What should always be given with methotrexate to reduce toxicity?

• A. Folic acid
• B. Vitamin B12
• C. Vitamin C
• D. Iron

Answer: (A)

Folic acid supplementation should be given with methotrexate to reduce toxicity. Methotrexate inhibits dihydrofolate reductase, depleting folate needed for DNA synthesis, which can lead to mucosal ulcers, liver enzyme changes, and low blood counts. Providing folic acid replenishes folate stores, lowering these adverse effects without substantially diminishing the drug’s effectiveness at typical rheumatology doses. In contrast, high-dose methotrexate therapy (as used in some cancer regimens) uses leucovorin rescue rather than routine folic acid. Common practice is to give folic acid on non-methotrexate days (for example, a small daily dose or a weekly higher dose), balancing toxicity reduction with maintaining MTX efficacy. Other vitamins or iron don’t specifically target methotrexate’s antifolate toxicity.