Methotrexate and Folic Acid

In This Article

Folate deficiency is a side effect of methotrexate, a commonly prescribed medication for rheumatoid arthritis (RA) sold under the brand names Rheumatrex and Trexall. If you take methotrexate, your doctor may also prescribe folic acid to prevent deficiency.

Taking folic acid alongside methotrexate has also been shown to reduce certain side effects of the drug, prevent adverse effects, and improve medication compliance. If you currently take methotrexate, talk to your doctor to find out if adding folic acid is right for you.

What Folate Does

Folate, also known as folic acid or vitamin B9, plays an important role in the formation of red and white blood cells and the production of DNA.

Found in beans, dark leafy green vegetables, citrus fruits, and whole grains, folate is a water-soluble vitamin, which means it is not stored in fat cells. As a result, the body does not maintain adequate stores of the nutrient for very long, and regular replenishment of folic acid is needed.

Folate deficiency can lead to fatigue, irritability, diarrhea, poor growth, and a smooth and tender tongue. Left unchecked, it can cause folate-deficient anemia, low levels of white blood cells, and a low platelet count. 

Methotrexate's Effect on Folate

Methotrexate is the most commonly prescribed disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis and other rheumatic conditions. Available in oral and injectable formulations, methotrexate is usually administered once a week (on the same day every time) in doses ranging from 7.5 milligrams (mg) to 25 mg.

Initially developed to treat cancer, methotrexate is an antifolate drug. It works to stop cancer cells from multiplying by blocking their access to folate. As a result, folate is quickly depleted in people who take methotrexate. To replenish this important vitamin, doctors commonly prescribe folic acid for their rheumatoid arthritis patients who are treated with methotrexate.

The complicated interplay of methotrexate and folate led to earlier speculation that taking folic acid alongside methotrexate may reduce the drug's effectiveness. However, more recent research indicates that folic acid supplementation does not interfere with methotrexate's ability to combat arthritis.

Benefits of the Combination

Taking folic acid alongside methotrexate does more than just prevent folate deficiency. Research shows it helps to reduce some side effects of the drug, including nausea, vomiting, and mouth sores.

Folic acid also appears to play a role in preventing liver failure, a potential adverse effect of methotrexate use.

A 2013 systematic review of published literature found folic acid significantly reduced the risk of elevated liver enzymes and gastrointestinal toxicity in people prescribed methotrexate.

A similar paper published in the Journal of Clinical Rheumatology in 2019 found that folate supplementation can lower the risk of liver toxicity in patients who take methotrexate and may prevent liver failure.

The study used data from six clinical trials for a combined total of 709 patients. Researchers found folic acid supplementation also improved medication compliance in patients taking methotrexate. In addition, investigators noted that folic acid appears to reduce methotrexate withdrawal symptoms.

Folic Acid Dosing

There is no standard dosing for folic acid taken alongside methotrexate. The minimum recommended dose of folic acid in patients taking methotrexate is 5 mg a week.

Some doctors may prescribe a single 5-mg or 10-mg dose to be taken once a week on the day after you take your weekly dose of methotrexate. 

Other doctors routinely prescribe 1 mg daily. If that's true in your case, your doctor may advise you not to take it on the day of your methotrexate dose. There is no research to support that not skipping this dose is harmful or that it provides any additional benefits.

Prescription-strength folic acid is available as a tablet (1 mg, 800 mcg, or 400 mcg), as well as a liquid (5 mg/mL). Over-the-counter folic acid supplements are also available, but keep in mind that supplements are not regulated by the U.S. Food & Drug Administration (FDA) and dosages are not standardized.

People taking folic acid with methotrexate should use the prescription-strength medication to ensure proper dosing.

For people not taking methotrexate, the recommended daily intake of folate is 400 mcg for adults and 600 mcg for women who are pregnant or may become pregnant. The maximum daily dose without doctor supervision is 1 mg.

Methotrexate is a pregnancy category X drug and should not be used by women who are pregnant or planning to become pregnant, as it could lead to miscarriage and birth defects.

A Word From Verywell

While folic acid appears to offer benefits to patients taking methotrexate for rheumatoid arthritis, it is important to talk to your doctor before adding folic acid to your medication regimen. If your doctor feels that folic acid supplementation is right for you, they will write you a prescription and instruct you on how best to take it.

Was this page helpful?
Article 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. U.S. National Library of Medicine: MedlinePlus. Folate deficiency. Updated July 8, 2019.

  2. Singh JA. Folic acid supplements for rheumatoid arthritis patients taking methotrexate: the good gets better (editorial). Cochrane Database of Systematic Reviews. 2013;7:ED000063. doi:10.1002/14651858.ED000063

  3. Taylor PC, Balsa Criado A, Mongey AB, Avouac J, Marotte H, Mueller RB. How to get the most from methotrexate (MTX) treatment for your rheumatoid arthritis patient?-MTX in the treat-to-target strategyJ Clin Med. 2019;8(4):515. doi:10.3390/jcm8040515

  4. Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2013;5:CD000951. doi:10.1002/14651858.CD000951.pub2

  5. U.S. National Library of Medicine: MedlinePlus. Folic acid. Updated April 22, 2020.

  6. Liu L, Liu S, Wang C, et al. Folate supplementation for methotrexate therapy in patients with rheumatoid arthritis: a systematic reviewJ Clin Rheumatol. 2019;25(5):197-202. doi:10.1097/RHU.0000000000000810

  7. NIH: Office of Dietary Supplements. Folate: Fact sheet for health professionals. Updated June 3, 2020.

  8. Dawson AL, Riehle-Colarusso T, Reefhuis J, Arena JF; National Birth Defects Prevention Study. Maternal exposure to methotrexate and birth defects: a population-based studyAm J Med Genet A. 2014;164A(9):2212-2216. doi:10.1002/ajmg.a.36625

Related Articles