Herb & supplement monograph

Folic Acid Drug Interactions, Uses, Effectiveness, Safety & More

Medically reviewed by Dr. Brian Staiger, PharmD, BCPS ·Updated July 2026

What is this page for?

First and foremost: how Folic Acid interacts with medications. The heart of this page is the interaction list — every drug Folic Acid is known to interact with, and how serious each one is.

But these pages have grown well beyond that into a full monograph — what Folic Acid is, what people use it for and how strong the evidence is, its safety and side effects, and answers to the questions we’re asked most — written and reviewed by the clinical staff at HelloPharmacist. It’s educational information from our licensed clinical databases, not medical advice, and we don’t sell or endorse products. Our editorial policy

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Folic Acid Drug Interactions: The Bottom Line

From the HelloPharmacist Editorial Team · Updated July 2026

Based on the available evidence, the overall risk of a clinically significant Folic Acid drug interaction is moderate, and it matters mainly for people taking a handful of specific medications. None of the listed interactions are rated major, but all are rated moderate, and several are backed by human evidence.

Interactions deserving the most attention

The best-documented concerns involve seizure medications such as phenytoin, phenobarbital, and primidone: folic acid can lower phenytoin levels or work against these drugs, and worsened seizure control has been reported in some people. Folic acid may also reduce the effectiveness of methotrexate when it is used to treat cancer, because methotrexate works by blocking how cells use folate. With certain chemotherapy drugs like 5-fluorouracil and capecitabine, high doses of folic acid might add to side effects such as diarrhea, though this evidence is more limited. Folic acid can also blunt pyrimethamine's effect against some infections.

What the rest of the list means

A list of several dozen interacting medications sounds worrying, but many of these concerns apply only to high folic acid doses or to specific treatment situations, such as cancer therapy. Some are theoretical or rest on limited case reports rather than proven harm in people. For most everyday medications, folic acid at usual doses has not shown meaningful problems in this data.

Check your medications against Folic Acid

Based on HelloPharmacist’s Folic Acid interaction data and reviewed under our editorial standards.

Interaction report

Drugs that interact with Folic Acid

40 medications have a known interaction with Folic Acid, graded by severity. Select any drug for the full evidence-based detail.

Don’t want to scroll the list? Just ask.

Tell us the medications you take and we’ll check each one against Folic Acid using our pharmacist-reviewed interaction data.

AI summaries are generated from our Folic Acid interaction data for education only — always confirm with your pharmacist. How we use AI

2,830 drugs

Read The List Like a Pharmacist

What Severity, Likelihood & Evidence Mean

Severity — How Serious It Can Be

Major. Clinically significant; generally best avoided, or used only under direct professional supervision.
Moderate. May need monitoring, a dose adjustment, or separating the times you take each one.
Minor. Generally not clinically significant, but still worth noting and mentioning to your pharmacist.
No known interaction. Checked against our sources with nothing documented — not the same as proven safety.

Likelihood — How Well It’s Documented

Likely. Well-controlled human studies have demonstrated the likely existence of this interaction
Probable. Interaction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
Possible. Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
Unlikely. Interaction has been demonstrated in animal or in lab research but has been shown not to occur in humans.

Where This Data Comes From

Interaction records are evidence-graded and sourced from the Natural Medicines database (TRC Healthcare), the same reference used by pharmacists and hospitals.
Each drug listed above links to the full report for that exact Folic Acid combination — clinical detail, likelihood, evidence level, and citations.
Content is reviewed by licensed HelloPharmacist pharmacists — see our data sources and editorial standards.

The big picture

The kinds of drugs Folic Acid affects

Every type of medication (drug category) Folic Acid is known to interact with. Open any category for the detail — or search your exact drug in the checker above.

All 7 drug categories Folic Acid interacts with

5-fluorouracilCapecitabine (xeloda)Methotrexate (trexall, Others)Phenobarbital (luminal)Phenytoin (dilantin)Primidone (mysoline)Pyrimethamine (daraprim)

5-Fluorouracil

Theoretically, high doses of folic acid might increase the toxicity of 5-fluorouracil.
Increases in gastrointestinal side effects of 5-fluorouracil, such as stomatitis and diarrhea, have been described in two clinical studies when leucovorin, a form of folic acid, was administered with 5-fluorouracil.

Likelihood Possible Evidence D

Capecitabine (Xeloda)

Use of high-dose folic acid might contribute to capecitabine toxicity.
Clinical research suggests that higher serum folate levels are associated with an increased risk for moderate or severe toxicity during capecitabine-based treatment for colorectal cancer. Additionally, in one case report, taking folic acid 15 mg daily might have contributed to increased toxicity, including severe diarrhea, vomiting, edema, hand-foot syndrome, and eventually death, in a patient prescribed capecitabine.

Likelihood Possible Evidence D

Methotrexate (Trexall, Others)

Folic acid might reduce the efficacy of methotrexate as a cancer treatment when given concurrently.
Methotrexate exerts its cytotoxic effects by preventing conversion of folic acid to the active form needed by cells. There is some evidence that folic acid supplements reduce the efficacy of methotrexate in the treatment of acute lymphoblastic leukemia, and theoretically they could reduce its efficacy in the treatment of other cancers. Advise cancer patients to consult their oncologist before using folic acid supplements. In patients treated with long-term, low-dose methotrexate for rheumatoid arthritis (RA) or psoriasis, folic acid supplements can reduce the incidence of side effects, without reducing efficacy.

Likelihood Probable Evidence B

Phenobarbital (Luminal)

Folic acid might have antagonistic effects on phenobarbital and increase the risk for seizures.
Folic acid can have direct convulsant activity in some people, reversing the effects of phenobarbital and worsening seizure control. Monitor closely for increased seizure activity.

Likelihood Probable Evidence B

Phenytoin (Dilantin)

Folic acid might reduce serum levels of phenytoin in some patients.
Folic acid may be a cofactor in phenytoin metabolism. Folic acid, in doses of 1 mg daily or more, can reduce serum levels of phenytoin in some patients. Increases in seizure frequency have been reported. If folic acid supplements are added to established phenytoin therapy, monitor serum phenytoin levels closely. If phenytoin and folic acid are started at the same time and continued together, adverse changes in phenytoin pharmacokinetics are avoided. Note that phenytoin also reduces serum folate levels.

Likelihood Probable Evidence B

Primidone (Mysoline)

Folic acid might have antagonistic effects on primidone and increase the risk for seizures.
Folic acid can have direct convulsant activity in some people, reversing the effects of primidone and worsening seizure control. Monitor closely for increased seizure activity. Note that primidone also reduces serum folate levels.

Likelihood Probable Evidence B

Pyrimethamine (Daraprim)

Folic acid might antagonize the effects of pyrimethamine.
Folic acid can antagonize the antiparasitic effects of pyrimethamine against toxoplasmosis and Pneumocystis carinii pneumonia. Folic acid doesn't antagonize the effects of pyrimethamine in the treatment of malaria, because malarial parasites cannot use exogenous folic acid. Use folinic acid as an alternative to folic acid when indicated.

Likelihood Probable Evidence D

Monograph

Folic Acid: Uses, Safety & Side Effects

Medically reviewed by Dr. Brian Staiger, PharmD, BCPS · Reviewed July 2026 ·

The bottom line

Folic acid is the man-made form of vitamin B9 and is one of the most well-studied supplements, especially for preventing serious birth defects when taken before and during early pregnancy. It is widely available, inexpensive, and generally safe at recommended doses, but you should still check with your pharmacist or doctor about the right amount for you.

Part used: Synthetic vitamin (not a plant part); natural folate is found in many foods
Common forms: Tablets, capsules, softgels, multivitamins, prenatal vitamins, fortified foods

People commonly use it for

Preventing neural tube birth defects
Treating or preventing folate deficiency
Supporting pregnancy health
Certain types of anemia
Heart and blood vessel health

Popular and traditional uses — not proof it works. See “Uses & effectiveness” below for the evidence.

Safety at a glance

OverallLikely safe

Generally safe at recommended doses for most adults.

PregnancyLikely Safe

When used orally and appropriately. Folic acid 300-400 mcg is commonly used during pregnancy for prevention of neural tube defects. Miscarriage rates...

Read the full pregnancy detail

BreastfeedingLikely Safe

When used orally and appropriately. Folic acid 300-400 mcg is commonly used during pregnancy for prevention of neural tube defects. Miscarriage rates...

Read the full breastfeeding detail

Pregnancy & breastfeeding ratings are from Natural Medicines (Therapeutic Research Center). Safety guidance is general; always confirm with your pharmacist or doctor for your situation.

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Overview

Folic acid is the synthetic (man-made) form of vitamin B9. The natural form found in foods is called folate. Both are needed for many basic body functions, including making DNA and helping cells grow and divide.

Folate occurs naturally in foods like leafy green vegetables, beans and other legumes, citrus fruits, and liver. Folic acid is the form added to supplements and to fortified foods. Since 1998, the United States has added folic acid to products like cereal, flour, pasta, and bread to help prevent deficiency in the general population.

Interestingly, the synthetic folic acid in supplements and fortified foods is absorbed more completely than the folate found naturally in foods. Some supplements use another form called L-5-methyltetrahydrofolate (L-5-MTHF), which is a body-ready ("active") form of folate.

How it works

Vitamin B9 acts as a helper (a "cofactor") in many chemical reactions in the body. It is especially important for making and repairing DNA and for helping cells divide. This is why it matters most during times of rapid growth, such as early pregnancy.

Folate also helps the body process an amino acid called homocysteine, converting it into other useful substances. Folate works closely with vitamin B12, and the two are linked in the body's chemistry. Because of this connection, taking large amounts of folic acid can sometimes hide a vitamin B12 deficiency.

The active form, L-5-MTHF, does not need to be converted by the body, which may matter for people with certain genetic differences (such as MTHFR gene variants).

Effectiveness

Does Folic Acid work?

Here’s what the research actually shows for each use — graded by Natural Medicines and reviewed by Dr. Brian Staiger, PharmD.

Evidence overview · 75 uses evaluated

1 Effective 3 Likely effective 6 Possibly effective 14 Leans ineffective 51 Insufficient evidence

How to read these evidence grades

Natural Medicines’ 7-point scale. We show each rating’s label word-for-word.

1EffectiveStrong, consistent evidence it works.

2Likely EffectiveGood evidence, though not yet conclusive.

3Possibly EffectiveSome evidence suggests a benefit.

4Possibly IneffectiveSome evidence it may not help.

5Likely IneffectiveFairly strong evidence it doesn’t help.

6IneffectiveStrong evidence it doesn’t work.

7Insufficient Reliable Evidence to RateToo little research to say either way.

Effective Folate deficiency