Do I need to take folic acid daily while receiving weekly low‑dose methotrexate?

Folic Acid Supplementation with Weekly Methotrexate

Yes, you absolutely need to take folic acid supplementation when on weekly methotrexate—this is a mandatory, non-negotiable component of safe methotrexate therapy. 1, 2

Standard Dosing Recommendation

The minimum effective dose is 5 mg folic acid weekly, which can be given as 1 mg daily for 5-6 days (skipping the methotrexate day) or as a single 5 mg dose once weekly. 1, 2

• The American College of Rheumatology strongly recommends at least 5 mg folic acid per week for all patients on methotrexate therapy 1, 2
• The American Academy of Dermatology recommends 1-5 mg daily, given on all days except the day(s) when methotrexate is administered 1
• Both dosing strategies (daily vs. once weekly) are effective, but daily dosing may provide more consistent protection 1

Critical Timing Rule

Never take folic acid on the same day as your methotrexate dose. 1

• Folic acid may theoretically compete with methotrexate for cellular uptake when given simultaneously, potentially reducing methotrexate's therapeutic effectiveness 1
• If you take methotrexate on Mondays, take folic acid Tuesday through Sunday 1
• If you split your methotrexate dose over 24 hours (e.g., Saturday and Sunday), skip folic acid both days and resume Monday 1

Why This Is Non-Negotiable

Lack of folate supplementation is a major risk factor for methotrexate-induced toxicity, including life-threatening complications. 1, 3

• Folic acid reduces gastrointestinal side effects by 58% (odds ratio 0.42) 1
• Hepatotoxicity is reduced by 83% (odds ratio 0.17) with folic acid supplementation 1, 2
• Meta-analysis of 788 rheumatoid arthritis patients demonstrated these benefits without reducing methotrexate efficacy 1
• Myelosuppression (bone marrow toxicity) accounts for the majority of methotrexate-associated fatalities, and folate deficiency significantly increases this risk 3

Evidence That Folic Acid Does Not Reduce Efficacy

Multiple high-quality studies confirm that folic acid at ≤5 mg/week does not compromise methotrexate's therapeutic effectiveness. 1, 2, 4, 5

• A landmark 1990 placebo-controlled trial showed that 1 mg daily folic acid significantly lowered toxicity without affecting disease activity measures 4
• More recent evidence from 2017 confirms that daily folic acid does not reduce methotrexate efficacy 5
• The concern about reduced efficacy has been definitively disproven in rheumatoid arthritis and psoriasis populations 1, 2

When to Consider Higher Doses

If you experience persistent gastrointestinal symptoms or are on higher methotrexate doses (>15 mg/week), consider increasing folic acid to 7-10 mg weekly. 1, 2

• Higher folic acid doses (7-35 mg/week) show significant GI protection, particularly with lower methotrexate doses (<10 mg/week) 2
• A 2015 randomized trial comparing 10 mg vs. 30 mg weekly folic acid found no additional benefit from the higher dose, but both were safe 6
• Patients on methotrexate 20-30 mg/week may benefit from proportionally higher folate supplementation 2

Important Distinction: Folic Acid vs. Folinic Acid

Use folic acid (the standard supplement), not folinic acid (leucovorin), for routine supplementation. 1, 2

• Folic acid is less expensive and equally effective for preventing side effects 1
• Folinic acid at doses >5 mg/week may paradoxically reduce methotrexate effectiveness (increased joint tenderness and swelling with odds ratios of 6.27 and 5.3 respectively) 1, 2
• Folinic acid (leucovorin) is reserved for methotrexate overdose or severe toxicity as an antidote, not for routine prevention 1, 3

Common Pitfalls to Avoid

• Do not skip folic acid supplementation thinking it will make methotrexate work better—this concern has been definitively disproven and only increases your toxicity risk 2, 7
• Do not take folic acid on the same day as methotrexate—this is the one exception to daily dosing 1
• Do not use less than 5 mg weekly—lower doses have insufficient evidence for adequate toxicity reduction 2
• Do not confuse folic acid with folinic acid—only folic acid should be used for routine supplementation 1

Monitoring Remains Essential

Even with folic acid supplementation, you still need regular blood work monitoring. 1, 3

• Complete blood count, liver function tests, and kidney function should be checked every 1-3 months 1
• Folic acid reduces but does not eliminate the need for vigilant monitoring 1
• Early signs of folate deficiency include rising mean corpuscular volume (MCV) before anemia develops 3