Folate and medications.
Folate is classified as a foundation supplement in the Distil database, evidence Grade A. The page below lists every medication we have explicitly assessed it against.
Folate is the B vitamin with the most definitive evidence in supplements: taking it before and in early pregnancy cuts neural tube defects substantially, which is why the NHS recommends 400mcg up to 12 weeks. It also supports methylation, lowers homocysteine, and is studied in male and female fertility. Folate has been trialled as an add-on in depression: short-term folate on top of an antidepressant did not improve symptoms in a meta-analysis of adults with depression, though one trial of the active methylfolate form at a prescription-level dose (15mg) did help as an add-on in people not responding to their SSRI. On its own it is not a treatment for low mood, and any use for mood is best guided by a clinician. The active form, L-5-MTHF or methylfolate, bypasses the MTHFR enzyme step that an estimated 40% of people convert poorly. For neural tube defect prevention in pregnancy, though, ordinary folic acid is the form with the randomised trial evidence (MRC 1991) and the NHS recommendation, so it is the default there; methylfolate is the preferred form for methylation, homocysteine and mental health, and is reserved for fertility or pregnancy only where an MTHFR variant is confirmed, under GP or midwife guidance. The interactions that matter are serious. Methotrexate works by blocking folate, so never supplement alongside it without oncology approval. Anticonvulsants such as phenytoin and carbamazepine lower folate and warrant a word with your prescriber. High-dose folic acid can mask a B12 deficiency, so the two are best kept adequate together. It is very well tolerated, with doses above 5mg reserved for medical supervision.
Below are the 5 documented pairs we have explicitly assessed for Folate: 5 amber. The pairs cluster around 4 mechanisms: Absorption interference, Anticonvulsant-induced folate depletion, Antifolate antagonism, and Folate-anticonvulsant (two-way). Every call is cited to either a clinical reference (PMID) or the British National Formulary. Anything not listed here is either still to be assessed or beyond our database scope. The checker beneath surfaces assessments by medication, and the missing-item form at the bottom of the page routes any uncatalogued medication into our next curation pass.
Documented interactions
Last reviewed 30 June 2026. Each interaction below lists the evidence its assessment drew on: some rest on studies of the exact pair, others on mechanism evidence, where a citation may support one part of the reasoning rather than the exact combination. The evidence line on each entry says which.
Absorption interference
Amber Does interact with Sulfasalazine?
Sulfasalazine reduces how well the gut absorbs folate, so people on it long-term can become low in folate. This is a reason to supplement rather than avoid, and folate is often recommended for people taking sulfasalazine, particularly for inflammatory bowel disease or rheumatoid arthritis. There is no need to space the doses apart in a complicated way: the issue is ongoing absorption, so the usual approach is simply to take a folate supplement and let your prescriber keep an eye on your folate level.
Evidence: Supported by human study data.
Anticonvulsant-induced folate depletion
Amber Does interact with Valproic acid?
Valproate tends to lower folate levels and can push up homocysteine. For most people this means folate is supportive rather than a problem. The important point is for anyone who could become pregnant: valproate carries a high risk of birth defects, and folate plays a part in that risk, so folic acid is usually recommended before and during early pregnancy. Doses and the bigger decision about valproate in pregnancy are a specialist matter, so do not start, stop, or change folate or valproate on your own. Talk to the team managing your epilepsy.
Evidence: Supported by human study data.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Antifolate antagonism
Amber Does interact with Methotrexate?
Whether folate is safe with methotrexate depends entirely on why the methotrexate is being taken, so do not change anything yourself. For rheumatoid arthritis, psoriasis or similar conditions, low weekly methotrexate is very often prescribed alongside folic acid on purpose: the folate reduces sickness, mouth ulcers and liver-enzyme problems without stopping the methotrexate from working, and it is usually taken on a different day from the methotrexate. The picture is different for high-dose methotrexate used in cancer treatment, where folate and a related rescue drug are timed precisely by the cancer team and you should never add or adjust folate around it. If you take methotrexate, let whoever prescribes it set your folate, rather than starting or stopping it on your own.
Evidence: Supported by human study data.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Folate-anticonvulsant (two-way)
Amber Does interact with Carbamazepine?
Carbamazepine tends to lower folate levels over time, so people on it for a long time often run low on folate, which can also push up a blood marker called homocysteine. This usually works in the direction of needing folate rather than avoiding it, and folate is often supplemented on purpose in people on carbamazepine. As with other epilepsy medicines, it is sensible to start folate with your prescriber's knowledge so your levels and seizure control can be kept under review. Let whoever manages your epilepsy know before you start or stop folate.
Evidence: Supported by human study data.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Phenytoin?
Phenytoin and folate affect each other in both directions. Phenytoin lowers folate levels over time, so people on it often run low. But starting a folate supplement can lower the amount of phenytoin in the blood, and if that drop is large enough it can make seizures harder to control. This does not mean folate is off-limits, and it is often given alongside phenytoin on purpose, but it is best started with your prescriber's knowledge so your phenytoin level and seizure control can be checked rather than changed blind. The safest approach is to tell whoever manages your epilepsy before you start or stop folate.
Evidence: Supported by human study data.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
What this list does not say. Pairs not flagged here are not implicitly safe. They are either not yet in our database, or fall outside our inclusion scope. Use the checker below to surface any medication, and submit a missing item if you take something we have not catalogued.
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How we grade severity, choose what's in scope, and what we exclude.
Every call on this page is reasoned. We publish the full rubric for severity tiers, the medication inclusion logic, the evidence grades we accept, and what we deliberately leave out. About three thousand words. Worth reading once if you use this tool more than occasionally.
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The free checker answers one interaction question at a time. A Distil report reviews the bigger picture: your goals, diet, medications, current supplements and any blood results you provide, then shows what appears worth keeping, changing, adding or leaving out.
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The interaction check is one section of the full report. You also get the reasoning behind each recommendation and the evidence references used.
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