Consider discontinaution of CBD product or use of another antiplatelet agent such as aspirin or another P2Y12 inhibitor. Monitor patient for ischemic events.
Clopidogrel is a prodrug that requires metabolism from cytochrome P450 2C19 (CYP2C19) to become an active drug. Concurrent use of clopidogrel and CYP2C19 inhibitors, such as cannabidiol (CBD), may potentially lead to significant decreases in active clopidogrel levels which can lead to ischemic events as result of a decrease in clopidogrel activity.
Preferred managment options can include discontinuation of the CYP2C19 inhibitor(s) or use of another antiplatelet agent (see the "Alternative Options" box). Patients should be monitored for signs of an ischemic event.
CYP2C19 is an important enzyme for the effectiveness of clopidogrel. A boxed warning for Plavix (clopidogrel) states “Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.” In addition, poor metabolizers (patients with poor functionality of CYP2C19) have been shown to have higher cardiovascular event rates following ACS or PCI than patients with normal CYP2C19 functionality. As a result, CYP2C19 inhibition of clopidogrel metabolism can cause significant issues for any patients using clopidogrel as a part of their treatment regimen.1
According to the product labeling for Epidiolex (prescription cannabidiol, CBD), CBD is a potent inhibitor of CYP2C19.2,3 One in-vivo study supports the effect on CYP2C19 activity by using substrate concentrations of 60 μM (S)-mephenytoin, 2 μM omeprazole, and 4 μM 3-O-Methylfluorescein. CBD showed concentration dependent inhibition with IC50 values of 8.70 μM, 1.55 μM, and 1.79 μM respectively.4 In another study that examined the interaction between CBD and clobazam in 13 children with refractory epilepsy, CBD was found to increase levels of clobazam, a CYP2C19 and CYP3A4 substrate, leading to the reduction of clobazam dose in 10 subjects who experienced side effects potentially from concurrent use with CBD. In addition, levels of clobazam were found to be increased 60 ± 80% and levels of nCLB, an active metabolite of clobazam, were found to be increased 500 ± 300%. Similarly, to clobazam, nCLB is also metabolized by CYP3A4 and CYP2C19. Although it is possible the nCLB levels could be caused by CYP3A4 inhibition, the study reports that poor metabolizers of CYP2C19 see a fivefold higher plasma level than extensive metabolizers in nCLB levels, supporting previous studies concerning CBD’s ability to inhibit CYP2C19.5 Due to the ability of cannabinoids to potently inhibit CYP2C19, concurrent use with clopidogrel should be done with caution.
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