Does CBD Interact Adversely With Pharmaceutical Drugs?

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

By Chris D. Meletis, N.D.

Cannabidiol (CBD) has been used safely and effectively in clinical practice in several applications, including supporting the health of patients with epilepsy, pain, anxiety, insomnia, attention deficit disorder, sleep issues, and joint problems. However, doctors and patients should be aware of potential interactions that may occur when taking CBD together with certain pharmaceutical medications. Hemp also contains more than one hundred other cannabinoids and hundreds more botanical compounds that may produce biological effects and potentially interact with medications. In this article, I’ll discuss the mechanism behind CBD’s ability to alter drug metabolism and the potential effects of medications on CBD bioavailability. The article will also address medicines that are of the most potential concern. 

CBD’s Cytochrome P450 (CYP450) Activity

Cytochrome P450are enzymes that metabolize 70% to 80% of all drugs in clinical use.1 CBD can inhibit or induce cytochrome P450 (CYP450) activity.2 It also has effects on isoforms of CYP450 such as CYP3A4/2C19, as well as on P-glycoprotein, which is involved in the excretion of medications.3 CBD also has been found in vitro to affect the activities of other CYP450 isoforms, including CYP3A5/7, 2D6, 2C9, 2A6, 2B6, 1A1, 1A2, 1B1, and 2J2. However, the implications of these interactions have not been established in vivo and their clinical relevance is not certain.3

One in vivo study investigated the potential of drug interaction between CBD and co-administered clobazam, which is a benzodiazepine drug used in patients with seizures.4 Clobazam is metabolized by CYP3A4, CYP2C19, and CYP2B6. Researchers studied 13 children with refractory epilepsy who were taking clobazam and CBD at the same time. Levels of  clobazam and its metabolite N-desmethylclobazam (norclobazam, nCLB) were elevated in patients taking both the medication and CBD. Clobazam levels increased by a mean of 60% and there was a 300% to 500% elevation in nCLB. In order to adjust for the increased level of the drug and its metabolite, researchers decreased the dosage of clobazam in 10 (77%) of the 13 children. Despite the reduced dosage, seizure frequency was reduced. 

According to the study authors, “Monitoring of CLB [clobazam] and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.”

The CYP450 isoforms 3A4 and 2C19 are important to CBD metabolism.1 Certain drugs also inhibit or induce these enzymes.1 Pharmaceuticals that affect these enzymes are likely to be used by people taking CBD who have epilepsy, chronic wasting disease in HIV/AIDS, and cancer. CYP2C and CYP3A isoforms are involved in metabolizing at least 25% to 30% of medications.

Therefore, some scientists believe that there is a high probability of interactions between CBD and these drugs.3  

Medications that inhibit or induce cytochrome P450 isoforms CYP3A4/2C19 or serve as substrates are commonly used acutely and long-term for hypertension, migraine, and heartburn. Because CBD also affects those isoforms, it may interact with those medications.3 

Yet, there are a lot of interindividual differences in the expression and function of CYP450 enzymes.5  These differences may have a significant effect on whether CBD and its metabolites interact with medications.5 Some people are simply slower clearers of medications than others. 

It is also important to note that some of the research in this area was done with Epidiolex, a highly purified prescription form of CBD, which may have different and possibly stronger effects than CBD-rich hemp oil. 

Table 1: Examples of Potential CYP-Mediated Interactions Between Cannabidiol and Some Medications3

Medications Possibly Interacting With CBDCYP Isoform InvolvedAdverse and Beneficial Effects
• Immunosuppressants  • Chemotherapeutics  • Antidepressants • Antipsychotics • Opioids • Benzodiazepines • z-hypnotics • Statins • Calcium channel blockers CYP3A4 substratesEnhances the adverse effects of the medications. Avoid administering CBD together with drugs or reduce medication dose. Monitor patient for adverse effects. 
• Protease inhibitors • Ketoconazole • Loperamide • Nefazodone • Amiodarone • Verapamil • Cimetidine • Aprepitant • ImatinibCYP3A4 InhibitionEnhanced CBD bioavailability. Reduce CBD dose.
• Enzalutamide • Phenytoin • Carbamazepine • Topiramate • Phenobarbital • Rifampicin • Efavirenz • PioglitazoneCYP3A4 InductionDecreased CBD bioavailability, potentially reducing effectiveness of CBD. Increase CBD dose.  
• Antidepressants • Antiepileptics • Proton pump inhibitors • Clopidogrel • Propranolol • Carisoprodol • Cyclophosphamide • WarfarinCYP2C19 substratesIncreased risk of drug side effects. Avoid administering with CBD or reduce dose of drug. Monitor for adverse effects.
• Fluvoxamine • Fluoxetine • Proton pump inhibitors • Cimetidine • Ketoconazole • Clopidogrel • Fluconazole • EfavirenzCYP2C19 InhibitionIncreased bioavailability of CBD. Use lower dose of CBD.
• Rifampin • Carbamazepine • Phenobarbital • PhenytoinCYP2C19 InductionReduced bioavailability of CBD, potentially decreasing its effectiveness. Increase dose of CBD.
• Rosiglitazone • Burprenorphine • Montelukast • Celecoxib • Sulfonylureas • Losartan • Naproxen • Phenobarbital • Phenytoin • Rosuvastatin • Valsartan • WarfarinCYP2C8/9 SubstratesPossible increased risk of side effects from medications. Avoid administering CBD with these drugs or reduce dose of drugs. Monitor patient for adverse effects. 

Non-Cytochrome P450 Interference With Drug Metabolism

CBD may impact the metabolism of medications through means beyond its effects on CYP450 enzymes. For example, CBD inhibits uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes such as UGT1A9, and UGT2B7.3 UGT enzymes play an important role in phase II metabolism and are important in the excretion of drugs. CBD’s inhibition of UGTs decreases excretion of the drug.3 An in vitro study using ethanol indicated CBD produced a 49% reduction in UGT1A9 activity and a 70% reduction in UGT2B7 activity, although the clinical importance of this has not been established.3 Medications associated with UGT1A9/2B7 include acetaminophen, naproxen, and ibuprofen as well as common medications used by people who take CBD such as tapentadol, canagliflozin, sorafenib, regorafenib, propofol, valproic acid, and mycophenolate. Brown and Winterstein state, “CBD should be used with caution in patients stabilized on or newly initiating these medications and side effects related specifically to the substrate’s toxicities should be monitored given UGT inhibition will decrease their excretion and increase bioavailability.”

Table 2: Examples of Potential UGT-Mediated Interactions Between Cannabidiol and Some Medications3

Medications Possibly Interacting with CBDUGT Isoform InvolvedAdverse Effects
• Regorafenib • Acetaminophen • Canagliflozin • Sorafenib • Irinotecan • Propofol • Mycophenolate • Valproic acid • Haloperidol • Ibuprofen • Dabigatran • DapagliflozinUGT1A9Increased risk of drug-related side effects. Avoid administering drugs with CBD or reduce the dose of drug. Monitor patient for adverse effects. 
• Hydromorphone • Losartan • Ibuprofen • Naproxen • Ezetimibe • Lovastatin • Simvastatin • Carbamazepine • ValproateUGT2B7Increased risk of drug-related side effects. Avoid administering drugs with CBD or reduce dose of drug. Monitor patient for adverse effects.

The Role of Food in CBD and Drug Metabolism

CBD is not the only substance that interferes with drug metabolism. Even common foods can alter the metabolism of drugs. The best known instance of this is grapefruit juice, but other foods and juices can alter the metabolism of medications. For example, one study found 22 juice-drug combinations that could potentially alter drug metabolism either beneficially or adversely.6 For example, orange juice had a beneficial effect on ferrous fumarate absorption while apple juice interfered with the bioavailability of fexofenadine, atenolol, and aliskiren. For a more extensive list of foods and beverages that alter drug metabolism, see tables 3 and 4.  

Table 3: Potential Beneficial Interactions Between Juices and Medications6

JuiceBeneficial Drug Interaction (Beneficially Increases Bioavailability)
Orange JuiceFerrous fumarate
Lemon Juice99mTc-tetrofosmin
Pomegranate JuiceIntravenous iron during hemodialysis
Cranberry JuiceTriple therapy medications for H. pylori
Blueberry JuiceEtanercept
Lime JuiceAntimalarials
Wheat Grass JuiceChemotherapy drugs

Table 4: Potential Reactions Between Foods, Beverages, or Botanicals and Medications6-8

Food, Beverage, or BotanicalAdverse Drug Interaction
Orange JuiceAliskiren, atenolol, celiprolol, montelukast, fluoroquinolones, alendronate (Decreased drug bioavailability) Felodipine (Seville orange juice), aluminum-containing antacids (Increased drug bioavailability)
Apple JuiceFexofenadine, atenolol, aliskiren (Decreased drug bioavailability)
Grape JuiceCyclosporine (Decreased drug bioavailability)
Pomelo JuiceSildenafil (Decreased drug bioavailability), Cyclosporine (Increased drug bioavailability)
Grapefruit JuiceStatin drugs, fexofenadine, calcium channel blockers, psychiatric medications (buspirone, triazolam, diazepam, sertraline), cyclosporine, tacrolimus, methadone, sildenafil, saquinavir, amiodarone (Increased drug bioavailability)  
St. John’s WortAmitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, methadone, midazolam, nevirapine, phenprocoumon, simvastatin, tacrolimus, theophylline and warfarin (Decreased drug bioavailability)
CheeseTranylcypromine (MAO inhibitor). Causes high tyramine levels leading to hypertension
Garlic ExtractParacetamol, chlorzoxazone, anaesthetics, calcium channel blockers, chemotherapy agents, antifungals, glucocorticoids (Increased drug bioavailability)
Dairy ProductsCiprofloxacine, tetracycline (Reduced drug bioavailability)

Foods also can impact the absorption of CBD. When CBD is administered with food or when a meal is eaten shortly after taking CBD, plasma levels of CBD are higher.9 In rodents, consuming CBD with fats was associated with a nearly 3-fold increase in systemic availability.

Conclusion

As a clinician, I adhere to the clinical rule of “start low and go slow,” which serves clinicians well when adding or removing medications and nutraceuticals. As reviewed in this discussion, even foods can interfere with medication metabolism.  This article is designed to merely reaffirm the importance of vigilance when changing a patient’s diet or nutraceuticals when relative to prescription medication.  

There is potential for interaction between CBD and certain medications. In some cases, these interactions can increase the bioavailability of CBD, permitting a reduced cannabidiol dosage. In other cases, the interaction may lead to increased or reduced bioavailability of the pharmaceutical medications. This may lead to adverse effects or ineffective amounts in the body. Some of this information is hypothesized from CBD’s known effects on the cytochrome P450 drug-metabolizing enzyme as well as its effects on other factors involved in drug metabolism. In other cases, rodent or human studies have demonstrated an effect of CBD on drug metabolism or a medication’s ability to increase or decrease CBD levels. However, drug interactions vary based on the disease state of patients, genetic predisposition for reduced or increased drug metabolism, or foods consumed. Nevertheless, it is prudent for healthcare practitioners to monitor their patients who are taking CBD together with pharmaceutical medications. 

References:

  1. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation.  Pharmacol Ther. 2013 Apr;138(1):103-41.
  2. Jiang R, Yamaori S, Takeda S, et al. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011 Aug 1;89(5-6):165-70. 
  3. Brown JD, Winterstein AG. Potential Adverse Drug Events and Drug–Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use. J Clin Med. 2019 Jul;8(7):989. 
  4. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015 Aug;56(8):1246-51. 
  5. Ujváry I, Hanus L. Human metabolites of cannabidiol: A review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res. 2016;1(1):90-101. 
  6. Chen M, Zhou SY, Fabriaga E, et al. Food-drug interactions precipitated by fruit juices other than grapefruit juice: An update review. J Food Drug Anal. 2018 Apr;26(2S):S61-71. 
  7. Alsherbiny MA, Li CG. Medicinal Cannabis—Potential Drug Interactions. Medicines (Basel). 2019 Mar;6(1):3. 
  8. Koziolek M, Alcaro S, Augustijns P, et al. The mechanisms of pharmacokinetic food-drug interactions – A perspective from the UNGAP group. Eur J Pharm Sci. 2019 Jun 15;134:31-59.
  9. Millar SA, Stone NL, Yates AS, O’Sullivan SE. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans.Front Pharmacol. 2018 Nov 26;9:1365.