The Signs of Methotrexate Toxicity and How It’s Treated

There’s a frequent misconception that methotrexate — a common medication used to treat a wide variety of health conditions — is very toxic. This is likely due to the fact that it’s often used in high doses to treat some forms of cancer. However, when used for autoimmune disorders, like for rheumatoid arthritis or psoriasis, it’s taken in much smaller doses, and it’s usually better tolerated. So methotrexate is safe when taken correctly and monitored appropriately.

But, in rare cases, someone may end up with too much methotrexate in their system. If taken or prescribed incorrectly, it’s possible to develop methotrexate toxicity. Thankfully, there are ways to treat and prevent potentially severe side effects caused by methotrexate.

In this article, we’ll discuss methotrexate’s common uses and potential toxicity, and how to prevent and treat toxicity if it develops.

Promotional Disclosureinfo_outlined

SPECIAL OFFER

Save over 40% on Qsymia with GoodRx

Discover the once daily Qsymia for weight management. Qsymia is for adults and children 12-17 in combination with a healthy diet and regular exercise.

Save now

What is methotrexate most commonly used for? 

Methotrexate is a medication in a class called antifolate antimetabolites, and it’s similar in structure to folic acid (vitamin B9). Folic acid is a vitamin that helps the body make DNA and new cells. Methotrexate comes as an oral tablet, oral liquid, and injectable product.

Methotrexate works by blocking dihydrofolate reductase (DHFR), which is an enzyme (protein) important in building and repairing DNA. This action affects the body’s ability to create new cells and is helpful for treating conditions that are caused by rapidly growing cells, like cancer. But the specific way it works for autoimmune conditions like rheumatoid arthritis isn’t fully understood. 

Blocking DHFR results in a lower amount of folic acid in the body. Having less folic acid causes many of the medication’s side effects. You can read more about the relationship between methotrexate and folic acid here.

Promotion disclosure

Methotrexate

Avg retail price

$31.41(Save 60.65%)

GoodRx discount

$12.36

Compare all prices

How is it dosed?

Methotrexate treatment is typically categorized by dose, which is usually based on body weight (mg/m²). Regardless of whether you take the medication by mouth or if it’s injected, there are different doses. 

• Low dose (less than 50 mg/m2): Low-dose methotrexate most commonly treats autoimmune diseases such as rheumatoid arthritis. It may also be used to treat certain kinds of cancer. 

• Intermediate dose (between 50 to 500 mg/m2): Intermediate-dose methotrexate is used most commonly for malignant gestational trophoblastic disease. This is a rare tumor that can develop during the early stages of pregnancy.

• High dose (doses greater than or equal to 500 mg/m2): High-dose methotrexate is used most commonly to treat cancers like leukemia, high-risk lymphomas, and osteosarcoma. 

What is methotrexate toxicity?

Methotrexate toxicity can occur if too much methotrexate is in the body. It’s more common with high-dose methotrexate, but it can happen with lower doses, too. Usually it’s caused by dosing errors, accidental methotrexate overdoses, or other risk factors that may raise a person’s chance of experiencing methotrexate toxicity. 

For example, methotrexate is often taken once weekly, while folic acid is taken daily at the same time. Folic acid is used alongside to help lower methotrexate’s side effects. It’s easy to get confused and accidentally take methotrexate daily instead of once a week. 

Interactions with other medications can also occur. This can lead to higher amounts of methotrexate in the body. Methotrexate can interact with several medications, including:

• Proton pump inhibitors (PPIs) like esomeprazole (Nexium) or omeprazole (Prilosec)

• Sulfamethoxazole/trimethoprim (Bactrim)

• Doxycycline

• Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Advil, Motrin) or naproxen (Aleve, Naprosyn)

• Salicylates like aspirin 

Other risk factors, like drinking alcohol or poor kidney function, can interfere with the body’s ability to get rid of methotrexate properly. This can lead to higher levels of methotrexate building up in the body.

What are the symptoms of methotrexate toxicity?

Symptoms of methotrexate toxicity are highly dependent on the dose of methotrexate, how often it’s given, and what else it’s given with. 

Minor toxicity symptoms occur in about 20% to 30% of people taking methotrexate. This is mostly due to lower levels of folic acid in the body. Minor toxicity symptoms can include:

• Stomach problems such as nausea, vomiting, or diarrhea

• Mouth sores (called stomatitis)

• Muscle pain

• Headache

• Fatigue

• Difficulty concentrating

• Feeling dizzy

• Generally not feeling well

• Hair loss

• Fever

More severe toxicity symptoms rarely occur, but they can be life-threatening. These are discussed next. 

Hepatotoxicity (liver damage) 

Methotrexate can build up in the liver and cause direct damage to liver cells. Liver damage is more common in people who have been taking methotrexate for a long time or are taking it in high doses. People should be screened for liver damage prior to starting methotrexate, and liver function should be monitored regularly throughout treatment

Pulmonary toxicity (lung damage)

Methotrexate can also gather in the lungs and damage lung cells. Lung damage is more common in people who have diabetes, chronic lung disease, or are older than 60. Symptoms can include a persistent dry cough (without mucus) and shortness of breath. People should have a chest X-ray prior to starting methotrexate to check for pre-existing lung disease.

Nephrotoxicity (kidney damage)

Methotrexate is removed from the body through the kidneys, so it can build up there. This can cause kidney damage. Treatment with methotrexate isn’t recommended in people with certain kidney problems.

Bone marrow suppression

Methotrexate can lower the amount of blood cells made by your bone marrow. This can include red blood cells that carry oxygen to your tissues, white blood cells that fight infections, and platelets that help your blood clot. This is usually related to high doses of methotrexate, kidney problems, and low folic acid levels. Older age and drug interactions can also be factors. 

Neurotoxicity (nerve cell damage)

Methotrexate can travel into the central nervous system and affect nerves. This is usually caused by high doses of methotrexate, especially when injected into the spine. Symptoms may include confusion, muscle weakness, and seizures.

What can reduce or treat methotrexate toxicity?

Multiple medications can prevent and treat methotrexate toxicity. Some of these medications are started when you begin taking the medication, and some are used only after developing this toxicity. The three main medications used are folic acid, leucovorin, and glucarpidase (Voraxaze).

Folic acid

Since methotrexate lowers the body’s supply of folic acid, it’s often recommended that people take a folic acid supplement. Folic acid supplementation allows the body to replete its stores of folic acid and lessen the side effects of methotrexate treatment. However, folic acid may not be recommended if you’re taking methotrexate for cancer, since this may affect how well the medication works.

One review evaluated six randomized controlled trials looking at whether folic acid could help improve methotrexate side effects in people taking it for rheumatoid arthritis. Folic acid supplementation was found to lessen side effects like nausea and stomach pain and lower the risk of liver problems. 

Folic acid is available both over-the-counter (OTC) and by prescription. Talk to your healthcare provider first to make sure it’s safe for you to take. They can also give you specific dosing recommendations so that you get the most benefit.

Leucovorin

Leucovorin can be used as a rescue medication while taking methotrexate. It works by “rescuing” — or rapidly treating — normal cells in the body from the side effects of high doses of methotrexate. 

This is helpful for people who receive high-dose methotrexate, which typically includes people with cancer. Giving leucovorin after methotrexate allows people to minimize side effects without making their cancer treatment less effective. Leucovorin works especially well at lessening side effects like low blood cell counts, stomach problems, and neurotoxicity. 

Leucovorin is available as an oral tablet taken by mouth, an intravenous (IV) medication given through the vein, or an intramuscular injection into the muscle.

Glucarpidase

Glucarpidase is an antidote (remedy) for methotrexate toxicity. It’s usually given in combination with leucovorin to help prevent severe and potentially life-threatening methotrexate toxicity. Glucarpidase inactivates methotrexate and quickly lowers the amount of it in the bloodstream. Glucarpidase has been shown to lower methotrexate levels by over 95% within 15 minutes of administering it. 

It’s not routinely stocked in hospitals, but it can be ordered for emergency use. Glucarpidase is an IV medication and is given as a single injection at a dose of 50 units per kg body weight.

Why trust our experts?

Written by:

Sonja Jacobsen, PharmD, BCPS, BCOP

Sonja Jacobsen, PharmD, BCPS, BCOP,  is a clinical oncology pharmacy specialist currently practicing in Seattle. She has been practicing as a pharmacist since 2015 and is licensed to practice in Washington state and North Carolina.

Edited 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.

Reviewed 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.

Our editorial standards

Meet our experts