Cannabinoids and drug-drug interactions with CV medications
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The role and status of cannabis in the United States have evolved both medically and legally. In 2020, 49.6 million people in the United States reported using a form of cannabis in the previous year.
Cannabinoids are defined as any group of closely related compounds, which include cannabinol (CBN) and the active constituents of substances found in the cannabis plant species, Cannabis sativa and Cannabis indica. The main cannabinoids widely used are THC, a psychoactive cannabinoid, and CBD, a non-psychoactive cannabinoid. The only FDA-approved cannabis products are cannabidiol (Epidiolex, Jazz Pharmaceuticals), a purified form of CBD used to treat seizures, and dronabinol (Marinol, AbbVie), indicated for the treatment of anorexia associated with weight loss in AIDS and nausea and vomiting associated with chemotherapy. However, other products containing CBD and THC are widely available. With the increasing use of cannabinoids for therapeutic and recreational use, drug-drug interactions (DDIs) with other medications are important to consider.
To date, the mechanism of action of cannabinoids is not fully understood. Given the complexity and variability of their pharmacology, there is potential for clinically significant DDIs. Though limited case reports and in vitro and clinical studies have evaluated DDIs between cannabinoids and other drugs, data remain lacking and there is no consensus regarding when these interactions become clinically significant. However, it is important to understand how cannabinoids may interact with other drugs, and the potential risks for patients on concomitant medications.
This article highlights clinically relevant interactions between cannabinoids and common CV medications.
Cannabinoids and drug metabolism
Different components of cannabinoids may affect cytochrome P450 (CYP) hepatic isoenzymes, UDP-glucuronosyltransferases (UGT), and P-glycoprotein (P-gp) to varying degrees. THC and CBD are primarily metabolized by CYP enzymes and UGT. CBD is a substrate of CYP2C19 and CYP3A4 and THC is metabolized by CYP3A4 and CYP2C9. CBD is a moderate CYP2C19 and CYP2C9 inhibitor, and has also been shown to inhibit P-gp. CBD also has the potential to inhibit CYP3A4 and CYP2D6, but its effect was limited based on pharmacokinetic studies. THC has also demonstrated inhibition of CYP2C9 through in vitro studies.
Interactions
Clopidogrel and CBD
Clopidogrel, an antiplatelet agent, requires CYP2C19 metabolism to convert to its active thiol metabolite. In vitro studies have demonstrated greater than 50% inhibition of CYP2C19 at concentrations that would result from use of typical CBD doses of 300 mg to 1,500 mg per day. Because CBD inhibits CYP2C19 at clinically relevant concentrations, this interaction may compromise clopidogrel’s antiplatelet activity, thereby increasing risk for CV events. It may be beneficial to consider close monitoring of signs and symptoms of diminished clopidogrel activity or consider an alternative agent such as prasugrel or ticagrelor, which do not rely on CYP2C19 for activation, particularly in those who have undergone recent deployment of drug-eluting stents.
Cilostazol and CBD
Cilostazol is another CV medication that may be affected by DDIs with CBD, as it is metabolized to an inactive compound by CYP2C19. CYP2C19 inhibition may lead to higher serum concentrations of cilostazol, which may increase the risk of adverse events like headache, diarrhea, hypotension, tachycardia and possible cardiac arrhythmias. Therefore, when used in combination with regular CBD, it is recommended to reduce the dose of cilostazol to 50 mg twice daily and monitor clinical response closely.
Warfarin and CBD/THC
As moderate inhibitors of CYP2C9, both THC and CBD may affect metabolism of S-warfarin, leading to increased risk of bleeding. Additionally, CYP2C19 genotypes have also been reported to influence clearance of both R-warfarin and S-warfarin. The combination of genetic polymorphisms of CYP2C9 and CYP2C19 along with cannabis drug interactions may affect a patient’s maintenance dose of warfarin, warranting close monitoring of INR and dose adjustments to decrease the risk for bleeding.
DOACs and CBD
While CBD has not been directly shown to affect direct oral anticoagulants (DOACs), DOACs — dabigratran (Pradaxa, Boehringer Ingelheim), apixaban (Eliquis, Bristol Myers Squibb/Pfizer), rivaroxaban (Xarelto, Janssen/Bayer) and edoxaban (Savaysa, Daiichi Sankyo) — are substrates of P-gp. Numerous studies have highlighted increased exposure of DOACs when used in combination with P-gp inhibitors. CBD inhibition of P-gp may lead to increased levels of DOACs, resulting in higher risk for bleeding, warranting close monitoring of these anticoagulants with CBD as well.
Digoxin and CBD
Digoxin may interact with CBD through inhibition of P-gp, with potential to increase digoxin’s area under the curve. As digoxin has a narrow therapeutic index, patients should be monitored patients more closely. Some patients may require a digoxin dose reduction by 15% to 30% or a modification in their therapeutic regimen.
Calcineurin inhibitors and CBD
Although not specifically a CV medication, tacrolimus is often used in patients who are recipients of heart transplants. Tacrolimus is a substrate of both CYP3A4 and P-gp. With conflicting information available, in vitro data suggest that CBD exhibits variable inhibition of CYP3A4 and potent, concentration-dependent inhibition of P-gp. One case report suggested that patients on tacrolimus and concomitant CBD were at increased risk for elevated tacrolimus blood levels and toxicity. Similar interactions may occur with CBD and sirolimus or everolimus. Therefore, it is important to be aware of the potential interaction that may influence drug levels and require maintenance dosage adjustments.
Dronabinol DDIs
Dronabinol is an FDA-approved cannabinoid indicated for the treatment of anorexia associated with weight loss in AIDS and nausea and vomiting associated with chemotherapy. Based on in vitro studies, dronabinol is primarily metabolized by CYP2C9 and CYP3A4. While dronabinol is not known to be a CYP inhibitor or inducer, it is subjected to increased systemic exposure with inhibitors of these enzymes (amiodarone, verapamil and diltiazem), which may increase the risk for dronabinol-related adverse events. When used in combination with inducers of these enzymes, there may be a loss of efficacy of dronabinol. Additionally, dronabinol may compete with other CYP2C9 substrates, such as warfarin. It is recommended to monitor patients for increased risks for adverse reactions on narrow therapeutic index drugs, like warfarin.
Additive CV effects with cannabinoids
Although cannabinoids can affect systemic exposure of other medications, they may also have additive systemic effects on CV health. This may increase the risk for adverse events, exacerbations, or difficulty in disease management. Cannabinoids may enhance sympathetic nervous system effects such as dizziness, confusion, sedation and somnolence, as well as CV effects including BP variations, syncope and tachycardia.
Additive effects can occur when THC and other substrates CYP3A and CYP2C9, including sympathomimetics (amphetamines, anticholinergics, norepinephrine) are used together, resulting in additive tachycardia and hypertension. When used with THC, other CV medications that are CYP2C9 substrates may result in elevated concentrations.
Summary and recommendations
Overall, cannabinoid use has substantially increased over the past several years. However, there are limited pharmacokinetic and pharmacodynamic data surrounding the drug interactions of cannabinoids, which makes this an important area of further research and understanding. The majority of information about drug interactions are derived from in vitro studies and case reports. There is potential for the outcomes of these DDIs to be additive, synergistic or antagonistic for multiple pharmacologic categories, including CV medications.
To factor these drug interactions into a patient’s pharmacotherapy, we should ask all patients about their use of cannabinoids. Discussions about this topic may be sensitive to patients; to encourage patients’ self-reporting about cannabinoid use or for any illicit drug, providers can prepare the patient by setting the context, asking for facts rather than judgment and normalizing the topic by using universal statements like: “Many people have started using cannabinoid products recently” and proceed with your question. Additionally, it is important to consider cannabinoid dose, as well as frequent vs. infrequent use, as chronic use has been linked to higher concentrations. It may be prudent to counsel patients to use cannabis products that include dosages on the packaging. When evaluating for drug interactions, consider therapeutic index and substrate specificity of each drug. Caution is recommended in order to closely monitor patients who utilize cannabinoids with potentially interacting medications, especially for drugs with narrow therapeutic index.
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- For more information:
- Tamia Jones, PharmD, is a PGY1 pharmacy practice resident at Self Regional Healthcare in Greenwood, South Carolina.
- Ashley Costello, PharmD, BCPS, is from Self Regional Healthcare in Greenwood, South Carolina.
- Christine Cadiz, PharmD, MA, BCPS, is health sciences clinical associate professor in the department of clinical pharmacy practice at UCI School of Pharmacy & Pharmaceutical Sciences in Irvine, California.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.
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