Table of ContentsView AllTable of ContentsMethotrexate and Folic AcidFolate DeficiencySymptoms of DeficiencySupplementationHow to Use Folic AcidFrequently Asked Questions

Table of ContentsView All

View All

Table of Contents

Methotrexate and Folic Acid

Folate Deficiency

Symptoms of Deficiency

Supplementation

How to Use Folic Acid

Frequently Asked Questions

If you take methotrexate, a drug commonly used to treatautoimmune diseasesand certain cancers, your healthcare provider will likely prescribefolic acidas well. Folic acid is a synthetic form offolate, a natural form of vitamin B9 derived from food.

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.

Verywell / JR Bee

How folic acid is used in the body

Methotrexate is classified as adisease-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.Methotrexate is available inoral and injectable forms.

Methotrexate injection is given under the skin (subcutaneously). It comes as 25 mg per 1 milliliter. In children with juvenile rheumatoid arthritis, the dose is based on the child’s weight.

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.

Why Methotrexate Is Taken Weekly

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 ofred blood cells,white blood cells, andplateletsas well as the production ofDNA(the molecule in cells that contains all your genetic information).

Folate is awater-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.

Symptoms of Folic Deficiency

If left untreated, folate deficiency can causeanemia(low red blood cells),leukopenia(low white blood cells), andthrombocytopenia(low platelets).

Symptoms of folate deficiency may include:

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.

Benefits of Taking Folic Acid With Methotrexate

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 ofliver failure.

A 2019 study published in theJournal of Clinical Rheumatologyreported 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.

Potential Side Effects of Methotrexate

Dosage: How to Take Folic Acid With Methotrexate

If you are taking methotrexate, your healthcare provider will likely prescribe folic acid supplements. It is available as a tablet and an oral liquid. Ask your doctor for complete instructions for using folic acid supplements because dosages and when you take them can vary.

Does folic acid reduce the effectiveness of methotrexate?Daily use of folic acid does not appear to affect methotrexate efficacy. However, dosing folinic acid (a different form of the vitamin available with a prescription) close to methotrexate administration may affect methotrexate efficacy.Research indicates that, while folic acid can be used with methotrexate daily to reduce side effects, folinic acid should only be used in cases of methotrexate toxicity.

Does folic acid reduce the effectiveness of methotrexate?

Daily use of folic acid does not appear to affect methotrexate efficacy. However, dosing folinic acid (a different form of the vitamin available with a prescription) close to methotrexate administration may affect methotrexate efficacy.Research indicates that, while folic acid can be used with methotrexate daily to reduce side effects, folinic acid should only be used in cases of methotrexate toxicity.

Daily use of folic acid does not appear to affect methotrexate efficacy. However, dosing folinic acid (a different form of the vitamin available with a prescription) close to methotrexate administration may affect methotrexate efficacy.

Research indicates that, while folic acid can be used with methotrexate daily to reduce side effects, folinic acid should only be used in cases of methotrexate toxicity.

Some physicians recommend taking 1 mg of folic acid daily, whereas others instruct patients to take a single 5 mg dose once a week. You may also be told to take folic acid 24 hours after receiving a dose of methotrexate.

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.Typically, patients take 1 mg per day, though recommendations vary based on individual practitioners.

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.(Some experts recommend skipping folic acid on the day of your methotrexate dose, although there is no evidence that taking it poses any harm.)

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

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.

Is Methotrexate Safe to Use During Pregnancy?

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 dayafterthe methotrexate dose. Other prescribers recommend a 1-mg dose taken once daily, sometimes skipping the dose on the day your methotrexate dose.

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 othernonsteroidal anti-inflammatory drugs (NSAIDs)may need to be avoided for the same reason, especially if you take them regularly or at high doses.Learn MoreWhat to Know About Methotrexate Interactions

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 othernonsteroidal anti-inflammatory drugs (NSAIDs)may need to be avoided for the same reason, especially if you take them regularly or at high doses.

Learn MoreWhat to Know About Methotrexate Interactions

8 SourcesVerywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.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 strategy.J Clin Med. 2019;8(4):515. doi:10.3390/jcm8040515MedlinePlus.Methotrexate.Arthritis Foundation.Methotrexate: Managing Side Effects.U.S. National Library of Medicine: MedlinePlus.Folate deficiency.Office of Dietary Supplements.Folate: fact sheet for health professionals.Liu L, Liu S, Wang C, et al.Folate supplementation for methotrexate therapy in patients with rheumatoid arthritis: a systematic review.J Clin Rheumatol. 2019;25(5):197-202. doi:10.1097/RHU.0000000000000810Cline A, Jorizzo JL.Does daily folic acid supplementation reduce methotrexate efficacy?Dermatol Online J. 2017;23(11):13030/qt4hf5v2vk. Published 2017 Nov 15.National Library of Medicine.Methotrexate boxed warning.

8 Sources

Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.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 strategy.J Clin Med. 2019;8(4):515. doi:10.3390/jcm8040515MedlinePlus.Methotrexate.Arthritis Foundation.Methotrexate: Managing Side Effects.U.S. National Library of Medicine: MedlinePlus.Folate deficiency.Office of Dietary Supplements.Folate: fact sheet for health professionals.Liu L, Liu S, Wang C, et al.Folate supplementation for methotrexate therapy in patients with rheumatoid arthritis: a systematic review.J Clin Rheumatol. 2019;25(5):197-202. doi:10.1097/RHU.0000000000000810Cline A, Jorizzo JL.Does daily folic acid supplementation reduce methotrexate efficacy?Dermatol Online J. 2017;23(11):13030/qt4hf5v2vk. Published 2017 Nov 15.National Library of Medicine.Methotrexate boxed warning.

Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.

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 strategy.J Clin Med. 2019;8(4):515. doi:10.3390/jcm8040515MedlinePlus.Methotrexate.Arthritis Foundation.Methotrexate: Managing Side Effects.U.S. National Library of Medicine: MedlinePlus.Folate deficiency.Office of Dietary Supplements.Folate: fact sheet for health professionals.Liu L, Liu S, Wang C, et al.Folate supplementation for methotrexate therapy in patients with rheumatoid arthritis: a systematic review.J Clin Rheumatol. 2019;25(5):197-202. doi:10.1097/RHU.0000000000000810Cline A, Jorizzo JL.Does daily folic acid supplementation reduce methotrexate efficacy?Dermatol Online J. 2017;23(11):13030/qt4hf5v2vk. Published 2017 Nov 15.National Library of Medicine.Methotrexate boxed warning.

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 strategy.J Clin Med. 2019;8(4):515. doi:10.3390/jcm8040515

MedlinePlus.Methotrexate.

Arthritis Foundation.Methotrexate: Managing Side Effects.

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

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

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

Cline A, Jorizzo JL.Does daily folic acid supplementation reduce methotrexate efficacy?Dermatol Online J. 2017;23(11):13030/qt4hf5v2vk. Published 2017 Nov 15.

National Library of Medicine.Methotrexate boxed warning.

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