What is the Connection Between Methotrexate and Folic Acid?

H. Colledge

Methotrexate is a drug used in the treatment of rheumatoid arthritis. Rheumatoid arthritis is a disease in which the immune system attacks joint tissue, causing joints throughout the body to become inflamed and damaged. Methotrexate works by decreasing the action of the immune system, but it can have toxic effects on bone marrow and heart and liver function. Taking a vitamin known as B9, or folic acid, is thought to reduce methotrexate toxicity, although this interaction between methotrexate and folic acid has caused controversy. Currently, there is no agreement regarding the correct dose of folic acid, or whether the dose can be raised enough to decrease methotrexate toxicity without preventing methotrexate from working properly.

Legumes contain folic acid.
Legumes contain folic acid.

When treating rheumatoid arthritis, a low dose of methotrexate is usually taken once a week in the form of either tablets or injections. Possible unwanted effects include mouth ulcers, rashes, diarrhea, nausea and hair loss. The drug may also cause liver problems and can affect the bone marrow, leading to too few blood cells being produced. Occasionally, taking methotrexate may lead to the lungs becoming inflamed, and breathlessness may be experienced. Using methotrexate and folic acid together has been recommended by some doctors as a way of lowering the risk of such side effects.

Leafy green vegetables are a good source of folic acid.
Leafy green vegetables are a good source of folic acid.

The reason for recommending that folic acid supplements be taken with methotrexate is that methotrexate is known to cause folate deficiency. Folate is the naturally occurring form of vitamin B9, while folic acid is the synthetic version. While some research studies have shown that folic acid can reduce methotrexate side effects, there are concerns that folic acid may also reduce the effectiveness of the drug. On the other hand, up to around a third of patients stop taking methotrexate within a year due to side effects, so combining methotrexate and folic acid could be beneficial if it allows patients to continue with their medication for longer.

Although combined methotrexate and folic acid effects are still being evaluated, some doctors advise taking folic acid weekly, a day after the methotrexate dose, to take advantage of possible benefits. Others recommend that folic acid should only be given to patients who may have increased requirements, for example as the result of an infection causing reduced folate levels. Until more research has been carried out on the use of methotrexate and folic acid together, patients should discuss the pros and cons of the treatment with their doctors.

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