Methotrexate: Managing Side Effects

Understand the side effects of methotrexate and how you can take measures to keep them to a minimum.


Methotrexate is one of the most effective and widely used medications for treating rheumatoid arthritis (RA) and other inflammatory types of arthritis. It’s also one of the safest arthritis 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 patients who use methotrexate to treat their inflammatory arthritis 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 arthritis 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 patients who take methotrexate at such doses, 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.)  

A few additional steps may help prevent or relieve GI and oral problems:

  • Split the dose. Most arthritis patients take methotrexate orally, in a dose consisting of several pills. Some find that splitting the dose eases GI side effects; take half the pills in the morning and the other half 12 hours later, preferably with food.
  • Ask about medication. For very severe stomach queasiness, your doctor can prescribe an anti-nausea drug such as ondansetron (Zofran), says pharmacist James Bennett of Children’s Hospital in Boston.
  • Swap your pills. When nothing else helps, switching from oral methotrexate to the injectable version can eliminate GI distress.
  • Try a rinse. To relieve painful mouth sores, a salt-water rinse or special mouthwash containing lidocaine (a pain reliever) may help, says Bennett.

Protecting the Liver

Since methotrexate blocks folate, taking folic acid – the manmade version of the vitamin – might seem like it would be counterproductive. However, methotrexate appears to relieve pain and other RA symptoms through actions that are largely unrelated to folate, explains Edwin Chan, MD, a rheumatologist and researcher at the New York University School of Medicine. Dr. Chan and other investigators discovered that methotrexate causes cells to release a molecule called adenosine, which blocks other chemicals that promote inflammation.

Fighting inflammation helps relieve painful, swollen joints. But Dr. Chan notes that adenosine also causes fibrosis, or buildup of scar tissue, in the liver; over time, that could result in liver disease. Your doctor will run routine blood tests to monitor your liver function, but it’s worth noting that only about one in 1,000 patients with RA who are taking methotrexate experience serious liver damage. Yet it’s important to note that alcohol also releases adenosine in the liver, says Dr. Chan. 

That’s why your physician may advise you to avoid booze while taking methotrexate in order to limit your risk for liver problems. In rare cases, methotrexate users may develop fibrosis and inflammation in the lungs, though this is unlikely to be related to adenosine release, says Dr. Chan. Report a dry cough, shortness of breath, or any other respiratory problem to your doctor.

Regular blood tests are also necessary to detect signs of other problems that can arise in methotrexate users, including a drop in white blood cells, which normally guard against infections. Also, some people experience a dip in production of blood platelets, which could cause abnormal bleeding. However, these changes in the blood often go away if you stop taking the drug temporarily (which should only be done under a doctor’s supervision).

Fear of side effects causes some primary care physicians who treat inflammatory arthritis to prescribe methotrexate in doses too small to provide adequate pain relief, says Yusuf Yazici, MD, an assistant professor of medicine and colleague of Chan’s at the New York University School of Medicine. But most people tolerate the drug quite well, especially if they take folic acid and practice other good habits.

Says Dr. Yazici: “There’s no reason to be afraid of methotrexate.”

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