Methotrexate Sodium & Nutrient Depletion
Also searched as Xatmep. What the clinical evidence reports, what it may mean, and what to discuss with your pharmacist.
Methotrexate Sodium has been associated with depletion of FOLIC ACID. This does not mean a deficiency will occur — it means these are worth knowing about and, if you take Methotrexate Sodium long-term, worth raising with your pharmacist or healthcare provider.
Take more than one medication? Open the checker with Methotrexate Sodium pre-loaded and add the rest to see overlapping nutrient signals.
Reported nutrient depletions with Methotrexate Sodium
Each record below is shown as published in our licensed clinical database, with its evidence rating and citations. Expand a section for food sources and talking points.
FOLIC ACID
Major DepletionMETHOTREXATE (Trexall, others)
Methotrexate is a folate antagonist which prevents conversion of folic acid to its active form, and lowers plasma and red blood cell folate levels. In patients treated with long-term, low-dose methotrexate for rheumatoid arthritis (RA) or psoriasis, the development of folate deficiency is associated with increased risk of certain side effects. These include gastrointestinal effects, stomatitis, alopecia, abnormal liver function tests, myelosuppression, megaloblastic anemia, and increased homocysteine levels. Folic acid 0.8-5 mg daily reduces these side effects without reducing the efficacy of methotrexate. Advise patients taking methotrexate for these conditions to take a folic acid supplement, especially if their dietary folate intake is low and they are experiencing the side effects described. It's likely that people who have experienced side effects will need to continue taking folic acid for the duration of methotrexate therapy. Advise patients being treated with methotrexate for cancer to avoid folic acid supplements, unless recommended by their oncologist. Folic acid could interfere with the anticancer effects of methotrexate.
Folate is a B vitamin your body needs to build healthy cells and keep homocysteine levels in a safe range. Methotrexate works by blocking the step that converts folic acid into the active form your body can actually use, so folate builds up less in your blood and red blood cells over time. Because this is a well-documented, major interaction, most people taking methotrexate long-term for conditions like rheumatoid arthritis or psoriasis are advised to take a daily folic acid supplement to help reduce side effects like mouth sores, hair loss, and stomach problems. Please talk with your pharmacist or doctor about whether a supplement is right for your situation.
What Folic acid (folate) does & food sources
Folate is needed for cell division, red blood cell formation, and healthy fetal development.
Common food sources:
- Leafy green vegetables
- Beans, lentils, and peas
- Fortified grains and cereals
- Citrus fruits
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
What to discuss with your clinician
Ask your provider whether folate monitoring or supplementation is appropriate for you — this matters most before and during pregnancy, and with long-term use of certain seizure or arthritis medications.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Supplement considerations
Folate needs are individual. With some medications (for example, methotrexate), folic acid is often prescribed deliberately on a specific schedule — follow your prescriber's instructions rather than adding your own.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Caution: High-dose folic acid can mask vitamin B12 deficiency, so the two are often evaluated together.
Learn more about this nutrient: Folic Acid — uses, safety & interactions
References (11)
- Leeb BF, Witzmann G, Ogris E, et al. Folic acid and cyanocobalamin levels in serum and erythrocytes during low-dose methotrexate therapy of rheumatoid arthritis and psoriatic arthritis patients. Clin Exp Rheumatol 1995;13:459-63.
- Morgan SL, Baggott JE, Lee JY, Alarcón GS. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease preventi
- Dijkmans BA. Folate supplementation and methotrexate. Br J Rheumatol 1995;34:1172-4. PubMed
- Amer College of Rheumatology ad hoc committee on clinical guidelines. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:723-31. DOI
- Duhra P. Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis. J Am Acad Dermatol 1993;28:466-9. PubMed
- Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994;121:833-41. PubMed
- Ortiz Z, Shea B, Suarez Almazor M, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Cochrane Review). Cochrane Database Syst Rev 2000;2:CD000951. PubMed
- Griffith SM, Fisher J, Clarke S, et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford) 2000;39:1102-9. PubMed
- Stamp LK, O'Donnell JL, Frampton C, et al. A Pilot Randomized Controlled Double-Blind Trial of High- Versus Low-Dose Weekly Folic Acid in People With Rheumatoid Arthritis Receiving Methotrexate. J Clin Rheumatol. 2019 Oct;25(7):284-287. PubMed
- Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposal for guidelines. Scand J Rheumatol 2001;30:129-34.
- Schroder H, Clausen N, Ostergard E, Pressler T. Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia. Ped Hematol Oncol 1986;3:241-7. PubMed
This tool is educational and is not a substitute for professional medical advice. An association is not a diagnosis and does not mean a deficiency will occur. Always talk to your pharmacist or healthcare provider before starting, stopping, or changing any medication or supplement.
Disclaimer: This checker finds which nutrients might be depleted by prescription or over-the-counter medications. Each nutrient depletion issue is rated based on clinical significance. Use your own professional judgment prior to making clinical decisions.© 2026 Therapeutic Research Center Licensed records refresh weekly · last updated July 3, 2026.
More about Methotrexate Sodium
What drug-induced nutrient depletion means
Some medications can, over time, lower the levels of certain vitamins, minerals, or other nutrients — through reduced absorption, increased loss, or changes in how the body uses them.
Association is not deficiency
An entry here means a depletion has been reported or studied — not that it happens to everyone, or that you are deficient. Dose, duration, diet, and your own health all matter.
Evidence varies by pair
Some drug–nutrient links (like metformin and vitamin B12) are well studied; others rest on limited or preliminary research. Each entry shows the evidence rating from our licensed clinical database.
When to ask about labs
If you take an associated medication long-term, ask your healthcare provider whether monitoring is appropriate for you. Not everyone needs testing — your provider can weigh your dose, duration, and symptoms.
Don't self-supplement blindly
Supplements are not risk-free: some can interact with medications, and some (like potassium or magnesium) can be risky with kidney disease. Talk to your pharmacist before adding anything.
Never stop a medication over this
These medications are prescribed for good reasons, and the benefit usually far outweighs a manageable nutrient consideration. Any change belongs in a conversation with your prescriber.
Food first, usually
For many nutrients, a varied diet covers the gap. Each entry lists common food sources; a supplement is a decision to make with your pharmacist or provider, not a default.
Methotrexate Sodium & nutrients: FAQs
Does Methotrexate Sodium deplete FOLIC ACID?
Should I take a supplement because I take Methotrexate Sodium?
Should I stop taking Methotrexate Sodium?
Where does this information come from?
Questions about Methotrexate Sodium and your nutrition?
Ask a licensed pharmacist — free, no appointment needed.
Sources & How We Checked
Nutrient depletion records for Methotrexate Sodium are evidence-graded and sourced from the Natural Medicines database, and are displayed as published with their citations.
- Natural Medicines (Therapeutic Research Center) — Evidence-graded clinical reference for drug-induced nutrient depletions, supplements, and interactions — the basis for this page.
- MedlinePlus, U.S. National Library of Medicine — NIH consumer drug information, used for medication overviews across the site.
Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.