Which intervention is recommended to counteract methotrexate toxicity in overdose?

• A. Leucovorin (Folinic acid)
• B. N-acetylcysteine
• C. Vitamin B12
• D. Activated charcoal

Answer: (A)

The key idea is that methotrexate toxicity is countered with leucovorin rescue because leucovorin supplies a usable form of folate that bypasses the blocked enzyme in the methotrexate pathway. Methotrexate inhibits dihydrofolate reductase, cutting off the production of tetrahydrofolate needed for DNA synthesis, which particularly harms rapidly dividing cells. Leucovorin (folinic acid) replenishes the folate pool downstream of that blockade, allowing normal cells to continue DNA synthesis and survive while the drug is cleared. This makes leucovorin the recommended intervention after an MTX overdose.

N-acetylcysteine is used for acetaminophen overdose, not MTX toxicity. Vitamin B12 isn’t the remedy for the folate pathway blockade caused by MTX. Activated charcoal may reduce absorption if administered very soon after ingestion, but it does not reverse established intracellular MTX toxicity, so it isn’t the primary countermeasure for overdose. In severe cases, additional strategies like glucarpidase or supportive measures may be considered, but leucovorin rescue is the main approach to counteract MTX toxicity.