Methylfolate, Folate and Folic Acid

They’re all forms of vitamin B9, but they’re not the same. Methylfolate is different from folic acid, and folic acid isn’t the same as folate.

Here’s what sets them apart.

Methylfolate (5-MTHF or [(6S)-5-MTHF]) is the active form of folate, which means your body can use it immediately without any further conversion or metabolism.¹ It’s a ready-to-go nutrient, which also makes it the most beneficial. All forms of folates - whether natural or synthetic - must first be converted to active methylfolate to be used in the body.

Methylfolate plays a key role in the re-methylation of homocysteine to produce methionine, which is then used to create S-adenosylmethionine (SAMe), the body’s main methyl donor and an essential component of neurotransmitter production² (i.e. generating serotonin).

Methylfolate is the predominant physiological form of folate found in your blood. It’s required for the synthesis and repair of DNA, cell division, the metabolism of homocysteine, producing neurotransmitters, fetal development during pregnancy, and much more.³

Studies show that methylfolate is the most effective alternative to folic acid supplementation.⁴

Folic acid is a synthetic form of folate, which means it’s made in a laboratory. It’s cheap to make and highly stable, so it’s often used in supplements and fortified foods (like breads, cereals, and snacks).

The problem with folic acid is that it’s not biologically active, so your body has to break it down first. This process requires several steps and a range of different enzymes, including the enzyme methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR) and serine hydroxymethyltransferase (SHMT). The MTHFR enzyme is produced by the MTHFR gene. However, if you’re one of 60-70% of people who have a mutation on the MTHFR gene, your body won’t be able to use folic acid as efficiently. DHFR is the enzyme responsible for converting folic acid to the usable form of folate, while SHMT (serine hydroxymethyltransferase) also plays a role in folate metabolism. Mutations on these genes can also affect how your body uses folic acid.

Folate is the generic term for vitamin B9. Like the other B vitamins, it is water-soluble and cannot be stored by the body, so it must be replaced through diet or supplements. Folate naturally is present in many foods such as leafy green vegetables, legumes, eggs, citrus, and animal products.

Folate includes compounds that are chemically similar to those required during periods of rapid cell growth and division, such as DNA and RNA synthesis, which is critical during pregnancy. This is why it is so important for women who are pregnant or planning to conceive.

However, folate from food sources is generally unstable, and can be broken down by heat, light, and/or metal ions, which means cooking can reduce its bioavailability.⁵

Methylated folic acid is another term for methylfolate, the active form of folate. Unlike synthetic folic acid, methylfolate is ready for your body to use immediately.

Folinic acid (also known as 5-formyl tetrahydrofolic acid or leucovorin) is an active form of folate. It is one step away from becoming the body’s active form of folate, methylfolate. It can be converted into methylfolate through enzymatic steps in the folate cycle.

Unlike folic acid, folinic acid is a naturally occurring form of folate.⁶ It can enter the brain via the reduced folate channel (RFC) rather than via folate receptor alpha (FRα). 

While folic acid must be converted to tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR), folinic acid bypasses this step and is directly converted into THF and its derivatives, which are then used for nucleotide synthesis (DNA/RNA).

Folinic acid can be converted into multiple folate cofactors that enter the folate cycle and eventually contribute to methylation (if it undergoes further conversion to become methylfolate). However, its main biochemical role is nucleotide synthesis.

Folinic acid is combined with 5-FU (Fluorouracil) as a treatment for various cancers. In patients with advanced, non-removable colon cancer, this combination improves response rates and helps slow disease progression.⁷

Leucovorin is also used as an antidote to folic acid antagonists such as methotrexate. 

Folic acid is a man-made form of folate that must be converted to its active form in the body. People with a MTHFR gene mutation often cannot process folic acid efficiently, which means much of it remains unmetabolized. Unmetabolized folic acid can accumulate in the blood, and studies show that it may increase the risk of serious health issues.

Folinic acid is a metabolically active form of folate, which means it can pass directly into the body’s cells and be used in various processes. Folinic acid (5‑formyltetrahydrofolate) bypasses dihydrofolate reductase and can be reconverted intracellularly into other folate cofactors, including 5‑methyltetrahydrofolate (methylfolate).⁸

Methylfolate is biologically active, while folic acid is not. Methylfolate can be used immediately by your body, even if you have the MTHFR gene mutation. This means methylfolate is better for those with MTHFR than folic acid.