Cannabidiol, or CBD, is one of over a 100 different types of a specific kind of compound called phytocannabinoids found in the Cannabis sativa plant.
CBD is has become increasingly popular in recent years due to its wide range of therapeutic effects as well as its ability to relieve a host of symptoms effectively , but also to do so safely and with few side effects. And unlike tetrahydrocannabinol (THC), the other most abundant phytocannabinoid found in the cannabis plant, CBD is non-intoxicating and non-psychoactive – something that for many people is an undesirable yet unavoidable part of taking a high-THC containing cannabis extract.
CBD is most widely known and has been popularized as being used for seizure disorders such as epilepsy, but has also proven to be effective in helping to relieve the symptoms of other conditions. These include anxiety, depression, schizophrenia, inflammatory and neuropathic pain, Parkinson’s disease, Crohn’s and other forms of inflammatory bowel disease, as well as certain types of cancer.
However, despite the fact that the vast majority of the science indicates CBD oil is safe to use on its own, CBD is a powerful compound that interacts with a variety of systems within the body. And as such, CBD not only shows potential as a powerful therapeutic agent, but can become less benign when taken together with other substances such as pharmaceutical drugs.
Let’s find out why.
Before we take a look at how CBD interacts with medications, first we need to understand how the body’s metabolism works in general, the systems involved in CBD metabolism, how CBD is metabolized and how CBD affects something called the Cytochrome P-450 system.
What Is Metabolism?
A lot of people think of metabolism in terms of how easily or slowly they gain and lose weight, often claiming to have a “fast” or “slow” metabolism. In scientific terms, this is what is known as the basal metabolic rate, or the amount of calories an individual requires in order to sustain normal body functions while at rest.
However, this basal metabolic rate is very different to metabolism – the way in which substances such as different types of food are broken down and used by the body – with much of this process happening in the gut and the liver in what is known as the ‘first-pass effect,’ or ‘first-pass metabolism’.
Explained very simplistically, when food is eaten, it is broken down by the liver into its individual compounds in order for it to be used by the body. So, for example, carbohydrates are broken down into sugars, fats into triglycerides, and proteins into amino acids. From there, the metabolism, under the control of chemicals called enzymes, transforms these compounds into metabolites that can then be used by the body, for instance as fuel for cellular processes or as building blocks for various systems and tissues.
Metabolism of CBD
Just like food has to go through this process, so too does a therapeutic compound such as CBD, but in what is more specifically called drug metabolism. Drug metabolism refers to the rate at which medications and other therapeutic compounds are broken down by the body into its individual metabolites and how long these metabolites stay in the body.
So, when CBD is ingested by mouth, either as an oil, tincture, capsule or edible, it has to pass through the digestive system where it is absorbed into the bloodstream by the intestines. From there, the CBD is transported by the blood to the liver where it enters the liver via the hepatic portal. Once the CBD is in the liver, it is broken down into its metabolites by enzymes, after which it can be circulated throughout the body in the bloodstream.
The Cytochrome P450 System
However, in addition to breaking compounds down into metabolites, is also has one other very specific and important role it plays during this metabolic process – the detoxification and excretion of foreign drugs (called xenobiotics) and other types of toxic substances.
It does through a system called the cytochrome P450 system (CYP) which consists of a special group of enzymes containing heme as a cofactor to convert fat-soluble compounds into more water-soluble compounds and aiding in their absorption and use.
It is estimated that the CYP system is responsible for metabolizing over 60% percent of any drug that has been consumed. And interestingly, pharmaceutical researchers and doctors also use cytochrome P450 system to understand, calculate and predict drug dosages effects as well as its potential side effects.
For instance, if only one therapeutic compound is being processed by the liver, and the system in general is healthy, scientist can use the average amount of time it takes for the drug or medication to be processed through the CYP to calculate accurate dosage information.
However, there are certain substances that have the ability to affect the way in which the CYP system processes compounds such as CBD that cause certain drugs to metabolize faster or slower than what they would normally have done.
CBD And The Cytochrome P450 System
As mentioned, CBD also has the ability to interact directly with the CYP system in the liver. Preclinical research is showing that the way in which CBD does is by binding to the site where the enzyme activity occurs acting as a “competitive inhibitor”, displacing its chemical competitors, and thus preventing the CYP system from metabolizing other compounds.
The extent to which CBD acts as a competitive inhibitor of the cytochrome P450 binding proteins is mainly dependent on how much CBD is ingested, the unique physiology of the individual as well as the type of CBD product used (e.g. CBD isolate vs. full-spectrum CBD extracts). This is due to these factors determining how tightly the CBD molecules bind to the active site of the metabolic enzyme, with increased and tighter bonds resulting in more competitive inhibition.
What this means in plain English is that CBD sort of “outcompetes” other medications when it comes to reaching first place for getting metabolized by the CYP enzymes. This, in essence, means that CBD deactivates the effects of all the other therapeutic compounds that pass through the CYP system.
How successful it is in its competition with other medicines depends on a few factors, but mostly the amount of CBD that enters into the bloodstream. If it’s not very much, it will have very little to no noticeable effect on the CYP activity and the majority of the medicine will be metabolized. On the other hand, if a large dose of CBD is taken, it will bind to a lot more of the site of enzyme activity and leave a lot more of the other medicine to not be metabolized.
Why CBD’s Competitive Inhibitory Effect On The Cytochrome P450 System Is Important
When the CYP system is affected in this way by CBD, it both changes and the way in which certain other drugs are metabolized as well as prevent a lot of the drug to be metabolized. When this happens, it leads to higher levels of other drug compounds to remain in the body at a single time.
At the very least these elevated concentrations can cause unwanted side effects like an increased risk of bleeding or a suppressed immune system, but more worryingly, it can quite easily result in an overdose.
CBD and Drug Interactions: Contraindications
As mentioned, and contrary to popular belief and anecdotal evidence, CBD is not a biologically inert compound. Rather, CBD has a complex pharmacokinetic and pharmacodynamic profile similar to any other medication, and has the potential to interact with other medications and medical conditions.
For instance, any therapeutic compound that is metabolized by the CYP system has the potential of being affected by CBD. One indication that your medicine might be metabolized by the CYP system is if your pharmacist told you not to eat grapefruit, or watercress or use St. John’s Wort or goldenseal supplements. However, this is by no means a solid test and you should always check with your pharmacist of doctor first (more on that later).
This, along with the rise in the popularity of the medical and complimentary use of CBD, researchers are also starting to investigate drug interactions with CBD more directly.
CBD and Drug Interactions in Studies
For instance, the CBD based drug, EPIDIOLEX® approved in the United States for seizures associated with Lennox‐Gastaut and Dravet syndromes, is increasingly either being used as a supplementary treatment, or even replacing the traditionally used anti-epileptic drugs clobazam, and valproate, as well as stiripentol, topiramate, rufinamide, and N‐desmethylclobazam respectively.
CBD and anti-epileptic drugs
This has spurred researchers to investigate whether there are drug–drug interactions (DDIs) and/or adverse drug events (ADEs) between these traditionally used anti-epileptic drugs and CBD. Data showed that, although there were no serious ADEs, deaths, or pregnancies during the trial, most subjects reported some ADEs of mild severity, while 10.4% subjects reported moderate ADEs, and 2.6% subjects reported severe ADEs, with severe events being characterized by popular rashes. Other moderate ADEs included feeling intoxicated, menstrual discomfort or other mild rashes.
Despite these ADEs, the researchers concluded that the effective dose of 750 mg of cannabidiol (approximately 20 mg/kg/day for a 75‐kg adult), was mostly well tolerated when co-administered with clobazam, stiripentol, or valproate and that ADEs only occurred in patients for which there was no dosage titration.
In another study investigating the interactions between CBD and commonly used anti-epileptic drugs, concluded that, although serum levels of the drugs topiramate, rufinamide, and N‐desmethylclobazam were found when use in conjunction with and increased CBD dosages. However, all changes were within the accepted therapeutic range but did underscore the importance of monitoring serum AED levels and LFTs during treatment with CBD.
CBD and anticancer agents
In yet another such study, but with researchers this time looking into the clinical implications and importance of DDIs between anticancer agents and CBD in patients with cancer, the reviewers found that there was limited information available, with most of the data coming from in vitro studies and that the true in vivo implications are not well-known. This lead them to believe that erring on the side of caution is the best option, and that doctors and pharmacists should always consider the possibility of interactions and their consequences whenever they are aware of a patient using CBD products.
Similarly, a study investigating the potential ADEs and DDIs the researchers highlighted that medical CBD users under clinical supervision should be screened for potential DDIs and ADEs between CBD, other pharmacotherapies, and their underlying conditions. They also recommended that an increase in awareness is needed among the lay public who are recreational or consumer CBD users. Similarly, healthcare providers should also be made aware of the potential for DDIs and ADEs with CBD and strategically prescribe and manage patient regimens while also considering patient desires for complementary or alternative therapies.
List of drugs and medications which could be contraindicated for use with CBD
According to the Indiana University Department of Medicine, pharmaceutical drugs and medications which could be contraindicated for use with CBD include:
- Steroids and corticosteroids for example hydrocortisone, cortisone, prednisone, triamcinolone and dexamethasone
HMG CoA reductase inhibitors (statins) for example atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, simvastatin and rosuvastatin
- Calcium channel blockers for example amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil
- Antihistamines for example brompheniramine. cetirizine, chlorpheniramine, clemastine, diphenhydramine, fexofenadine and loratadine
- Prokinetics (motility drugs) for example domperidone, metoclopromide, levosulpiride, renzapride and pruclopride
- HIV antivirals for example abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir alafenamide and disoproxil fumarate as well as zidovudine
- Immune modulators for example immune globulins, immunosuppressive agents and immunostimulants, for example bacterial and viral vaccines
- Benzodiazepines for example alprazolam, clobazam, clonazepam, clorazepate, chlordiazepoxide, diazepam, estazolam and lorazepam
- Antiarrythmics for example amiodarone, flecainide, procainamide, propafenone, quinidine and tocainide
- Antibiotics for example amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole-trimethoprim, amoxicillin-clavulanate and levofloxacin
- Anesthetics for example barbiturates, amobarbital, methohexital, thiamylal, etomidate., ketamine and propofol
- Antipsychotics for example aripiprazole, asenapine, cariprazine, clozapine, lurasidone, olanzapine, quetiapine, risperidone and ziprasidone
- Antidepressants for example citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine and vilazodone
- Anticonvulsants / Anti-Seizure Medications for example 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
- Beta blockers for example acebutolol, atenolol, betaxolol, betaxolol, bisoprolol fumarate, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, propranolol, sotalol and timolol
- Proton-Pump Inhibitors (PPIs) for example omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole and dexlansoprazole
- Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) for example aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin
Angiotension II Blockers for example azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan
- Oral Hypoglycemic Agents for example sulfonylureas, meglitinides, biguanides, thiazolidinediones, α-Glucosidase inhibitors, DPP-4 inhibitors, SGLT2 inhibitors and cycloset
- Sulfonylureas for example glynase, micronase, amaryl, diabinese, glucotrol, tolinase and tolbutamide
There are also other medications known as “prodrugs” that first need to be metabolized into its therapeutic compounds as opposed to being a therapeutic compound in and of itself (like most medications). In other words, the inactive compound is ingested, and once in the body, it is processed into its active compound.
If this processing is dependent on the CYP system, then inhibitors can cause an insufficient amount of the active drug compound to be available in the body, which can result in the desired therapeutic effect not being reached.
One such prodrug for example is codeine which is metabolized into morphine. Similarly, lisdexamfetamine under the brand names Vyvanse and Concerta are two other popular ADHD medications which also fall into this category.
Why You Should Always Speak To Your Doctor First
The above mentioned list of drugs that could interact with CBD is by no means exhaustive and does not include all the medications on which CBD may have an interaction with. Similarly, not all the medication categories listed above will necessarily cause and interaction (although if you are taking one of these medications it is recommended to rather err on the side of caution).
For this reason, it is vital that you should consult your doctor or treating physician before using any CBD oil or product. Your doctor is not only able to advise you with regard to a possible CBD-drug interaction, but can also monitor the therapeutic as well as side effects of both the CBD and the medications you are on. Similarly, your doctor can also help you adjust the dosages of both the medication and CBD so you can take both simultaneously but also do so safely.
The safety profile of CBD is well established with study after study showing that it is well tolerated and safe to use, while at the same time rarely producing any serious side effects. Similarly, CBD is a compound that has a profound impact on a wide variety of systems within the body, which is what makes it such an effective therapeutic agent for so many conditions. But at the same time it is good to remember that it is also this, that is the reason why it has the potential to interact with other drugs and why CBD should be consumed with care and respect.