Methotrexate is the leading disease-modifying anti-rheumatic drug (DMARD) given to people with rheumatoid arthritis (RA) and many other types of inflammatory arthritis. By reducing your immune system’s ability to produce cells that cause inflammation, methotrexate (MTX) reduces arthritis symptoms and, over time, the destruction of affected joints. MTX also boosts the release of adenosine, a highly anti-inflammatory chemical that is found in all human cells. 

Unfortunately, MTX causes bothersome side effects in many people, but some of these can be lessened with a simple supplement of vitamin B9, also known as folate (usually taken as a folic acid supplement).

“It is impossible to predict who will suffer side effects [from methotrexate]. Because folic acid supplements have a very low risk of harm, recommending them to all patients starting MTX is a worthwhile investment in preventing side effects and increasing the likelihood that patients will stay on this often extremely effective rheumatoid arthritis medication,” says Amanda Steiman, MD, M.Sc, a rheumatologist at Sinai Health System/University Health Network in Toronto, Canada and an assistant professor of medicine at the University of Toronto.

Here’s more information about the importance of folic acid while taking methotrexate.

1. Why is my doctor recommending that I take folic acid?

Folic acid and folinic acid are forms of vitamin B9, which you need to keep your cells dividing and growing normally. Folic acid is also essential in the production of red blood cells. Methotrexate blocks some of the actions of folic acid, which can lead to side effects such as mouth sores, abdominal pain, liver problems, hair loss, and anemia. For some people, the side effects are bad enough that they stop taking their methotrexate.

2. Does folic acid really help reduce methotrexate side effects?

Yes. In 2013, a Cochrane review of six studies found that taking folic acid or folinic acid reduced the proportion of people on methotrexte experiencing stomach problems (from 35 percent to 25 percent), abnormal liver tests (from 21 percent to 5 percent), and mouth sores (from 22 percent to 16 percent, which was not a statistically significant difference).

Overall, fewer people dropped out of methotrexate treatment studies if they used folic acid (10 percent) than if they did not (25 percent).

3. But could taking folic acid keep my methotrexate from working?

No. Large doses of MTX are used to treat some cancers, and the drug’s anti-cancer activity results from its interference with folate. So cancer patients taking methotrexate should not take supplemental folic acid.

However, the actions of MTX on folic acid are not related to its ability to reduce inflammation and joint damage at the low doses used in treating rheumatoid arthritis, says rheumatologist Gabby Schmajuk, MD, MS, associate professor of medicine at the University of California San Francisco. 

You can safely take folic acid without any impact on the efficacy of methotrexate. 

4. Does my multivitamin give me enough folic acid?

Probably not enough if you’re on methotrexate for arthritis and trying to avoid side effects. The amount of folic acid in common multis is 400 micrograms for most adults, and up to 800 micrograms for women who are pregnant or planning to be. 

But for arthritis patients, “we recommend taking a supplement with at least 1,000 micrograms, and some patients report fewer MTX side effects taking 2,000 micrograms or more,” says Dr. Schmajuk.

5. Do I need a prescription for that amount of folic acid?

The daily doses of folic acid usually recommended by rheumatologists are available over the counter, but some doctors prescribe a 5 mg dose (that’s 5,000 micrograms) to use once a week. After folic acid is consumed, it’s converted to its active form in the body by the action of an enzyme. 

Another form of folate, called folinic acid, is already metabolically active and doesn’t require the enzyme conversion. Folinic acid (also called leucovorin) requires a prescription and is usually taken as a 5 mg dose once a week. The Cochrane Review found that folic acid and folinic acid have similar power to reduce MTX side effects. Rheumate, a medical food that contains folate, vitamin B12, and curcumin, also requires a prescription.

“I rarely use folinic acid, as it is costly and, for most patients, provides no additional benefit,” says Dr. Steiman.

6. When should I take folic acid?

Take your folic acid supplement as directed (either daily or weekly), with or without food. You may hear people suggest that you skip taking folic acid the same day that you take your methotrexate, but the jury is out on the benefit of doing this.

“There are studies suggesting no decrease in the efficacy of MTX if taken the same day as folic acid, but the same may not be true for folinic acid. Still, many of us still prescribe folic acid six days a week as a matter of convention. There’s no strong scientific rationale for one regimen over another,” Dr. Steiman says. Ask your doctor what they suggest, and go with that.

7. Can I get enough vitamin B9 through my diet and skip supplements altogether?

Not as much as you need if you take MTX. However, you can raise your intake by enjoying these folate-rich foods:

  • Breads, cornmeal, flour, pasta, and cereal fortified with folic acid;
  • Foods that naturally contain more than 20 percent of the standard recommended intake in each serving, such as beef liver, spinach, black-eyed peas, asparagus, and Brussel sprouts.

8. Are there any risks to taking folic acid supplements?

“It’s a very safe supplement taken in the doses we prescribe,” says Dr. Schmajuk.

9. What if my doctor doesn’t mention folic acid to me?

Bring it up. When Dr. Schmajuk and her colleagues examined records from the Veterans Administration, they found that about one in four rheumatoid arthritis patients prescribed methotrexate were not prescribed folic acid. Patients treated by rheumatologists were more likely to be given folic acid than those seeing other doctors.

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