Folic Acid - Methotrexate Interaction
Herbal: Folic Acid
Drug: Methotrexate
Brand names:
Rheumatrex, Otrexup, Rasuvo, Reditrex

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
May 25, 2025
Interaction Details
Methotrexate is classified as belonging to the following category: Methotrexate (Trexall, Others)
Folic acid might reduce the efficacy of methotrexate as a cancer treatment when given concurrently.
Methotrexate exerts its cytotoxic effects by preventing conversion of folic acid to the active form needed by cells. There is some evidence that folic acid supplements reduce the efficacy of methotrexate in the treatment of acute lymphoblastic leukemia, and theoretically they could reduce its efficacy in the treatment of other cancers. Advise cancer patients to consult their oncologist before using folic acid supplements. In patients treated with long-term, low-dose methotrexate for rheumatoid arthritis (RA) or psoriasis, folic acid supplements can reduce the incidence of side effects, without reducing efficacy.
Interaction Rating
Likelihood of Occurrence
ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
References
- Duhra P. Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis. J Am Acad Dermatol 1993;28:466-9.
- 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.
- 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.
- Amer College of Rheumatology ad hoc committee on clinical guidelines. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:723-31.
- 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.
- 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.
Folic Acid Overview
Methotrexate Overview
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Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments. Methotrexate is also used along with rest, physical therapy, and sometimes other medications to treat severe active rheumatoid arthritis (RA; a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) that cannot be controlled by certain other medications. Methotrexate is also used to treat certain types of cancer including cancers that begin in the tissues that form around a fertilized egg in the uterus, breast cancer, lung cancer, certain cancers of the head and neck, certain types of lymphoma, and leukemia (cancer that begins in the white blood cells). Methotrexate is in a class of medications called antimetabolites. Methotrexate treats cancer by slowing the growth of cancer cells. Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.
Folic Acid - More Interactions
Folic Acid interacts with 40 drugs
Interaction Rating Key
These severity listings are for informational use only. Never start, stop or otherwise change your therapy before speaking with your provider.
Major | The combined use of these agents is strongly discouraged as serious side effects or other negative outcomes could occur. |
Moderate | Use cautiously under the care of a healthcare professional or avoid this combination. A significant interaction or negative outcome could occur. |
Minor | Be aware that there is a chance of an interaction. Watch for warning signs of a potential interaction. |
Unknown | No interactions have been reported or no interaction data is currently available. |
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DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.
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Drug descriptions are provided by MedlinePlus.