Understanding How Much Folic Acid Should I Take If I'm on Methotrexate?

October 10, 2025 •

4 min read

According to a Cochrane review, supplementing with folic or folinic acid can lead to a significant reduction in the incidence of gastrointestinal side effects and elevated liver enzymes for patients taking methotrexate. For this reason, many patients with autoimmune conditions are prescribed a folic acid supplement to take alongside their methotrexate therapy.

Quick Summary

Folic acid is often recommended with methotrexate therapy to help prevent side effects. The appropriate amount and frequency can vary based on individual needs and should be determined in consultation with a healthcare provider. The supplement is generally advised to be taken on a different day than the methotrexate dose.

Key Points

Determining Amount: The appropriate amount of folic acid is determined by a healthcare provider based on individual needs and methotrexate dosage.
Timing: Take folic acid on a different day than your weekly methotrexate dose to avoid interfering with its efficacy.
Purpose: Folic acid supplementation helps reduce methotrexate side effects like nausea, mouth sores, and elevated liver enzymes, promoting better treatment adherence.
Cancer vs. Autoimmune: Folic acid supplementation is for autoimmune diseases, but is contraindicated with high-dose methotrexate for cancer, unless part of a specific 'rescue' protocol.
Persistence: Continue taking the folic acid supplement for the entire duration of your methotrexate therapy as directed by your doctor.
Consult Your Doctor: Always follow the specific instructions given by your healthcare provider, as individual needs vary.
Folinic Acid: While an alternative, folinic acid is more expensive and has not shown superior efficacy to folic acid for managing side effects in autoimmune patients.

Why You Need Folic Acid with Methotrexate

Methotrexate is a powerful medication used to treat various autoimmune diseases, such as rheumatoid arthritis, psoriasis, and psoriatic arthritis. In these conditions, it works by suppressing the overactive immune system to reduce inflammation. While effective, methotrexate can also disrupt the body's natural folate metabolism, as it acts as a folate antagonist.

Folate, a B vitamin, is essential for healthy cell growth, division, and repair. By interfering with folate, methotrexate can cause a deficiency that leads to side effects in fast-growing cells, such as those lining the gastrointestinal tract and blood cells in the bone marrow. Common side effects include:

Nausea and vomiting
Mouth sores or ulcers
Diarrhea
Elevated liver enzymes
Fatigue
Hair loss
Anemia due to bone marrow toxicity

To counteract these side effects, healthcare providers typically prescribe a folic acid supplement. Folic acid is the synthetic form of folate and helps replenish the body's folate stores, preventing or reducing the severity of these adverse events without compromising the medication's effectiveness against autoimmune inflammation.

Understanding Folic Acid Supplementation

Determining the appropriate amount of folic acid when taking methotrexate is a key aspect of managing treatment side effects. The specific amount and frequency of folic acid supplementation can vary based on individual factors, the dose of methotrexate being taken, and the patient's tolerance and response to treatment.

Healthcare providers consider several factors when recommending a folic acid regimen. These may include the severity of side effects experienced by the patient, the presence of other medical conditions, and the results of blood tests monitoring folate levels and liver function. Your doctor will tailor the recommendation based on your medical history and test results to find a balance that maximizes the benefits of methotrexate while minimizing potential harm from folate depletion.

It is essential to follow your healthcare provider's specific instructions regarding the amount and timing of folic acid, as they are best equipped to determine the most suitable regimen for your individual needs. They may adjust the recommendation over time based on how you respond to treatment.

Timing Considerations

For most people taking methotrexate for autoimmune conditions, it is generally recommended to take your folic acid supplement on a different day than your methotrexate dose. While studies show that supplementation for autoimmune diseases does not impact methotrexate efficacy, avoiding taking them on the same day is a standard precaution. This helps to minimize any theoretical interference and ensures the anti-inflammatory effects of methotrexate are not dampened. Some healthcare providers recommend a specific interval, such as 24 to 48 hours, after your methotrexate dose. Adhering to your doctor's recommended schedule is important for optimal results.

Folic Acid vs. Folinic Acid

In some cases, patients may be prescribed folinic acid (also known as leucovorin) instead of folic acid. While both are forms of folate, they differ in how they work and are used. Here is a comparison:


Feature	Folic Acid	Folinic Acid (Leucovorin)
Form	Synthetic form of Vitamin B9.	Metabolically active form of folate.
Activation	Requires conversion by an enzyme to become active.	Does not require enzyme conversion; is active immediately.
Cost	Generally low cost and widely available.	Substantially higher cost.
Typical Use	Routine prevention of methotrexate side effects in autoimmune conditions.	Used for 'rescue' therapy after high-dose methotrexate chemotherapy to protect healthy cells.
Efficacy	Effective for reducing toxicity at low methotrexate doses.	Similar effectiveness to folic acid for managing autoimmune therapy side effects.

For the low doses of methotrexate used to treat rheumatoid arthritis or psoriasis, studies have found no significant difference in effectiveness between folic acid and folinic acid for reducing side effects. Because of its lower cost, folic acid is the more common and appropriate choice for most patients with autoimmune diseases.

What About High-Dose Methotrexate for Cancer?

The recommendations for folic acid are significantly different for patients taking high-dose methotrexate for cancer treatment. In this context, methotrexate's mechanism relies on blocking folate metabolism to inhibit the rapid growth of cancer cells. Taking folic acid would interfere with this primary therapeutic action. Therefore, patients receiving high-dose methotrexate for cancer should not take folic acid unless specifically instructed by their oncologist, often as part of a carefully timed "leucovorin rescue" protocol.

How to Ensure Adequate Folate

While your supplement is the primary source of extra folate, it's important not to rely on multivitamins or dietary sources alone. Multivitamins often do not contain a high enough amount of folic acid to counteract methotrexate's effects. Your doctor will typically prescribe a specific supplement to ensure you receive an adequate amount.

Continue taking your folic acid for the entire duration of your methotrexate therapy, as directed by your doctor. Discontinuing the supplement can increase your risk of experiencing side effects. Regular blood tests will also help monitor your folate levels, liver function, and blood cell counts throughout your treatment.

Conclusion

For patients with autoimmune conditions like rheumatoid arthritis and psoriasis, taking folic acid alongside methotrexate is a standard practice to mitigate common side effects such as nausea, mouth ulcers, and abnormal liver enzymes. The specific amount and schedule of folic acid supplementation are determined by your healthcare provider to best suit your individual needs and response to treatment. Always consult your healthcare provider to determine the best regimen for your specific situation. Adhering to your prescribed folic acid plan can significantly improve your tolerance of methotrexate and help you maintain your long-term treatment plan.

For more detailed information on methotrexate side effects and management, you can refer to authoritative sources like the Arthritis Foundation.

Final Recommendations

Never adjust your folic acid or methotrexate dosage without consulting your doctor.
Do not take folic acid supplements if you are taking high-dose methotrexate for cancer, unless directed by your oncologist.
Inform your doctor of any side effects you experience, as your folic acid supplementation may need adjustment.
Be aware that dietary intake and standard multivitamins are typically insufficient to meet the increased folate needs caused by methotrexate.

Frequently Asked Questions

Methotrexate works by interfering with folate metabolism in the body, which can cause a folate deficiency. This deficiency can lead to side effects like mouth sores, nausea, and liver problems. Taking a folic acid supplement helps replenish your body's folate stores and prevents or reduces these adverse effects.

No, it is generally recommended to take your folic acid on a different day of the week than your methotrexate dose. This practice helps minimize any theoretical interaction between the two and ensures the methotrexate's therapeutic effect is not compromised.

The appropriate amount of folic acid is determined by your doctor based on your individual needs and how you tolerate the medication. It is important to follow their specific instructions.

For the low doses of methotrexate used to treat autoimmune conditions, taking folic acid should not significantly reduce its efficacy. The anti-inflammatory mechanisms of methotrexate in these conditions are not thought to be affected by supplementation.

If you forget your weekly folic acid dose, take it as soon as you remember, unless it is the day you are scheduled to take your methotrexate. In that case, wait until the following day to take it. Never take two doses to make up for a missed one. Consistency is important, so if you frequently forget, consider setting a reminder.

The higher amounts of folic acid needed to counteract methotrexate's effects are often prescribed by a doctor. While smaller amounts of folic acid are available over-the-counter, multivitamins generally don't contain enough. You should use the specific amount and formulation prescribed by your healthcare provider.

While it is always good to have a healthy diet rich in folate (found in leafy greens, legumes, and fortified grains), dietary intake alone is typically not enough to overcome the folate deficiency caused by methotrexate. A doctor-prescribed supplement is necessary to ensure adequate levels.