Methotrexate is one of the most effective and widely used medications for treating rheumatoid arthritis (RA). It’s also one of the safest RA drugs, insist rheumatologists, despite a common misconception among many patients and even some primary care physicians that methotrexate is highly toxic.

Confusion about this important medication’s safety profile seems to exist because it is also used — in much higher doses — for treating some forms of cancer. Most RA patients who use methotrexate take between 10 and 25 milligrams (mg) per week. By contrast, the doses used to treat leukemia and certain other types of cancer may be hundreds of times larger.

That’s not to suggest that taking methotrexate is risk free. A 2009 review of 21 studies found that 73 percent of RA patients who used the medication experienced at least one side effect. Yet the study indicates that most of these problems were relatively minor. What’s more, doctors who prescribe methotrexate for RA say that following a few simple steps can make this drug even safer to use.

Folic Acid Is a Must

Understanding how methotrexate works helps explain why it can cause unwanted effects. Researchers originally developed methotrexate in the 1940s as a cancer drug. It stops malignant (or cancerous) cells from rapidly multiplying and spreading by blocking their access to folate, a form of vitamin B, which these cells need to survive.

Unfortunately, depleting the body of folate can affect healthy cells, too, especially those in the gastrointestinal (GI) tract, mouth, hair follicles and liver, says Prabha Ranganathan, MD, an associate professor of medicine in the division of rheumatology at Washington University School of Medicine. GI problems such as nausea and vomiting are the most common side effects associated with methotrexate, affecting between 20and 65 percent of RA patients who take the drug. While hair loss is a relatively uncommon side effect in RA patients who take methotrexate, up to one third develop mouth ulcers, or sores. Many also complain of headaches, fatigue and an overall “blah” feeling — sometimes called “methotrexate fog” — that can occur a day after receiving a dose of methotrexate (which is taken in pill form or injected once a week).

The good news: These side effects can often be short-circuited by taking a folic acid supplement. Folic acid is the synthetic form of folate. One study found that RA patients on methotrexate who took folic acid supplements lowered the risk of GI problems and mouth sores by 79 percent.

Dr. Ranganathan recommends taking 1 mg of folic acid daily, though for convenience some other physicians instruct patients to pop a single 5 mg dose once a week. (Some doctors recommend taking folic acid 24 hours after receiving a dose of methotrexate; ask your physician for complete instructions on using folic acid supplements.)