The Benefits of Taking Folic Acid with Methotrexate

If you take methotrexate, a drug commonly used to treat autoimmune diseases and certain cancers, your healthcare provider will likely prescribe folic acid as well. Folic acid is a synthetic form of folate, a natural form of vitamin B9 derived from food.

Folate deficiency is a common side effect of methotrexate use. Taking folic acid with methotrexate reduces the risk of this by replacing lost folate in the blood. Folic acid can also help prevent other side effects of the drug, including nausea, vomiting, and mouth sores.

This article explains what folate deficiency is and how methotrexate contributes to it. It also describes how folic acid is taken while you are on methotrexate therapy.

What Is Folate Deficiency?

Folate deficiency, also known as vitamin B9 deficiency, is when you have abnormally low levels of folate in the blood.

Folate is the type of vitamin B derived from beans, citrus fruits, whole grains, and dark leafy green vegetables. It plays an important role in the formation of red blood cells, white blood cells, and platelets as well as the production of DNA (the molecule in cells that contains all your genetic information).

How folic acid is used in the body
 Verywell / JR Bee

Folate is also needed for a process known as mitosis, in which cells divide to form two identical cells. It also plays a central role in acquired immunity, a disease-specific form of immunity caused by exposure to viruses and other pathogens.

Folate is a water-soluble vitamin, meaning that it is not stored in fat cells. As a result, the body does not maintain adequate stores of it in the body and you need to constantly replenish it through diet.

How Methotrexate Causes Folate Deficiency

Methotrexate is classified as a disease-modifying anti-rheumatic drug (DMARD) used to treat rheumatoid arthritis and other autoimmune diseases. It is also sometimes used to treat certain cancers like breast cancer, lung cancer, and lymphoma.

Available in oral and injectable forms, methotrexate is usually given once weekly in doses ranging from 7.5 milligrams (mg) to 25 mg.

Methotrexate works by preventing your body from using folate, which it needs to make more cells and regulate the immune response. By doing so, cancer cells are less able to multiply and the immune system is less able to overact and cause inflammation that makes autoimmune diseases worse.

Despite these beneficial effects, methotrexate can deplete folate faster than it can be replenished with food. To avoid folate deficiency, folic acid may be prescribed alongside methotrexate to supplement your natural stores of folate.

Symptoms of Folic Deficiency

If left untreated, folate deficiency can cause anemia (low red blood cells), leukopenia (low white blood cells), and thrombocytopenia (low platelets). 

Symptoms of folate deficiency may include:

  • Headache
  • Chronic fatigue
  • Weakness
  • Dizziness or lightheadedness
  • Pale skin
  • Sore tongue
  • Easy bruising or bleeding
  • Heart palpitations
  • Irritability
  • Changes in behavior
  • Loss of appetite
  • Weight loss
  • Increased risk of infection

Some of these—like fatigue, weakness, and increased infection risk—may only compound issues related to the condition you're taking methotrexate for in the first place.

Methotrexate and Folic Acid Supplementation

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

Folic acid also appears to reduce the risk of liver toxicity that can occur with methotrexate as well as the long-term risk of liver failure.

A 2019 study published in the Journal of Clinical Rheumatology reported that people who took folic acid with methotrexate were more likely to remain compliant to treatment, in part because of the lower risk of side effects.

Moreover, folic acid can reduce the risk of methotrexate withdrawal if ever treatment is stopped.

How to Use Folic Acid With Methotrexate

If you are taking methotrexate, your healthcare provider will likely prescribe folic acid supplements in a tablet or liquid form. The tablet comes in 400-microgram (mcg), 800-mcg, or 1,000-mcg (equivalent to one gram) formulations. The liquid suspension delivers 2.5 mg of folic acid per 5 milliliters dose (2mg/5mL).

There is no standard dose of folic acid when taken alongside methotrexate. The minimum recommended dose is 5 mg per week, taken as a single or split dose.

Some healthcare providers will prescribe a single 5-mg or 10-mg oral dose of folic acid the day after you've received your weekly methotrexate doses. 

Other practitioners will prescribe a 1-mg oral dose of folic acid taken once daily. (Some experts recommend skipping folic acid on the day of your methotrexate dose, although there is no evidence that taking it poses any harm.)

People taking methotrexate should get their folic acid by prescription rather than buying it over the counter. Over-the-counter supplements are not strictly regulated in the United States, and the dose may not be as accurate as prescription supplements.

Folic acid is generally well tolerated and usually causes few side effects. High doses may cause nausea, stomach upset, bloating, gas, and diarrhea in some people. If this happens, talk to your healthcare provider about switching from a larger once-weekly dose to a smaller once-daily dose.

Summary

Methotrexate, a drug used to treat autoimmune diseases and certain cancers, works by blocking the action of folate (also known as vitamin B9). By doing so, methotrexate can cause folate deficiency, leading to anemia and other potentially serious complications.

Folic acid, a synthetic form of folate, can be taken with methotrexate to replenish stores of the nutrient in the body and prevent folate deficiency. Folic acid can be taken by mouth once daily or once weekly in either tablet or liquid form, depending on the recommendations of your healthcare provider.

A Word From Verywell

Because folic acid is quickly cleared from the body once you take it, you need to be vigilant in your dosing to ensure levels in the blood are consistent. This means taking it at the same time every day if you are once-daily dose and at the same time and day every week if you are on a once-weekly dose.

In most cases, you will be advised to keep taking folic acid for as long as you are on methotrexate. You should also continue to eat foods rich in folate, including beans, whole grains, green leafy vegetables, and citrus fruits like oranges.

Frequently Asked Questions

  • What happens if I don't take folic acid with methotrexate?

    Methotrexate works by blocking the action of folate, also known as vitamin B9. This can lead to folate deficiency and complications such as anemia.

  • When is the best time to take folic acid with methotrexate?

    Folic acid is often given as a single 5-milligram (mg) dose for people on methotrexate. In such cases, the folic acid should be taken the day after the methotrexate dose. Other prescribers recommend a 1-mg dose taken once daily, sometimes skipping the dose on the day your methotrexate dose.

  • What should you avoid while taking methotrexate?

    You may be advised to avoid or reduce your alcohol intake while on methotrexate as it can increase the risk of liver toxicity and damage. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may need to be avoided for the same reason, especially if you take them regularly or at high doses.

7 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.
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  2. U.S. National Library of Medicine: MedlinePlus. Folate deficiency.

  3. 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

  4. Singh JA. Folic acid supplements for rheumatoid arthritis patients taking methotrexate: the good gets better. Cochrane Database of System Rev. 2013;7:ED000063. doi:10.1002/14651858.ED000063

  5. Office of Dietary Supplements. Folate: fact sheet for health professionals.

  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. National Library of Medicine. Methotrexate boxed warning.

By Carol Eustice
Carol Eustice is a writer covering arthritis and chronic illness, who herself has been diagnosed with both rheumatoid arthritis and osteoarthritis.