Benefits of Folic Acid While Taking Methotrexate for Autoimmune Arthritis

For many people living with rheumatoid arthritis, methotrexate (Trexall, Rasuvo) is a first-choice medication. It’s typically taken orally, as a pill or liquid, but it’s also available as an injection. And if you’re prescribed methotrexate, your provider may recommend that you take folic acid along with it.

Folate, the naturally-occuring form of folic acid, is an important vitamin that’s involved in making DNA, forming red blood cells, and helping new cells grow. Methotrexate can lower your body’s supply of folate. But supplementing with folic acid during treatment can help prevent this — and lessen certain methotrexate side effects.

What is methotrexate, and how does it work?

Methotrexate is a disease-modifying antirheumatic drug (DMARD) that’s commonly used to treat rheumatoid arthritis. It’s also approved for other autoimmune disorders, including psoriasis and polyarticular juvenile idiopathic arthritis (pJIA). And it’s available as a tablet, oral liquid, and injection.

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Autoimmune disorders are a result of the immune systems attacking healthy parts of the body, including organs, joints, and tissues. This can result in pain and inflammation in the affected areas. Methotrexate treats autoimmune disorders by calming the immune system and reducing inflammation. This can help slow down damage and disease progression.

At very high doses, methotrexate is also used to treat certain types of cancer (unhealthy cells dividing at an out-of-control rate). Methotrexate fights cancer by blocking an enzyme (protein) that’s needed to activate folate to make DNA. This helps slow down the growth and spread of cancer cells.

Good to know: Lower methotrexate doses are typically used to treat autoimmune disorders, while much higher doses are used to treat cancer. At lower doses, most people are able to tolerate methotrexate well.

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What is folic acid?

Folate is a B vitamin your body uses to replenish cells you lose every day, like hair, skin, and nail cells. It naturally occurs in a variety of foods, including many fruits and leafy green vegetables.

Folic acid is a man-made (synthetic) form of folate. It’s added to many foods — including breads, breakfast cereals, and rice — to help get people enough folate in their diet. You can also find it in many over-the-counter (OTC) supplements or in higher doses as a prescription-only treatment.

How can folic acid help you if you take methotrexate?

Methotrexate can lower folate stores in your body. This can contribute to side effects such as nausea, vomiting, and mouth sores. Supplementing with folic acid can help lower the risk of these side effects, as well as help fight fatigue that can occur after taking a dose and hair loss. It can also help prevent abnormalities in your blood work, such as abnormal blood counts and liver tests.

A 2019 systematic review found that people taking methotrexate for rheumatoid arthritis were less likely to experience side effects like nausea and vomiting if they were supplementing with folic acid. Elevated liver enzymes, which indicate liver inflammation or damage, were also less likely.

Not everyone who takes methotrexate experiences side effects. But for some people who do, they can make methotrexate difficult to tolerate. Taking folic acid is one way to make it easier to stick with treatment.

Methotrexate’s manufacturer recommends supplementing with folic acid if you’re taking methotrexate for rheumatoid arthritis, pJIA, or psoriasis to lower the likelihood of side effects. If you’re taking methotrexate for a different autoimmune disorder, such as lupus, your provider may recommend folic acid as well.

Keep in mind: You may still experience side effects from methotrexate, such as nausea and vomiting, if you’re taking folic acid. If needed, your healthcare provider may switch you to the injectable form of methotrexate or a different medication altogether.

What happens if you don’t take folic acid with methotrexate?

If you don’t take folic acid with methotrexate for an autoimmune disorder, you may be more likely to experience certain side effects. Because of that, many healthcare providers recommend taking folic acid during treatment.

Will folic acid make methotrexate less effective?

If you’re taking methotrexate for an autoimmune disorder, folic acid supplementation shouldn’t interfere with how well the medication works. And you don’t need to skip taking folic acid on the days you take methotrexate, either. This is because folate isn’t thought to be involved in how methotrexate treats autoimmune disorders. But this isn’t the case for cancer.

If you’re taking methotrexate for cancer, you shouldn’t take folic acid unless your oncologist (cancer specialist) prescribes it for you. This is because methotrexate treats cancer by affecting folate. So taking folic acid may interfere with how effective methotrexate is at treating cancer.

What’s the typical folic acid dosage with methotrexate?

If your healthcare provider recommends that you take folic acid, they’ll usually write you a prescription for it. The typical dosage is 1 mg by mouth daily, or 5 mg once weekly. But your provider may give you different instructions or recommend that you take OTC folic acid if cost is an issue.

Keep in mind: To treat autoimmune disorders, oral methotrexate is taken once weekly. And since methotrexate and folic acid pills often look similar (small, yellow tablets), it can be easy to mix them up. So be careful if you’re taking folic acid daily, as accidentally taking methotrexate every day can have serious effects on the body. 

Always follow your healthcare provider’s instructions for taking folic acid and methotrexate. If you’re having difficulty keeping your pills straight, it might be helpful to use a pill organizer. If you have any doubts about which medication is which, ask your pharmacist for help.

What are common folic acid side effects?

Most people don’t experience side effects from taking folic acid. But, in rare cases, allergic reactions have been reported. An allergic reaction to folic acid can cause:

• A rash

• Itching

• Redness

• Trouble breathing

Contact your provider immediately if you experience any of these symptoms while taking folic acid. If any of your symptoms feel life-threatening, go to the nearest emergency room.

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Written by:

Alex Evans, PharmD, MBA

Alex Evans, PharmD, MBA, has been a pharmacist for 12 years. His first job was floating in a community chain pharmacy.

Edited by:

Alyssa Billingsley, PharmD

Alyssa Billingsley, PharmD, is the director of pharmacy content for GoodRx. She has over a decade of experience as a pharmacist and has worked in clinical, academic, and administrative roles.

Reviewed by:

Samantha C. Shapiro, MD

Samantha Shapiro, MD, is a board-certified rheumatologist and internist with expertise in autoimmune and inflammatory conditions. She founded the division of rheumatology at Dell Medical School at The University of Texas at Austin.

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