What is the Difference Between Folate, Folic Acid, Folinic Acid, and Methylfolate?

We have all heard of vitamin B9 and its importance in overall health, especially with neurological well-being. And we have all seen the following words associated with Vitamin B9:

• Folate
• Folic acid
• Folinic acid
• Methylfolate

What are all these words!?! D

Do they mean the same thing? Or are they different? How can we decipher this? Wow – that is certainly confusing for anyone!

With that in mind, let’s try and outline this.

Folate, folic acid, folinic acid, and methylfolate are all related to vitamin B9, but they differ in their chemical structures, bioavailability, and how they are metabolized in the body.

We can break it down as follows:

• Definition: Folate is the natural form of vitamin B9 found in foods such as leafy green vegetables, legumes, eggs, and citrus fruits. This is the nutrient that we consume through eating natural foods.
• Form: It is a water-soluble B vitamin that exists in various forms in nature.
• Bioavailability: Folate from food is generally less bioavailable than synthetic folic acid because it must be converted into active forms (e.g., methylfolate) in the body. Additionally, it is degraded via various cooking processes. So, we get it, but it in a form that is less potent and bioavailable.
• Function: Folate is essential for DNA synthesis, repair, and methylation, as well as red blood cell formation.

• Definition: Folic acid is the synthetic form of vitamin B9, commonly used in dietary supplements and fortified foods. In fact, if you live in the United States, folic acid is readily found in your food supply after a government mandate, aimed at reducing neural tube defects, initiated folic acid fortification. Folic acid will be found in various breads, cereals, and pastas.
• Form: It is a fully oxidized, stable compound that does not occur naturally in foods.
• Bioavailability: Folic acid is more bioavailable than natural folate because it is easily absorbed. However, it must be converted into its active form (methylfolate) in the liver through a multi-step process.
• Function: Like folate, it supports DNA synthesis, cell division, and red blood cell production. It is particularly important during pregnancy to prevent neural tube defects.

• Definition: Folinic acid is a metabolically active form of folate that does not require the enzyme dihydrofolate reductase (DHFR) for conversion, unlike folic acid.
• Form: Folinic acid is a naturally occurring form of folate. It is found in foods in small amounts and is also produced in the body as an intermediate in the folate metabolism cycle. However, when used in supplements or medications, it is typically in a synthetically derived form, though it remains biologically identical to what the body naturally produces. Unlike folic acid, folinic acid does not require conversion by the MTHFR enzyme to be used effectively by the body, making it a better choice for people with MTHFR mutations or other folate metabolism issues.
• Bioavailability: Folinic acid is readily converted into active folate forms in the body, making it a good option for individuals with certain genetic mutations (e.g., MTHFR mutations) that impair folate metabolism.
• Function: It is used clinically to counteract the effects of folate antagonists (e.g., methotrexate) and to support folate-dependent processes.

• Definition: Methylfolate (5-methyltetrahydrofolate) is the biologically active form of folate that the body can directly use.
• Form: It is the end product of folate metabolism and is found naturally in some foods.
• Bioavailability: Methylfolate does not require conversion in the liver, making it the most bioavailable form of folate. It is especially beneficial for individuals with MTHFR mutations or impaired folate metabolism.
• Function: It plays a critical role in methylation processes, including the conversion of homocysteine to methionine, and supports neurological and cardiovascular health.

• Natural vs. Synthetic: Folate is natural, while folic acid, folinic acid, and methylfolate are synthetic or semi-synthetic.
• Metabolism: Folic acid requires enzymatic conversion to become active, whereas folinic acid and methylfolate are more readily usable by the body.
• Use Cases: Folic acid is commonly used in supplements and fortification, folinic acid is used medically, and methylfolate is preferred for individuals with genetic or metabolic issues.

Each form has specific applications and benefits, depending on individual health needs and genetic factors.

Most recently, folinic acid has been used in autistic children who have tested positive for folate receptor autoantibodies. In these cases, folinic acid is able to bypass the dysfunctional folate receptor alpha and enters via the reduced folate carrier. Additionally, folinic acid can partially bypass the MTHFR (methylenetetrahydrofolate reductase) enzyme, making it a useful option for individuals with MTHFR gene mutations.

1. Bypassing MTHFR: Folinic acid (also called leucovorin) is already in a reduced form (5-formyltetrahydrofolate) and does not require the MTHFR enzyme to be converted into active folate. Instead, it can be converted directly into methylfolate (5-MTHF) or other active folate forms through alternative pathways.
2. Alternative Pathways: Folinic acid can be converted into dihydrofolate (DHF) and then into tetrahydrofolate (THF), which can enter the folate cycle downstream of the MTHFR enzyme. This makes it a good option for people with MTHFR mutations who have difficulty converting folic acid or folate into the active form (methylfolate).

• Folic acid requires the MTHFR enzyme to be fully activated into methylfolate. In individuals with MTHFR mutations, this conversion is impaired, leading to potential folate deficiency and elevated homocysteine levels.
• Folinic acid, on the other hand, bypasses this bottleneck and can still support folate-dependent processes even in the presence of MTHFR mutations.

• MTHFR Mutations: Folinic acid is often recommended for individuals with MTHFR mutations (e.g., C677T or A1298C) who cannot efficiently process folic acid.
• Medical Treatments: It is used in medical settings to counteract the effects of drugs like methotrexate (a folate antagonist) and to support folate metabolism in chemotherapy patients. Additionally, it has been used, off label (not approved by the FDA) in children with autism that have tested positive for folate receptor autoantibodies.
• Prenatal Health: Folinic acid may be used as an alternative to folic acid for pregnant women with MTHFR mutations to support fetal development.

While folinic acid bypasses MTHFR, it is not as direct as methylfolate (5-MTHF), which is the fully active form of folate and does not require any conversion. For some individuals with severe MTHFR mutations, methylfolate may still be the most effective option.

Folinic acid is a valuable alternative for individuals with MTHFR mutations or those that have folate receptor autoantibodies. However, its effectiveness depends on the severity of the mutation and the individual’s overall health.

Always consult a healthcare provider to determine the best form of folate for your specific needs.