How Does Methotrexate Work? Learn the Many Uses of This Medication

Methotrexate is a medication that’s been around for decades. It has proven to be effective in treating rheumatoid arthritis (RA) and continues to be used for other health conditions, such as psoriasis and various types of cancer.

Since methotrexate can be used for many different conditions, it’s a versatile medication. But, as with any medication, it comes with its own set of benefits and risks. If you or a loved one take methotrexate, it’s important to understand its nuances, uses, and how it works.

What is methotrexate?

Methotrexate is a prescription medication. It’s a type of antifolate medication that’s often prescribed as an oral tablet. But it can also be administered intravenously (into a vein), intramuscularly (into a muscle), or subcutaneously (under the skin).

Methotrexate’s prescribed dosage impacts how it works. At lower doses, methotrexate can lower inflammation. This makes it especially useful for treating inflammatory, autoimmune conditions like RA and psoriasis. In these cases, it works as an immunosuppressant (not chemotherapy). At higher doses, methotrexate has anticancer properties. This makes it useful for treating certain types of cancer.

What is methotrexate used for?

Methotrexate is commonly used to treat autoimmune disorders that cause inflammation. It’s FDA approved to treat:

• Rheumatoid arthritis

• Juvenile idiopathic arthritis

• Severe psoriasis

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In addition to inflammatory conditions, methotrexate is also approved to treat many types of cancer:

• Acute lymphoblastic leukemia

• Head and neck cancer

• Breast cancer

• Non-Hodgkin lymphoma

• Osteosarcoma

• T-cell lymphoma

What’s more, methotrexate is occasionally used off-label for different purposes. This includes conditions like Crohn’s disease, lupus, and other types of cancer not mentioned above.

Is methotrexate a chemotherapy drug?

Sometimes. When used to treat cancer (high doses given IV — through the vein), methotrexate is considered a chemotherapy drug. Chemotherapy is a type of treatment that attacks fast-spreading cancer cells. Methotrexate works by stopping the development of mutated DNA in cancer cells.

When methotrexate is administered as pills, it’s used more commonly to treat autoimmune disorders. Oral methotrexate isn't used as a chemotherapy medication too often.

How does methotrexate work?

It’s not fully understood how methotrexate works, but researchers suspect that it works in many ways.

How does methotrexate treat autoimmune disorders?

Methotrexate is an example of disease-modifying anti-rheumatic drug (DMARD). This means that it doesn’t just lessen pain and inflammation — it treats the underlying cause of pain and inflammation. This helps protect the body from damage down the line. For example, methotrexate can help prevent permanent joint damage from RA.

When used to treat autoimmune disorders like RA, methotrexate behaves like an immunosuppressant. It calms your immune system and lowers inflammation. It’s not well known how methotrexate helps lower inflammation, but some researchers believe it raises the level of adenosine in your body. Adenosine is a natural chemical that has anti-inflammatory effects.

Recent RA treatment guidelines stress that methotrexate should be used as a first-choice treatment for moderate to severe RA. This is because of its effectiveness and low cost. Methotrexate can also be combined with biologic medications when it’s not effective enough on its own. Biologics are medications that come from living sources, and they often treat hard-to-treat health conditions. Examples include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira).

How does it treat cancer?

Methotrexate can help stop the growth of cancer cells. It blocks a chemical in your body called dihydrofolate reductase (DHFR), a substance necessary to make DNA. DHFR works by blocking the formation of folate in the body. This slows down how fast cancer cells can grow and spread.

However, methotrexate is considered nonselective. It doesn’t only affect cancer cells. It can also harm normal cells. This may lead to side effects or other complications.

How long does it take for methotrexate to work?

Many factors can affect how quickly methotrexate begins to work. In general, a person with a condition like RA should experience some response to the medication within 6 to 8 weeks. Full effects of the medication generally appear after 3 to 6 months.

For cancer, methotrexate starts working more quickly. It kicks in almost immediately to help slow down the growth of rapidly-dividing cancer cells. It’s hard to predict how soon you will see a response in the size of your tumor — as everyone responds to chemotherapy differently — but your healthcare provider will periodically assess your response to treatment.

Keep in mind: It’s important to take methotrexate as prescribed to experience its maximum benefits.

How do I know if methotrexate is working?

Improvement in your symptoms is the main way to tell if methotrexate is working. 

For RA, this may feel like less pain and stiffness in your joints. For psoriasis, this may look like an improvement in skin lesions. If you’re taking methotrexate to treat a certain type of cancer, your healthcare provider may notice an improvement in your tumor size or another tumor marker. 

How long do you stay on methotrexate?

There’s no magic number or recommended length of time. How long you’ll take methotrexate boils down to your response to the medication and the health condition you’re taking it for. 

If you’re taking methotrexate and you’re experiencing a positive response, your healthcare provider may encourage you to keep taking it.

If side effects are a burden, you may need to adjust your regimen in order to keep taking it. Some people are more likely to experience side effects when taking the tablet and may be switched to the injectable form of methotrexate.

It’s recommended to talk with your healthcare provider to determine how long you will need to take methotrexate.

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Written by:

Sonja Jacobsen, PharmD, BCPS, BCOP

Sonja Jacobsen, PharmD, BCPS, BCOP,  is a clinical oncology pharmacy specialist currently practicing in Seattle. She has been practicing as a pharmacist since 2015 and is licensed to practice in Washington state and North Carolina.

Edited by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

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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