Folates

Folates encompass all the different forms of vitamin B9 (the ninth of the B-vitamins discovered). These include folic acid (used in food fortification and most supplements), folinic acid (also called calcium folinate) and L-5'-methyltetrahydrofolate. Folates got their name from the Latin word for leaf (folium), because leafy green vegetables (e.g., lettuce, spinach) are one of the better food sources. Beans, lentils, nuts, and seeds are also good sources. Folates are critical for the production and maintenance of new cells, playing a key role in DNA expression and repair. Folates are a central player in a process called methylation or methyl donation. This process has widespread interactions with metabolic function. As an example, methylation is one of the main ways the expression of genes is changed to match our genes to diet, lifestyle and environment.*

Top Benefits of Folates

Supports genetic stability*

Supports production and maintenance of new cells*

Neurohacker’s Folate Sourcing

The main form of folate used in dietary supplements and food fortification is folic acid. Calcium folinate and L-5'-methyltetrahydrofolate are used less commonly: these two forms are often described as "active" forms because they require less metabolic work to be used in the body than folic acid. 

Gene polymorphisms affecting folate metabolism are fairly common. The folic acid form is most affected by gene polymorphisms (i.e., it's more difficult for some people to activate this form). Because of this, some experts believe it's better to avoid supplementing the folic acid form, and instead use the calcium folinate and L-5'-methyltetrahydrofolate forms. In our folate stack, we use both of these active forms and do not include folic acid. We believe it's important to include both calcium folinate and L-5'-methyltetrahydrofolate, because they enter the folate cycle at different points, which is consistent with one of our principles of offering full pathway support.

Folate sourcing is focused on ensuring they are non-GMO, gluten-free and vegan.

Folate Formulating Principles and Rationale

Folates follow a threshold dosing pattern (see Neurohacker Dosing Principles) where most of the functional benefits occur at amounts close to the advised intake (400 µg DFE* for non-pregnant adults). In general, the folic acid form used in food fortification and many supplements has high bioavailability (absorption is excellent). But it’s fully converted to metabolically active folates in the digestive tract and liver only when given at low-to-moderate amounts (< 260 µg DFE^‡). Some folic acid might not be activated at higher amounts (it goes into the blood as unmetabolized folic acid) [1,2]. It’s thought that unmetabolized folic acid in the blood, but not biologically active folates, might not be ideal for health [3–5]. Because of this, we opt to use a low amount of folic acid (50 µg DFE^‡) to be safely below the threshold where the body would be unable to metabolize folic acid into folates, and augment the folate stack with the more metabolically active forms (calcium folinate and L-5'-methyltetrahydrofolate) to increase DFE amount given. These other forms of folate also have the advantage of being better used by persons that have some gene variants affecting folate metabolism. Put another way, the goal is to increase folates, but not folic acid, that reach the blood and tissues. A low-to-moderate serving of folic acid plus additional folates as calcium folinate and L-5'-methyltetrahydrofolate accomplishes this goal.

^‡DFE stands for dietary folate equivalents.

Folate Key Mechanisms

Supports cellular function*

Folate coenzymes mediate the transfer of one-carbon units (one-carbon metabolism)* [6,7]

Folate coenzymes act as cofactors for several enzymes involved in key metabolic pathways, specifically in nucleic acid (DNA and RNA) and amino acid metabolism* [6,7]

Methyltetrahydrofolate is used by the cytosolic enzyme methionine synthase to generate methionine and tetrahydrofolate from homocysteine* [6,7]

Methionine is required for the synthesis of S-adenosylmethionine (SAMe), a methyl group donor used in many biological methylation reactions* [6,7]

Methionine synthase is essential for the methylation of nucleic acids (DNA and RNA) and proteins* [6,7]

Adequate folate status is needed to maintain NAD⁺ levels* [8–10]

Complementary ingredients*

Vitamin B6 and vitamin B12 in supporting healthy homocysteine levels* [11–13]

Vitamin B12 - The main safety concern associated with high doses of folic acid supplementation is that it might mask a vitamin B12 deficiency. Because of this, vitamin B12 is often given in combination with folic acid, especially if higher amounts of folic acid or other folates are used.*

Methyl Donors - Key methyl donor nutrients include trimethylglycine (betaine), folates, vitamin B6, vitamin B12, and S-adenosylmethionine: One or more of these nutrients are often given together.*

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

REFERENCES

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[5] A. M. Troen et al., J. Nutr. 136, 189–194 (2006).

[6] J. M. Berg, J. L. Tymoczko, G. J. Gatto, L. Stryer, Eds., Biochemistry (W.H. Freeman and Company, 8th ed., 2015).

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[11] J. Selhub, Annu. Rev. Nutr. 19, 217–246 (1999).

[12] E. Lonn et al., N. Engl. J. Med. 354, 1567–1577 (2006).

[13] D. Serapinas et al., Reprod. Toxicol. 72, 159–163 (2017).