Folate (as L-5'-methyltetrahydrofolate calcium salt)

L-5'-methyltetrahydrofolate (L-5-MTHF) is the primary biologically active form of folate or vitamin B9. Other forms of this vitamin include folic acid (used in food fortification and most supplements) and folinic acid (also called calcium folinate). 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. L-5-MTHF is the folate form found in circulation and transported across the blood–brain barrier. Folate is critical for the production and maintenance of new cells, playing a key role in DNA expression and repair. Folate is 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 FOLATE

Supports genetic stability*

Supports production and maintenance of new cells*

Supports cardiovascular function*

NEUROHACKER’S FOLATE SOURCING 

In general, the folic acid 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 doses (< 260 µg DFE*). Some folic acid might not be activated at higher doses (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 opted to use the more metabolically active form L-5'-methyltetrahydrofolate. This form of folate also has the advantage of being better used by persons that have some gene variants affecting folate metabolism. 

L-5'-methyltetrahydrofolate calcium salt is non-GMO, gluten-free, and vegan.

FOLATE FORMULATING PRINCIPLES AND RATIONALE

L-5'-methyltetrahydrofolate calcium salt follows 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). When used as a nootropic, servings of up to 500 µg are used by neurohackers. Since there’s some contribution of folates from the diet (partly through food fortification with folic acid), our serving is selected to ensure that the combination of what we provide, and what’s found even in a diet that’s low in folates, will provide at least the advised intake, but not an excessive amount of folates.

^‡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]

Supports brain function*

Supports healthy cognitive function in older adults* [11–16]

Supports neurotransmitter synthesis (e.g., dopamine, norepinephrine, serotonin)* [17,18]

Supports healthy blood-brain barrier function* [19]

Supports neuroprotective and neuronal repair functions* [20–25]

Supports a healthy mood and positive outlook* [26–30]

Complementary ingredients*

Vitamin B6 and vitamin B12 in supporting healthy homocysteine levels* [31–33]

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

[1]P. Kelly, J. McPartlin, M. Goggins, D.G. Weir, J.M. Scott, Am. J. Clin. Nutr. 65 (1997) 1790–1795.

[2]M.R. Sweeney, J. McPartlin, J. Scott, BMC Public Health 7 (2007) 41.

[3]M.S. Morris, P.F. Jacques, I.H. Rosenberg, J. Selhub, Am. J. Clin. Nutr. 91 (2010) 1733–1744.

[4]K.E. Christensen, L.G. Mikael, K.-Y. Leung, N. Lévesque, L. Deng, Q. Wu, O.V. Malysheva, A. Best, M.A. Caudill, N.D.E. Greene, R. Rozen, Am. J. Clin. Nutr. 101 (2015) 646–658.

[5]A.M. Troen, B. Mitchell, B. Sorensen, M.H. Wener, A. Johnston, B. Wood, J. Selhub, A. McTiernan, Y. Yasui, E. Oral, J.D. Potter, C.M. Ulrich, J. Nutr. 136 (2006) 189–194.

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

[7]O. Stanger, Curr. Drug Metab. 3 (2002) 211–223.

[8]I.G. Beraia, Vopr. Pitan. (1984) 36–38.

[9]S.J. James, L. Yin, M.E. Swendseid, J. Nutr. 119 (1989) 661–664.

[10]S.M. Henning, M.E. Swendseid, W.F. Coulson, The Journal of Nutrition 127 (1997) 30–36.

[11]F. Ma, X. Zhou, Q. Li, J. Zhao, A. Song, P. An, Y. Du, W. Xu, G. Huang, Curr. Alzheimer Res. 16 (2019) 622–632.

[12]H. Chen, S. Liu, L. Ji, T. Wu, Y. Ji, Y. Zhou, M. Zheng, M. Zhang, W. Xu, G. Huang, Mediators Inflamm. 2016 (2016) 5912146.

[13]F. Ma, Q. Li, X. Zhou, J. Zhao, A. Song, W. Li, H. Liu, W. Xu, G. Huang, Eur. J. Nutr. 58 (2019) 345–356.

[14]F. Ma, T. Wu, J. Zhao, F. Han, A. Marseglia, H. Liu, G. Huang, J. Gerontol. A Biol. Sci. Med. Sci. 71 (2016) 1376–1383.

[15]J. Durga, M.P.J. van Boxtel, E.G. Schouten, F.J. Kok, J. Jolles, M.B. Katan, P. Verhoef, Lancet 369 (2007) 208–216.

[16]J.G. Walker, P.J. Batterham, A.J. Mackinnon, A.F. Jorm, I. Hickie, M. Fenech, M. Kljakovic, D. Crisp, H. Christensen, Am. J. Clin. Nutr. 95 (2012) 194–203.

[17]S.M. Stahl, J. Clin. Psychiatry 69 (2008) 1352–1353.

[18]A.L. Miller, Altern. Med. Rev. 13 (2008) 216–226.

[19]P.J. Stover, J. Durga, M.S. Field, Curr. Opin. Biotechnol. 44 (2017) 146–152.

[20]Y. Lin, A. Desbois, S. Jiang, S.T. Hou, Neuroreport 15 (2004) 2241–2244.

[21]H.-L. Yu, L. Li, X.-H. Zhang, L. Xiang, J. Zhang, J.-F. Feng, R. Xiao, Br. J. Nutr. 102 (2009) 655–662.

[22]F.S. Quan, X.F. Yu, Y. Gao, W.Z. Ren, Genet. Mol. Res. 14 (2015) 12466–12471.

[23]I.I. Kruman, T.S. Kumaravel, A. Lohani, W.A. Pedersen, R.G. Cutler, Y. Kruman, N. Haughey, J. Lee, M. Evans, M.P. Mattson, J. Neurosci. 22 (2002) 1752–1762.

[24]G. Kronenberg, C. Harms, R.W. Sobol, F. Cardozo-Pelaez, H. Linhart, B. Winter, M. Balkaya, K. Gertz, S.B. Gay, D. Cox, S. Eckart, M. Ahmadi, G. Juckel, G. Kempermann, R. Hellweg, R. Sohr, H. Hörtnagl, S.H. Wilson, R. Jaenisch, M. Endres, J. Neurosci. 28 (2008) 7219–7230.

[25]B.J. Iskandar, A. Nelson, D. Resnick, J.H.P. Skene, P. Gao, C. Johnson, T.D. Cook, N. Hariharan, Ann. Neurol. 56 (2004) 221–227.

[26]W. Zheng, W. Li, H. Qi, L. Xiao, K. Sim, G.S. Ungvari, X.-B. Lu, X. Huang, Y.-P. Ning, Y.-T. Xiang, J. Affect. Disord. 267 (2020) 123–130.

[27]D. Mischoulon, M.F. Raab, J. Clin. Psychiatry 68 Suppl 10 (2007) 28–33.

[28]M.J. Taylor, S. Carney, J. Geddes, G. Goodwin, Cochrane Database Syst. Rev. (2003) CD003390.

[29]J.E. Alpert, M. Fava, Nutr. Rev. 55 (1997) 145–149.

[30]S.N. Young, A.M. Ghadirian, Prog. Neuropsychopharmacol. Biol. Psychiatry 13 (1989) 841–863.

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

[32]E. Lonn, S. Yusuf, M.J. Arnold, P. Sheridan, J. Pogue, M. Micks, M.J. McQueen, J. Probstfield, G. Fodor, C. Held, J. Genest Jr, Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators, N. Engl. J. Med. 354 (2006) 1567–1577.

[33]D. Serapinas, E. Boreikaite, A. Bartkeviciute, R. Bandzeviciene, M. Silkunas, D. Bartkeviciene, Reprod. Toxicol. 72 (2017) 159–163.