Studies have shown CBD to be a safe substance, but as with any new drug, you must make sure it doesn’t negatively interact with other medications.
By Dr. Dustin Sulak
November 5, 2021
Originally published on University Health News
Cannabidiol (CBD) is a well-known component of hemp with diverse health benefits such as reducing pain and inflammation after physical activity, relief from occasional sleeplessness, as well as improvements in focus, mood and resilience to stress.
Numerous studies have shown that CBD is a safe, non-impairing, and non-habit-forming substance. The safety profile of CBD has been acknowledged by major health agencies, such as the World Health Organization (WHO), showing that it’s well-tolerated by animals and humans and rarely produces any dangerous side effects.
However, while CBD is safe to take with many medications, it has the potential to produce problematic interactions with others. Most often, CBD interacts with other drugs via liver metabolism.
In this article I’ll explain how and why these interactions occur and describe the classes of medications that are processed by the same liver enzymes the body uses to process CBD.
The key takeaways for you to remember are:
- CBD is unlikely to cause drug interactions at low and moderate doses used by most consumers of artisanal products. Drug interactions reported in the scientific literature most often occur at very high doses used in clinical trials of epilepsy and other conditions.
- The most important drug interactions can be predicted by comparing the CYP450 metabolic pathways used by CBD and other drugs.
- You can help educate your medical providers on drug interactions and other aspects of CBD and medical cannabis by using the information you’ve learned from this article and our cannabis education site to ask informed questions.
How Do CBD Drug Interactions Occur?
There are two main types of drug interactions: those that change the absorption, metabolism, and excretion of one or both drugs (pharmacokinetic interactions), and those based on the mechanism of action of the drugs (pharmacodynamic interactions). Since cannabinoids, including CBD, share metabolic pathways with other drugs, and have similar mechanisms of action with other drugs, the potential for interaction exists. Most of the clinically relevant interactions of CBD with other drugs are related to competition in the liver’s detoxification pathways. Sometimes the combination can make each substance stronger, by slowing metabolism and increasing the levels of the drugs in the body, or one can weaken the effects of the other by speeding up its metabolism. Either can lead to unintended side effects.
Of the 50+ liver enzymes that make up the CYP450 family of drug-metabolising enzymes, two are primarily responsible for metabolizing CBD: CYP3A4 and CYP2C19. Knowing these can allow you or your healthcare provider to look up the metabolism of a pharmaceutical drug and determine if a CBD-drug interaction is possible.
Most of the documented CBD-drug interactions in humans, as well as in rodent studies, have resulted from high doses of CBD that are not typical of most users, but may be used under medical supervision in the treatment of seizures or other serious conditions.
In general, most of the potential drug interactions are theoretical and unlikely to occur in most CBD users. Based on my clinical experience, it is rare for people to experience CBD-drug interactions at doses below 100mg daily.
Most Common CBD Drug Interactions
CBD and Warfarin and other blood thinners
I’m most often asked about interactions that can occur with the blood thinner warfarin (also known as by the brand names Coumadin® and Jantoven®). The more accurate concern with warfarin is its interaction with THC because both warfarin and THC are metabolized by the liver enzyme CYP2C9. When warfarin and THC compete for processing by this enzyme, warfarin levels can increase and thereby increase the risk of bleeding. Patients using warfarin need to have their blood INR level tested after adding THC-containing cannabis to their regimen.
While it is possible that taking large amounts of CBD with warfarin or other blood thinners can cause a harmful interaction, the risk is less concerning because the enzyme that metabolizes CBD (CYP2C19) is different. One case report, however, was published demonstrating the need to adjust warfarin dosage after starting and titrating CBD to a very high dose.
Based on this one report, individuals using high doses of CBD concurrently with warfarin should also notify their medical provider and have their blood INR tested. In my clinic, I have never seen any changes in INR when my patients add CBD.
There is also a theoretical interaction between CBD and the direct-acting oral anticoagulants like apixaban and rivaroxaban, based on the CYP3A enzyme (and P-gp efflux transporter), potentially increasing the risk of bleeding. While no cases of interactions between CBD and these drugs have been reported in the scientific literature, people using these drugs and high doses of CBD should monitor for signs of easy bruising and bleeding.
Finally, the antiplatelet drug clopidogrel is metabolized into its active metabolite by CYP2C19, and to a lesser extent, CYP3A4. Therefore, taking CBD with clopidogrel could result in decreased therapeutic effects of the clopidogrel, and clinicians may choose to monitor for appropriate platelet response and aggregation. Again, this interaction is theoretical, with no case reports in the scientific literature.
CBD and Seizure Disorder Medications
Drug interactions with CBD are most common in patients with seizures, especially those using high doses of CBD. When administered with CBD, the blood levels of the following drugs may increase:
- n-des-methylclobazam (an active metabolite of the drug clobazam)
Patients combining CBD with the seizure drug valproic acid should monitor liver function for potential abnormalities.
CBD and Statin Cholesterol Medications
Statins are a common family of drugs to consider for interaction with CBD because most are processed by the CYP3A4 enzyme. Taking CBD with statins can theoretically raise the levels of statins in the body, increasing the risk of side effects. Additionally, statins are less compatible with CBD because statins tend to cause side effects that are common and similar to the symptoms we tend to treat with CBD. For example, most statin drugs can cause memory issues, muscle pain, fatigue and muscle weakness.
Because I treat a large number of patients with chronic pain, who are already are taking the maximum allowed daily dose of their statin, I frequently discuss alternatives with their prescriber, including switching to pravastatin, a statin that is metabolized by other routes, reducing the amount of the current statin, or adding coenzyme Q10 to mitigate potential statin-related adverse effects.
CBD and Erythromycin and Azole Antifungals
The antibiotic erythromycin and the azole family of antifungals are common medications that inhibit CYP enzymes that metabolize CBD. Taking them together could theoretically increase the risk of adverse effects.
CBD and Antidepressant Drugs
Several antidepressant and antipsychotic drugs are metabolized by the same enzymes as CBD, and taking them in combination could theoretically increase the likelihood of adverse effects. In six patients on citalopram or escitalopram, the addition of CBD (200 – 800 mg daily) significantly increased citalopram blood concentrations. Adverse events reported for these participants were mild and included fatigue, diarrhea, and nausea.
Furthermore, like many antidepressants, CBD stimulates serotonin receptors, and taking more than one drug with this mechanism of action could theoretically increase the risk of a rare condition called serotonin syndrome. No case reports of this interaction have been described in the scientific literature.
CBD and Immunosuppressant Medications
CBD has the potential to affect the metabolism of the immunosuppressant drugs cyclosporine and tacrolimus via liver metabolism, which may result in increased blood levels of these drugs and an increase in the potential toxic side effects.
CBD and Glaucoma
Glaucoma is still the first condition many people think of when they consider cannabis as a medicine. The evidence is clear that THC can reduce elevated intraocular (eye) pressure (IOP), a hallmark of the condition.
Does CBD also help? While the answer is not entirely straightforward, the evidence suggests that it does not, and may actually cause harm.
- A recent animal study found that, unlike THC, CBD actually raised intraocular pressure. The researchers determined the pressure elevation was caused by the effects of CBD on the CB1 receptor (negative allosteric modulation). The same study found that adding CBD to THC completely blocked the IOP-lowering effects of the THC.
- One human study on patients with elevated IOP found that 20 mg of CBD had no effect, but 40mg caused a slight increase in IOP.
Unlike CBD, CBDA is not likely to have any impact on IOP since it does not share CBD’s activity on the CB1 receptor.
If you have glaucoma and start using CBD products, I recommend having your eye pressures checked to determine if the CBD is causing elevated pressure.
People with glaucoma wishing to use cannabis to lower their IOP will likely do best with THC-dominant, low-CBD preparations. People with glaucoma who wish to use hemp products to address other symptoms will likely do best with CBDA formulas.
People with glaucoma who have well-controlled IOPs wishing to use cannabis to protect the retina are most likely to benefit from a combination of CBD and THC.
Talk with Your Doctor Before CBD Use
If you take several different medicines, see more than one doctor, or have certain health conditions, you and your doctors need to be aware of all the medicines you take to avoid potential drug interactions.
A consultation with a doctor experienced in CBD and cannabis use can help you establish the right routine for your medications and supplements to avoid potentially negative interactions. Some compounds work synergistically with CBD, so asking your doctor can help you maximize the effect of your treatment.
Use online drug interaction checkers to see which cytochrome p450 enzymes are used. If they overlap with CBD (You may have to enter “Epidiolex” if it does not recognize cannabidiol), then monitor more closely and be sure to tell your medical provider. The need for caution increases with higher doses. Using small amounts poses a very low risk of drug interactions.
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