Folate

What it is

"Folate" covers many chemical forms of the same vitamin. Folic acid is the most oxidized and stable form. It occurs rarely in food but is the form used in fortified foods and most supplements.^[1] The folates in food carry a tail of extra glutamate units, which the gut trims off before absorption in the upper small intestine.^[1]

Folate coenzymes are needed to make the building blocks of DNA and to convert homocysteine to methionine, a step that also needs vitamin B12.^[1][2] Because of that shared step, a lack of either vitamin produces the same anemia, with large, abnormal red blood cells.^[2]

Folic acid and 5-MTHF. L-5-methyltetrahydrofolate (L-5-MTHF, or 5-MTHF) is the main form of folate in food and the only form normally found circulating in blood. Folic acid has no coenzyme activity of its own; cells must first reduce it, using the enzyme dihydrofolate reductase.^[3] 5-MTHF is sold as a crystalline calcium salt stable enough for supplements.^[3] In the US, folic acid is the only form that may be added to conventional foods; supplements may also use salts of L-5-MTHF.^[4] Replenish uses L-5-methyltetrahydrofolate calcium.

Food sources. Legumes such as chickpeas, beans and lentils, dark green vegetables such as spinach and turnip greens, and liver are rich in folate.^[1] Since January 1, 1998, enriched cereal grains in the US, such as bread, pasta, flour and rice, have been required to carry added folic acid.^[1] Beans and lentils also bring fiber; see how much fiber you need on a GLP-1.

How much adults need

Source: Institute of Medicine, Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998).^[1] *The UL is stated as mcg of folate from fortified food or supplements; folate naturally present in food does not count toward it. RDA = Recommended Dietary Allowance; UL = Tolerable Upper Intake Level; DFE = dietary folate equivalents.

Amount in Replenish: confirmed at launch

What DFE means. Folate from food is absorbed less well than folic acid, by nearly half, so the RDA is written in dietary folate equivalents. One mcg DFE equals 1 mcg of food folate, 0.6 mcg of folic acid from fortified food or a supplement taken with a meal, or 0.5 mcg of a folic acid supplement taken on an empty stomach.^[1] On US labels, FDA uses 1.7 as the factor for folic acid, so 100 mcg of folic acid counts as 170 mcg DFE.^[4] For L-5-MTHF salts, FDA lets manufacturers use their own established conversion factor, provided the label is truthful, and does not expect any synthetic form to exceed 1.7.^[4]

Separately from the RDA, the DRI report recommends that women capable of becoming pregnant take 400 mcg of folic acid a day from fortified foods, supplements or both, on top of food folate.^[1] If that applies to you, ask your clinician which form and dose suit you.

What the evidence says

Neural tube defects. This is the strongest evidence for any B vitamin. In the Medical Research Council trial, 1,817 women who had already had an affected pregnancy were randomized at 33 centers in seven countries. Neural tube defects occurred in 6 pregnancies in the folic acid groups and 21 in the others, a 72% protective effect (relative risk 0.28).^[5] A Hungarian trial then tested first occurrence: among more than 4,000 pregnancies with known outcomes, there were 6 neural tube defects in the group given trace elements and none in the group given a multivitamin with 0.8 mg folic acid.^[6] Both trials used folic acid.

5-MTHF compared with folic acid. A 2010 review of the pharmacology concluded that the two have comparable physiological activity, bioavailability and absorption at equimolar doses.^[3] In a 24-week randomized trial in 144 women aged 19 to 33, 416 mcg of 5-MTHF a day raised red blood cell folate more than 400 mcg of folic acid did.^[7] No trial has tested 5-MTHF for preventing neural tube defects. The review and the trial share an author.

Stroke and heart disease. Results depend on the population. In HOPE-2, 5,522 people with vascular disease or diabetes took folic acid, B6 and B12 or placebo for about five years. Major cardiovascular events did not fall, though strokes did (relative risk 0.75).^[8] In the China Stroke Primary Prevention Trial, 20,702 adults with high blood pressure took enalapril (an ACE inhibitor) with or without 0.8 mg folic acid for a median 4.5 years. First stroke occurred in 2.7% of the folic acid group against 3.4% (hazard ratio 0.79).^[9] The authors described the result as consistent with benefit among adults with high blood pressure and low baseline folate.^[9] US grain has carried added folic acid since 1998, a different starting point.^[1]

Eating less. Folate is not on the 2025 joint advisory's list of nutrients most at risk for people taking GLP-1 medications.^[10] It does track the foods that tend to drop off small plates: beans, greens and enriched grains. Our article on vitamins on a GLP-1 covers it with vitamin B6.

Safety and interactions

Why there is an upper limit. No adverse effects have been linked to the folate in fortified foods.^[1] The concern is vitamin B12 deficiency. Folate corrects the anemia that B12 deficiency causes, but not the nerve damage, so high folate intake can hide the deficiency and delay diagnosis while the neurological harm continues. That harm can be serious and irreversible.^[1] The committee took 5 mg a day as the lowest dose with observed harm in case reports, divided by an uncertainty factor of 5, and set the adult UL at 1,000 mcg a day from fortified food or supplements.^[1]

The UL was set in 1998, when folic acid was the form used in supplements and fortified foods, and the report does not set a separate figure for 5-MTHF.^[1] A 2010 review suggests that 5-MTHF may carry less potential to mask B12 deficiency, but this has not been established in trials.^[3] The practical point is the same for any form: if you take extra folate, it is worth asking your clinician whether your B12 status should be checked, especially if you are older or take metformin or acid-reducing medicine. See vitamin B12 for why those groups absorb less.

Methotrexate. Methotrexate is a folate antagonist used for rheumatoid arthritis, psoriasis and other conditions. In patients on long-term methotrexate for these conditions, extra dietary or supplemental folate reduced toxic effects without reducing the drug's efficacy, according to the DRI report.^[1] Folate in this setting is prescribed on a schedule set by the treating clinician. Do not add or change folate on your own.

Antiepileptic drugs. Long-term use of phenytoin and phenobarbital has been linked with poor folate status, and phenytoin inhibits folate absorption, though few studies controlled for diet.^[1] Other medicines with antifolate activity include pyrimethamine, trimethoprim, triamterene and sulfasalazine.^[1]

If you take prescription medicine, ask your pharmacist or prescriber before adding a supplement.

In Replenish

Replenish contains folate as L-5-methyltetrahydrofolate calcium, the 5-MTHF form, declared in mcg DFE. It is one of the 6 vitamins that, with the minerals, provide key vitamins and minerals^† on lighter appetite days. Replenish also contains vitamin B12. The amount per serving is published with the Supplement Facts panel on the Replenish page.