What You Should Know About CBD and Methotrexate

Cannabidiol, also known as CBD, is a non-psychoactive cannabinoid produced by the Cannabis sativa L. plant. It has garnered attention as a natural alternative for treating chronic pain and inflammation for arthritis. However, it can interact with medications that people with conditions like rheumatoid arthritis (RA) are already taking, namely methotrexate. Those taking methotrexate need to know how also using CBD to manage their symptoms can impact their liver functioning.

Man looking at CBD oil bottle in kitchen
Man looking at CBD oil bottle in kitchen.  PeopleImages, Getty Images

How CBD Helps Arthritis

CBD has shown therapeutic properties that are potentially useful in the treatment of different forms of arthritis, including anti-inflammatory effects, pain-relieving (analgesic) effects, and possible anti-insomnia effects. These benefits, however, have only been demonstrated in animal studies, not human ones, meaning these findings may not apply to people.

A medical literature review found that some of the evidence supporting the use of CBD is of low quality. The authors concluded that there is insufficient evidence for recommendation for any cannabinoid preparations for symptom management in patients with chronic pain associated with rheumatic diseases.

A more recent study in 2019 showed that CBD can potentially help with RA, but highlights the importance of targeting the right cannabinoid receptors in the right place. Even so, the study authors suggested that further research based on their findings to pinpoint the exact mechanism through which CBD works for people with RA is needed.

The current evidence supporting the use of CBD for arthritis pain is largely anecdotal and derives from animal research. More well-designed, scientifically valid, and rigorous clinical trials are needed to answer the question of how helpful CBD is to people with chronic arthritis pain.

How CBD Works For Pain

Cannabinoids, like non-psychoactive CBD, are said to reduce pain by activating central and peripheral cannabinoid type 1 (CBD1) receptors, peripheral cannabinoid type 2 receptors (CB2) receptors, and CBD-sensitive non-cannabinoid receptor targets.

Cannabinoids show anti-inflammatory effects by activating cannabinoid type 2 receptors (CB2), which decrease cytokine (protein secreted by immune system cells) production and immune cell mobilization. Cannabinoid type 1 receptor (CB1) activation on immune cells is pro-inflammatory, while CB1 antagonism provides anti-inflammatory effects.

Potential Interactions

CBD is a chemical substance metabolized in the liver with the help of cytochrome P450 enzymes, namely the CYP3A4 enzyme. It is estimated that 60% of clinically prescribed drugs, including methotrexate, are also metabolized via CYP3A4. This means some medications can either inhibit CBD's therapeutic potential or lead to slower substance degradation, leading to higher CBD doses that are active in the body longer. 

Animal studies have linked the use of CBD to increased liver enzyme levels, which raise the risk of liver toxicity in people taking methotrexate, which has also been associated with elevated liver enzyme levels. Increased liver enzyme levels indicate problems with the liver. This is why it’s crucial to be transparent with your healthcare provider about any medications (including over-the-counter drugs), supplements, vitamins, or herbs you may be consuming to reduce risk of negative interactions. Never begin, alter, or stop the use of CBD without consulting your healthcare provider.

CBD, Methotrexate, and Alcohol

While using CBD or taking methotrexate, you should limit or avoid consumption of alcohol. Alcohol is a known toxic substance that adds stress to your liver—the organ responsible for detoxifying and removing alcohol from your bloodstream. Increasing the toxic load on your liver can increase your risk of liver damage since CBD and methotrexate are tied to a higher risk of liver toxicity.

Any amount of alcohol in your system will take metabolic priority, which interferes with your ability to effectively metabolize medications like CBD and methotrexate.

When to Call Your Healthcare Provider

You should call your healthcare provider if you have any of the following symptoms of liver damage:

  • Fever
  • Chills
  • Joint pain or swelling
  • Unusual bleeding or bruising
  • Skin rash or itching
  • Loss of appetite
  • Fatigue
  • Nausea or vomiting
  • Abdominal pain
  • Dark urine
  • Pale stools
  • Yellowing of the skin or eyes

Monitoring Liver Function

If your healthcare provider decides CBD and methotrexate are appropriate for your arthritis, they will also recommend liver function monitoring. Your healthcare provider will order periodic liver panels, which are a group of lab tests that will check everything from your liver enzyme levels to the rate at which your liver metabolizes certain substances.

These tests offer early detection of liver problems and toxicity to prevent further issues and potential damage as well as preserve optimal functioning. You can also have individual tests conducted to monitor specific liver enzymes such as AST and ASL.

The elderly needs to take extra precautions because the liver's ability to metabolize many substances decreases with aging.

How to Use CBD Safely

Taking CBD and methotrexate together should only ever be done under the supervision of a medical professional who knows your current list of prescriptions, vitamins, supplements, and over-the-counter medications. 

Tips for safely using CBD when you have arthritis:

  • Do not use CBD as a substitute for disease-modifying treatment for inflammatory arthritis
  • Always talk to your prescribing healthcare provider or rheumatologist before starting or stopping CBD treatment
  • As with any cannabis product, start low (dose) and go slow (when titrating)
  • Avoid vaping CBD because the inhalation of vapor oils and chemical byproducts carry unknown risks, particularly for people with inflammatory arthritis
  • If you experience negative side effects like drowsiness or nausea when using any CBD product, contact your healthcare provider

Tips for safely using CBD and methotrexate: 

  • Talk to your healthcare provider about recommended dosing times
  • Keep a diary of symptoms and responses to your medications
  • Avoid taking CBD edibles like gummies and chocolates because onset and dosing is unreliable 
  • Do try topical CBD creams and salves on the skin area over painful joints, but know that more research is needed to confirm how CBD is delivered through the skin barrier

What to Look For

CBD products exist outside the regulations that ensure safe handling, processing, and administering of prescription drugs. This means you can find CBD products everywhere from online to farmer’s markets, so there may be concerns about purity and potency of the products you purchase. 

According to one study on currently available CBD products, nearly 43% were under-labeled, meaning their cannabinoid content was higher than the label claimed, around 26% were over-labeled, meaning they contained more CBD than claimed, and just 30% were accurate.

Other considerations include THC content and the presence of additional ingredients, preservatives, and contaminants. 

When looking for a CBD product:

  • Look for products manufactured in the United States with ingredients grown domestically
  • Choose products made by companies that follow good manufacturing practices established by the FDA for pharmaceuticals or dietary supplements or required by the state where they are manufactured
  • Buy from companies that test each batch and provide a certificate of analysis from an independent lab that uses validated standardized testing methods approved by the American Herbal Pharmacopoeia (AHP), the U.S. Pharmacopeia (USP), or the Association of Official Agricultural Chemists (AOAC)
  • Avoid companies that claim their products have disease benefits
  • Be aware that marketers and people behind retail counters are not health professionals; they are salespeople  

A Word From Verywell

Taking CBD along with methotrexate increases your risk of liver toxicity and requires periodic liver monitoring to preserve overall health and function. While the CBD market expands and continues to go unregulated, claims of all kinds are repeated by manufacturers looking to sell products to people who care about their health. Put your healthcare provider’s professional opinion above any company’s claims and remember human studies are still needed to understand the full potential and risks of using CBD for RA.

9 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Lowin T, Schneider M, Pongratz G. Joints for joints: cannabinoids in the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2019;31(3):271-78. doi:10.1097/BOR.0000000000000590.x

  2. Urits I, Borchart M, Hasegawa M, Kochanski J, Orhurhu V, Viswanath O. An update of current cannabis-based pharmaceuticals in pain medicine. Pain Ther. 2019;8(1):41–51. doi:10.1007/s40122-019-0114-4.x

  3. Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in anxiety and sleep: A large case series. Perm J. 2019;23:18–041. doi:10.7812/TPP/18-041.x

  4. Fitzcharles MA, Baerwald C, Ablin J, Häuser W. Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials. Schmerz. 2016 Feb;30(1):47-61. doi: 10.1007/s00482-015-0084-3

  5. Iffland K, Grotenhermen F. An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studiesCannabis Cannabinoid Res. 2017;2(1):139-154. doi:10.1089/can.2016.0034.x

  6. Cleveland Clinic. 6 Surprising ways alcohol affects your health—not just your liver.

  7. Arthritis Foundation. CBD for arthritis pain: What you should know.

  8. Harvard Health Publishing. Does CBD help with arthritis pain?

  9. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318(17):1708–09. doi:10.1001/jama.2017.11909.x

By Michelle Pugle
Michelle Pugle, BA, MA, is an expert health writer with nearly a decade of contributing accurate and accessible health news and information to authority websites and print magazines. Her work focuses on lifestyle management, chronic illness, and mental health. Michelle is the author of Ana, Mia & Me: A Memoir From an Anorexic Teen Mind.