Asking yourself the question 'does CBD interact with other medications?' Well, here's the REAL answer that you've been looking for… Cannabidiol (CBD) may interact with the analgesic naproxen, enhancing its anti-inflammatory and painkilling effects but also increasing the risk of side effects. Cannabidiol and Non-Steroidal Anti-Inflammatory Drug Interactions: A Case of Drug-Induced Aseptic Meningitis
Does CBD Interact with Other Medications? [Answered]
A drug interaction is a reaction between medication and food, drink, or supplements. It also relates to a reaction between two or more drugs. It is also possible to have a drug interaction when you take medication while suffering from a particular medical condition. An example of this is using a nasal decongestant when you have high blood pressure.
Although medicine is supposed to improve our health, a drug interaction could cause harmful side effects; it could also increase or decrease the effectiveness of the medication. Critics point to the United States’ over-reliance on prescription and OTC drugs and suggest it is a heavily medicated society.
Medicine is meant to improve our health; however, drug interaction could cause harmful side effects.
The practice of using a myriad of supplements and drugs is known as polypharmacy. Medical professionals use the term when a person consumes five or more different types of medicine daily. However, a study by Qato et al., published in JAMA Internal Medicine in April 2016, found that almost 36% of American adults fall into the ‘polypharmacy’ category!
Aside from a penchant to overuse medication in general, our increased life expectancy has also played a major role in the excessive consumption of drugs. Conditions such as osteoporosis and cardiovascular disease are now more prevalent than ever before, and a fast, easy, and sometimes useful means of treating these issues is prescription medication.
How About CBD?
CBD is the latest treatment option for a wide range of medical conditions, although it is not FDA approved. Instead, sellers must ensure their CBD comes from hemp, and they are not allowed to make any medical claims. Even so, millions of patients around the world have begun trying cannabidiol to treat problems such as anxiety, depression, chronic pain, and osteoporosis.
The nature of chemical compounds means practically every substance interacts with another, and CBD is not exempt from this process. While the list of side effects associated with CBD is relatively short (pending further research); this situation only relates to healthy individuals who are not using other drugs.
As you may know, cannabidiol is the most prevalent non-intoxicating compound in marijuana and industrial hemp. It interacts with cannabinoid (CB) receptors throughout the body’s endocannabinoid system (ECS). CBD also inhibits the activity of a group of liver enzymes called cytochrome P450.
How CBD Affects Cytochrome P450
Cytochrome P450 (CYP450) enzymes help break down drugs and toxins that enter your body. As a result of CBD’s actions on CYP450, it deactivates the enzymes’ activity temporarily and alters the metabolization of other compounds.
Ultimately, this system metabolizes a large percentage of the drugs we consume. These enzymes break down the substances that enter our bodies and transform them into something the body can use.
When you use a hefty dose of CBD, it prevents the CYP450 enzymes from doing their job; thus, the body finds it hard to process specific medications. In case you were wondering, when a medicine is not metabolized properly, it remains in your system longer than is necessary and causes unintended adverse effects.
One interesting fact is that CBD interacts with drugs in the same way as grapefruit. Both substances inhibit the metabolic process in a similar fashion. Therefore, it is a good idea to avoid the same drugs when using CBD as you would when consuming grapefruit. Helpfully, several medications specifically tell you to avoid drinking grapefruit juice or eating the fruit! These drugs include, but are not limited to:
In this article, we look at several commonly used drug types and analyze their potential interaction with CBD.
1 – Antidepressants
According to the CDC, over 12% of Americans aged 12+ have used an antidepressant in the last month; and fluoxetine (Prozac and Sarafem) is the most commonly used. CBD is often used to combat depression, and it isn’t unusual for patients to use CBD and Prozac in a bid to beat the blues.
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and is also used to treat bulimia, OCD, and anxiety. Typical side effects include sweating, diarrhea, abnormal dreams, and skin rash. Experts say SSRIs work by boosting the level of chemicals such as serotonin and dopamine in the brain.
SSRIs are among the best-researched medications around, but not everyone can find relief using a drug such as Prozac alone. Research suggests that CBD’s impact on the ECS helps improve symptoms of depression, primarily because of the ECS’ effect on mood, anxiety, and emotions.
To date, there is little evidence of negative drug interaction when using SSRIs in conjunction with CBD. Indeed, an increasing number of patients with depression report improvement when using both drugs together. However, CBD’s impact on the CYP450 enzymes means it could cause an increased amount of antidepressant medication to remain in the system.
A possible, albeit rare, side effect from this is a mild form of mania known as hypomania.
Is taking CBD oil with Lexapro…
2 – Blood Thinners
Along with other cannabinoids in plants, CBD can increase the effects of blood-thinning drugs such as warfarin or drugs capable of thinning the blood, such as ibuprofen. A study by Grayson et al., published in Epilepsy & Behavior Case Reports in October 2017, discovered an interaction between warfarin and CBD.
The research team pointed out the importance of studying potential drug interactions involving cannabis products and any drug metabolized by the CYP450 enzyme system.
Once again, it is a case of the drug and CBD getting metabolized in the same pathway. The result is an elevated level of warfarin, which causes an increase in the drug’s blood-thinning effects. Make sure you monitor INR levels. INR is a test used to check the effects of warfarin. You may find that you need less than the recommended dose of the drug.
3 – Drugs for Epilepsy & Seizures
According to proponents, one of CBD’s plus points is the lack of an intoxicating ‘high.’ Therefore, an increasing number of parents are happy to use the cannabinoid to treat children with epilepsy. The remarkable case of Charlotte Figi was a massive boost to the industry.
Young Charlotte has Dravet’s Syndrome, and one of the symptoms is frequent seizures. Charlotte had hundreds of seizures each month. After using a high-CBD strain called Charlotte’s Web, the number of seizures fell to just two or three each month.
While research suggests that high doses of CBD could help treat the symptoms of epilepsy, Lester Bornheim found out something interesting back in 1992. It turns out that a low dose of CBD doesn’t provide antiepileptic effects but still inhibits CYP450 enzymes. The result is prolonged concentrations of antiepileptic drugs like norclobazam and clobazam, which cause more aggressive seizures.
At the 70th Annual Meeting of the American Epilepsy Society in January 2017, Jerzy P. Szaflarski, MD, Ph.D., discussed the results of a study into CBD and antiepileptic drugs. He said that CBD has a ‘significant’ interaction with drugs such as rufinamide, zonisamide, and topiramate.
A study by Chang, published in Epilepsy Currents in January 2018, reviewed the findings of Szaflarski and his team. Szaflarski’s research involved 81 volunteers, 42 of whom were children. From an initial dose of 5mg of CBD per kilogram of body weight daily, the dose was increased by another 5mg/kg daily every two weeks to a maximum 50mg/kg per day.
As part of the study, the team regularly checked serum antiepileptic drug (AED) levels to identify interactions between the drugs and CBD. Interestingly, while AED levels increased in several drugs, the level of clobazam decreased. Therefore, you may need less of most AEDs when using cannabidiol but might need more clobazam.
4 – Cold and Flu Drugs
There are even drug interactions between CBD and OTC cold and flu medication. Here is a quick list of the substances in various cold and flu drugs that are capable of causing side effects when used with CBD:
- Doxylamine: Found in drugs like Nyquil, this antihistamine could increase the calming or drowsy effects of CBD.
- Naproxen: Found in anti-inflammatory medicines such as Aleve, naproxen could reduce the effectiveness of CBD.
- Chlorpheniramine: Found in different antihistamines, chlorpheniramine could increase drowsiness.
- Pseudoephedrine: Found in decongestants such as Sudafed Congestion, this compound could increase the risk of serotonin syndrome when used with CBD.
- Pheniramine: Found in cold and flu combination products, this compound could increase drowsiness and general risk of side effects.
Other possible effects of drug interaction with cold and flu medicines are confusion, decreased motor function, and cognitive impairment.
5 – Antiretroviral Drugs
An estimated 40 million people worldwide live with HIV/AIDS. HIV weakens the immune system, which leaves patients vulnerable to infections. At present, antiretroviral drugs such as Saquinavir and Ritonavir are used to treat HIV/AIDS.
It seems that using these drugs with CBD can increase the efficacy and duration of cannabidiol but may also increase serum concentration and cause side effects. At the time of writing, research into a potential interaction between CBD and antiretroviral drugs has not been studied.
However, Costiniuk et al. published a report in the British Medical Journal in January 2019. The team outlined their intention to study the safety, tolerability, and effect on immune activation of oral cannabinoids in people living with HIV. Hopefully, we will soon learn a little more about how cannabis impacts the health of individuals with an HIV diagnosis.
Until we discover more, it is advisable to begin with a low dosage of CBD if using an antiretroviral drug.
Understanding the science…
6 – Anti-Anxiety Drugs
The dangers of mixing an anti-anxiety medication such as Xanax with opioids and alcohol are well known. However, we don’t yet have enough research to provide a conclusive outline of what happens when you mix CBD with such a drug. CBD’s effect on the CYP450 system means you will probably have an increased level of the drug in your blood. As a result, side effects such as confusion, loss of focus, and drowsiness are likely.
7 – Drugs to Control Blood Pressure
Beta-blockers are among the most popular options to reduce blood pressure. As CBD may also help keep your blood pressure under control, it is tempting to combine the two. However, you may experience some side effects. Beta-blockers are designed to reduce your heart rate by stopping the release of adrenaline, a stress hormone.
If you use CBD and beta-blockers together, there is a danger that your blood pressure will drop too quickly and lead to an unhealthily low rate. Side effects include feeling faint, dizzy, weak, and possibly going into shock.
What Drugs Should Not be Taken with CBD?
As previously highlighted in this article, taking CBD alongside drugs normally broken down by CYP450 enzymes increases the risk of potential interactions from high amounts of those drugs in the bloodstream.
In this section, we will address what drugs should not be taken with CBD. We will outline a list of drugs that are metabolized by CYP450 enzymes. If you are taking any of these types of drugs, you should consult with your doctor if you are considering taking CBD.
- Immunosuppressants – used in the treatment of autoimmune disorders such as psoriasis and rheumatoid arthritis
- Chemotherapeutics – used in the treatment of cancer
- Antidepressants – used to treat major depressive disorder (MDD) and other mood disorders, including anxiety and post-traumatic stress disorder (PTSD)
- Antipsychotics – used to treat schizophrenia and other psychotic disorders
- Opioids – used for pain relief and post-surgery
- Benzodiazepines – used for anxiety disorders and insomnia
- Calcium channel blockers – used for high blood pressure and other heart conditions
- Anti-epileptics – used in the treatment of epilepsy
- Proton pump inhibitors – used to treat acid reflux and stomach ulcers
- Propranolol – used to treat high blood pressure and sometimes physical symptoms associated with anxiety
- Warfarin – used to treat blood clots
If you are concerned about how CBD may interact with other medications that you are taking, then speak with your doctor to ensure that it is safe to do so.
Does The Form Matter For CBD Drug Interactions?
CBD topicals, including creams, balms, and lotions, are rubbed onto the skin surface, where CBD is directly absorbed and provides local pain relief.
Because topicals aren’t absorbed into the bloodstream at significant levels, topical CBD doesn’t have the same sedative effect as CBD oils or edibles. It also means a reduced risk for potential interactions with prescription drugs.
Lastly, topical CBD does not enter the liver in any significant amount. Therefore, it shouldn’t majorly interact with other medications broken down by CPY450 enzymes. These combined effects mean topicals are less likely to cause CBD drug interactions or enhanced drug side effects.
CBD’s Interaction with Other Medications: Conclusion
While there are a few studies that look at potential drug interactions between CBD and other medications, we are still in the dark, according to experts like Yasmin Hurd of Mount Sinai. She suspects that cannabidiol interacts with the majority of drugs taken orally.
It is a suggestion that makes sense. After all, approximately 60% of the drugs on the market interact with the CYP450 liver enzymes. When using these drugs with CBD, more of the medication gets into your system due to CBD’s ability to block these enzymes.
If you are using an OTC or prescription drug, it’s essential to consult with your physician before using CBD.
This is terrible news for patients who use drugs such as warfarin because if CBD blocks the metabolization of the blood thinner, the level of the drug becomes higher and could reach toxic levels. In the case of warfarin, using CBD with it may result in a dangerous hemorrhage or traumatic bleed.
If you use CBD with anti-anxiety drugs like Xanax or Ativan, it may lead to a higher degree of sedation. In rare instances, this combination could cause problems with your respiratory system. CBD could even increase the serum concentration (amount of a drug in your blood) when combined with drugs such as antihistamines, antiretrovirals, and beta-blockers.
While low doses of CBD are unlikely to cause drug interactions, there is no research that outlines the ‘safe’ amount. Ultimately, if you are using CBD to treat a specific medical condition, consult with your physician before considering its use when you are already using an OTC or prescription drug.
Additionally, if you are going to use CBD oil, always choose a high-quality product, like those in our list below!
Can you take CBD with Benadryl?
Common side effects of Benadryl include drowsiness and increased sleepiness. Because these are also common side effects of CBD, taking Benadryl and CBD together may enhance these effects and could be potentially dangerous. Please speak with your physician first before taking CBD with Benadryl to ensure that it is safe to do so.
Can I take CBD oil and lorazepam?
Common side effects of lorazepam include drowsiness, fatigue, and problems with memory and coordination. Because of the sedating effects of CBD, taking lorazepam and CBD may enhance the side effects of lorazepam which could be dangerous, especially in situations like driving. Please speak with your physician first before taking CBD oil with lorazepam to ensure that it is safe to do so.
Can you take CBD with Prozac?
There is no published research to date about dangerous interactions between fluoxetine (Prozac) and CBD. However, fluoxetine is broken down by CYP2D6 enzymes into norfluoxetine and the action of norfluoxetine is largely responsible for fluoxetine’s antidepressant effect. As CBD inhibits CYP450 enzymes, which include CYP2D6, CBD may therefore inhibit CYP2D6 and prevent the production of norfluoxetine from fluoxetine, dampening fluoxetine’s effect. Please speak with your physician first before taking CBD with Prozac to ensure that it is safe to do so.
Can I take CBD oil with naproxen?
The body breaks down naproxen using CYP450 enzymes. Because CBD inhibits CYP450 enzymes, CBD could increase the amount of naproxen in the blood, meaning there may be an increased chance of experiencing unwanted side effects of naproxen. Please speak with your physician first before taking CBD with naproxen to ensure that it is safe to do so.
Does CBD Interact With Naproxen (Aleve)?
This combination is considered low-risk — but proceed with caution.
Naproxen, an analgesic drug belonging to the class of nonsteroidal anti-inflammatory drugs (NSAIDs), is used to treat different conditions such as osteoarthritis, rheumatoid arthritis, dysmenorrhea, and others. It also has antipyretic abilities.
CBD (cannabidiol) is a naturally-occurring cannabinoid with similar effects. Some people report taking both compounds together for added benefit.
Will CBD and naproxen (Aleve) interact? Is this combination safe?
Table of Contents
Does CBD Interact With Naproxen (Aleve)?
CBD can interact with naproxen, but the interaction is mostly mild. Some even consider this combination synergistic — offering a greater level of benefit in combination than either compound can offer on its own.
Both CBD and naproxen offer potent anti-inflammatory and analgesic benefits. They even work through similar mechanisms of action (inhibition of COX-2 and other pro-inflammatory mediators).
There’s also a possibility CBD and naproxen will interact through a concept called metabolic competition as well. Both CBD and naproxen require at least some activity from the CYP2C9 enzyme in the liver. Since both compounds require the same pathway, they can become overburdened and slower than expected — increasing the half-life of both substances. This is unlikely to result in side effects unless both substances are taken on a daily basis for several days, weeks, or months.
Similar Medications: CBD & NSAIDs
Naproxen is classified as an NSAID painkiller. CBD and NSAIDS all share similar risks for interaction and side effects.
Here’s a list of similar medications that share a similar level of risk when combined with CBD:
- Aspirin (Ascriptin, Aspergum, Aspirtab, Bayer, Easprin, Ecotrin, Ecpirin, Entercote)
- Ibuprofen (Motrin, Advil, Nuprin, Caldolor & Neoprofen)
- Celecoxib (Celebrex & Onsenal)
- Ketorolac (Toradol)
- Etodolac (Ultradol)
- Meloxicam (Mobic)
Is It Safe to Take CBD & Naproxen (Aleve) Together?
CBD and naproxen have a low risk of interaction and are generally considered safe to take in combination (if following the safe recommended dosages for both compounds).
Long-term use or large doses of CBD or naproxen may lead to some side effects. Too much naproxen in the body could cause side effects like liver failure, gastrointestinal upset, and ulcer formation.
Talk to your doctor first if you wish to start using CBD while taking a daily dose of naproxen.
Is CBD A Viable Alternative to Naproxen (Aleve)?
CBD may be a viable alternative to naproxen for certain symptoms.
CBD is an effective painkiller, especially in mild to moderate conditions like mild arthritis, pain, and inflammation. It works by binding to the transient receptor potential (TRP) channels, antioxidant effects, and various endocannabinoid-regulated pro-inflammatory pathways [1,2].
For mild conditions, CBD may be even more effective and carry fewer side effects than naproxen.
However, in some severe pain and inflammatory conditions, CBD may not provide enough relief as naproxen. Additionally, CBD lacks the antipyretic (fever-reducing) activity of naproxen.
What is Naproxen (Aleve)?
Naproxen is a nonsteroidal anti-inflammatory drug (NSAIDs). It’s used to treat mild to moderate pain, like rheumatoid arthritis, osteoarthritis, tendinitis, bursitis, muscle pains, acute gout, dysmenorrhea, and others.
It was approved as a prescription drug in 1976 and then for over-the-counter (OTC) use in 1994.
Naproxen (Aleve) Specs:
|Trade Name||Aleve, Aleve PM, Aleve-D, Anaprox, EC-Naprosyn, Naprelan, Naprosyn, Sallus, Sudafed Sinus & Pain, Treximet, Vimovo|
|Interaction With CBD||Agonistic, Metabolic competition,|
|Risk of Interaction||Mild|
What Does Naproxen (Aleve) Do?
Naproxen works by inhibiting cyclo-oxygenase (COX) isoenzymes. These enzymes are key mediators in the inflammatory process. By blocking these enzymes, inflammation is halted, reducing pain and swelling along with it.
The COX-1 enzymes are also found in normal tissues like the stomach lining, while the COX-2 enzyme is induced and makes prostaglandins that mediate pain, fever, and inflammation.
Stopping the production of these substances stops the inflammatory actions on the body and provides relief. Naproxen’s actions on the COX-2 enzyme give the desired antipyretic, analgesic, and anti-inflammatory properties, while its actions on COX-1 enzymes can give undesired adverse effects such as gastrointestinal upset and renal damage. Naproxen can thus stop the effects of inflammation but may cause some unwanted side effects.
The half-life of naproxen is 12-17 hours.
Side Effects of Naproxen
Naproxen has few deleterious effects on the health of its users. Long-term use of naproxen can increase blood pressure and cause upper gastrointestinal bleeding.
Naproxen should be avoided in patients with hypersensitivity, perioperative pain in the setting of coronary artery bypass graft (CABG) surgery, bleeding disorders, liver diseases, kidney failure.
Because naproxen is so easily available as an OTC drug, it is also more liable to be misused and overdosed. It can produce effects such as drowsiness, lethargy, epigastric pain, nausea, and vomiting.
Side effects of naproxen include:
- Abdominal pain
- Fluid retention
- Gastrointestinal bleeding
- Gastrointestinal perforation and ulcer
- Hearing disturbances
- Muscle cramps
Key Takeaways: Is it Safe to Take Naproxen (Aleve) With CBD?
CBD and naproxen are generally regarded as safe when taken in combination — however, be cautious with this combination and always follow the recommended dosages for both substances. Never consume alcohol when taking naproxen and CBD.
CBD and naproxen both decrease pain and inflammation, but both of them have different mechanisms of action. Naproxen works by acting on the COX enzymes. CBD decreases pain by acting on the endocannabinoids and TRP channels.
Some reports suggest an even greater level of pain reduction when combining CBD and naproxen together, but there are no studies to confirm whether this is safe or effective yet.
Can I Take Naproxen With CBD Oil
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|Journal of Neurology Research, ISSN 1923-2845 print, 1923-2853 online, Open Access|
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Volume 10, Number 4, August 2020, pages 132-135
Cannabidiol and Non-Steroidal Anti-Inflammatory Drug Interactions: A Case of Drug-Induced Aseptic Meningitis
Mallory Emig a, b , Jafar Kafaie a , Samantha Ong a , Xujia Li a
a Saint Louis University Hospital, Saint Louis, MO, USA
b Corresponding Author: Mallory Emig, Saint Louis University Hospital, Saint Louis, MO 63110, USA
Manuscript submitted May 8, 2020, accepted June 5, 2020, published online June 20, 2020
Short title: Cannabidiol and NSAIDs
Cannabidiol (CBD) and other marijuana derivatives are being more widely used in the medical community by people in an attempt to alleviate a variety of symptoms. While these products have shown promise in their analgesic properties, little is known about the potential pharmacological interactions of these and other drugs. We present a case of a 57-year-old Caucasian woman who presented with altered mental status, ataxia, left-sided numbness, and slurred speech. An extensive workup was completed and found to be largely unremarkable, though a thorough history revealed that her symptoms were likely caused by concurrent use of CBD and non-steroidal anti-inflammatory drugs (NSAIDs) resulting in drug-induced aseptic meningitis. The benign nature of CBD makes it a promising avenue for pain relief. Physicians and patients should be informed about the potential drug-drug interactions of CBD and other medications.
Keywords: Cannabidiol; NSAIDs; Drug-induced aseptic meningitis
Cannabidiol (CBD) is a phytocannabinoid that is derived from Cannabis sativa and Cannabis indica that has become more frequently used for its medicinal qualities. The consumer market of CBD-infused products is continuously growing, although its therapeutic benefits are still under question by the US Food and Drug Administration (FDA) [ 1 ]. Due to its low tetrahydrocannabinol (THC) concentration, CBD oils and other derivatives provide medicinal benefits without the psychoactive effects of recreational marijuana, one of the most commonly used illicit drugs in the USA [ 2 ]. CBD is generally used for the side effects of chemotherapy, pain, anxiety, and other neurological and psychiatric illnesses, including but not limited to post-traumatic stress disorder, seizures, and Tourette’s syndrome [ 3 ]. Generally, in the medical community, CBD is considered a low-risk drug and has been used for decades for its neuroprotective effects. However, CBD’s actions throughout the body are not fully understood and there are many side effects that should be considered before prescribing to patients.
CBD extracts usually contain no or very low amounts of THC, which is the component in marijuana that induces the euphoric psychoactive effect. However, CBD still has side effects including diarrhea, nausea, irritability, and weight/appetite changes that should not be ignored [ 4 ]. More importantly, because CBD interacts with common biological targets implicated in drug metabolism and excretion, it increases the likelihood of drug-drug interactions (DDIs) with commonly prescribed and over-the-counter medications such as non-steroidal anti-inflammatory drugs (NSAIDs), antimicrobials, and antiepileptics [ 5 ]. The mean half-life of CBD is 2 -5 days, so the drug can cause effects even if the patient stopped using before any symptoms of DDIs present [ 6 ]. As CBD is implicated as both a subject and a cause of DDIs, physicians and patients should be made aware of potential safety concerns with CBD use.
The adverse drug effects and DDIs of CBD are based on its pharmacologic targets and pharmacodynamic qualities related to metabolism, absorption, and elimination. Molecular targets of CBD include a wide variety of receptors and channels, and its metabolites can act on a multitude of cytochrome P450 (CYP) enzymes. In particular, CYP enzymes are responsible for the metabolism of NSAIDs, one of the most widely used drugs worldwide. In the USA alone, more than 30 billion doses of NSAIDs are consumed and more than 70 million prescriptions are written for NSAIDs [ 7 ]. These drugs (e.g. ibuprofen, diclofenac, ketoprofen, naproxen, flurbiprofen, meloxicam, piroxicam, and tenoxicam) are metabolized by two enzymes of the CYP superfamily, mainly the CYP2C8 and CYP2C9 [ 8 ]. CBD decreases the activity of both CYP2C8 and CYP2C9 in vitro [ 9 , 10 ]. Because the activity of CBD on the enzymes in vivo has not been established, clinical data is needed to fully understand the DDIs between CBD and NSAIDs. Physicians should strongly consider DDIs when the use of CBD is reported in concurrence with the use of commonly prescribed medications such as NSAIDs.
Although studies have shown the various adverse effects of CBD on different organ systems, clinical data demonstrating the negative consequences of CBD DDIs are minimal. One prior clinical study by Geffrey et al presented DDIs between CBD and clobazam, supporting the fact that concomitant use of CBD with other medications should be monitored carefully [ 11 ]. In fact, though CBD has shown promising results in treating a variety of symptoms, its effects on different processes throughout the body remain poorly understood and therefore should be treated/recommended with caution. The current case study offers further evidence that DDIs between CBD and common medications such as NSAIDs can lead to unforeseen and potentially severe nervous system pathology such as aseptic meningitis.
Our patient is a 57-year-old woman with a medical history significant for occasional headaches, thyroid nodules, a Warthin’s tumor of the left parotid gland resected in 2009, coronary artery disease, hypertension, thyroid nodules, rheumatoid arthritis and a 40-pack-year smoking history, who presented with altered mental status, ataxia, left sided numbness, and slurred speech.
She initially presented to an outside facility with the above symptoms for 9 days. She underwent routine testing including magnetic resonance imaging (MRI) of her brain without contrast which was unremarkable. She was discharged home after 2 days. Two days after being discharged, she returned to the facility with agitation, aggressive behavior, and staring spells along with ongoing altered mental status and ataxia. She was somnolent and complained of headaches. She had no fever and routine labs were again unremarkable. She underwent a lumbar puncture (LP) and extensive lab testing, the results of which were largely non-specific. Urinalysis and toxicology were negative. There were no metabolic or vitamin abnormalities. Thyroid studies were significant for a thyroid stimulating hormone (TSH) of 0.18. Inflammatory markers were not elevated. Autoimmune panels were within normal limits. Human immunodeficiency virus (HIV) and rapid plasma reagent (RPR) for syphilis were non-reactive. Cerebrospinal fluid (CSF) analysis revealed a white blood cell (WBC) count of 180, 96% lymphocytes, red blood cell (RBC) count of 5, glucose 62, protein 280, and cytology and flow cytometry were negative. Comprehensive cultures were sent and were all negative. MRI total spine was done and MRI brain with and without contrast was repeated, this time showing diffuse leptomeningeal enhancement. Routine electroencephalogram (EEG) was unremarkable. She was transferred to our hospital for further evaluation.
Upon arrival at our facility, she was awake and alert without agitation. A detailed history was taken, which noted worsening of her intermittent headaches starting in April 2019. At that time, she began to use CBD oil for her rheumatoid arthritis along with her prescribed NSAIDs. Around that time, her headaches became more frequent and more painful, leading her to increased NSAID use. Over the next few months, she experienced persistent headaches and developed gait difficulties. The memory issues and confusion were the newest symptoms she experienced, leading to her wandering the streets around the neighborhood lost and confused. Upon further questioning, she recalled having episodes of subjective fevers and night sweats as well as unintentional weight loss of 25 LBS. Review of systems was otherwise negative.
She reported a family history of thyroid disease as well as rheumatoid arthritis. She denied a recent history of travel, dietary changes, and knowledge of any exposure to toxins. Neurological exam was non-focal and was significant for decreased orientation (only oriented to self and place), fatigue, and mild weakness. Palpation of the thyroid revealed an enlarged goiter. She had diffuse bruising of her extremities. No rashes were noted.
Over the next 24 h, the patient’s headaches worsened and she again became aggressive and agitated. She was started on hydrocodone-acetaminophen for headaches. She underwent thyroid ultrasound which showed a large multinodular thyroid as well as a second LP. LP showed protein 182, WBC 238 w/93% lymphocyte, glucose 60, and flow cytometry and cytology were pending but eventually were unremarkable. Infectious labs were all negative. Encephalopathy, encephalitis, and paraneoplastic panels were sent out to Mayo clinic. The patient continued to have episodes of agitation and aggression, particularly at night, eventually requiring scheduled quetiapine. In the mornings, she had a poor recollection of the events that occurred overnight.
Due to high concern for an underlying malignancy, she underwent a whole-body positron emission tomography-computed tomography (PET-CT) which was significant for “intense fluorodeoxyglucose (FDG) uptake in the right parotid gland with subsegmental and tonsillar lymph nodes demonstrating increased FDG avidity concerning for malignancy”. Hematology was consulted for the significant PET findings. They recommended a biopsy of the parotid gland. Due to her negative infectious workup and lack of fever, the patient was not started on antibiotics. An ear, nose, and throat (ENT) specialist was consulted for fine needle aspiration (FNA) of the right parietal mass which showed recurrence of a Warthin’s tumor.
After discussion with the patient and family about the unclear etiology of her presentation, she denied leptomeningeal biopsy and the decision was made to trial a dose of intravenous (IV) steroids. She was started on IV methylprednisolone 500 mg twice a day (BID) for 3 days. She was given intravenous immunoglobulin (IVIG) 2 g/kg in 2 days after receiving solu-medrol for 3 days. The patient reported significant improvement in her headaches and cognition. She was able to be discharged home under the care of her family.
Encephalitis, encephalopathy, and paraneoplastic panels resulted in no abnormalities. She was seen in a follow-up clinic 1 month after being discharged and reported that she felt completely back to her baseline which was confirmed by family members. She underwent a follow-up MRI which showed no leptomeningeal enhancement or signal abnormality and no other findings.
The patient’s presentation and complicated medical history led to a concern for a wide range of etiologies. Malignancy was high on the differential given her smoking history and B symptoms. Metabolic disorders were also considered though it was difficult to pursue this differential with a lack of abnormal lab findings. Careful history taking helped support the possibility of medication-induced encephalitis given that her headaches worsened with an increase in the use of her NSAIDs and subsequent administration of topical CBD. Infection was considered, but the patient was never febrile while in the hospital and she did not improve with antibiotics. Extensive infectious labs were sent with no significant results, helping us rule out this possibility. Because of all the negative lab findings, a diagnosis of drug-induced aseptic meningitis was highly considered.
The current case study found that the concomitant use of CBD with meloxicam could have precipitated drug-induced aseptic meningitis (DIAM). DIAM is a rarer cause of meningitis that is associated with NSAID use [ 12 ]. The symptoms of DIAM are similar to those that are found in cases of meningoencephalitis, including fever, headache, altered mental status, arthralgia, and myalgia [ 13 ]. The diagnosis of DIAM is a diagnosis of exclusion and is made by ruling out other possible causes of meningitis. The fact that all the laboratory tests, in this case, were negative for malignancy, infections, and autoimmunity and she returned to her baseline with complete resolution of the brain MRI findings, supporting the likelihood that our patient’s aseptic meningitis was caused primarily by the use of medications. The pathogenesis of DIAM can be attributed to two proposed mechanisms, one being direct meningeal irritation by the drug and the other being a hypersensitivity reaction to the drug [ 14 ].
Although there are no published clinical cases about meloxicam specifically inducing aseptic meningitis, NSAIDs have been shown to be related to this pathology [ 12 ]. Therefore, it is possible that meloxicam can have similar effects as other NSAIDs that have been shown to cause DIAM. Meloxicam is primarily metabolized to a 5’-hydroxymethyl metabolite by CYP2C9 (major) and CYP3A4 (minor) [ 15 ]. As stated before, CBD decreases the activity of CYP2C9 in vitro. It is possible that the inhibitory effect of CBD on CYP2C9 led to a higher concentration of meloxicam, which led to the DIAM. Given the increasing popularity of CBD, it is important for both physicians and patients to be aware of possible DDIs of these substances and the symptoms that may result.
None to declare.
None to declare.
Conflict of Interest
None to declare.
Consent to write and publish the case was obtained from the patient.
ME provided the body of the case report and summarized the case as well as contributing to the discussion, revising the final draft, and submitting the final paper for review. JK revised the final draft and provided expertise on the clinical importance of the case. SO and XL drafted the Introduction and Discussion and compiled and reformatted the references section.
The authors declare that data supporting the findings of this study are available within the article.
- U.S. Food and Drug Administration [Internet]. cited on May 3, 2020. What you need to know (and what we’re working to find out) about products containing cannabis or cannabis-derived compounds; [about 4 screens]. Available from: https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-conta.
- Results from the 2015 national survey on drug use and health: detailed tables. 2015. Accessed on March 14, 2020. https://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015.pdf.
- Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016;35:41-44.
- Iffland K, Grotenhermen F. An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoid Res. 2017;2(1):139-154.
- Brown JD, Winterstein AG. Potential adverse drug events and drug-drug interactions with medical and consumer Cannabidiol (CBD) use. J Clin Med. 2019;8(7):989.
- Consroe P, Kennedy K, Schram K. Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans. Pharmacol Biochem Behav. 1991;40(3):517-522.
- Medscape [Internet]. 1994-2020. cited on May 3, 2020. Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity; [about 2 screens]. Available from: March 13, 2020. https://emedicine.medscape.com/article/816117-overview.
- Jaja C, Bowman L, Wells L, Patel N, Xu H, Lyon M, Kutlar A. Preemptive genotyping of CYP2C8 and CYP2C9 allelic variants involved in NSAIDs metabolism for sickle cell disease pain management. Clin Transl Sci. 2015;8(4):272-280.
- Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet. 2012;27(3):294-300.
- Highlights of prescribing information. 2018. Accessed on March 29, 2020. https://www.epidiolex.com/sites/default/files/EPIDIOLEX_Full_Prescribing_Information.pdf.
- Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246-1251.
- O’Brien WM, Bagby GF. Rare adverse reactions to nonsteroidal antiinflammatory drugs. J Rheumatol. 1985;12(1):13-20.
- Tattevin P, Revest M, Lavoue S. Meningites et meningoencephalitesaseptiques. Reanimation. 2008;17(7):639-650.
- Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf. 2000;22(3):215-226.
- Schmid J, Busch U, Heinzel G, Bozler G, Kaschke S, Kummer M. Pharmacokinetics and metabolic pattern after intravenous infusion and oral administration to healthy subjects. Drug Metab Dispos. 1995;23(11):1206-1213.
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