Methotrexate and folic acid for rheumatoid arthritis

Methotrexate is a medication that doctors prescribe to treat certain conditions, including adult rheumatoid arthritis, some cancers, and severe psoriasis.

However, methotrexate drains the body of folic acid, which may lead to folic acid deficiencies.

The body needs folic acid to maintain a healthy gastrointestinal (GI) tract and liver, as well as healthy bones and hair.

Methotrexate can also cause side effects, such as nausea, vomiting, and stomach pain. A person taking the medication for rheumatoid arthritis (RA) can take a folic acid supplement to help reduce these unwanted side effects.

In this article, learn more about how methotrexate affects folic acid, as well as about the other possible side effects.

How does methotrexate affect folic acid?

methotrexate yellow pills being poured into hand from bottle
Methotrexate can treat a range of conditions, including RA.

Folic acid is a B vitamin. An enzyme in the liver converts folic acid into folate, which plays many essential roles in the body, including helping with cell division and DNA replication.

Methotrexate works by reducing the amount of folic acid in the body, which means that harmful cells cannot replicate. This is the reason why some people with cancer take the medication.

Doctors do not know exactly how methotrexate works to reduce RA symptoms.

However, according to the U.S. Food and Drug Administration (FDA) drug information document, methotrexate might affect immune system function, reducing the body’s immune response that causes RA symptoms.

The FDA information document also notes that methotrexate can reduce swelling, inflammation, and tenderness caused by RA within 3 to 6 weeks of starting to take the medication.

Because methotrexate also depletes folic acid levels, it can cause a variety of side effects, including, mouth ulcers, headaches, and fatigue. Taking a folic acid supplement can reduce the risk of these side effects.

Taking a folic acid supplement does not seem to change methotrexate’s effectiveness in treating RA.

Ways to reduce side effects

A doctor will make recommendations on how much folic acid to take and when to take it.

According to the Arthritis Foundation, some doctors suggest taking 1 milligram (mg) of folic acid a day. Other doctors may recommend taking a single 5-mg dose weekly.

Some people will take the folic acid supplement 24 hours after taking a methotrexate dose.

In a multi-study review of placebo-controlled clinical trials on the effects of folic acid supplementation, the authors made several conclusions:

  • GI side effects: Folic acid reduced the risk of methotrexate side effects, such as nausea, vomiting, and stomach pain by 26 percent.
  • Liver enzymes: Taking methotrexate can increase liver enzymes, which could be toxic to the liver. The study showed that taking folic acid can reduce a person’s relative risk of developing liver enzyme problems by 76.9 percent compared to someone who didn’t take it.
  • Mouth sores: The authors did not find a statistically significant reduction in mouth sores when a person took folic acid.

Also, the researchers did not find a link between taking folic acid and the effectiveness of methotrexate for treating RA.

In addition to taking folic acid supplements, a person can also reduce the side effects of methotrexate by:

  • Talking to a doctor about dosage. Some people who take methotrexate may experience fewer digestive problems if they take half the dose in the morning and a half at night, both with food.
  • Considering switching to an injectable medication. Sometimes, injectable methotrexate causes fewer GI side effects than the tablet does.
  • Asking a doctor about anti-nausea medications. Taking anti-nausea medications, such as ondansetron (Zofran) may help reduce methotrexate-related side effects.
  • Using mouth rinses to reduce sores. Doctors may sometimes prescribe special mouthwashes or a person may choose to use a warm saltwater rinse.

A person can also ask their doctor about other ways to reduce methotrexate-related side effects.

Other side effects and risks

Pregnant women should not take methotrexate because of the potential risks that a folic acid deficiency and other side effects can have on a developing fetus.

Those with alcohol use disorder should also avoid methotrexate because it increases liver enzymes and can be toxic to the liver.

Other side effects that can occur as a result of taking methotrexate include:

  • anemia, or low red blood cell counts
  • changes in mood
  • gastrointestinal bleeding
  • headaches
  • increased risk for stress fractures
  • leukopenia, or low white blood cell counts
  • non-productive dry cough
  • pancreatitis
  • rashes
  • trouble thinking clearly

It is a good idea to discuss possible side effects with a doctor before taking methotrexate.

When to call a doctor

Man with fever temperature lying in bed looking at thermometer
A person should call a doctor if they experience side effects, such as fever,

A person should call a doctor right away if they experience any of the following side effects:

While some of these side effects are relatively widespread among people who take methotrexate, anyone experiencing them should let their doctor know. A doctor can recommend other interventions for these side effects.

If anyone experiences severe side effects, such as bleeding, they may require hospitalization to check blood levels and for other treatments.


While methotrexate can help treat RA, it can lead to folate deficiency and cause other side effects, such as an upset stomach.

Taking a folic acid supplement can help reduce some of these side effects.

People should talk to a doctor about how much folic acid to take and when to take it for RA.

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