What You Need to Know About Methotrexate Interactions (2023)

Methotrexate is the first-line treatment for most people with moderate to severerheumatoid arthritis (RA). Beyond RA, methotrexate is also used in the treatment of severe psoriasis and some types of cancer, such as breast cancer, lung cancer, lymphoma, and leukemia.

For each condition, methotrexate works by slowing the growth of cells—including cancer cells in cancer and skin cells in psoriasis. In rheumatoid arthritis, methotrexate helps decrease the activity of the immune system.

Some medications, however, can interact with methotrexate and cause adverse effects. It's important to be mindful of these potential drug interactions to make sure you reap the benefit of the medication and keep side effects to a minimum.

What You Need to Know About Methotrexate Interactions (1)

Severe Drug Interactions

Methotrexate is known to cause severe drug interactions when taken with many types of medications. Those taking methotrexate should be aware of the drug interactions and speak with their healthcare provider about the drugs or supplements they are taking prior to starting treatment with methotrexate.


Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and decrease inflammation. Because NSAIDS can affect kidney function and methotrexate is metabolized by the kidney, monitoring of the creatinine is recommended.

Some specific NSAIDs that should be avoided while taking methotrexate include:

  • Aspirin (Zorprin, Excedrin)
  • Bromfenac (Prolensa, Bromday)
  • Etodolac (Lodine)
  • Fenoprofen (Nalfon)
  • Ibuprofen (Advil, Motrin)
  • Naproxen (Aleve, Naprosyn)
  • Magnesium salicylate (Doan's)
  • Salsalate

Methotrexate (Rheumatrex) Side Effects

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Other RA Medications

For those with RA, which is an autoimmune disease, medication is needed to hinder the overactivity of the immune system. Using two medications that affect the immune system at the same time can hinder the ability of the body's natural defense system to fight off infections. It may also increase the risk of cancer over long-term treatment.

Some immunosuppressive medications that should be avoided while on methotrexate include:

  • Etanercept (Enbrel, Erelzi)
  • Leflunomide (Arava)

These medications have been shown to cause adverse side effects when taken with methotrexate, including hypertension, respiratory infections, gastrointestinal distress, and headaches.

Drugs such as diclofenac (Zorvolex) are more likely to affect the liver, so monitoring of the liver is recommended.

Medications to Treat Rheumatoid Arthritis


Medications that may affect how the kidneys function, such as the antiviral Adefovir, may increase health risks for someone taking methotrexate. This is because too much methotrexate in the body can lead to toxic effects while antiviral medications are taken at the same time.

Antiviral medications that pose serious risks while taking methotrexate include:

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  • Adefovir (Hepsera)
  • Cidofovir (Vistide)
  • Tenofovir (Viread)

Cancer Medications

Using cancer medications in conjunction with methotrexate can lead to adverse health effects. One such effect, toxicity, can occur when benzimidazoles are used with methotrexate simultaneously.

Other cancer medications that pose serious and possibly life-threatening effects when used in conjunction with methotrexate include:

  • Temsirolimus (Torisel)
  • Talimogene laherparepvec (Imlygic)
  • Thalidomide (Contergan, Thalomid)


If you are taking methotrexate, you should completely avoid taking any antibiotic that contains trimethoprim-sulfa, such as Bactrim, Sulfatrim, and Septra. Adverse effects are caused by the antibiotic's ability to reduce methotrexate absorption in the body. When the absorption rate is slowed, it can lead to a buildup of the medication in the body over time and cause toxicity.

Some other antibiotic medications that should not be taken with methotrexate include:

  • Amoxicillin (Amoxil, Moxatag, Trimox)
  • Ampicillin (Ampi, Omnipen, Principen)
  • Bacampicillin (Spectrobid, Penglobe)
  • Carbenicillin (Geocillin)
  • Cloxacillin (Cloxapen, Cloxacap, Tegopen, Orbenin)
  • Dicloxacillin (Dynapen)

You should also avoid gettingimmunized with live vaccines while using methotrexate. Speak to your healthcare provider about any possible immunizations you can and cannot receive.

If you experience liver problems, unusual bleeding, kidney problems, or signs of tumor lysis syndrome, call your healthcare provider immediately.

Moderate Drug Interactions

Taking methotrexate and some medications will pose a moderate risk of drug interactions. These interactions are not as dangerous as those above, but they do pose health risks.


Since low doses of methotrexate are typically used to treat inflammatory arthritis like RA, the interaction with NSAIDS is typically not clinically significant. Some NSAIDs can be used under direct supervision in people who take low-dose methotrexate, including:

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  • Celecoxib (Celebrex)
  • Diclofenac topical (Flector, Pennsaid, Rexaphenac, Solaraze, Voltaren)
  • Acetaminophen (Tylenol, Paracetamol)

Mental Disorder Medications

Taking methotrexate with some mental disorder medications can pose a moderate risk for adverse health effects. The antipsychotic medications that increase the risk for adverse effects are those that affect the liver. One such medication is chlorpromazine. Another medication that can increase the risk for liver toxicity is duloxetine (Cymbalta).

Diabetes Medication

People with diabetes are often at an increased risk of liver disease and infection, and the use of methotrexate together with some diabetes medications may increase that risk even further. Using methotrexate over a long period of time has also been linked to liver conditions such as cirrhosis.

Specific medications that should be avoided or used with caution include:

  • Quinapril (Accupril)
  • Acarbose (Precose)
  • Pioglitazone (Actos)
  • Rosiglitazone (Avandia)
  • Exenatide (Byetta, Bydureon)


For those taking diuretics, methotrexate may pose a moderate risk because methotrexate may hinder the actions of the diuretic medication, diminishing its therapeutic effect. Some specific diuretics that you should look out for when taking or starting methotrexate include:

  • Chlorpromazine (Thorazine, Largactil)
  • Indapamide (Natrilix, Indipam XL, Rawel XL, Tensaid XL, Alkapamid XL)
  • Bendroflumethiazide (Aprinox, Neo-Naclex)


Methotrexate has been reported as a seizure inducer and should be avoided by most on antiepileptic drugs. Some antiepileptic medications have been shown to reduce how well methotrexate works. Some specific seizure medications that should not be taken with methotrexate include:

  • Phenytoin (Dilantin, Phenytek)
  • Carbamazepine (Tegretol)
  • Valproic acid

Minor Drug Interactions

Some medications can be taken safely with methotrexate and may cause only minor effects. Typically, taking these drugs along with methotrexate wouldn’t require any change in dose or medication.


When used in conjunction with methotrexate, many immunosuppressants should be avoided. However, some are safe to use. For example, azathioprine (Imuran, Azasan) is an immunosuppressant that can be taken with methotrexate safely and effectively.


An antipsychotic medication that doesn’t have severe or moderate interactions with the medication is haloperidol (Haldol).


Since some people may need to take a seizure medication as well as methotrexate, it may be comforting to know that some epilepsy medications don’t pose a severe or moderate risk when taken with the drug. Anticonvulsants that are safe to take while on methotrexate include:

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  • Lamotrigine (Lamictal)
  • Levetiracetam (Keppra)


Although many NSAIDs should not be taken with methotrexate because of the increased risk of liver toxicity, tromethamine (Tham) is one that can be safely taken with only a small risk of increasing the natural side effects of methotrexate alone.

Folic Acid and Methotrexate

Some people who take methotrexate will need to take folic acid supplements because the medication can diminish the amount of folate in the body. Methotrexate causes the body to waste more of the nutrient than it normally would, causing a deficiency. Speak to your healthcare provider about whether you should be taking folic acid to prevent the deficiency before supplementing on your own.

Food Interactions

Many people don’t consider food interactions when taking new medications. When it comes to methotrexate, some foods or nutritional supplements can lead to adverse health effects or worsen the existing side effects of the drug.


There is some debate about whether caffeine poses a moderate risk of adverse effects when taking methotrexate. Some research suggests that it can limit the efficacy of methotrexate, while others have found that adding caffeine to a treatment plan can actually reduce symptoms of methotrexate intolerance. Although caffeine is listed as having the ability to reduce the efficacy of methotrexate in arthritis treatment, much of the literature suggests that claim is not accurate.


Methotrexate may cause liver damage if taken for an extended period of time, so those who take the medication should avoid alcohol as much as they can. Drinking alcohol while taking this medication has been shown to increase the risk of liver toxicity.

Other Foods and Beverages

Some research has shown that those who drink grapefruit juice regularly should speak to their healthcare provider prior to starting methotrexate. It has also been found that taking willow bark while on methotrexate could lead to adverse interactions. People taking methotrexate should also avoid acidic diet cola since it can lead to a buildup of the drug in the body by hindering the body's ability to expel it.

A Word From Verywell

Methotrexate has the potential to improve your quality of life significantly by helping you manage your condition, but it also has the potential to add to your existing health problems through drug interactions. The best thing to do before starting a new treatment is discuss all your medications and supplements thoroughly with your healthcare provider to avoid drug interactions. If you’re already taking methotrexate, it’s also important to speak with your healthcare provider before taking any new natural health supplements or medications. If you do experience any side effects, be sure to contact your healthcare provider.

Reducing Your Risk of Adverse Medication Interactions

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