Given the exponential increase in use, and emerging research on the effective application of cannabidiol (CBD) for pain, anxiety, PTSD, seizures, and more, the concern for potential drug interactions is both reasonable and prudent. Consumers often consider natural substances to be safer than pharmaceuticals, and while this may often be true, it is important for consumers and healthcare providers (HCPs) alike to familiarize themselves with the possible interactions that can occur when CBD is mixed with common medications.
Studies of CBD inhibition and induction of major CYP450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking.1 To date there are seven major isoforms identified that CBD is known to affect: CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5. It is important to note that much of this data is based on studies in animals and so while interaction is possible, we must be cautious when extrapolating about possible relationships with drugs that share those routes.
CYP3A4, the most abundant cytochrome P450 in the human liver,2 metabolizes approximately 40% of all clinically prescribed drugs,3 and as such, CBD has the potential to increase serum concentrations4 of macrolides, calcium channel blockers, benzodiazepines, cyclosporine, PDE5 inhibitors like sildenafil, antihistamines, haloperidol, antiretrovirals, and some statins.
CYP2D6 metabolizes many antidepressants, so CBD could increase serum concentrations5 of SSRIs, tricyclic antidepressants, antipsychotics, beta blockers and opioids as well. Many patients come to HCPs seeking CBD recommendations for mental health issues like anxiety, PTSD, and depression, as well as chronic pain, and many are already on medications to treat these issues. As such, HCP awareness of potential interaction is crucial.
In one 2015 study, the researchers confirmed CBD’s interaction with the anti-epileptic drug clobazam (CLB) in an 8 week study of 13 children with epilepsy on CLB and CBD (both metabolized via CYP3A4 and CYP2C19). As patients began taking CBD at a dose of 5 mg/kg/day and titrated up by 5 mg/kg/day each week to a goal of 25 mg/kg/day, results showed 9 of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70% even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction.
These results are supported by another study6 with 33 children treated with CBD administered with an average of 3 other drugs, including CLB, which led to sedation that was alleviated by reduction of the medication. These studies point to the importance of monitoring blood levels of CLB with concomitant CBD use, as well as other anti-epileptics as a precautionary measure.
It is also worth noting that there is one case study7 involving a 44-year-old male with Marfan Syndrome, mechanical mitral valve replacement, warfarin therapy, and post-stroke epilepsy who was enrolled in the University of Alabama at Birmingham open-label program for compassionate use of cannabidiol for the management of treatment-resistant epilepsy. The patient began at 5 mg/kg/day divided twice daily and every 2 weeks, that amount was doubled. The researchers found that as CBD was increased, a non-linear increase in the INR was noted. Warfarin dosage adjustments were made by the HCP to keep his INR within the therapeutic range leading to, at the last noted study visit, a warfarin dose reduction of approximately 30%. The patient was followed clinically without bleeding complications. Five of the 7 CYP isoforms that metabolize CBD are also involved with metabolism of warfarin, including CYP2C9, which is the dominant enzyme for S-warfarin, and CYP3A4, which is the dominant enzyme for R-warfarin.
In summary, given growing interest in the use of CBD, it is essential to consider the interactions CBD may have with drugs. As of now, limited published human data are available on these interactions. Our understanding of hepatic biochemistry suggests the potential for CBD to increase the effect of common medications that undergo CYP2C9, CYP2C19, CYP2D6, and CYP3A4 clearance, and possibly others. As a result, HCPs should speak to patients on these medications about how to monitor for increased drug effects, planned dose reductions, or other adjustments during use of CBD. Additionally, common sense supports using caution with potentially synergistic agents, ie: pain meds, antidepressants, anti-anxiety and sleep meds regardless of metabolic pathway when using CBD.
Finally, when recommending CBD, HCPs should consider full-spectrum hemp oils (FSHOs) with CBD to reduce risk of interactions. A 2018 review of cannabinoid-drug interactions8 found, “to the extent that there have been issues with adverse drug interactions, these have involved high doses of CBD isolates” including the CLB and warfarin examples above. While this disparity may be due to the fact that most CBD research to date has used CBD isolates, it is an important distinction for HCPs to consider since FSHOs are federally lawful and easily accessible.
This blog post is sponsored by CV Sciences.
- Zendulka O, et al. Cannabinoids and Cytochrome P450 Interactions. Current Drug Metabolism. 2015; 17(999)
- Klein K, et al. Pharmacogenomics of cytochrome P450 3A4: recent progress toward the “missing heritability” problem. Frontiers in Genetics. 2013; 4:12.
- Zanger U, et al. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and Bioanalytical Chemistry. 2008; 392(6):1093-108.
- Yamaori S, et al. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences. 2011; 88(15-16):730-6.
- Yamaori S, et al. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metabolism and Disposition. 2011; 39(11):2049-56.
- Geffrey AL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015; 56(8):1246-51.
- Grayson L, et al. An interaction between warfarin and cannabidiol, a case report. Epilepsy & Behavior Case Reports. 2018; 9:10-11.
- “Project CBD Releases Educational Primer on Cannabinoid-Drug Interactions.” | Project CBD, 14 Jan. 2019, www.projectcbd.org/how-to/cbd-drug-interactions.