Methotrexate and Folic Acid Interaction
Folic acid supplementation at a minimum of 5 mg per week is strongly recommended for all patients receiving methotrexate therapy, as it significantly reduces gastrointestinal and hepatic toxicity without compromising therapeutic efficacy. 1
The Interaction Explained
Mechanism of Interaction
Methotrexate functions as a folate antagonist, inhibiting folate-dependent purine and pyrimidine synthesis pathways, which is both its therapeutic mechanism and the source of most adverse effects. 2
Folic acid supplementation replenishes folate stores depleted by methotrexate, thereby reducing toxicity while maintaining therapeutic benefit. 2
The interaction is beneficial and protective rather than antagonistic when dosed appropriately—folic acid does not significantly interfere with methotrexate's efficacy at recommended doses. 1
Context-Dependent Recommendations
For Rheumatoid Arthritis and Inflammatory Conditions:
Prescribe at least 5 mg folic acid per week for all patients on methotrexate therapy. 1
Higher doses (7-35 mg/week) may be needed with higher methotrexate doses (>15 mg/week), as the protective effect is most significant at lower methotrexate doses (<10 mg/week). 1
Administer folic acid daily except on the day(s) of methotrexate administration to avoid potential interference with efficacy. 2
Meta-analysis of 788 RA patients demonstrated that folic acid supplementation reduces gastrointestinal side effects (OR 0.42) and hepatotoxicity (OR 0.17) without reducing methotrexate efficacy. 1
For Ectopic Pregnancy Treatment:
Folic acid should be avoided during methotrexate treatment for ectopic pregnancy, as it may directly counteract methotrexate's primary action as a folate antagonist in this acute, high-dose setting. 1
This represents a critical exception where the interaction is genuinely antagonistic and clinically harmful.
Evidence-Based Benefits of Supplementation
Toxicity Reduction
Hepatotoxicity: Folic acid supplementation reduces hepatic adverse effects by 35.8% (95% CI -0.467 to -0.248), with 1 mg/day showing significant protective effect (OR 0.17). 1, 3
Gastrointestinal effects: Reduction in nausea, stomatitis, and other GI symptoms, particularly with doses of 7-35 mg/week. 1
Hematologic toxicity: Lack of folate supplementation is a major risk factor for methotrexate-induced bone marrow suppression. 2
Cardiovascular protection: Folic acid prevents methotrexate-induced hyperhomocysteinemia, which is considered a cardiovascular risk factor. 4
Impact on Efficacy
Folic acid at ≤5 mg/week does not reduce methotrexate efficacy in rheumatoid arthritis or psoriasis. 1
One study showed folic acid may slightly reduce plasma methotrexate levels (20% reduction in AUC), possibly due to increased cellular uptake, but this does not translate to reduced clinical efficacy. 5
Critical caveat: Folinic acid at doses >5 mg/week was associated with increased tender and swollen joints (OR 6.27 and 5.3 respectively), suggesting potential interference with efficacy at higher doses. 1
Practical Implementation
Preferred Formulation
- Folic acid is preferred over folinic acid due to lower cost, similar effectiveness for toxicity reduction, and better safety profile at standard doses. 2, 3
Dosing Algorithm
Start with 5 mg folic acid weekly (can be given as 1 mg daily for 5-6 days, avoiding methotrexate day). 1, 2
For patients on methotrexate >15 mg/week, consider increasing to 7-10 mg folic acid weekly. 1
If persistent GI or mucocutaneous toxicity occurs despite 5 mg weekly, escalate folic acid dose before reducing methotrexate. 1
Important Caveats
The FDA label warns that "vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate," but this primarily applies to high-dose chemotherapy regimens, not low-dose inflammatory disease treatment. 6
Regular monitoring of liver function (ALT/AST), CBC, and creatinine remains essential every 1-1.5 months initially, then every 1-3 months, even with folic acid supplementation. 1, 2
Folate deficiency states increase methotrexate toxicity, making supplementation even more critical in at-risk populations. 6