Optimal Regimen for Methotrexate and Folic Acid

Rheumatologists Can Differ in Folic Acid Supplementation

Folic acid
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Methotrexate is the most commonly prescribed DMARD (disease modifying anti-rheumatic drug) for rheumatoid arthritis and other rheumatic conditions. Methotrexate is available in oral and injectable formulations. Either way, methotrexate is usually administered once a week (on the same day every week).

It is common practice for doctors to prescribe folic acid for their patients who are treated with methotrexate.

Folic acid is depleted by methotrexate, so it must be replenished through supplementation. 

What Medical Resources Say About Folic Acid

The Ohio State University Wexner Medical Center website says, "Folic Acid 1 mg daily will be prescribed while taking methotrexate to prevent any red blood cell abnormalities (anemia). This is a prescription strength supplement. Over-the-counter preparations are not adequate."

Researchers covered the topic in the journal Rheumatology in 2004 and concluded, "We recommend a pragmatic dosing schedule of 5 mg of oral folic acid given on the morning following the day of methotrexate administration."

According to yet another resource, the National Rheumatoid Arthritis Society in the UK, "Methotrexate depletes the body of folic acid and the frequency of side effects can be reduced by taking supplements of folic acid. This can be taken as 5-10 mg weekly. Taking higher doses may reduce the efficacy of methotrexate and most rheumatologists recommend taking the folic acid one or two days after the methotrexate, and in particular not taking it on the same day as the methotrexate."

It became apparent that there is more than one recommended way to take folic acid. Why the difference of opinion? What really is the optimal way to take the supplement? I took my question to Scott Zashin, MD, clinical assistant professor at University of Texas Southwestern Medical School and an attending physician at Presbyterian Hospitals of Dallas and Plano, Texas.

Dr. Zashin remarked, "I have my patients take it daily, including the day of methotrexate. I think either is fine—including it or skipping it the day of. It has not been studied, but it is unlikely that either protocol is harmful."

Conclusions From Cochrane Review

In an editorial about a Cochrane review published in July 2013, which considered evidence supporting the use of folic acid to reduce side effects associated with methotrexate, it was pointed out that folic acid use is quite variable—some doctors prescribe folic acid to be used regularly by patients taking methotrexate, while other doctors prescribe it only to patients with side effects from methotrexate. Still, others don't prescribe it at all because they believe folic acid reduces the effectiveness of methotrexate. The review, based on results from six randomized clinical trials, supported the use of low-dose folic acid in rheumatoid arthritis patients treated with methotrexate. Folic acid supplementation reduced gastrointestinal toxicity and liver enzyme elevation. The editorial suggested that folic acid 1 mg daily is the most common utilization of the supplement for methotrexate-treated patients.

The review and subsequent editorial also raised questions.

Should folic acid be used for the rest of a patient's life? Would higher doses of folic acid be more beneficial or would it interfere with methotrexate? Should patients taking higher doses of methotrexate, accordingly, increase their dose of folic acid? It was concluded that the dose-effect association will require more study.

The Bottom Line

There are various acceptable protocols for taking folic acid when being treated with methotrexate. Follow your doctor's orders.


Methotrexate. The Ohio State University Wexner Medical Center.

Bamji A. Methotrexate and folic acid - What is the optimal combination? Rheumatology (Oxford) (2004) 43 (8): 1060-1061.

Butler, Robin, MD. Methotrexate in Rheumatoid Arthritis. National Rheumatoid Arthritis Society.

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

Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, 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. dx.doi.org/10.1002/14651858.CD000951.pub2