Methotrexate (Rheumatrex) Side Effects

Drug Used to Treat Several Autoimmune Diseases

Methotrexate is a drug that interferes with cell metabolism, therefore it is used to treat conditions where cell growth needs to be impeded, such as psoriasis and cancer. Methotrexate also suppresses the immune system, which is why it is prescribed for autoimmune conditions such as rheumatoid arthritis and inflammatory bowel disease (IBD).

Methotrexate pills on a gray background
Pillbox / National Library of Medicine

Methotrexate can be an effective and usually safe drug, but it does have a long list of dose-dependent side effects. People who have Crohn's disease typically do not receive this drug in high doses, so, although all of these side effects are possible, people taking it for Crohn's disease are less likely to develop them. Methotrexate is to be taken only in close consultation and with close follow-up from a healthcare provider and any and all side effects should be discussed with your healthcare provider.

Important Information

Methotrexate prescribing information comes with what's called a black box warning. This is a special statement at the top of the methotrexate prescribing information that's surrounded by an outline (which is commonly called a "black box"). The black box warning for methotrexate is quite long and can be a little scary. If there are concerns, talk with a healthcare provider about the risks of methotrexate versus the benefits to health. The risk for certain complications may be more or less, and only a healthcare provider can help put that into perspective. What's more, it's important for a healthcare provider to understand individual concerns because every patient will have different ones. 

Methotrexate can cause serious birth defects and should not be taken during pregnancy or by women who plan to become pregnant. This is because of the risk of birth defects or fetal death. If you become pregnant while taking methotrexate, notify your healthcare provider immediately.

Some of the key points outlined in the black box warning are:

  • Methotrexate should only be used under the care of healthcare providers experienced with the use of antimetabolite medications
  • Methotrexate should only be used in the case of "disabling disease" that doesn't respond to other therapy
  • Patients need regular monitoring for toxicities (specifically bone marrow, liver, lung, and kidney)
  • Healthcare providers should educate patients on the risks of therapy with methotrexate
  • Methotrexate should not be used by women who are or who will become pregnant 
  • Patients with renal dysfunction, ascites, or pleural effusions require special monitoring
  • Toxicities have been reported in people taking high doses of methotrexate along with certain nonsteroidal anti-inflammatory drugs (NSAIDs) 
  • Long use of methotrexate can cause hepatotoxicity, fibrosis, cirrhosis, and elevated liver enzymes
  • Lung disease has been reported, and any symptoms such as a dry cough should be investigated
  • If diarrhea and ulcerative stomatitis occur, the drug needs to be stopped
  • Malignant lymphomas can occur but may reverse when the drug is stopped
  • Tumor lysis syndrome has been reported and may need to be prevented or treated
  • Skin reactions are a possibility, usually within days of an injection
  • Infections have been reported, especially Pneumocystis carinii pneumonia 
  • There is a risk of soft tissue necrosis and osteonecrosis when methotrexate is used with radiotherapy 
  • The use of proton pump inhibitors (PPIs) can increase the time methotrexate is in the body

Temporary Side Effects

Check with your healthcare provider if any of the following side effects continue or are bothersome:

  • Acne
  • Boils
  • Lack of appetite
  • Nausea or vomiting
  • Pale skin
  • Sensitivity to sunlight
  • Itching or rash
  • Temporary hair loss

Notify Your Healthcare Provider If You Experience

  • Back pain
  • Dark urine
  • Dizziness
  • Drowsiness
  • Headache
  • Unusual weakness or fatigue
  • Yellow eyes or skin (jaundice)

Notify Your Healthcare Provider Immediately If You Experience

  • Diarrhea
  • Reddening of skin
  • Sores on mouth and lips
  • Stomach pain

Less Common or Rare

  • Allergic reaction
  • Blurred vision
  • Chest pains
  • Confusion
  • Dead or loose skin layers
  • Fever or chills
  • Pinpoint red spots on the skin
  • Painful peeling of skin patches
  • Painful or difficult urination
  • Red blisters or ulcers on the lip, mouth, eye, nasal passages, and genital area
  • Reddening of the skin with or without hair loss
  • Seizures (convulsions)
  • Shortness of breath, cough, hoarseness or wheezing
  • Side or lower back pain
  • Sloughing of skin, muscle, and bone
  • Unusual bleeding or bruising

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your healthcare provider. This information is meant only as a guideline — always consult a healthcare provider or pharmacist for complete information about prescription medications.

3 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. US National Library of Medicine. Methotrexate boxed warning.

  2. PDR. Methotrexate—boxed warning.

  3. PDR. Methotrexate. Adverse reactions.

Additional Reading
  • Hospira, Inc. "Methotrexate Injection, USP."

  • Roxane Laboratories. "METHOTREXATE Tablets USP, 2.5 mg."

By Amber J. Tresca
Amber J. Tresca is a freelance writer and speaker who covers digestive conditions, including IBD. She was diagnosed with ulcerative colitis at age 16.