Is methylfolate better than folic acid?

Two forms of the same vitamin

Folate is the name for all forms of vitamin B9. Food contains natural folates. Folic acid is the synthetic form in fortified foods and most supplements. Some supplements contain 5-MTHF, also called L-methylfolate or methylfolate.^[1] The main form of folate in the blood is 5-MTHF.^[1]

How the body handles folic acid

Before folic acid reaches the blood, an enzyme called dihydrofolate reductase changes it into active forms. How active this enzyme is differs a lot from person to person. When a dose is larger than the enzyme can handle, unchanged folic acid appears in the blood. It is not known whether this has any effect.^[1]

What studies found

NIH ODS says that the body absorbs 5-MTHF as well as folic acid or better.^[1] A 24-week trial included 144 healthy women aged 19 to 33. Each day they took 400 µg of folic acid, 416 µg of 5-MTHF (the same amount of folate), 208 µg of 5-MTHF or a placebo. Red blood cell folate rose more with 416 µg of 5-MTHF than with folic acid.^[2]

The trials that prevented neural tube defects gave folic acid.^[3]

The MTHFR gene variant

People with the 677C>T variant of the MTHFR gene have a less active enzyme. They make less 5-MTHF from other forms of folate, and their homocysteine and risk of neural tube defects may be higher.^[1] Two copies of this variant are found in about 25% of Hispanic people, 10% of white and Asian people and 1% of African American people.^[1]

Research on whether people with this variant benefit from folate supplements is not conclusive. Some of them might do better with 5-MTHF.^[1] Still, the US Centers for Disease Control and Prevention recommends 400 µg of folic acid a day, not 5-MTHF, for everyone who could become pregnant, even with this variant. This dose helps prevent neural tube defects in these women too.^[1] When EFSA set the daily need for folate in Europe, it added a margin for people with two copies of the variant.^[4]

Labels and limits

In the US, there is no official factor to convert 5-MTHF into dietary folate equivalents (DFE). Makers may use a factor of up to 1.7, the same as for folic acid.^[1] In the EU, the upper limit of 1,000 µg a day for adults covers folic acid and the 5-MTHF forms together.^[5]

In depression trials

Some trials added L-methylfolate at 15 mg a day to antidepressants.^[1] A 2022 review of trials that added L-methylfolate to antidepressants found a small effect.^[6] This dose is far above the upper limit and is taken only under medical care.^[1]

Who should ask first

People who take methotrexate, medicines for epilepsy or sulfasalazine, or who may be low in vitamin B12, should ask a doctor or pharmacist before taking either form.^[1]