September 22, 2022
6 min learn
The function and standing of hashish in the US have advanced each medically and legally. In 2020, 49.6 million individuals in the US reported utilizing a type of hashish within the earlier 12 months.
Cannabinoids are outlined as any group of carefully associated compounds, which embrace cannabinol (CBN) and the lively constituents of gear discovered within the hashish plant species, Hashish sativa and Hashish indica. The primary cannabinoids broadly used are THC, a psychoactive cannabinoid, and CBD, a non-psychoactive cannabinoid. The one FDA-approved hashish merchandise are cannabidiol (Epidiolex, Jazz Prescribed drugs), a purified type of CBD used to deal with seizures, and dronabinol (Marinol, AbbVie), indicated for the therapy of anorexia related to weight reduction in AIDS and nausea and vomiting related to chemotherapy. Nonetheless, different merchandise containing CBD and THC are broadly obtainable. With the growing use of cannabinoids for therapeutic and leisure use, drug-drug interactions (DDIs) with different medicines are necessary to contemplate.
To this point, the mechanism of motion of cannabinoids is just not absolutely understood. Given the complexity and variability of their pharmacology, there may be potential for clinically vital DDIs. Although restricted case reviews and in vitro and medical research have evaluated DDIs between cannabinoids and different medication, knowledge stay missing and there’s no consensus relating to when these interactions grow to be clinically vital. Nonetheless, you will need to perceive how cannabinoids could work together with different medication, and the potential dangers for sufferers on concomitant medicines.
This text highlights clinically related interactions between cannabinoids and customary CV medicines.
Cannabinoids and drug metabolism
Completely different parts of cannabinoids could have an effect on cytochrome P450 (CYP) hepatic isoenzymes, UDP-glucuronosyltransferases (UGT), and P-glycoprotein (P-gp) to various levels. 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 reasonable CYP2C19 and CYP2C9 inhibitor, and has additionally been proven to inhibit P-gp. CBD additionally has the potential to inhibit CYP3A4 and CYP2D6, however its impact was restricted primarily based on pharmacokinetic research. THC has additionally demonstrated inhibition of CYP2C9 by way of in vitro research.
Clopidogrel and CBD
Clopidogrel, an antiplatelet agent, requires CYP2C19 metabolism to transform to its lively thiol metabolite. In vitro research have demonstrated better than 50% inhibition of CYP2C19 at concentrations that may outcome from use of typical CBD doses of 300 mg to 1,500 mg per day. As a result of CBD inhibits CYP2C19 at clinically related concentrations, this interplay could compromise clopidogrel’s antiplatelet exercise, thereby growing threat for CV occasions. It could be helpful to contemplate shut monitoring of indicators and signs of diminished clopidogrel exercise or contemplate another agent comparable to prasugrel or ticagrelor, which don’t depend on CYP2C19 for activation, significantly in those that have undergone current deployment of drug-eluting stents.
Cilostazol and CBD
Cilostazol is one other CV remedy that could be affected by DDIs with CBD, as it’s metabolized to an inactive compound by CYP2C19. CYP2C19 inhibition could result in larger serum concentrations of cilostazol, which can improve the chance of antagonistic occasions like headache, diarrhea, hypotension, tachycardia and potential cardiac arrhythmias. Due to this fact, when utilized in mixture with common CBD, it is suggested to cut back the dose of cilostazol to 50 mg twice every day and monitor medical response carefully.
Warfarin and CBD/THC
As reasonable inhibitors of CYP2C9, each THC and CBD could have an effect on metabolism of S-warfarin, resulting in elevated threat of bleeding. Moreover, CYP2C19 genotypes have additionally been reported to affect clearance of each R-warfarin and S-warfarin. The mixture of genetic polymorphisms of CYP2C9 and CYP2C19 together with hashish drug interactions could have an effect on a affected person’s upkeep dose of warfarin, warranting shut monitoring of INR and dose changes to lower the chance for bleeding.
DOACs and CBD
Whereas CBD has not been instantly proven to have an effect on 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. Quite a few research have highlighted elevated publicity of DOACs when utilized in mixture with P-gp inhibitors. CBD inhibition of P-gp could result in elevated ranges of DOACs, leading to larger threat for bleeding, warranting shut monitoring of those anticoagulants with CBD as effectively.
Digoxin and CBD
Digoxin could work together with CBD by way of inhibition of P-gp, with potential to extend digoxin’s space beneath the curve. As digoxin has a slim therapeutic index, sufferers ought to be monitored sufferers extra carefully. Some sufferers could require a digoxin dose discount by 15% to 30% or a modification of their therapeutic routine.
Calcineurin inhibitors and CBD
Though not particularly a CV remedy, tacrolimus is commonly utilized in sufferers who’re recipients of coronary heart transplants. Tacrolimus is a substrate of each CYP3A4 and P-gp. With conflicting info obtainable, in vitro knowledge counsel that CBD reveals variable inhibition of CYP3A4 and potent, concentration-dependent inhibition of P-gp. One case report advised that sufferers on tacrolimus and concomitant CBD have been at elevated threat for elevated tacrolimus blood ranges and toxicity. Related interactions could happen with CBD and sirolimus or everolimus. Due to this fact, you will need to concentrate on the potential interplay which will affect drug ranges and require upkeep dosage changes.
Dronabinol is an FDA-approved cannabinoid indicated for the therapy of anorexia related to weight reduction in AIDS and nausea and vomiting related to chemotherapy. Primarily based on in vitro research, dronabinol is primarily metabolized by CYP2C9 and CYP3A4. Whereas dronabinol is just not recognized to be a CYP inhibitor or inducer, it’s subjected to elevated systemic publicity with inhibitors of those enzymes (amiodarone, verapamil and diltiazem), which can improve the chance for dronabinol-related antagonistic occasions. When utilized in mixture with inducers of those enzymes, there could also be a lack of efficacy of dronabinol. Moreover, dronabinol could compete with different CYP2C9 substrates, comparable to warfarin. It is suggested to watch sufferers for elevated dangers for antagonistic reactions on slim therapeutic index medication, like warfarin.
Additive CV results with cannabinoids
Though cannabinoids can have an effect on systemic publicity of different medicines, they could even have additive systemic results on CV well being. This may occasionally improve the chance for antagonistic occasions, exacerbations, or problem in illness administration. Cannabinoids could improve sympathetic nervous system results comparable to dizziness, confusion, sedation and somnolence, in addition to CV results together with BP variations, syncope and tachycardia.
Additive results can happen when THC and different substrates CYP3A and CYP2C9, together with sympathomimetics (amphetamines, anticholinergics, norepinephrine) are used collectively, leading to additive tachycardia and hypertension. When used with THC, different CV medicines which can be CYP2C9 substrates could lead to elevated concentrations.
Abstract and suggestions
Total, cannabinoid use has considerably elevated over the previous a number of years. Nonetheless, there are restricted pharmacokinetic and pharmacodynamic knowledge surrounding the drug interactions of cannabinoids, which makes this an necessary space of additional analysis and understanding. Nearly all of details about drug interactions are derived from in vitro research and case reviews. There’s potential for the outcomes of those DDIs to be additive, synergistic or antagonistic for a number of pharmacologic classes, together with CV medicines.
To issue these drug interactions right into a affected person’s pharmacotherapy, we must always ask all sufferers about their use of cannabinoids. Discussions about this subject could also be delicate to sufferers; to encourage sufferers’ self-reporting about cannabinoid use or for any illicit drug, suppliers can put together the affected person by setting the context, asking for info moderately than judgment and normalizing the subject through the use of common statements like: “Many individuals have began utilizing cannabinoid merchandise not too long ago” and proceed together with your query. Moreover, you will need to contemplate cannabinoid dose, in addition to frequent vs. rare use, as power use has been linked to larger concentrations. It could be prudent to counsel sufferers to make use of hashish merchandise that embrace dosages on the packaging. When evaluating for drug interactions, contemplate therapeutic index and substrate specificity of every drug. Warning is really helpful so as to carefully monitor sufferers who make the most of cannabinoids with probably interacting medicines, particularly for medication with slim therapeutic index.
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- For extra info:
- Tamia Jones, PharmD, is a PGY1 pharmacy apply 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 well being sciences medical affiliate professor within the division of medical pharmacy apply at UCI Faculty of Pharmacy & Pharmaceutical Sciences in Irvine, California.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology In the present day Pharmacology Seek the advice of column editor. She is professor and chair of the division of pharmacy companies within the Faculty of Pharmacy and Pharmaceutical Sciences at Binghamton College. Spinler might be reached at email@example.com.