A doctor holding out a CBD oil bottle and a CBD capsule - CBD drug interactions concept

CBD is one of over 100 different cannabinoids, which are the active ingredients in cannabis plants (1). It is also one of the major compounds in the plant (next to THC), and the best researched one to date.

The popularity of CBD is reaching an all-time high due to its wide range of health benefits as well as its ability to alleviate plenty of symptoms effectively and with few side effects. Unlike its intoxicating cousin THC, CBD doesn’t have high-inducing properties, so you won’t get buzzed after taking CBD oil as long as it contains no more than 0.3% of THC.

The vast majority of researchers, as well as numerous health organizations, have acknowledged CBD as generally safe to use. According to studies, doses as high as 1,500 mg of CBD daily are well tolerated by humans.

However, despite its excellent safety profile and remarkable wellness value, CBD is also known to interact with pharmaceutical substances due to its effect on drug metabolism.

How does CBD interact with medications? Which pharmaceuticals should be avoided? Finally, what’s the best time of the day to take CBD without causing negative cross-reactions?

Today we leave no stone unturned.

Everything You Need to Know About CBD Drug Interactions

Research says CBD has over 65 molecular targets. Some of them rely on specific receptors, others take a receptor-free route, but the fact is CBD works on many levels in the body. That’s why it offers so many benefits. On top of that, CBD modulates the endocannabinoid system (ECS) — the master regulatory network in humans and all vertebrae.

CBD also affects different enzymes in the body, including those in the liver. As with everything we ingest, CBD is metabolized by this organ before being released into the bloodstream.

Let’s take a look at the relationship between CBD and drug metabolism to get a better understanding of the CBD-induced drug interactions.

Understanding CBD Effects on Metabolism

Metabolism with Fruit and Other Foods

Before we elaborate on how CBD interacts with medications, first we need to get a good grasp of the body’s metabolism, the systems involved in metabolizing drugs, how CBD is processed, and how it affects a group of enzymes known as the Cytochrome P-450.

What Is Metabolism?

When you think of metabolism, you probably associate it with people’s ability to gain and lose weight, often using terms like “fast” or “slow” metabolism. From a scientific standpoint, this is known as the basal metabolic rate or the number of calories required by individuals to sustain normal body functions while not engaging in physical activity.

However, the basal metabolic rate isn’t the same as metabolism — the way in which different compounds from food are processed and used by the body. Much of this process takes place in the gut and the liver; this phenomenon is known as the “first-pass effect” or first-pass metabolism.”

In simple terms, when you eat food, your liver breaks it down into its individual compounds so they can be effectively used by the body. For instance, proteins are broken down into amino acids, fats into triglycerides, and carbohydrates into sugars. Then, the metabolism, controlled by chemicals known as enzymes, transforms these compounds into metabolites that can be used for a variety of purposes, such as building blocks for various systems and tissues or as fuel for cellular processes.

The metabolism of CBD follows the same pattern. When you take CBD, either as an oil, capsule, or edible, it has to be broken down in the digestive system where it is absorbed into the bloodstream by the gut. From there, CBD enters the liver through the hepatic portal. Once in the liver, CBD is broken down into its metabolites by enzymes.

This is how CBD starts circulating through the body in the bloodstream.

Drug Metabolism and CYP450 Enzymes

Aside from breaking compounds down into metabolites, the liver has one other substantial role during metabolic processes; it detoxifies and excretes foreign drugs (xenobiotics) and other types of toxic compounds.

This role can be performed thanks to a system called cytochrome P450 (CYP450) which is made of a special group of enzymes capable of using heme as a cofactor to turn fat-soluble compounds into more water-soluble compounds, improving their absorption and efficacy (2).

According to various estimates, the CYP450 enzymes are responsible for metabolizing over 60% of the available drugs. Doctors and researchers use them to understand, predict, and calculate drug dosages, as well as their potential adverse reactions.

For example, if only one active ingredient is being processed by the liver — and the CYP450 system works correctly — researchers can use the average amount of time it takes for the medication to be processed through the CYP450 enzymes to predict a safe and effective dosage range.

However, certain substances that we take have the ability to compromise the activity of the CYP450 system — CBD is one of them. The cannabinoid affects the way in which the enzymes in the liver metabolize compounds. It can speed up or slow down their metabolism depending on the type of interaction.

How Does CBD Affect the Cytochrome P450 System?

P450 Cytochrome Molecular Structure
The molecular structure of cytochrome P450

As mentioned, CBD directly interacts with the CYP450 system in the liver. According to preclinical studies, the way in which CBD engages with these enzymes is through “competitive inhibition,” displacing its chemical competitors, and thus blocking the CYP from metabolizing other substances (3).

The potency of CBD’s inhibitory effects on the CYP450 system depends on how much CBD is ingested, the unique body chemistry of the user as well as the type of CBD product (e.g. full-spectrum CBD extracts vs CBD isolate). These factors determine how tightly CBD binds to the active site of the liver enzyme; the tighter the bonds, the more competitive the inhibition.

In plain English, this means that CBD out-competes other metabolized substances when it comes to reaching the first place in the liver. This means that CBD diminishes the effect of all other compounds that pass through the CYP450 system.

The rate of success in ints competition with medications depends on a few factors, but mostly on the dose of CBD that ends up in the bloodstream. If you don’t use large amounts of CBD oil, it will have little to no real effect on the CYP450 activity and most of the medicine will be metabolized. On the other hand, if you take a large dose of CBD, it will affect the site of enzyme activity to a greater extent, preventing the metabolism of the medicine.

Why Does CYP450 Matter When It Comes to CBD and Medications?

The influence of CBD on the CYP450 system changes the way in which certain drugs are metabolized and also prevents a lot of the drug from being processed in the liver. This, in turn, may lead to increased concentrations of your medicine, carrying a risk of unwanted side effects such as weakened immune system, bleeding, but most importantly, it can result in an overdose.

What Drugs Should Not Be Taken with CBD?

Any medication that is metabolized by the CYP450 system has the potential of being diminished due to the use of CBD. One indication that your medicine may interact with CBD is if your pharmacist tells you not to use St. John’s Wort or goldenseal, or to eat grapefruit. However, this isn’t solid proof and you should always check with your doctor if you want to avoid potentially negative interactions.

List of Drugs

As reported by the researchers from the Indiana University Department of Medicine, pharmaceutical drugs and medications that shouldn’t be taken with CBD include (4):

  • Anesthetics such as barbiturates, amobarbital, methohexital, thiamylal, etomidate., ketamine, and propofol
  • Angiotensin II Blockers such as azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan
  • Antibiotics such as amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole-trimethoprim, amoxicillin-clavulanate, and levofloxacin
  • Antiarrhythmics such as amiodarone, flecainide, procainamide, propafenone, quinidine, and tocainide
  • Anticonvulsants such as acetazolamide, carbamazepine, clobazam, clonazepam, ethosuximide, fosphenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, methsuximide, nitrazepam, oxcarbazepine, paraldehyde, phenobarbital, phenytoin, primidone, topiramate, valproic acid, vigabatrin, felbamate, tiagabine hydrochloride and zonisamide
  • Antidepressants such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine, and vilazodone
  • Antihistamines such as brompheniramine, cetirizine, chlorpheniramine, clemastine, diphenhydramine, fexofenadine, and loratadine
  • Antipsychotics such as aripiprazole, asenapine, cariprazine, clozapine, lurasidone, olanzapine, quetiapine, risperidone and ziprasidone
  • Beta-blockers such as acebutolol, atenolol, betaxolol, betaxolol, bisoprolol fumarate, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, propranolol, sotalol, and timolol
  • Benzodiazepines such as alprazolam, clobazam, clonazepam, clorazepate, chlordiazepoxide, diazepam, estazolam and lorazepam
  • Calcium channel blockers such as amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil
  • HIV antivirals such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir alafenamide and disoproxil fumarate as well as zidovudine
  • HMG CoA reductase inhibitors (statins) such as atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, simvastatin, and rosuvastatin
  • Immune Modulators such as immune globulins, immunosuppressive agents, and immunostimulants for example bacterial and viral vaccines
  • Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin
  • Oral Hypoglycemic Agents such as sulfonylureas, meglitinides, biguanides, thiazolidinediones, α-Glucosidase inhibitors, DPP-4 inhibitors, SGLT2 inhibitors, and cycloset
  • Prokinetics (motility drugs) such as domperidone, metoclopramide, levosulpiride, renzapride, and prucalopride
  • Proton-Pump Inhibitors (PPIs) such as omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole and dexlansoprazole
  • Steroids and corticosteroids such as hydrocortisone, cortisone, prednisone, triamcinolone, and dexamethasone
  • Sulfonylureas such as Glynase, Micronase, Amaryl, Diabinese, Glucotrol, Tolinase, and Tolbutamide

There’s also another class of medications known as “prodrugs” that first need to be processed into its therapeutic compounds as opposed to being a therapeutic substance itself (like the majority of medications). Simply put, first, you ingest the inactive ingredient, and once in the body, it gets processed into its active form (5).

If this type of drug metabolism relies on the CYP450 system, inhibitors like CBD can lead to insufficient amounts of the active drug compound circulating in the body. This, in turn, may cause a subtherapeutic effect.

Some of the commonly known prodrugs include lisdexamfetamine and codeine. The latter is metabolized into morphine.

Safety & Side Effects: What Are the Consequences of CBD-drug Interactions?

Woman Consults a Pharmacist

Taking CBD with one of the drugs we’ve mentioned above could lead to unpleasant side effects, including severe ones such as overdose. Although it’s recommended to err on the side of caution, not all of the medication categories from the said list will interact with CBD. This is, of course, by no means an exhaustive list; there are a lot more medications out there that could compete with CBD in the liver.

If you’re concerned about the potential CBD-drug interactions, we encourage you to visit a holistic doctor experienced in CBD and cannabis use in general. Doing so will help you not only avoid these interactions but also establish the right dosage for your situation. The doctor can also help you adjust the doses of both so that you can take them simultaneously without dangerous side effects.

Final Thoughts: Why You Should Pay Attention to CBD Interactions?

CBD itself has an excellent safety profile. Studies are continuously showing that it has no life-threatening side effects and is well tolerated in doses of up to 1,500 mg daily for several weeks. CBD is also a compound that profoundly affects the activity of many systems within the body — hence its wide range of health benefits (6).

For the same reason, CBD should be consumed with care and respect if you take any medications. That’s because CBD inhibits other compounds from being properly metabolized; these effects derive from CBD’s interaction with the CYP450 system, which is a group of enzymes that break down the active ingredients in pharmaceutical medications.

Taking CBD with your medications may result in a negative interaction, causing either a subtherapeutic effect or substance toxicity, both of which are anything but desired. Given this, CBD’s potential to interact with drugs should be discussed with a physician in order to avoid the above reactions.

References:

  1. Pertwee, Roger G. “Cannabinoid pharmacology: the first 66 years.” British journal of pharmacology vol. 147 Suppl 1,Suppl 1 (2006): S163-71. doi:10.1038/sj.bjp.0706406
  2. McDonnell, Anne M, and Cathyyen H Dang. “Basic review of the cytochrome p450 system.” Journal of the advanced practitioner in oncology vol. 4,4 (2013): 263-8. doi:10.6004/jadpro.2013.4.4.7
  3. Bornheim, L M et al. “Characterization of cannabidiol-mediated cytochrome P450 inactivation.” Biochemical pharmacology vol. 45,6 (1993): 1323-31. doi:10.1016/0006-2952(93)90286-6
  4. Flockhart, A.D. “Drug Interactions: Flockhart Table.” Retrieved from: https://drug-interactions.medicine.iu.edu/MainTable.aspx
  5. Waller, D G, and C F George. “Prodrugs.” British journal of clinical pharmacology vol. 28,5 (1989): 497-507. doi:10.1111/j.1365-2125.1989.tb03535.x
  6. Iffland, Kerstin, and Franjo Grotenhermen. “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” Cannabis and cannabinoid research vol. 2,1 139-154. 1 Jun. 2017, doi:10.1089/can.2016.0034
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