cbd and antipsychotics interactionDecember 15, 2021
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.
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 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.
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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.
CBD and anti-epileptic drugs.
According to the Indiana University Department of Medicine, pharmaceutical drugs and medications which could be contraindicated for use with CBD include:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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.
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.
What Is Metabolism?
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.
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.
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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’.
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.
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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.
Rheumatologists are always on the alert for liver problems that may result from arthritis medications, and that includes CBD as well as NSAIDs and methotrexate.
“The manufacturer of Epidiolex was asked by the FDA to conduct more drug-drug interaction studies, so we will learn more about CBD’s interactions with other drugs in the future,” says Dr. Bemben.
Dr. Patel worries in particular about any side effects or interactions that result in dizziness and may increase the risk of falls in the elderly. For example, using the antidepressant fluoxetine together with cannabis products can increase dizziness and drowsiness.
Are older people more at risk of CBD drug interactions?
One common concern among people with chronic illness who use CBD is whether CBD can interfere with prescription drugs you may take for arthritis or other conditions.
Yes, for several reasons. “As we age, our livers and kidneys may be slower to eliminate drugs from the body. In addition, older patients and those with chronic health problems are more likely to be using multiple medications, so the risk for drug interactions increases,” says Dr. Bemben.
“If you fill all of your medications at the same pharmacy, your pharmacist will be able to assess for drug interactions for all of them, regardless of who prescribed them. You should still let the pharmacist know about over-the-counter medications, herbs, and supplements — including CBD — that you don’t get through the pharmacy. It is important to bring the CBD product to your doctor and pharmacist so they can check the amount of CBD and other ingredients it contains,” says Dr. Bemben.
As examples, you may experience increased side effects if CBD is used along with these drugs:
While topical CBD products may not be absorbed deeply enough to raise concerns about drug interactions, that also means they may not be as effective for arthritis pain. “If you just have one joint hurting and it’s close to the surface, using a topical would be appropriate. It’s not as likely to help a hip or other deep joint,” says Dr. Patel.
According to CreakyJoints research presented at the 2019 Annual European Congress of Rheumatology meeting earlier this year, 52 percent of respondents reported having tried CBD for a medical reason. Of those who did, 93 percent said it helped. More than half said they wanted more information on CBD from their doctor, but 58 percent of those who told their doctors about their CBD use did not get the information on safety, effectiveness, and dosing they were looking for.
We put commonly asked questions to Nina M. Bemben, PharmD, BCPS, a specialist in drug interactions who is trying to educate other pharmacists about possible drug-drug interactions with CBD, as well as Rachna Patel, DO, a physician who does consultations about medical marijuana and CBD and sells her own line of CBD products.
Can CBD interact with medications I take specifically for arthritis?
People who take Epidiolex for epilepsy are more likely to develop abnormal liver enzymes, as well as sleepiness and other symptoms, if they are also using valproic acid to control seizures.
“Based on what we know now about the way CBD is metabolized, I would not expect significant drug-drug interactions with drugs commonly used in arthritis treatment, such as methotrexate, and most nonsteroidal anti-inflammatory drugs (NSAIDs). I would advise caution on one NSAID, diclofenac, because there isn’t information on how CBD affects — if at all — the enzyme that metabolizes it,” says Dr. Bemben.
“We use other therapies that cause liver injury, like nonsteroidal anti-inflammatories (NSAIDs). If liver enzymes go up in someone on methotrexate, we would generally hold the drug other than methotrexate [for example, CBD or an NSAID] to see if the enzyme levels normalize,” says Michael Weinblatt, MD, professor of medicine at Harvard Medical School in Boston.
CBD, a type of chemical known as a cannabinoid, is a mainingredient in hemp, one type of cannabis plant. Marijuana, another type of cannabis plant, also has some CBD but an abundance of THC (tetrahydrocannabinol), an intoxicating cannabinoid known for making users feel “stoned” or “high.” While CBD won’t get you high, it interacts with cannabinoid receptors in your body and may have effects that are sought by people with arthritis, such as pain relief, reduced inflammation, and improvements in sleep and anxiety.
Online databases are available to help health professionals evaluate potential drug-drug interactions, at a price. “Freely available resources tend to be less reliable, and this highlights the importance of discussing all your medications, including CBD, with your doctor and pharmacist,” says Dr. Bemben.
If I stick with a CBD cream, does that reduce the risk of drug interactions?
“This is important for people with arthritis to know because valproic acid is sometimes used for pain that isn’t controlled by other medications,” says Dr. Patel.
A huge number of medications, including CBD, are broken down by the same large family of liver enzymes, called CYP450.
CBD inhibits some enzymes in this family. This makes them break down certain drugs more slowly, which could potentially increase side effects unless your doctor adjusts the dose. On the other hand, CBD induces other enzymes in this family, which speeds the breakdown of certain drugs so they may potentially be less effective unless the dose is increased.
One source available to patients is drugs.com, where you can plug in either cannabidiol (which will give you the FDA-approved oral product Epidiolex) or cannabis (which will give you both THC and CBD) and check for possible interactions with other medications you take.
“There is still a lot of uncertainty about how CBD interacts with drug-metabolizing enzymes in the body. We know that there are some drug-metabolizing enzymes that are affected by CBD, some that are not, and many others where we just don’t have any information yet,” says Dr. Bemben.
Probably, since little if any of a topical product is likely to be absorbed into your system. “Unfortunately, we just don’t have good information about how much of a topical CBD product gets absorbed. This can be influenced by the inactive ingredients in the product, where on the body it’s applied, and whether you apply a bandage over the area after applying it,” says Dr. Bemben.