Moderate interactionModerate
Methylfolate and Methotrexate: interaction, severity and spacing
Methylfolate and Methotrexate interact because methotrexate is a folate antagonist. Supplemental folate reduces side effects without compromising efficacy, but timing and dose matter. Take them with care. Moderate risk.
Last reviewed: 2026-09-20Reviewed by: StackingRight clinical review
The interaction in detail
| Pair | Methylfolate and Methotrexate |
|---|---|
| Type | Nutrient–drug interaction |
| Severity | Moderate |
| Required spacing | None specified |
| Onset | At the time of dosing |
Mechanism
Methotrexate is a folate antagonist. Supplemental folate reduces side effects without compromising efficacy, but timing and dose matter.
What to do
Folic acid is usually prescribed alongside methotrexate — take it as directed rather than doubling up on your own.
How to fit both into one day
Methylfolate
morningwith food
Take folate with B12 so one-carbon metabolism is supported at both ends. Check B12 before starting high-dose folate.
Putting Methylfolate in the morning and Methotrexate in the evening satisfies the 0-hour separation without disrupting either one's absorption window.