By Miguel Ordoñez

One of the oft-asked questions in regards to health and pharmaceuticals is whether or not cannabis can be mixed with medication. It is, indeed, a valid concern to raise, especially for those who regularly take cannabidiol for whatever purpose. It is understandable that some to argue in support of it, especially when it comes to CBD oil. After all, it’s non-psychotropic and used by thousands every single day, so it should be safe, right?

Well, in case you didn't know, the cannabis plant contains over a hundred chemical compounds. Some of these compounds can react with one another, which cannot be perceived as a major health problem. But the question is, will occur an innocuous reaction when it comes to CBD interacting with other drugs?

This article should provide you with a clear answer, once and for all. Hopefully, the information will be helpful for you down the line.

Can CBD Oil Affect Medication?

Before answering this, let’s first address another important question: how exactly does CBD interact with our bodies?

There is not a simple answer but basically: CBD interfaces with the main receptors in the endocannabinoid system—CB1 and CB2— among other molecular targets, including serotonin and vanilloid receptors. Intriguingly, CBD hinders the breakdown of certain chemicals—including anandamide—that directly affect our mood, pain perception, or some mental functions as the memory.

In doing so, CBD is able to modify the homeostasis (dynamic balance) between our physiological systems. Therefore, the use CBD rich cannabis strains or CBD derivates could be beneficial for some users under some delimitated situations.

However, is important to know that CBD also affects the metabolism of medications, a process that takes place primarily in the liver.

How Does the Body Metabolise CBD?

Cannabinoids, including CBD, are mainly metabolized by the liver, and more exactly by the cytochrome P450 system’s isoenzymes there present. Soon after the ingestion, CBD is then chemically modified and distributed throughout the entire body, where it can trigger a determined reaction after binding to its selective receptors. Unlike this route, when CBD is smoked, it has a first step in the blood stream that avoids the liver. Therefore the effects are produced faster, but they do not last much.

Depending on the dose and administration, CBD can remain in the body for about four weeks. During that time, it is stored within fatty tissues until it is gradually released in small doses back into the bloodstream. From there, cannabidiol is excreted of the body through the renal (aka urinary) and biliary systems.

Now, we mentioned cytochrome P450 enzymes and the vital role they play in metabolising CBD. But, what are they exactly?

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What Is the Cytochrome P450 System?

CBD's interactions with other drugs largely stem from their common metabolizing process and effects produced in the cytochrome P450 system. This group of liver enzymes (isoenzymes) is mainly responsible of modifying toxins, drugs, and other substances in our system. These enzymes basically alter these substances to make them easier to eliminate from the body.

But, when CBD enters the body, the liver may reduce the metabolising rate of other drugs that also rely on cytochrome P450 enzymes.

Albeit temporarily, in some cases, CBD can almost completely block the cytochrome P450 activity, affecting the metabolic activity of compounds found in certain drugs. So, for example, if you’re taking a powerhouse painkiller like oxycodone alongside cannabidiol (CBD), the former may linger in your system for longer and in higher concentrations than expected— which isn’t necessarily a good thing.

What can be problematic is that a drug like oxycodone is only supposed to stay in your system in determinate amounts for a certain period of time. Going beyond that duration may elicit overdoses or increase of side effects like nausea and drowsiness. All this could be an issue if you’re driving a car or operating heavy machinery. At worst, these interactions can also cause other damages to your body.

Drugs CBD Oil Can Interact With

The fact of the matter is, cytochrome P450 enzymes metabolise around 90%[1] of all medications on the market, with two izoenzymes in particular—CYP3A4 and CYP2D6—being responsible for the lion’s share of the work. So, here’s a simplified answer: almost any drug metabolised by cytochrome P450 enzymes will interact with CBD oil. Some of these drug interactions will bear no notable adverse effects, while others will.

Let’s get a little more specific. A 2016 study[2] delved into how CBD reacted with a known anti-seizure medication called clobazam, which is largely used to treat epilepsy among children. This interaction is particularly intriguing, as CBD (in synthetic form, "Epidiolex") has also been approved for treatment-resistant forms of Lennox–Gastaut syndrome and Dravet syndrome.

The study found that cannabidiol slowed down the metabolism of clobazam, which led to a significant increase in plasma levels of medication in the body—around 60–80%. As a result, researchers were able to lower the dose of clobazam administered to the subjects, without sacrificing efficacy. Even more interesting, the drug’s side effects, like insomnia, loss of coordination, drowsiness, and constipation, were all curbed with this lower dose.

  • Pharmacodynamics’ Basics and CBD-Drug Interaction: Examples

A substrate is every substance modified by an enzyme. In respect of drugs, there are two kinds of substrates: the ones that are already active when are ingested, which are simply called drugs (in example THC, the main compound of cannabis) and the ones which require a first to metabolize for them to become active, called pro-drugs (in example psilocybin, which is the pro-drug of psilocin, the main active compound of the “magic mushrooms”).

These substrates usually do not affect the normal activity of the enzyme that metabolizes them. However, there exist other substances that can increase the metabolic activity of the cytochrome P450 enzymes: the enzymatic inducers. Otherwise, there are also other ones that can reduce or even block the normal enzymatic activity: the enzymatic inhibitors. All of them can interact with one another, too.

Kind of substrate Drug Pro-drug
Effect when combined with an enzymatic inhibitor (including CBD) Increase Reduction
Effect when combined with an enzymatic inducer Reduction Increase
Effect when combined with an enzymatic inducer + CBD Variable Variable

Also included are some considerations on whether or not cannabidiol should be used.

Drugs CBD Oil Can Interact With

  • CYP3A4 Substrates

CYP3A4, specifically, is an liver and intestines isoenzyme forming part of the cytochrome P450 that oxidises toxins or drugs for easier excretion from the body.

Some Iimmunosuppressants and antidepressants alongside antipsychotics, calcium channel blockers, and opioids are substrates of this isoenzyme. Also part of these substrates are benzodiazepines, z-hypnotics, statins, and chemotherapeutics.

The risk of side effects, loss of effect or on the contrary, overdose may be increased when in co-administration with CBD – an enzymatic inhibitor. The safest situation is to not combine these drugs until receiving an expert recommendation.

Some medications metabolized by the CYP3A4 iso
Amlodipine Sinvastatin
Haloperidol Citalopram
Fentanyl Cabazitaxel
Zolpidem Tacrolimus

  • CYP34 Inhibitors

Protease inhibitors are antiviral drugs that are usually prescribed to patients diagnosed with HIV. Valproic acid, on the other hand, is a medication used for epilepsy treatment.

These drugs are examples of CYP3A4 inhibitors, and they are quite similar to their substrate counterparts.

When CBD interacts with any of these drugs, its bioavailability—or the bloodstream drug concentration —tends to increase. As a result, the risk of adverse effects may rise.

Experts don’t advice taking CBD alongside these medications, but a reduced dose is recommended, should you decide to combine both medications.

Protease inhibitors and valproic acid are examples of stronger CYP34 inhibitors. Other ones are amiodarone, verapamil, aprepitant, and cimetidine.

Some medications that inhibit CYP3A4 activity
Allopurinol Fluconazole
Amiodarone Fluoxetine
Amprenavir Quinolones
Aprepitant Valproic acid
Atazanavir Erythromycin juice
Chloramphenicol Imatinib
Cimetidine Indinavir
Clarithromycin Isoniazid
Nifedipedine Itraconazole
Tamoxifen Ketoconazole
Cyclosporine Nefazodone
Darunavir Nelfinavir
Dasatinib Ritonavir
Delavirdine Verapamil
Diltiazem Saquinavir
  • CYP3A4 Inducers

Barbiturates are medications used to treat people suffering from seizures. In some cases, they can also be used as a mild, short-term sedative. Enzalutamide, on the other hand, is used for prostate cancer treatment. It is a hormone blocker that prevents testosterone from reaching prostate cancer cells.

These drugs are examples of CYP3A4 inducers. Unlike inhibitors, upon interacting with these drugs, CBD’s bioavailability, along with its effectiveness, decreases. In this case, increasing cannabidiol dose might seem to be logical, however this idea should be not pursued due the intrinsical risks of overdose and side effects when it is combined with some medications.

Other examples of CYP3A4 inducers are detailed in the following table.

Some medications and herbs which induce the CYP3A4 activity
Carbamazepine Omeprazole
Corticosteroids Rifampin
Efavirenz Oxacarbazepine
Rifabutin Phenytoin
Modafinil Primidone
Nevirapine St. John's wort
  • CYP2C19 Substrates

CYP2C19 isoenzyme metabolizes xenobiotics like anti-seizure medications. And, like CYP34 substrates, they could carry some side effects when mixed with CBD.

Similarly, co-administration with cannabidiol isn’t advised, and adverse effects and toxicity need to be monitored closely.

Other examples of CYP2C19 substrates are proton pump inhibitors, antidepressants, antiplatelet drugs, muscle relaxants, and blood thiners.

Some medications metabolized by the CYP2C19 isoenzyme
Aripiprazole (Abilify) Lansoprazole (Prevacid)
Carisoprodol (Soma) Mephenytoin (Mesantoin)
Citalopram (Celexa) Methadone
Clomipramine (Anafranil) Propranolol
Clopidogrel (Plavix) Voriconazole (Vfend)
Clozapine (Clozaril) R-warfarin
Desipramine (Norpramin) Moclobemide (Manerix)
Diazepam (Valium) Nelfinavir (Viracept)
Sertraline (Zoloft) Olanzapine (Zyprexa)
Thalidomide Omeprazole (Prilosec)
Proguanil Pantoprazole (Protonix)
Diphenhydramine (Benadryl) Pentamidine
Doxepin (Sinequan) Phenobarbital
Escitakopram (Lexapro) Phenytoin
Fluoxertine (Prozac) Rabeprazole
Imipramine (Tofranil)
  • CYP2C19 Inhibitors

Those who use anxiolytics are maybe familiar with fluoxetine. It is also used to treat specific mental conditions like depression and even bulimia. Similarly, fluvoxamine is an antidepressant that is mainly used by people with obsessive-compulsive disorder.

These two drugs are primary examples of CYP2C19 inhibitors. As it is with these medications, CBD’s bioavailability could primary increase. The risk of adverse effects may rise as a result, which is why lower CBD doses are advised, despite drugs combination avoidance being a better option.

Other drugs that fall under the CYP2C19 inhibitor category are efavirenz, fluconazole, ketoconazole, and clopidogrel.

Some medications that inhibit CYP2C19 activity
Chloramphenicol Isoniazid
Cimetidine (Tagamet) Moclobemide (Manerix)
Clopidogrel (Plavix) Modafinil (Provigil)
Delavirdine (Rescriptor) Omeprazole (Priosec)
Efavirenz (Sustiva) Oxcarbazepine (Trileptal)
Esomeprazole (Nexium) Ticlopidine (Ticlid)
Felbamate (Felbatol) Voriconazole (Vfend)
Fluconazole (Prozac) Fluconazole (Diflucan)
  • CYP2C19 Inducers

Tuberculosis patients will be greatly familiar with rifampicine. It’s a oral medication used as an antibiotic to treat bacterial infections. Meanwhile, carbamazepine is an anticonvulsant used to treat seizures and neurological pain.

These two drugs are the best examples of CYP2C19 inducers. Theoretically, they could be safer when taken with CBD because, unlike inhibitors, the bioavailability of the cannabinoid decreases upon interaction, resulting in a reduction in effectiveness. In any case, it is not recommend an increase in CBD dose if administered with CYP2C19 inducers.

Other drugs that belong to this category are phenytoin, phenobarbital, and St. John’s wort.

Some medications and herbs that induce CYP2C19 activity
Aminoglutethimide Primidone
Artemisinin Rifampin
Barbiturates Rifapentine
Carbamazepine St. John's wort
  • CYP2C8/9 Substrates

Both CYP2C8 and CYP2C9 enzymes are some of the responsible for metabolising xenobiotics. However, the former can also metabolise polyunsaturated fatty acids.

Therefore there is an increased risk of side effects when combined with CYP2C8/9 inhibitors. Co- administration with CBD isn’t advised, and lower substrate doses to obtain the same CBD effect are neither recommended.

A good example of a CYP2C8 and CYP2C9 substrate is rosiglitazone, a medication for type 2 diabetes. Antihypertensive drug losartan is also part of this list, along with naproxen, celecoxib, rosuvastatin, and sulfonylureas—just to name a few.

Some other medications metabolized by the CYP2C8/9 isoenzyme
Amiodarone (Cordarone) Carbamazepine (Tegretol)
Diclofenac (Voltaren) Paclitaxel (Taxol)
Repaglinide (Prandin) Cabazitaxel (Jevtana)
Chloroquine (Aralen) Ibuprofen (Advil)
Rosiglitazone (Avandia) Treprostinil (Tyvaso)

What Is the Grapefruit Test?

You’ve probably seen the “grapefruit warning” on some of your medications. If you’re taking one of these drugs, you’re advised to avoid consuming any grapefruit and other citrics. But why is that?

Like CBD, grapefruit and other citrics also inhibits cytochrome P450 enzymes, which directly affects the metabolism of these substances. That means consuming grapefruit could modify the dose of the drug or the pro-drug in the bloodstream, which may result in an overdose or in the efficacy’s reduction.

Research shows that more than 85 drugs[3] share this same interaction with grapefruit. Among them are fentanyl, erythromycin, losartan, loratadine, and alprazolam.

If in Doubt, Speak to Your Doctor

So, with all the hype behind it, is it safe to take CBD oil while on medication? If you’ve read through the entire article, the most logical answer would be: it depends on what you are taking, the administration way and in which dose.

Nothing good ever came out by not knowing doses or practicing an excessive use.

But, if you want to be on the safest side, ask your doctor. They can speak to you in lay terms about the effects of these drugs and how CBD may interact with them. This is the best way to obtain sound advice and answers to any questions you may have.

Medical DisclaimerInformation listed, referenced or linked to on this website is for general educational purposes only and does not provide professional medical or legal advice.

Royal Queen Seeds does not condone, advocate or promote licit or illicit drug use. Royal Queen Seeds Cannot be held responsible for material from references on our pages or on pages to which we provide links, which condone, advocate or promote licit or illicit drug use or illegal activities. Please consult your Doctor/Health care Practitioner before using any products/methods listed, referenced or linked to on this website.

External Resources:
  1. The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects - American Family Physician
  2. Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy
  3. Common Grapefruit Juice Drug Interactions -
This content is for educational purposes only. The information provided is derived from research gathered from external sources.

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