY, for a refill of his medical cannabis (MC). The patient asked to speak with the pharmacist, and during their discussion the patient stated that he had a supratherapeutic INR level of 5.2 measured at home with a self-test device. The patient had no evidence of bleeding, and administration of warfarin was held for 2 days before the INR level returned to a normal range. The supratherapeutic level occurred when the patient was self-titrating his dose of THC and scored an 8, or "probable," on the Naranjo Adverse Drug Effect Probability Scale.

Warfarin and cannabinoids such as THC are both metabolized by cytochrome P450 (CYP) isozymes present in the liver and gastrointestinal tract. In the case described, a dose increase of 7.35 mg THC preceded an INR elevation of 5.2, but did not result in any bleeding. These observations are suggestive of a DDI involving warfarin and THC. Clinicians involved with MC should have adequate knowledge of the drugs that act as substrates, inhibitors, and inducers of CYP enzymes, including the major cannabinoids.