Medication·Interactions & depletion·Reviewed June 9, 2026
Methotrexate interactions.
Methotrexate has 7 documented interactions in the NutriStack database, including 1 flagged to avoid or as a serious conflict. Prolonged use is also associated with lower Folate. The full interaction list, depletion table, and replacement suggestions are below. None of this is a substitute for your prescriber's advice.
Methotrexate at a glance.
A quick, data-grounded summary. The full tables are below.
Methotrexate has 7 documented interactions in the NutriStack database, including 1 flagged to avoid or as a serious conflict. Prolonged use is also associated with lower Folate. The full interaction list, depletion table, and replacement suggestions are below. None of this is a substitute for your prescriber's advice.
Substances that interact with methotrexate.
Every supplement and medication in the NutriStack database with a documented interaction with this drug, highest-severity first. Open any pair for the mechanism and sources.
| Substance | Interaction | What happens |
|---|---|---|
| St. John's Wort | Conflict | St. John's Wort induces CYP enzymes and P-glycoprotein that may affect methotrexate metabolism and transport. While methotrexate is primarily... details → |
| Alcohol | Caution | Alcohol can add to methotrexate's liver toxicity risk, especially with regular or heavy use. The risk is most important for people with rheumatoid... details → |
| Ibuprofen | Caution | NSAIDs reduce renal clearance of methotrexate, potentially leading to toxic methotrexate accumulation. This can cause severe bone marrow... details → |
| Naproxen | Caution | Naproxen, like other NSAIDs, reduces renal clearance of methotrexate. The longer half-life of naproxen may pose even greater accumulation risk... details → |
| Fish Oil | Synergy | Fish oil (EPA/DHA) may have additive anti-inflammatory effects when combined with methotrexate for rheumatic conditions. Some studies suggest that... details → |
| Methylfolate | Synergy | Folic acid supplementation is standard of care during methotrexate therapy. Methotrexate is a folate antagonist that depletes intracellular folate,... details → |
| Vitamin B9 | Synergy | Vitamin B9 supplementation reduces common methotrexate side effects such as mouth sores, nausea, elevated liver enzymes, and blood-count problems in... details → |
What methotrexate can deplete.
Nutrients this medication is associated with lowering over time, with the mechanism, a suggested replacement where one applies, and the biomarker to monitor. Discuss any replacement with your prescriber first.
| Nutrient | Severity | How it happens | Replace with | Monitor |
|---|---|---|---|---|
| Folate | Significant | Methotrexate directly inhibits dihydrofolate reductase, lowering reduced folate pools and increasing mucosal and hematologic toxicity risk. | Prescriber-directed folic acid or folinic acid | CBC trend + liver enzymes; folate rescue should follow the prescriber's protocol |
The full methotrexate profile.
Uses, typical dosing, side effects, and the cited evidence for this medication.
Common methotrexate questions.
Quick answers drawn from the tables above.
What interacts with Methotrexate?
In the NutriStack database, Methotrexate has 7 documented interactions. The most notable include St. John's Wort, Alcohol, Ibuprofen, Naproxen, and Fish Oil. Check any specific combination before taking it and confirm with your prescriber.
Which substances should I avoid with Methotrexate?
Methotrexate is flagged against 1 substance in the database, including St. John's Wort. These pairings carry a higher risk and should be reviewed with a clinician before combining.
Does Methotrexate deplete any nutrients?
Methotrexate is associated with lowering Folate with prolonged use. Useful biomarkers to monitor include CBC trend + liver enzymes; folate rescue should follow the prescriber's protocol. Ask your prescriber before adding any replacement supplement.
Is it safe to take St. John's Wort with Methotrexate?
NutriStack classifies the St. John's Wort and Methotrexate pairing as conflict: St. John's Wort induces CYP enzymes and P-glycoprotein that may affect methotrexate metabolism and transport. While methotrexate is primarily renally cleared, changes... Avoid St. John's Wort while on methotrexate. The potential for unpredictable changes in drug levels and the serious consequences of both... Always confirm with your prescriber.
Check your whole stack
See how methotrexate fits your supplements.
NutriStack screens your full routine for interactions and depletions, and updates the moment you change it.