Folic Acid and Methotrexate: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate
Folic Acid
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Reduced folic acid exposure, reduced methotrexate exposure and reduced efficacy of methotrexate
Interaction Deep Dive
Avoid folic acid supplements on the day of oral methotrexate administration. Generally, separate the time of administration of oral methotrexate from folic acid due to interfere of folic acid with gastrointestinal absorption of methotrexate2. Concomitant use of folic acid and a folic acid antagonist such as methotrexate may result in reduced folic acid blood levels 3. If coadministered, monitor for reduced efficacy and adjust the dose of folic acid as needed 2. Coadministration of methotrexate with folic acid or its derivatives may reduce the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. For neoplastic diseases: instruct patients not to take products containing folic acid or folinic acid unless directed to do so by their healthcare provider. For Non-neoplastic diseases: administer folic acid or folinic acid for patients with rheumatoid arthritis, pJIA, and psoriasis 1.
Why it happens (mechanism)
Reduced folate absorption; competition of methotrexate with reduced folates for active transport; interference with gastrointestinal absorption of methotrexate
Common questions
Can I take Folic Acid and Methotrexate together?
Reduced folic acid exposure, reduced methotrexate exposure and reduced efficacy of methotrexate Always confirm with your pharmacist or prescriber before making any change.
How serious is the Folic Acid and Methotrexate interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Folic Acid or Methotrexate need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (3)
- Product Information: JYLAMVO oral solution, methotrexate oral solution. Shorla Oncology Inc (per FDA), Cambridge, MA, 2024. DailyMed
- Product Information: QUIOFIC™ oral solution, folic acid oral solution. Solubiomix, LLC (per Dailymed), Madisonville, LA, 2026. DailyMed
- Product Information: folic acid oral tablets, folic acid oral tablets. Trimarc Laboratories, Oklahoma City, OK, 2006. DailyMed
Keep reading about Methotrexate
Keep reading about Folic Acid
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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