Supplement·Interactions·Reviewed June 9, 2026
Methylfolate interactions.
Methylfolate has 21 documented interactions in the NutriStack database: 1 to avoid or watch closely, 5 that need timing or caution, and 15 that work synergistically. The full list, with what each pairing does, is below.
Methylfolate at a glance.
A quick, data-grounded summary. The full table is below.
Methylfolate has 21 documented interactions in the NutriStack database: 1 to avoid or watch closely, 5 that need timing or caution, and 15 that work synergistically. The full list, with what each pairing does, is below.
Everything that interacts with methylfolate.
Every supplement and medication in the NutriStack database with a documented interaction with this substance, highest-severity first. Open any pair for the mechanism and sources.
| Substance | Interaction | What happens |
|---|---|---|
| Methotrexate (Cancer) | Contraindicated | Folate can interfere with methotrexate's anticancer mechanism. Note: folate supplementation IS beneficial with low-dose MTX for rheumatoid arthritis. |
| Colchicine | Caution | Colchicine can impair intestinal absorption of multiple nutrients through its disruption of microtubule-dependent enterocyte function. While the... |
| Lamotrigine | Caution | Lamotrigine is a weak inhibitor of dihydrofolate reductase, though clinical studies show minimal effect on serum or RBC folate in most patients.... details → |
| Phenytoin | Caution | Phenytoin depletes folate levels through increased catabolism and impaired absorption, potentially causing megaloblastic anemia. However, folate... details → |
| Trimethoprim-Sulfamethoxazole | Caution | Trimethoprim inhibits dihydrofolate reductase and can cause folate deficiency with prolonged use, particularly in people with marginal folate... details → |
| Zinc | Caution | High-dose zinc (>40mg) may impair folate absorption by inhibiting the folate conjugase enzyme in the gut. |
| Carbamazepine | Synergy | Carbamazepine depletes folate through enzyme induction effects on folate metabolism. Folate deficiency during carbamazepine therapy can cause... details → |
| Combined Oral Contraceptive | Synergy | Methylfolate (5-MTHF) is the active circulating form of folate and is the preferred supplement for women on combined oral contraceptives,... details → |
| L-Methionine | Synergy | Methylfolate is the methyl donor that enables homocysteine remethylation to methionine via methionine synthase. |
| Metformin | Synergy | Metformin can lower serum folate as well as vitamin B12, with longer treatment duration linked to lower folate levels and higher homocysteine.... details → |
| Methotrexate | Synergy | Folic acid supplementation is standard of care during methotrexate therapy. Methotrexate is a folate antagonist that depletes intracellular folate,... details → |
| Myo-Inositol & D-Chiro-Inositol | Synergy | Folate is often paired with inositol in reproductive-age PCOS users, especially when pregnancy is possible. |
| Niacinamide | Synergy | Folate status complements B-vitamin metabolism but does not replace niacinamide. |
| Phosphatidylcholine | Synergy | Both contribute to the methyl donor pool; choline can compensate for low folate in some methylation reactions and vice versa. |
| Risperidone | Synergy | Methylfolate has been studied as an adjunct in medicated schizophrenia patients with residual symptoms. Benefits appear selective and may depend on... details → |
| Trimethylglycine | Synergy | TMG and methylfolate act on parallel homocysteine remethylation routes: TMG drives the folate-independent BHMT pathway while methylfolate (with B12)... |
| Valproic Acid | Synergy | Valproic acid has been associated with disturbances in one-carbon metabolism and higher homocysteine in epilepsy studies. Methylfolate may help... details → |
| Vitamin B12 | Synergy | B9 (folate) and B12 work together in the methionine cycle. B12 deficiency can be masked by high folate intake. details → |
| Vitamin B2 | Synergy | Riboflavin is the cofactor for the MTHFR enzyme that converts folate to its active form, so good riboflavin status improves folate-mediated lowering... |
| Vitamin B6 | Synergy | B6 is required for the conversion of serine to glycine, which generates 5,10-methyleneTHF needed for folate-dependent one-carbon metabolism. |
| Vitamin C | Synergy | Vitamin C protects folate from oxidative degradation and helps maintain it in its reduced, active form. |
The full methylfolate profile.
Benefits, dosing by goal, forms, and the cited evidence for this supplement.
Common methylfolate questions.
Quick answers drawn from the table above.
What interacts with Methylfolate?
In the NutriStack database, Methylfolate has 21 documented interactions with other supplements and medications. The most notable include Methotrexate (Cancer), Colchicine, Lamotrigine, Phenytoin, and Trimethoprim-Sulfamethoxazole.
What should you not take with Methylfolate?
Methylfolate is flagged against 1 substance in the database, including Methotrexate (Cancer). Review these with a clinician before combining, especially alongside prescription medications.
What works well with Methylfolate?
Methylfolate pairs synergistically with Carbamazepine, Combined Oral Contraceptive, L-Methionine, Metformin, and Methotrexate in the NutriStack database. Synergy still depends on dose and timing; open any pair for the detail.
Can you take Methylfolate with Methotrexate (Cancer)?
NutriStack classifies the Methylfolate and Methotrexate (Cancer) pairing as contraindicated: Folate can interfere with methotrexate's anticancer mechanism. Note: folate supplementation IS beneficial with low-dose MTX for rheumatoid arthritis. Cancer patients on MTX should NOT take folate without oncologist approval.
Check your whole stack
See how methylfolate fits your routine.
NutriStack screens your full stack for interactions and timing conflicts, and updates the moment you change it.