Leucovorin Dosing for Methylation Issues
For methylation issues unrelated to chemotherapy, there is no established evidence-based dosing of leucovorin, as this indication is not supported by FDA labeling or clinical guidelines.
Critical Context
The term "methylation issues" typically refers to genetic polymorphisms (such as MTHFR variants) affecting folate metabolism, which is fundamentally different from the established medical uses of leucovorin. The available evidence exclusively addresses leucovorin in two contexts:
Established Medical Uses (Not Applicable to Methylation Issues)
Chemotherapy Enhancement:
- Standard dosing is leucovorin 400 mg/m² IV over 2 hours on day 1 as part of FOLFOX or FOLFIRI regimens for colorectal cancer, repeated every 2 weeks 1, 2, 3
- This equals levoleucovorin 200 mg/m² (the active L-isomer requires half the dose) 1, 2, 3
Methotrexate Rescue:
- Standard rescue dosing is 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses starting 24 hours after methotrexate infusion 4
- Dosing escalates to 150 mg IV every 3 hours if methotrexate levels remain dangerously elevated 4
Why Standard Dosing Does Not Apply to "Methylation Issues"
Mechanism Mismatch:
- Leucovorin (folinic acid) bypasses the dihydrofolate reductase step but does not address MTHFR enzyme deficiencies that affect conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate 5
- For MTHFR-related methylation issues, methylfolate (5-MTHF) would be the theoretically appropriate supplement, not leucovorin
Oral Bioavailability Limitations:
- Oral leucovorin demonstrates saturable absorption with bioavailability dropping from 78% at 40 mg to only 31% at 200 mg due to saturation of folate uptake mechanisms 6, 7
- Peak serum concentrations plateau above 800 mg total dose, indicating no benefit to higher oral doses 6
Common Pitfall to Avoid
Do not confuse leucovorin with appropriate folate supplementation for methylation disorders. If the clinical concern is MTHFR polymorphisms or impaired methylation pathways, the appropriate intervention is methylfolate (L-5-MTHF) supplementation at typical doses of 1-15 mg daily, not leucovorin. Leucovorin is a chemotherapy adjunct and methotrexate antidote, not a treatment for genetic methylation variants.