What nutrients does methotrexate deplete? A guide to managing folate, B12, and more

October 13, 2025 •

3 min read

Methotrexate, a widely used medication for autoimmune diseases and cancer, is an antifolate agent by design, leading to a well-documented depletion of folate (vitamin B9) in the body. For patients, knowing what nutrients does methotrexate deplete is crucial for managing potential side effects and mitigating health risks through proper nutritional support.

Quick Summary

Methotrexate treatment interferes with the metabolism and absorption of key vitamins, primarily folate, but also potentially vitamin B12 and vitamin D. These depletions can lead to side effects and elevated homocysteine levels. Understanding these nutritional impacts is vital for managing long-term health through appropriate dietary strategies and supplementation under a doctor's supervision.

Key Points

Folate Depletion: Methotrexate is an antifolate drug that directly blocks the body's ability to use vitamin B9, leading to deficiency.
Folic Acid Supplementation: Folic acid is routinely prescribed to counteract folate depletion and reduce side effects like nausea and mouth sores.
Vitamin B12 Interaction: Methotrexate can indirectly influence B12 metabolism and may cause malabsorption, which is sometimes indicated by elevated homocysteine levels.
Homocysteine Elevation: The drug's effects on folate and B12 can increase homocysteine, a risk factor for cardiovascular disease.
Vitamin D and Bone Health: Especially with higher doses or long-term use, methotrexate can cause intestinal damage that impairs vitamin D absorption, potentially contributing to bone loss.
Need for Monitoring: Regular monitoring of vitamin levels and biomarkers like homocysteine is important for managing therapy and detecting potential deficiencies early.

The Primary Depletion: Folate (Vitamin B9)

Methotrexate (MTX) is a folate antagonist that works by blocking the function of folate, a key B vitamin. It inhibits the enzyme dihydrofolate reductase (DHFR), which is essential for activating folate needed for cell growth and DNA synthesis. While this is therapeutic in conditions involving rapid cell division, it also affects healthy cells, causing systemic folate depletion and side effects.

Common adverse effects of folate deficiency from MTX include fatigue, weakness (due to megaloblastic anemia), gastrointestinal issues, mouth sores, hair thinning, and headaches. To mitigate these, folic acid is typically co-prescribed, which replenishes folate and reduces side effects without compromising MTX's effectiveness. Folic acid is usually taken weekly on a different day than MTX.

Secondary Depletions: B12 and Vitamin D

Methotrexate can also impact other nutrients, particularly with long-term use.

The Link to Vitamin B12

Methotrexate's effect on folate can indirectly affect vitamin B12 status due to their interconnected metabolic pathways. Some studies link MTX to elevated homocysteine, a marker for both folate and B12 deficiency. MTX might also cause gastrointestinal damage, potentially leading to B12 malabsorption. High homocysteine is a cardiovascular risk factor. Monitoring B12 and homocysteine may be needed, especially for older patients or those with B12 deficiency risks.

How Methotrexate Affects Vitamin D

Research suggests MTX, especially in higher doses, is associated with vitamin D deficiency. Intestinal damage from the drug can impair the absorption of dietary vitamin D and calcium. Vitamin D deficiency can contribute to bone loss.

Managing Nutrient Depletion: Supplementation and Diet

Managing nutrient depletion is vital for patients on methotrexate. A healthcare provider will typically recommend a supplementation plan.

Folic Acid and Methotrexate:

Standard practice involves weekly or daily folic acid to minimize side effects without impacting treatment.
Taking folic acid on a different day than MTX is often advised to prevent interference.
Folinic acid (leucovorin) may be used, especially to counteract high-dose MTX.

Broader Nutritional Support:

Vitamin B12: Monitoring B12 and homocysteine is recommended. Supplements might be needed if deficiency is found.
Vitamin D: Monitoring levels and supplementing with vitamin D and calcium is important due to the risk of bone loss.
Diet: A nutrient-dense diet supports overall health and provides essential nutrients.

Comparison of Key Nutrient Depletions


Nutrient	Primary Depletion Mechanism	Key Symptoms of Deficiency	Standard Management
Folate (B9)	Inhibition of DHFR enzyme.	Fatigue, mouth sores, nausea, weakness, anemia.	Weekly or daily folic acid supplementation, separate from MTX dose.
Vitamin B12	Indirectly via disturbed folate metabolism and potential malabsorption.	Elevated homocysteine, fatigue, neurological issues.	Monitoring of levels, supplementation if deficient.
Vitamin D	Impaired intestinal absorption.	Bone loss, osteoporosis.	Monitoring of levels, vitamin D and calcium supplementation.

Conclusion

Methotrexate effectively treats autoimmune diseases, but its effect on nutrient metabolism requires attention. It directly depletes folate, making folic acid co-prescription essential to reduce side effects. Long-term use can also affect B12 and vitamin D, potentially causing elevated homocysteine and bone issues. Patients should work with their doctor for a personalized plan, including monitoring and supplementation, to maximize MTX's benefits while minimizing nutritional risks. NIH offers further information on medical research related to this topic.

Frequently Asked Questions

Doctors prescribe folic acid with methotrexate because methotrexate works by interfering with the body's use of folate. Folic acid supplementation helps to replenish the body's folate stores, which significantly reduces the common side effects of methotrexate, such as nausea, mouth sores, and fatigue, without affecting its therapeutic efficacy for autoimmune diseases.

Yes, methotrexate can indirectly affect vitamin B12 levels. The metabolic pathways for folate and B12 are linked, and methotrexate's impact on folate can lead to functional B12 deficiencies. Some research also suggests it can cause malabsorption due to intestinal damage.

Methotrexate can cause intestinal mucosal damage, particularly at higher doses, which impairs the absorption of dietary vitamin D. This can lead to vitamin D deficiency and contribute to bone loss over time.

The depletion of folate and sometimes vitamin B12 caused by methotrexate can lead to an increase in plasma homocysteine levels. Elevated homocysteine is a known risk factor for cardiovascular disease. Folate supplementation is effective in lowering these levels.

It is generally recommended to take folic acid on a different day than your methotrexate dose to prevent any potential interference. Many doctors advise a weekly dose of folic acid, taken 24 hours after the methotrexate.

Common side effects related to nutrient depletion include fatigue, nausea, vomiting, mouth sores (stomatitis), headache, and diarrhea. These symptoms are often linked to folate deficiency.

Given the risk of impaired vitamin D absorption, it is advisable to discuss vitamin D and calcium supplementation with your doctor. Regular monitoring of your vitamin D levels can help determine if supplementation is necessary, especially with long-term methotrexate use.