Cannabidiol (CBD) continues to rise in popularity as more research suggests a variety of health benefits, including relief for ailments such as chronic pain and inflammation, anxiety, depression, epilepsy, and high blood pressure.
Part of the allure of CBD also comes from the fact that it does not cause a “high,” even though it comes from Cannabis sativa L., the plant that produces both hemp and marijuana strains of CBD. or marijuana plant. The marijuana plant contains over 100 compounds known as cannabinoids. Most famous among them is tetrahydrocannabinol (THC), the main psychoactive cannabinoid. CBD is the main non-inebriating cannabinoid.
Additionally, CBD tends to be more tolerable and produces less side effects than traditional prescribed medications. The promising health benefits without the “high” or severe side effects make CBD an appealing alternative or adjunct to prescription medications. However, like with all drugs, consideration of possible drug-drug and drug-food interactions is necessary.
This article discusses medications that interact with CBD, how these interactions work, and what this means for you as a patient and consumer.
Does CBD Affect Other Medications?
The simple answer is yes. CBD can interact with most currently available prescription and over-the-counter medications because the body metabolizes, or breaks down, CBD and other drugs using similar enzymes in the cytochrome P450 (CYP450) class.
Classes of medications that can interact with CBD include:
· Angiotensin II blockers
· Calcium channel blockers
If you are currently taking any medications, it is important to check with your doctor or pharmacist before adding CBD to your treatment regimen. A change in dosage or medication may be necessary.
What Are Cytochrome P450 Enzymes?
There are over 50 enzymes in the CYP450 class that metabolize and expel foreign compounds, including drugs and toxins, in addition to performing other functions (i.e., producing cholesterol and steroids). Among these enzymes, there are six that metabolize 90 percent of all drugs. The table below—adapted from the Flockhart Table of drug interactions—lists some of the most common medications metabolized by these six key CYP450 enzymes.
Table 1: The Six CYP450 Enzymes That Break Down the Majority of All Drugs
Amitriptyline, caffeine, clozapine, duloxetine, estradiol, mirtazapine, naproxen, ondansetron, propranolol, R-warfarin, theophylline
Carvedilol, celecoxib, diclofenac, fluoxetine, fluvastatin, glimepiride, ibuprofen, irbesartan, losartan, montelukast, phenytoin, torsemide, S-warfarin
Amitriptyline, citalopram, diazepam, lansoprazole, phenytoin, omeprazole, R-warfarin
Amitriptyline, carvedilol, clozapine, codeine, dextromethorphan, dihydrocodeine, donepezil, fluoxetine, hydrocodone, loratadine, methamphetamine, metoprolol, mirtazapine, oxycodone, propranolol, risperidone, ritonavir, tramadol, trazodone, venlafaxine
CYP3A4 and CYP3A5
Alprazolam, atorvastatin, buspirone, carbamazepine, citalopram, corticosteroids, dapsone, diazepam, erythromycin, fentanyl, finasteride, ketoconazole, lansoprazole, losartan, lovastatin, methadone, montelukast, quetiapine, quinidine, quinine, sertraline, sildenafil, simvastatin, testosterone, R-warfarin, zolpidem
How Do Drug Interactions Work?
Most drug-drug and drug-food interactions occur because the substances share a similar metabolic pathway. Interactions with CYP450 enzymes usually occur either because:
- a substance is metabolized by the enzyme
- a substance inhibits the enzyme
- a substance induces or boosts the activity of the enzyme.
In the first scenario, competition between two or more substances that are metabolized by the same enzymes reduces the rate at which one or all of those substances are broken down. This can amplify the effects of one or all of those substances. This can also cause liver problems due to overloading. For example, if a patient with high blood pressure regularly takes ibuprofen (e.g., for joint pain), their doctor may avoid prescribing the angiotensin receptor blocker losartan, because both ibuprofen and losartan are metabolized by CYP1A2.
In the second scenario, one substance may inhibit the enzyme that metabolizes another substance. This action reduces the rate of clearance of the second substance, elevating its levels in the blood and enhancing its effects and side effects. For example, the antidepressant fluvoxamine is a potent inhibitor of CYP1A2, the enzyme that metabolizes the antipsychotic clozapine. Taking the two together may require reducing the dose of clozapine to one-third the standard dosage to avoid side effects such as low blood pressure, fever, and seizures.
However, not all inhibition is bad. Some drugs take advantage of enzyme inhibition to boost their therapeutic effects. For example, ritonavir, an HIV antiviral and inhibitor of CYP3A4, is often prescribed in a fixed-ratio combination with lopinavir, another antiviral, to boost blood levels of lopinavir.
In the third scenario, one substance may induce or enhance the activity of the enzyme that metabolizes another substance. This action increases the rate of clearance of the second substance, making it less effective or even non-effective. For example, carbamazepine, an anticonvulsant, is a potent inducer of all six key CYP450 enzymes. When it is prescribed in conjunction with another medication, such as nefazodone, an antidepressant, the doctor may need to increase the dosage of nefazodone in order to achieve the desired therapeutic effect.
The Grapefruit-Drug Interaction Example
Consideration of how various drugs and foods interact with one another is part of what doctors and pharmacists do before they calculate appropriate dosages and prescribe medications to patients. A classic example is the grapefruit-drug interaction. You may have been advised to avoid consuming grapefruit juice when taking certain medications like statins or antibiotics. This is because furanocoumarins in grapefruit (and some other citrus fruits) are metabolized by CYP3A4 enzymes, the same enzyme that breaks down 50% of all drugs. The resulting metabolite then binds and inhibits CYP3A4 enzymes. This leads to elevated blood levels of any medications that are taken with grapefruit juice.
How Does CBD Interact With Other Drugs?
Because CBD and many other drugs and supplements are metabolized by the same enzymes, the competition reduces the body’s ability to metabolize multiple drugs that are taken at the same time. Recent studies have also shown CBD to be a potent inhibitor of CYP3A4, CYP3A5, and CYP2C19—some of the major CYP450 enzymes that metabolize CBD.
The competitive and inhibitory actions of CBD on these enzymes means that taking CBD can raise the blood levels of other medications taken concurrently. While this can enhance the desired effects of those medications, it can also enhance the side effects and increase the risk of overdosing.
Does CBD Interact With Antidepressants?
Multiple recent studies have found that CBD can have antidepressant-like effects through its action on the endocannabinoid system and 5-HT1A receptors, making it an attractive treatment option for depression. However, these studies were performed in animals, and to date, there are no studies on specific CBD-antidepressant drug interactions in humans. What we do know is that CYP2D6 enzymes metabolize common SSRIs and tricyclic antidepressants, such as amitriptyline, clomipramine, desipramine, fluoxetine, imipramine, paroxetine, and venlafaxine, but that CBD inhibits the enzyme’s action. Although in some cases, this can be an advantage (i.e., adding CBD to increase or prolong the effects of an antidepressant), there is also the risk of increasing the severity of the side effects.
Summary: More research is needed on how CBD affects antidepressants, the safety of taking CBD with antidepressants, and what the appropriate dosages may be. If you are considering adding CBD to your treatment regimen, talk to your doctor or pharmacist first.
Does CBD Interact With Antipsychotics?
Management of psychosis continues to be a great challenge, with few medications having enough efficacy to justify the risk of severe side effects. This has caused many patients to abandon their treatment regimen and look for possible alternatives. Over the past couple of decades, many studies have looked at whether CBD is a viable alternative treatment to typical antipsychotics. Results from clinical trials and neuroimaging studies show great promise for CBD as an effective antipsychotic that is more tolerable than conventional antipsychotics.
Despite the positive results, little is known about what the appropriate CBD dosage is and how it may interact with other antipsychotics. However, the District of Columbia Department of Health warns against use of cannabis products in people with acute psychosis and other unstable psychiatric conditions. This is due to the fact that, like antidepressants, most antipsychotics are metabolized by CYP2D6, which is inhibited by CBD.
Summary: Although CBD shows great promise as an effective and more tolerable antipsychotic, it has not been approved by the FDA. Not much is known about how it interacts with other antipsychotics, and there is concern about the use of CBD in people with severe psychosis. If you are currently taking or are considering taking CBD for psychosis, it is important to discuss this with your doctor. This may change what medications they prescribe to you and in what dosage.
Does CBD Interact With NSAIDs?
There are currently no studies on how CBD may interact with NSAIDs like ibuprofen. Among the many claimed benefits, CBD is marketed as a good pain reliever and anti-inflammatory. But while recent research does show evidence that CBD can reduce inflammation and prevent joint and neuropathic pain, most studies use animal models and few studies have been done in humans. A 2018 study published in Osteoarthritis and Cartilage found a marginally improved average knee pain score after taking CBD, but the result was not statistically different from the placebo group. None of these studies determined the effect of taking CBD with another anti-inflammatory or pain reliever.
NSAIDs like diclofenac, ibuprofen, and meloxicam are metabolized by CYP2C9, which also metabolizes CBD. So although both NSAIDs and CBD can be safe and effective on their own, in combination, they can amplify each other’s actions, leading to adverse side effects and increased risk of overdose.
Summary: More human studies are needed to determine the proper dosage and safety of taking CBD to reduce inflammation and pain—especially in combination with other pain relievers.
Can I Take CBD Oil When Drinking Alcohol?
There is not enough current research to determine the benefits or risks of taking CBD with alcohol. The last one, published in Psychopharmacology, dates back to 1979 in which 10 volunteers were given either a placebo with no alcohol, a placebo with alcohol, CBD (200 mg capsule) with no alcohol, or CBD (200 mg capsule with alcohol). The study found that the combination of CBD with alcohol significantly decreased blood alcohol levels compared to alcohol alone. However, the combination also caused significant motor and cognitive impairments. It is important to note that the study is outdated and the sample size used was too small to make any reliable conclusions. However, like with sleep medications, benzodiazepines, and opioids, taking CBD with alcohol can amplify the effects of both substances.
Bottom line: Because so few studies have been done to determine the possible benefits and risks of combining CBD and alcohol, it is generally not advisable.
Most CBD Products Are Not Currently Approved by the FDA
Currently, the FDA has not approved any CBD products for use in any treatments outside of one prescription medication—Epidiolex—used to treat a rare form of epilepsy. The FDA also does not regulate CBD products, so product labels are often misleading. A 2017 study published in JAMA analyzed 84 CBD products from 31 companies and found that only 26 of those products accurately labeled the concentration of CBD in the product. The lack of regulation further complicates the process of determining effective dosage and avoiding adverse interactions with other medications.
In addition, the researchers detected THC (up to 6.43 mg/mL) in 18 of the 84 products analyzed. Depending on the concentration of THC in a CBD product, this could further alter the activity of other medications—especially those metabolized by CYP3A4 and CYP2C9, the two enzymes that metabolize both THC and CBD. Like CBD, THC also has an inhibitory effect on some CYP450 enzymes. THC may also induce unwanted side effects such as anxiety when taken in high doses.
What This Means for You
Although there are many studies that suggest a variety of benefits from CBD, more studies—particularly human studies—are needed to determine the efficacy and safety of CBD. If you have a pre-existing condition or are currently taking any supplements or medications and you are considering taking CBD in addition to your current treatment, talk to a doctor or pharmacist. This will help them determine what drugs they can safely prescribe to you and whether they need to alter the standard dosage.
If it is your first time using a CBD product, “start low and go slow.” Because it is unregulated and few studies have been able to determine standard dosing requirements, there will be some trial and error. Make sure to take notes on how you respond to CBD, and keep your doctor in the loop.
When buying a CBD product, purchase only from reputable companies, and ask for a certificate of analysis (COA), which shows results from analyses of CBD, THC, and contaminant concentrations in the product.
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