10 Side Effects of Methotrexate You Should Know About

Methotrexate is a medication with many uses. As chemotherapy, it can treat different types of cancer. Methotrexate also has anti-inflammatory effects and can be used to treat autoimmune disorders, like rheumatoid arthritis (RA). Your dosage can vary widely depending on why you’re taking the medication. 

Methotrexate can be given a few different ways, including by mouth, as a pill or liquid, and as an infusion into the vein (IV). It can also be injected under the skin (subcutaneous), into the muscle (intramuscular), or into the spine (intrathecal). 

While it’s a versatile medication, there are a number of methotrexate side effects to know about. Some of the most common ones can be managed early. But others are more serious and require monitoring by your healthcare provider. This includes several that have boxed warnings, the FDA’s strictest warning for medications. 

Below, we’ll review 10 methotrexate side effects — and some risk factors — to watch out for with treatment.

1. Mouth sores

Mouth sores (mucositis or stomatitis) are a common methotrexate side effect. Sometimes, these spread to the esophagus or stomach. They can feel like pain, discomfort, or sensitivity when you eat, chew, or swallow. You may notice small ulcers, white or yellow patches, or bleeding in your mouth.

Talk to your healthcare provider about their recommendations for preventing and treating mouth sores from methotrexate. Unless directed, avoid self-treating with certain over-the-counter (OTC) pain medications, like non-steroidal anti-inflammatory drugs (NSAIDS). NSAIDs can interact with methotrexate, resulting in worse side effects. 

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2. Nausea and vomiting

Nausea (and sometimes vomiting) is another common methotrexate side effect. Diet can also play a role in nausea and vomiting symptoms. Things like big meals and strong smells may make it worse. If you vomit, drinking clear liquids and eating mild foods, like bananas, rice, or toast, can help.

If nausea is still an issue, talk to your healthcare provider about other strategies to help manage it. If you’re taking methotrexate by mouth, the number of pills you’re taking at a time may be spaced out to help with nausea and other gastrointestinal (GI) side effects (like diarrhea). Or, you might be switched to a different dosage form, like an injection. Your healthcare provider may also prescribe an anti-nausea medication.

3. Hair loss

Alopecia (hair loss) depends on the dose of methotrexate. Higher doses, like those used as chemotherapy, can damage the hair follicles. In this case, hair loss tends to be more likely. At lower doses (such as those used to treat RA), hair loss is less common.

Ask your healthcare provider if hair loss is likely with your dose of methotrexate. If you notice changes, there are resources to help cope with hair loss.

4. Diarrhea

Diarrhea is another common GI side effect. Minor cases can be managed at home with OTC medications or diet changes. But some cases of diarrhea can be serious. 

Call your healthcare provider if you experience:

• Fever of 100.4°F or higher

• Four more bowel movements than your normal number per day

• Diarrhea that lasts for more than one day

• Bleeding or soreness in your rectal area

• Dizziness

It’s also important to stay hydrated if you experience diarrhea. Try to drink at least 8 to 10 glasses of clear fluids per day.

5. Rash

Both high and low doses of methotrexate have been associated with rashes and other skin problems. Methotrexate can also make your skin more sensitive to the sun. Avoid spending a lot of time in the sun, and make sure to wear protective clothing and apply sunscreen.  

Report any skin irritation, redness, or swelling to your healthcare provider. Though rare, severe skin reactions, including Stevens-Johnson syndrome, have been reported.

6. Liver problems

Low, long-term methotrexate dosing (like for RA) can cause changes in liver function tests and fibrosis (scarring in the liver). These are usually mild and can get better without treatment. Serious hepatotoxicity (liver damage) is rare, but it’s still possible. And it’s less common with high doses of methotrexate. 

Still, your healthcare provider should screen for liver damage prior to treatment and monitor liver tests periodically during treatment.

You should also avoid or limit other medications that could be toxic to the liver, like acetaminophen (Tylenol). Limiting excessive alcohol intake is also important. Talk to your healthcare provider about ways to limit other potential harm to your liver.

7. Lung problems

Pulmonary toxicity (lung damage) can also happen with methotrexate. Symptoms include a persistent dry cough or shortness of breath. Lung problems are rare, occurring in less than 1% of people who take low-dose methotrexate for RA. It’s even less common with high doses of methotrexate.

8. Kidney problems

The kidneys are the main organ responsible for getting rid of methotrexate. Pre-existing kidney problems can put you at higher risk for methotrexate side effects, including kidney damage. Even without kidney issues, new kidney problems can happen in up to 12% of people taking high-dose methotrexate. 

If you take methotrexate at home, watch for any worsening side effects. This can be a sign that your kidneys aren’t removing the medication as well. There are also lab tests that your healthcare provider may order to monitor your kidneys. 

9. Blood cell effects

Methotrexate may also cause myelosuppression. This is when your bone marrow makes much fewer red blood cells, white blood cells, and platelets than normal. This can raise your risk of infection, make you feel tired, and/or put you at risk for bleeding. 

The risk of myelosuppression is greater with high doses of methotrexate. But even lower doses of methotrexate can also cause blood cell effects. 

Contact your healthcare provider if you notice symptoms like unexplained bruising, feeling extremely tired, or signs of an infection. They should also monitor your labs with a complete blood count periodically during treatment.

10. Nerve cell damage

Methotrexate can cause different brain or spinal cord problems that cause seizures, confusion, or blindness. Though rare, this can even occur with low doses of methotrexate. High doses may cause stroke-like symptoms. 

If injected into the spine, methotrexate can cause inflammation around the spinal nerves that cause headache, back pain, or stiff neck. Benzyl alcohol, a preservative found in some methotrexate injections, can cause serious neurotoxicity. Because of this, these products should be avoided for spinal injections and high-dose regimens.

When should I contact my healthcare provider about side effects from methotrexate?

Side effects can happen at any time. So, it’s never too soon to ask questions. Some common side effects, like mouth sores, nausea, and diarrhea, can become serious issues that require medical attention. Tell your healthcare provider about any side effects you’re experiencing.

In some cases, leucovorin (also called folinic acid) is used as a “rescue” to help protect healthy tissues from the toxic effects of methotrexate. 

If you’re worried about a new side effect, or if your current side effects are getting worse, contact your healthcare provider right away.

What can I do to manage the side effects of methotrexate?

When used as an IV treatment for cancer, methotrexate is typically given in the hospital. Your healthcare provider will monitor for side effects and watch your labs. 

When higher doses of methotrexate are given, leucovorin is used to help reduce the risk of side effects. If methotrexate levels are too high, an enzyme-based medication called glucarpidase can be used.

Your healthcare provider may recommend taking a folic acid supplement to help lower the risk of certain side effects. But this isn’t an option for everyone. In some cases, folic acid may interfere with how methotrexate works, especially for cancer. You should only take folic acid if directed by your healthcare provider.

Switching to a different formulation of methotrexate may also help. One review of methotrexate for RA found that switching from oral pills to a SC injection may be better tolerated with fewer GI side effects. In some cases, your healthcare provider may have you stop taking the medication for a period of time until the side effects resolve. But you shouldn’t try to do this on your own.

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Written by:

Emmeline C. Academia, PharmD, BCOP

Emmeline C. Academia, PharmD, BCOP, has been a practicing clinical pharmacist in adult oncology since 2020. She is a clinical pharmacy specialist in oncology at Beth Israel Deaconess Medical Center, in Boston.

Edited by:

Alyssa Billingsley, PharmD

Alyssa Billingsley, PharmD, is the director of pharmacy content for GoodRx. She has over a decade of experience as a pharmacist and has worked in clinical, academic, and administrative roles.

Reviewed by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

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