Methotrexate and Folate Deficiency
Methotrexate directly causes folate deficiency but does not cause vitamin B12 deficiency. 1, 2
Mechanism of Folate Depletion
Methotrexate is a folate antagonist that inhibits dihydrofolate reductase, the enzyme responsible for converting dietary folates to their biologically active tetrahydrofolate form. 3 This mechanism directly depletes folate stores through:
- Inhibition of folate metabolism required for DNA synthesis, amino acid metabolism, and methylation reactions 3, 4
- Dose-dependent depletion that correlates with weekly administered dose rather than cumulative total dose 5
- Progressive decline in folate nutriture during long-term therapy, with plasma homocysteine levels increasing significantly over one year without supplementation 6
Clinical Evidence of Folate Deficiency
Patients on methotrexate demonstrate significantly lower folate levels compared to untreated controls (median 4.36 vs 7.37 ng/ml, p < 0.001). 5 The degree of folate depletion is primarily determined by the weekly dose administered rather than cumulative exposure. 5
Key manifestations include:
- Hematologic toxicity: Megaloblastic anemia, pancytopenia, and myelosuppression (responsible for 67 of 164 methotrexate-associated fatalities) 1
- Gastrointestinal effects: Nausea, anorexia, stomatitis 1
- Elevated homocysteine levels: A cardiovascular risk factor that develops without folic acid supplementation 6
Vitamin B12 Status
Methotrexate does not cause vitamin B12 deficiency. 1 However, one study found lower B12 levels in red blood cells (not serum) among methotrexate-treated patients, suggesting a possible indirect effect on B12 distribution rather than true deficiency. 5
The distinction is critical: Always exclude or treat vitamin B12 deficiency before initiating folate therapy to prevent masking hematologic manifestations of B12 deficiency while allowing irreversible neurological damage to progress. 7
Universal Folate Supplementation Recommendation
All patients receiving methotrexate should receive prophylactic folate supplementation at treatment initiation. 1, 4, 8 This represents the consensus position across multiple guidelines and is associated with a high benefit-to-risk ratio. 4
Dosing Regimens
The evidence supports the following approaches:
- Standard regimen: 1-5 mg folic acid daily (except on the day of methotrexate administration) 1, 9, 7
- Alternative regimen: 5 mg once weekly, administered 24-72 hours after methotrexate dose 1, 7
- Alternative regimen: 1 mg daily for 5 days per week 1, 7
Folic acid is preferred over folinic acid due to equal efficacy at lower cost, though folinic acid may be more efficient for restoring body stores in patients on sulfasalazine. 7, 8
Benefits of Supplementation
Multiple studies demonstrate that folate supplementation:
- Reduces hepatotoxicity and gastrointestinal intolerance without impairing methotrexate efficacy 8
- Prevents deficient blood folate levels and hyperhomocysteinemia during long-term therapy 6
- Decreases hematologic toxicity, with lack of folate supplementation identified as a major risk factor for bone marrow suppression 1
- May allow dose escalation in patients who develop side effects while on folate 1
Critical Risk Factors for Toxicity
The absence of folate supplementation is consistently identified as a major risk factor for methotrexate toxicity, alongside: 1
- Advanced age
- Renal impairment
- Drug interactions (particularly NSAIDs, sulfonamides, penicillins)
- Hypoalbuminemia
- Alcohol consumption
Common Pitfall
Do not withhold folate supplementation based on concerns about reduced efficacy. 1, 8 While one small study suggested a slight decrease in efficacy with 5 mg daily folic acid, its methodology has been questioned, and the preponderance of evidence shows no impairment of therapeutic effect. 1, 8 The FDA label notes that vitamin preparations containing folic acid may decrease responses to methotrexate, but this theoretical concern is outweighed by the documented benefits of supplementation in clinical practice. 2