Vitamins

Key limiting factor vitamins in specific activated forms required for major neuroregulatory and neurodevelopmental processes.

Vitamin B6 (Pyridoxal-5-Phosphate)

Common Name

Vitamin B6 | Pyridoxal-5-Phosphate | Pyridoxal Phosphate | P-5-P | P5P | PLP


Top Benefits of Pyridoxal 5'-phosphate 

Supports energy metabolism*

Supports brain function*

Supports general immune health*


What is Pyridoxal 5'-phosphate?

Pyridoxal 5'-phosphate (P5P) is the active form of (vitamin B6), which is part of the B complex—a group of water-soluble vitamins that play important roles in cellular metabolism and energy production. The term vitamin B6 refers to six forms—pyridoxal, pyridoxamine, pyridoxine, and their phosphorylated forms. The P5P form is the bioactive form of vitamin B6: it requires less metabolic “work” to be used as coenzyme in vitamin B6-dependent enzyme reactions. The more common form of vitamin B6 used in dietary supplements, pyridoxine, must undergo metabolic transformation and requires ATP to be converted into P5P. P5P is a cofactor involved in over 4% of all enzymatic activities, including many metabolic pathways important for cellular energy generation [1]. Major functions of P5P include (1) metabolism of fats, sugars, and proteins, (2) neurotransmitter synthesis, (3) synthesis of the hemoglobin used in red blood cells, and (4) increasing and decreasing the expression of certain genes.*

  

Neurohacker’s Pyridoxal 5'-phosphate Sourcing

Pyridoxal 5'-phosphate (P5P) is our preferred form of vitamin B6, because it’s the active (i.e, coenzyme) form of the vitamin. The pyridoxine form requires ATP to be “activated.” In general, we think it’s a good idea to conserve ATP for more important uses in our cells and tissues.

Pyridoxal 5'-phosphate sourcing is focused on identifying and purchasing from a reputable supplier and ensuring it’s NON-GMO, gluten-free, and vegan.


Pyridoxal 5'-phosphate Dosing Principles and Rationale

Vitamin B6, no matter the form, is subject to a dosing threshold (see Neurohacker Dosing Principles), which means, while more might be better within a low to moderate range, very high amounts would be unlikely to add significant additional nutritional or functional benefits for most people but could increase the risk of unwanted responses. Our goal in formulating products is to make sure that vitamin B6 amounts will be comfortably below the levels where risk for unwanted responses exists, even if several of our products with vitamin B6 are used together. In general, we tend to dose vitamin B6 at higher amounts in formulations where it would be used to support neurotransmitter production, and lower levels when we are using it to complement a full B complex stack. The main role of vitamin B6 in the body is as a coenzyme for metabolic reactions. It is important to have sufficient amounts of vitamin B6 in the diet to allow proper functioning of these enzymes.*


Pyridoxal 5'-phosphate Key Mechanisms

Supports energy metabolism*

Pyridoxal 5'-phosphate (P5P) is a cofactor in about 100 essential enzyme reactions, including enzymes of glucose, fatty acid, and amino acid metabolism [2]

P5P is a cofactor in the kynurenine pathway; it is required for the synthesis of NAD+ from tryptophan [3]


Supports hemoglobin synthesis

P5P is required as a cofactor in the synthesis of heme, an iron-containing molecule found in hemoglobin [4]


Supports brain function*

Cofactor for the enzyme aromatic L-amino acid decarboxylase, which catalyzes the synthesis of serotonin from 5-hydroxytryptophan (5-HTP) and dopamine from L-3,4-dihydroxyphenylalanine (L-DOPA) [5–9]

Since dopamine is a precursor for noradrenaline, P5P is required for its synthesis [8]

Since serotonin is a precursor for melatonin, P5P is required for its synthesis [9]

Supports glutamate decarboxylase (GAD) enzyme - GAD catalyzes the synthesis of gamma-aminobutyric acid (GABA) from glutamate [10–15]

Supports gamma aminobutyric acid transaminase (GABA-T) enzyme - GABA-T catalyzes the breakdown of gamma-aminobutyric acid (GABA) [10,12]

Participates in the metabolism of the neurotransmitters glycine, D-serine, and histamine [16]

Supports the synthesis of neurotransmitters involved in memory, executive function, mood regulation, focus, motivation, and sleep regulation [17]

May support aspects of dream recall (studies have been at doses ≥100 mg) [18,19]


Supports healthy immune function*

Supports adaptive immunity [20–26]

Supports immune system communication [27]


Complementary ingredients*

Vitamin B12 and folic acid (vitamin B9) for cardiovascular support and homocysteine metabolism [28–30], brain support [31], mood [32], and for general well-being [33]

L-tryptophan and melatonin for sleep support [34–38]

Magnesium, other B-complex vitamins, and melatonin supplementation for sleep support [39]


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

[2]Linus Pauling Institute Oregon State University, (n.d.).

[3]A.A.-B. Badawy, Int. J. Tryptophan Res. 10 (2017) 1178646917691938.

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[8]M.E. Gnegy, in: S.T. Brady, G.J. Siegel, R.W. Albers, D.L. Price (Eds.), Basic Neurochemistry (Eighth Edition), Academic Press, New York, 2012, pp. 283–299.

[9]J.G. Hensler, in: S.T. Brady, G.J. Siegel, R.W. Albers, D.L. Price (Eds.), Basic Neurochemistry (Eighth Edition), Academic Press, New York, 2012, pp. 300–322.

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[12]V.V. Tsybul’skiĭ, E.R. Nagiev, Radiobiologiia 31 (1991) 201–208.

[13]O.A.C. Petroff, Neuroscientist 8 (2002) 562–573.

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[16]P.T. Clayton, J. Inherit. Metab. Dis. 29 (2006) 317–326.

[17]M. Ebadi, Neurochem. Int. 3 (1981) 181–205.

[18]M. Ebben, A. Lequerica, A. Spielman, Percept. Mot. Skills 94 (2002) 135–140.

[19]D.J. Aspy, N.A. Madden, P. Delfabbro, Percept. Mot. Skills 125 (2018) 451–462.

[20]M.C. Talbott, L.T. Miller, N.I. Kerkvliet, Am. J. Clin. Nutr. 46 (1987) 659–664.

[21]S.N. Meydani, J.D. Ribaya-Mercado, American Journal of … (1991).

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[25]C.-H. Cheng, S.-J. Chang, B.-J. Lee, K.-L. Lin, Y.-C. Huang, Eur. J. Clin. Nutr. 60 (2006) 1207–1213.

[26]C. Kobayashi, K. Kurohane, Y. Imai, Biol. Pharm. Bull. 35 (2012) 532–538.

[27]S.-C. Huang, J.C.-C. Wei, D.J. Wu, Y.-C. Huang, Eur. J. Clin. Nutr. 64 (2010) 1007–1013.

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

[29]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.

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

[31]G. Douaud, H. Refsum, C.A. de Jager, R. Jacoby, T.E. Nichols, S.M. Smith, A.D. Smith, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 9523–9528.

[32]O.P. Almeida, K. Marsh, H. Alfonso, L. Flicker, T.M.E. Davis, G.J. Hankey, Ann. Neurol. 68 (2010) 503–510.

[33]C. Hallert, M. Svensson, J. Tholstrup, B. Hultberg, Aliment. Pharmacol. Ther. 29 (2009) 811–816.

[34]A.D. Volpe, A.D. Lucia, C. Pirozzi, V. Pastore, J Int Adv Otol 13 (2017) 69–73.

[35]A. Della Volpe, L. Dipietro, G. Ricci, V. Pastore, M. Paccone, C. Pirozzi, A. Di Stadio, Int. J. Pediatr. Otorhinolaryngol. 115 (2018) 171–174.

[36]S. Picone, P. Ariganello, V. Mondì, F. Di Palma, L. Martini, S. Marziali, G. Fariello, P. Paolillo, Ital. J. Pediatr. 45 (2019) 122.

[37]P. Lemoine, J.-C. Bablon, C. Da Silva, Complement. Ther. Med. 45 (2019) 104–108.

[38]C. Bravaccio, G. Terrone, R. Rizzo, M. Gulisano, M. Tosi, P. Curatolo, L. Emberti Gialloreti, Minerva Pediatr. 72 (2020) 30–36.

[39]G. Djokic, P. Vojvodic, D. Korcok, A. Agic, A. Rankovic, V. Djordjevic, A. Vojvodic, T. Vlaskovic-Jovicevic, Z. Peric-Hajzler, J. Vojvodic, D. Matovic, G. Sijan, U. Wollina, M. Tirant, V.T. Nguyen, M. Fioranelli, Torello, Open Access Macedonian Journal of Medical Sciences 7 (2019).

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

COMMON NAMES

Folate | Vitamin B9 | 5'-Methyltetrahydrofolate | L-methylfolate | Methyl THF | Levomefolic acid | L-5-MTHF


TOP BENEFITS OF FOLATE

Supports genetic stability*

Supports production and maintenance of new cells*

Supports cardiovascular function*


WHAT IS FOLATE?

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.*

 

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 DOSING 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, doses 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 dosing 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 [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]


Supports cardiovascular and cerebrovascular function*

Influences homocysteine levels (supports protection of cardiovascular function); complementary to vitamin B6 and vitamin B12 [31–33]


Complementary ingredients*

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.

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[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.

Vitamin D3 (Cholecalciferol)

Scientific Name:
(3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol

COMMON NAME

Vitamin D | Vitamin D3 | Cholecalciferol


Top Benefits of Vitamin D3 

Supports bone health*

Supports cognitive function*

Supports a healthy mood*

Supports cardiovascular health*

Supports general immune health*

Supports upper respiratory health* 


What is Vitamin D3? 

Vitamin D is an essential fat-soluble vitamin. It is found in animal foods—fatty fish are a good source—where, because it is fat-soluble, it concentrates in fat. But a large amount of the body stores of vitamin D are not obtained from the diet; it is produced from skin exposure to sunlight. This is true for humans and animals. In addition to fatty fish, other animal foods such as dairy and eggs will have varying amounts of vitamin D depending on whether the food has been fortified with vitamin D (most milk has been) and whether the animal the product originated from had sufficient exposure to sunlight (or ate food that did). In addition to milk, some milk alternatives (such as beverages made from soy, almond, or oats), ready-to-eat breakfast cereals, orange juices, margarine and other food products can be fortified with vitamin D. Mushrooms can also be a good source of vitamin D, but again this will be dependent on their exposure to sunlight. Vitamin D is usually supplemented as either vitamin D2 (Ergocalciferol) or D3 (Cholecalciferol). Of the two, vitamin D3 is considered superior for supporting healthy vitamin D levels[1]. Vitamin D is essential for general health, and is especially important for supporting the health of bones, the brain and nervous system, the heart, and the immune system.*


Neurohacker’s Vitamin D3 Sourcing

Vitamin D3 is produced from wild crafted lichen, which is responsibly harvested from a sustainable source.

Vitamin D3 is Non-GMO, gluten-free, certified Kosher, and vegan


Vitamin D3 Dosing Principle and Rationale

Since much of the body stores of vitamin D are made from sunlight exposure, and the intensity of sunlight varies seasonally, especially in more northern locations, maintaining optimal vitamin D status throughout the year can be a challenge. A combination of a diet with insufficient vitamin D (estimated to occur in 95% of adults[2]) and inadequate sun exposure exacerbates this challenge. Because of these challenges, many adults do not have adequate vitamin D status. To ensure against inadequacy, in the United States the recommended dietary allowance for adults is currently set at 600-800 IU/day, with the exact amount varying by age; however, a dose of 800 IU is considered 100% of the daily value (DV) for supplement labeling. Vitamin D follows hormetic principles (see Neurohacker Dosing Principles). The key point is that vitamin D3 is not a “more is better” vitamin. In fact, for general immune support and upper respiratory health, as an example, evidence suggests that an average person would be better off taking amounts closer to the DV than amounts several times higher[3]. When determining the dose of vitamin D3 to include in a product, our goal is to ensure we’ve supplied enough to support healthy function, while being within the hormetic range. We also take into account that a person may be taking more than one of our products, and use a dose that would still ensure they would be within this range if this is the case. Taking vitamin D (and other fat-soluble compounds) with food that contains fat is recommended for better absorption.*


Vitamin D3 Key Mechanisms

Supports brain function*

Supports memory [4,5]

Supports working memory [6]

Supports cognitive health [7–9]

Supports the expression of neurotrophic factors (NT-3, BDNF, GDNF, CNTF, and NGF) [10–12]

Supports neurogenesis [6,10]

Supports neuronal structure [13–15] [7,16]

Supports brain antioxidant defenses and counters oxidative stress [7,17–19]

Supports healthy neural immune signaling [7,14,20]

Supports neuroprotective functions [7,13,17,18,21,22]


Supports a healthy mood*

Supports positive affect [19,23–25]

Supports a calm/relaxed mood [24–26]

 

Supports healthy immune function*

Supports general immune health [3,27,28]

Supports innate immunity [29,30]

Supports adaptive immunity [31–38]

Supports mucosal immunity [39–47]   

Supports immune tolerance [31,33–38,48–52]

Supports immune balance [31,53]

Supports healthy dendritic cell function [29,30]

Supports healthy natural killer cell function [30]

Supports healthy microglia function [14,54–59] 

Supports healthy T cell function [31–38] 

Supports healthy B cell function [31,33,34,48–51]  

 

Supports a healthy gut microbiota*

Supports a healthy gut microbiota [60–66]

 

Supports cardiometabolic health*

Supports healthy cardiovascular function [67–70]

Supports healthy insulin levels [19,71,72]

Supports healthy glucose levels [19]


Supports healthy aging and longevity*

Supports balance during aging (i.e., may help reduce risk of falls) [73,74]

Supports healthy bone function during aging [74,75]

Supports healthy muscle function during aging [74]

Supports healthspan extension (Caenorhabditis elegans) [76]

Supports mitochondrial function [77,78]  

Supports Nrf2 function [79–86]


Complementary ingredients*

Vitamin D is involved in intestinal absorption and homeostasis of minerals such as calcium and magnesium [87,88]

Vitamin K is potentially complementary to vitamin D [89]


*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. Autier, S. Gandini, P. Mullie, J. Clin. Endocrinol. Metab. 97 (2012) 2606–2613.
[2] C.A. Reider, R.-Y. Chung, P.P. Devarshi, R.W. Grant, S. Hazels Mitmesser, Nutrients 12 (2020).
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[4] J.A. Pettersen, Exp. Gerontol. 90 (2017) 90–97.
[5] H. Darwish, R. Haddad, S. Osman, S. Ghassan, B. Yamout, H. Tamim, S. Khoury, Sci. Rep. 7 (2017) 45926.
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Folate (as Calcium Folinate)

COMMON NAME

Folate | Vitamin B9 | Calcium folinate | Folinic Acid

TOP BENEFITS OF FOLATE

Supports genetic stability*

Supports production and maintenance of new cells*

Supports cardiovascular function* 

WHAT IS FOLATE?

Folates can be thought of as a family of related but slightly different vitamer forms all of which have vitamin B9 activity (the ninth of the B-vitamins discovered). They include folic acid, calcium folinate (also called folinic acid) 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. 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. Calcium folinate is considered to be an active form of folic acid [1,2], because it does not require the action of an enzyme (dihydrofolate reductase) needed to activate folic acid [3], is rapidly converted into 5-methyltetrahydrofolate (the major transport and storage form of folate in the body) [4–9]. 

NEUROHACKER’S FOLATE SOURCING

The main form of folate typically used in dietary supplements is folic acid. 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) [10,11]. It’s been hypothesized that unmetabolized folic acid in the blood, but not biologically active folates, might not be ideal for health [12–14]. Because of this, we opted to use the more metabolically active form of calcium folinate, which requires less metabolic work to be used in the body than folic acid and which is rapidly converted into 5-methyltetrahydrofolate [4–6].* 

Folate as calcium folinate is a non-GMO, gluten-free, and vegan ingredient.

FOLATE DOSING PRINCIPLES AND RATIONALE

Research suggest that 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). Since there’s some contribution of folates from the diet (partly through food fortification with folic acid), our recommended dosing 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) [15,16]

Folate coenzymes act as cofactors for several enzymes involved in key metabolic pathways, specifically in nucleic acid (DNA and RNA) and amino acid metabolism [15,16]

Adequate folate status is needed to maintain NAD+ levels [17–19]


Supports Healthy Brain Function*

Supports healthy cognitive function [20–25]

Supports neurotransmitter synthesis (e.g., dopamine, norepinephrine, serotonin) [26,27]

Supports healthy blood-brain barrier function [28]

Supports neuroprotective and neuronal repair functions [29–34]

Supports a healthy mood and positive outlook [35–39]


Supports Healthy Cardiovascular and Cerebrovascular Function*

Influences homocysteine levels (supports protection of cardiovascular function); complementary to vitamin B6 and vitamin B12 [40–42]


Complementary Ingredients*

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, cure, or prevent any disease.


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Biotin

Common Name

Vitamin B7 | Vitamin H


Top Benefits of Biotin

Supports cellular metabolic pathways*

Supports gene expression* 


What is Biotin?

Biotin, or vitamin B7, is part of the B complex—a group of water-soluble vitamins that play important roles in cellular metabolism and energy production. Biotin was originally called vitamin H, with “H” standing in for Haar und Haut, German words for hair and skin. This is because deficiency symptoms that led to the eventual discovery of biotin included skin rash and thinning hair. Diet, lifestyle and genetic factors influence absorption of biotin in the diet, and the ability of the gut microflora to make biotin, so some subsets of the population have more difficulty maintaining adequate biotin status than others. Biotin is an important cofactor in some enzymes involved in metabolizing fats and carbohydrates, influencing cell growth, and affecting amino acids involved in protein synthesis.*


Neurohacker’s Biotin Sourcing

Biotin sourcing is focused on identifying and purchasing from a reputable supplier and ensuring it’s NON-GMO, gluten-free and vegan.


Biotin Dosing Principles and Rationale

While the Institute of Medicine (IOM) hasn’t placed an upper limit on biotin, the advised intake (daily value [DV] on a supplement) is very low. We dose biotin in amounts consistent with the adult DV. Except for subsets of the population with certain genetic disorders that affect biotin metabolism, persons eating raw egg whites, and other rare situations, this low amount of biotin is expected to be sufficient to maintain good health [1].* 

Note: Recent information has suggested that mega doses of biotin (5,000-10,000 mcg or more) may interfere with some lab tests, so several national lab testing services recommend ceasing supplementation with mega doses of biotin starting two days prior to certain lab tests. The mega dose amounts are 166 to 333 times higher than the DV amount used in Qualia products. In the FDA’s safety communication about this topic, they mention that the DV amount does not typically cause interference in lab tests. But if you are taking any Qualia supplements containing biotin, it is a good idea to let your doctor know and follow any recommendation they may have about stopping it prior to lab testing.*


Biotin Key Mechanisms*

Biotin is required for the activity of acetyl-CoA carboxylase 1 (ACC1) and ACC2, pyruvate carboxylase, methylcrotonyl-CoA carboxylase, and propionyl-CoA carboxylase [2–4]

Biotin-dependent enzymes have important roles in pathways associated with gluconeogenesis, lipid catabolism, and branched chain amino acid catabolism [2–4]

Biotin regulates chromatin structure and gene expression [2,3]


Supports skin health*
Supports nail structure and health [5–7]
Supports hair health [8]
Supports skin zinc homeostasis [9] 


*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]F. Saleem, M.P. Soos, in: StatPearls, StatPearls Publishing, Treasure Island (FL), 2021.

[2]L. Riveron-Negrete, C. Fernandez-Mejia, Mini Rev. Med. Chem. 17 (2017) 529–540.

[3]D.M. Mock, J. Nutr. 147 (2017) 1487–1492.

[4]L. Tong, Cell. Mol. Life Sci. 70 (2013) 863–891.

[5]V.E. Colombo, F. Gerber, M. Bronhofer, G.L. Floersheim, J. Am. Acad. Dermatol. 23 (1990) 1127–1132.

[6]G.L. Floersheim, Z. Hautkr. 64 (1989) 41–48.

[7]L.G. Hochman, R.K. Scher, M.S. Meyerson, Cutis 51 (1993) 303–305.

[8]D.P. Patel, S.M. Swink, L. Castelo-Soccio, Skin Appendage Disord 3 (2017) 166–169.

[9]Y. Ogawa, M. Kinoshita, T. Sato, S. Shimada, T. Kawamura, Nutrients 11 (2019).


Vitamin B1 (Thiamine)

Common Name

Thiamine | Thiamin


Top Benefits of Thiamine

Supports energy metabolism*

Supports metabolic health*

Supports cognitive function*


What is Thiamine?

Thiamine (vitamin B1) is part of the B complex—a group of water-soluble vitamins that play important roles in cellular metabolism and energy production. It was the first of the B complex vitamins to be isolated, which is why it’s called B1. Thiamine is on the World Health Organization's List of Essential Medicines, the most effective and safe compounds needed in a health system, because of its essential role in preventing thiamine deficiency disorders. The body concentrates thiamine in metabolically active tissues, including skeletal muscle, heart, brain, liver, and kidneys. But the body only stores a small amount of thiamine (about 20-30 mg), so it needs to be consumed consistently in the diet. Thiamine is involved in many cellular processes. It is essential for the metabolism of sugars, proteins, and fats, and is instrumental in several important processes needed to make cellular energy.*


Neurohacker’s Thiamine Sourcing

Thiamine is supplied as thiamine HCL (hydrochloride) because oral supplementation with this form of vitamin B1 can rapidly increase blood levels of thiamine [1].

Thiamine HCl is NON-GMO, gluten-free and vegan.


Thiamine Dosing Principles and Rationale

Thiamine has a wide dosing range that varies from about the daily value amount of 1.2 mg to several hundred milligrams. We consider it to be subject to a dosing threshold (see Neurohacker Dosing Principles), which means, while more might be better within a range, increasing amounts beyond that range is unlikely to add significant additional nutritional or functional benefits for most people. Depending on the goal of a formulation, the dose of thiamine used can vary. If we are using it in combination with the rest of the B-complex family of vitamins to complement this family’s functional activities, especially for energy production, a low-to-modest dose will be used. If we are using thiamine for a more specific purpose—as a nootropic for example—a higher dose may be used.*


Thiamine Key Mechanisms 

Supports energy metabolism*

Supports energy generation (ATP) from carbohydrate and sugar metabolism [2]


Cofactor in the pyruvate dehydrogenase complex*

Thiamine pyrophosphate (TPP) is required as a cofactor in the E1 subunit of the pyruvate dehydrogenase (PDH) complex [2]

TPP is essential for the generation by the PDH complex of acetyl-CoA, used in the citric acid cycle to generate ATP [2]

TPP is essential for the generation by the PDH complex of nicotinamide adenine dinucleotide (NADH), required for the production of ATP [2]

Cofactor in the citric acid cycle [2]

TPP is required as a cofactor in the alpha-ketoglutarate dehydrogenase reaction of the citric acid cycle (conversion of alpha-ketoglutarate to succinyl-CoA) [2]

TPP is essential in propagating the citric acid cycle to generate ATP [2]


Cofactor in the pentose phosphate pathway*

TPP is required as a cofactor in the transketolase reaction of the pentose phosphate pathway (PPP) [2]

The PPP provides nicotinamide adenine dinucleotide phosphate (NADPH), used in several biochemical pathways such as in steroid, fatty acid, amino acid, neurotransmitter, and glutathione synthesis [2]

The PPP provides ribose-5-phosphate, an essential building block in nucleic acids [2]

Ribose-5-phosphate can enter the non-oxidative phase of the PPP where transketolase and TPP help transform ribose-5-phosphate back into glycolysis intermediates (such as glucose-6-phosphate) [2]


Supports antioxidant defenses*

Participates in the synthesis of NADPH to be used in the recycling of the antioxidant glutathione (GSH) [2]


Supports brain function*

Essential for the production by the pyruvate dehydrogenase complex of acetyl-CoA used for the production of acetylcholine [2]

The alpha-ketoglutarate dehydrogenase reaction of the citric acid cycle reaction has a role in maintaining glutamate and gamma-aminobutyric acid (GABA) levels [2]


Other mechanisms*

May help counter the production of advanced glycation end-products (AGEs) [3,4]

Supports healthy blood pressure [5]

Supports healthy blood glucose levels [6]

Supports healthy insulin sensitivity [6]


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


REFERENCES

[1] H.A. Smithline, M. Donnino, D.J. Greenblatt, BMC Clin. Pharmacol. 12 (2012) 4.
[2] D. A. Bender, in Nutritional Biochemistry of the Vitamins (Cambridge University Press, 2003), pp. 148–171.
[3] S. Kousar, M. A. Sheikh, M. Asghar, J. Pak. Med. Assoc. 62, 1033–1038 (2012).
[4] N. Karachalias, R. Babaei-Jadidi, C. Kupich, N. Ahmed, P. J. Thornalley, Ann. N. Y. Acad. Sci. 1043, 777–783 (2005).
[5] F. Alaei-Shahmiri, M. J. Soares, Y. Zhao, J. Sherriff, Diabetes Metab. Syndr. 9, 213–217 (2015).
[6] F. Alaei Shahmiri, M. J. Soares, Y. Zhao, J. Sherriff, Eur. J. Nutr. 52, 1821–1824 (2013).

Inositol (as Myo-Inositol and D-chiro-inositol from Ceratonia siliqua Pod Extract)

Common Name

Inositol | Myo-Inositol | D-Chiro-Inositol


Top Benefits of Inositol

Supports insulin signaling *

Supports thyroid function *

Supports cardiometabolic health *

Supports female fertility *

Supports healthy gut microbiota *


What is Inositol?

Inositol is a family of nine different stereoisomers. This is a chemistry term. It means that all inositols share the same atoms and the sequence of how the atoms are bonded together, but differ in the three-dimensional orientation of their atoms in space. An analogy would be a folding beach chair that can be put in multiple positions. The most stable form of inositol in the body is called myo-inositol. It’s also the most abundant form. The most commonly supplemented form of inositol is myo-inositol (myo-inositol functions as a synonym for inositol in dietary supplements). Myo-inositol and the D-chiro-inositol form exist in plasma in a 40:1 ratio. This combination and ratio is complementary, producing far greater functional responses at much lower doses than myo-inositol alone [1,2]. Historically, inositol was considered part of the B-complex of vitamins (it was called vitamin B8), but because we can make it in the body, it’s no longer classified as a vitamin. While lots of foods contain inositol, its bioavailability in plant foods such as seeds, beans, and grains is low. In the body inositol is found in cell membrane phospholipids, plasma lipoproteins, and (as the phosphate form) in the cell nucleus (the home of our DNA). Our main interest in inositol is for support of hormone signaling—insulin and thyroid especially. Inositol acts as a second messenger, translating hormone messages that act on the outside of cells into intracellular signals involved in energy production, growth, and repair.*


Neurohacker’s Inositol Sourcing

Our main reason for including inositol is because of its role in supporting healthy insulin and thyroid signaling functions. When these work better, cellular energy can be made more efficiently.

The most important inositol criteria is opting for complementarity and using a stack of myo-inositol and D-chiro-inositol in a 40:1 ratio. Compared to either form of inositol on its own, this ratio (1) better matches physiology, (2) produces enhanced functional responses at lower doses, and (3) overcomes interference in cellular enzyme production of D-chiro-inositol from myo-inositol that can occur with insulin resistance and aging.

Myo-inositol sourcing is focused on identifying and purchasing from a reputable supplier and ensuring the myo-inositol is non-GMO, gluten-free and vegan.

We use Chirositol® from Bioriginal as a source of D-chiro-inositol. It is extracted without the use of solvents from carob pods (Ceratonia siliqua) and contains greater than 95% D-chiro-inositol. Chirositol® is non-GMO Project verified, gluten-free and vegan. 


Inositol Dosing Principles and Rationale

Inositol is generally considered to be dose-dependent (see Neurohacker Dosing Principles) and is often used in very high amounts, especially when trying to affect the brain and mental health. But for general cellular signaling purposes, much lower doses can be used, especially when myo-inositol and D-chiro-inositol are included at a ratio of 40:1. This is their physiological ratio in the plasma. The stacking of myo-inositol and D-chiro-inositol is complementary at this ratio, allowing for the use of lower doses of both [1, 2].*


Inositol Key Mechanisms

Supports mitochondrial function*

D-chiro-inositol supports mitochondrial structure and function [3]

D-chiro-inositol downregulates oxidative stress [4]

D-chiro-inositol upregulates AMPK activity through the LKB1-dependent pathway [4]


Supports healthy insulin signaling*

Supports healthy insulin sensitivity [1,5–11] 

Myo-inositol and D-chiro-inositol are precursors of intracellular second messengers of insulin signaling pathways (e.g.inositol 1,4,5-triphosphate [IP3]; phosphatidylinositol (3,4,5)-triphosphate [PIP3], D-chiro-inositol-containing-inositolphosphoglycan ([DCI-IPG]) [12,13]  

Myo-inositol and D-chiro-inositol stimulate the translocation to the cell membrane of the glucose transporter GLUT4 [14–16]

D-chiro-inositol-containing-inositolphosphoglycan (DCI-IPG) activates the pyruvate dehydrogenase complex (PDC) — supports the production acetyl-CoA to be used in the citric acid cycle [17]

Myo-inositol (via PIP3) and D-chiro-inositol (via DCI-IPG) stimulate glycogen synthase - support glucose storage as glycogen [18,19] 


Supports healthy cardiometabolic function*

Supports healthy blood pressure [7,8]

Supports healthy blood triglycerides and cholesterol levels [1,7,8,20] 

Supports healthy body mass index (BMI) [7,10]


Supports healthy thyroid function*

Inositol derivatives are second messengers  in the TSH signaling pathway [21]

Regulates thyroid-stimulating hormone (TSH) levels [22–24] 

Supports cellular thyroid function [22–24] 


Supports female reproductive health*

Inositol derivatives are second messengers in the FSH signaling pathway [25]

Supports oocyte maturation [26–29]

Supports ovary function [2,9,20,30]


Supports a healthy gut microbiota*

Regulates the composition of the gut microbiota [31]


Complementary ingredients*

Lipoic acid, N-acetyl cysteine - healthy insulin sensitivity [19]

Selenium - healthy thyroid function [22]

Resveratrol - healthy metabolic profile [32]


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


REFERENCES

[1]M. Minozzi, M. Nordio, R. Pajalich, Eur. Rev. Med. Pharmacol. Sci. 17 (2013) 537–540.

[2]M. Nordio, E. Proietti, Eur. Rev. Med. Pharmacol. Sci. 16 (2012) 575–581.

[3]B. Zhang, C. Gao, Y. Li, M. Wang, J. Ethnopharmacol. 214 (2018) 83–89.

[4]B. Zhang, X. Guo, Y. Li, Q. Peng, J. Gao, B. Liu, M. Wang, Mol. Nutr. Food Res. 61 (2017).

[5]V. Unfer, F. Facchinetti, B. Orrù, B. Giordani, J. Nestler, Endocr Connect 6 (2017) 647–658.

[6]F. Corrado, R. D’Anna, G. Di Vieste, D. Giordano, B. Pintaudi, A. Santamaria, A. Di Benedetto, Diabet. Med. 28 (2011) 972–975.

[7]A. Santamaria, D. Giordano, F. Corrado, B. Pintaudi, M.L. Interdonato, G.D. Vieste, A.D. Benedetto, R. D’Anna, Climacteric 15 (2012) 490–495.

[8]D. Giordano, F. Corrado, A. Santamaria, S. Quattrone, B. Pintaudi, A. Di Benedetto, R. D’Anna, Menopause 18 (2011) 102–104.

[9]E. Benelli, S. Del Ghianda, C. Di Cosmo, M. Tonacchera, Int. J. Endocrinol. 2016 (2016) 3204083.

[10]L. Pkhaladze, L. Barbakadze, N. Kvashilava, Int. J. Endocrinol. 2016 (2016) 1473612.

[11]A.D. Genazzani, C. Lanzoni, F. Ricchieri, V.M. Jasonni, Gynecol. Endocrinol. 24 (2008) 139–144.

[12]R.A. Haeusler, T.E. McGraw, D. Accili, Nat. Rev. Mol. Cell Biol. 19 (2018) 31–44.

[13]J. Larner, D.L. Brautigan, M.O. Thorner, Mol. Med. 16 (2010) 543–552.

[14]A. Yap, S. Nishiumi, K.-I. Yoshida, H. Ashida, Cytotechnology 55 (2007) 103–108.

[15]N.T. Dang, R. Mukai, K.-I. Yoshida, H. Ashida, Biosci. Biotechnol. Biochem. 74 (2010) 1062–1067.

[16]Y. Yamashita, M. Yamaoka, T. Hasunuma, H. Ashida, K.-I. Yoshida, J. Agric. Food Chem. 61 (2013) 4850–4854.

[17]T.E. Roche, J.C. Baker, X. Yan, Y. Hiromasa, X. Gong, T. Peng, J. Dong, A. Turkan, S.A. Kasten, Prog. Nucleic Acid Res. Mol. Biol. 70 (2001) 33–75.

[18]H.K. Ortmeyer, N.L. Bodkin, B.C. Hansen, J. Larner, J. Nutr. Biochem. 6 (1995) 499–503.

[19]C. Paul, A.S. Laganà, P. Maniglio, O. Triolo, D.M. Brady, Gynecol. Endocrinol. 32 (2016) 431–438.

[20]J.E. Nestler, D.J. Jakubowicz, P. Reamer, R.D. Gunn, G. Allan, N. Engl. J. Med. 340 (1999) 1314–1320.

[21]S. Benvenga, A. Antonelli, Rev. Endocr. Metab. Disord. 17 (2016) 471–484.

[22]M. Nordio, S. Basciani, Eur. Rev. Med. Pharmacol. Sci. 22 (2018) 2153–2159.

[23]S.M. Ferrari, P. Fallahi, F. Di Bari, R. Vita, S. Benvenga, A. Antonelli, Eur. Rev. Med. Pharmacol. Sci. 21 (2017) 36–42.

[24]M. Nordio, S. Basciani, Int. J. Endocrinol. 2017 (2017) 2549491.

[25]P. Gloaguen, P. Crépieux, D. Heitzler, A. Poupon, E. Reiter, Front. Endocrinol. 2 (2011) 45.

[26]L. Ciotta, M. Stracquadanio, I. Pagano, A. Carbonaro, M. Palumbo, F. Gulino, Eur. Rev. Med. Pharmacol. Sci. 15 (2011) 509–514.

[27]T.T.Y. Chiu, M.S. Rogers, C. Briton-Jones, C. Haines, Hum. Reprod. 18 (2003) 408–416.

[28]T.T.Y. Chiu, M.S. Rogers, E.L.K. Law, C.M. Briton-Jones, L.P. Cheung, C.J. Haines, Hum. Reprod. 17 (2002) 1591–1596.

[29]S.G. Vitale, P. Rossetti, F. Corrado, A.M.C. Rapisarda, S. La Vignera, R.A. Condorelli, G. Valenti, F. Sapia, A.S. Laganà, M. Buscema, Int. J. Endocrinol. 2016 (2016) 4987436.

[30]S. Gerli, M. Mignosa, G.C. Di Renzo, Eur. Rev. Med. Pharmacol. Sci. 7 (2003) 151–159.

[31]Y. Okazaki, A. Sekita, T. Katayama, Biomed Rep 8 (2018) 466–474.

[32]A. Malvasi, I. Kosmas, O.A. Mynbaev, R. Sparic, S. Gustapane, M. Guido, A. Tinelli, Clin. Ter. 168 (2017) e240–e247.

Vitamin B5 (Calcium Pantothenate)

Vitamin B5 (Calcium Pantothenate) Common Name

Pantothenate | Pantothenic acid | Vitamin B5


Top Benefits of Calcium Pantothenate

Supports energy metabolism*

Supports brain function*


What is Calcium Pantothenate?

Pantothenic acid (vitamin B5) is part of the B complex—a group of water-soluble vitamins that play important roles in cellular metabolism and energy production. It is an essential vitamin and the precursor of Coenzyme A (CoA), a molecule that is ubiquitous in the human body and that participates in the key metabolic pathways for cellular energy generation. CoA is also used in the synthesis of the neurotransmitter acetylcholine and is therefore essential for proper nervous system function. Vitamin B5 supports healthy adrenal function, which is why it is sometimes described as an “anti-stress” vitamin.*


Neurohacker’s Calcium Pantothenate Sourcing

Calcium pantothenate—the calcium salt of pantothenic acid—is used in dietary supplements, because it’s shown to be more stable than pantothenic acid.

Calcium pantothenate sourcing is focused on identifying and purchasing from a reputable supplier and ensuring it’s a NON-GMO, gluten-free and vegan ingredient.


Calcium Pantothenate Dosing Principle and Rationale

Vitamin B5 generally has a wide dosing range, however, from our interpretation of the research, we consider it to be subject to a dosing threshold (see Neurohacker Dosing Principles), which means, while more might be better within a range, increasing amounts beyond that is unlikely to add significant additional nutritional or functional benefits for most people. Our goal in formulating products is to make sure that pantothenic acid amounts will be within this threshold range, even if several of our products with vitamin B5 are used together. In general, we tend to include a recommended dose of vitamin B5 at higher amounts in formulations where it would be used to support neurotransmitter production, and lower levels when we are using it to complement a full B complex stack.*


Calcium Pantothenate Key Mechanisms 

Vitamin B5 is required for the synthesis of coenzyme A (CoA) [1]

Coenzyme A is a cofactor in several important cellular metabolic pathways [2]

Coenzyme A has a key role in energy metabolism, especially the conversion of sugars and fats into energy [3]

Coenzyme A is required for the synthesis of the neurotransmitter acetylcholine [4]

Vitamin B5 supports healthy adrenal function* [5–11]


*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] A. G. Tahiliani, C. J. Beinlich, in Vitamins & Hormones, G. D. Aurbach, Ed. (Academic Press, 1991), vol. 46, pp. 165–228.
[2] R. Leonardi, Y.-M. Zhang, C. O. Rock, S. Jackowski, Prog. Lipid Res. 44, 125–153 (2005).
[3] F. Pietrocola, L. Galluzzi, J. M. Bravo-San Pedro, F. Madeo, G. Kroemer, Cell Metab. 21, 805–821 (2015).
[4] S. K. Fisher, S. Wonnacott, in Basic Neurochemistry (Eighth Edition), S. T. Brady, G. J. Siegel, R. W. Albers, D. L. Price, Eds. (Academic Press, New York, 2012), pp. 258–282.


Vitamin K2 (MK-7)

Common Name

Vitamin K2 | MK-7 | Menaquinone 7


Top Benefits of Vitamin K2 (MK-7)

Supports bone health*

Supports metabolism*

Supports exercise performance*

Supports ATP production*

Support cardiovascular function*

Supports brain function*

Supports antioxidant defenses*

Supports cellular signaling*


What is Vitamin K2 (MK-7)?

Vitamin K is a collective term for a group of structurally related fat-soluble molecules (vitamers) that act as a cofactor for a carboxylase enzyme. This enzyme transforms glutamate residues in proteins to carboxyglutamate residues, which plays an important role in blood clotting and bone health. Dietary vitamin K1 (phylloquinone) is obtained from vegetables, whereas dietary vitamin K2 (menaquinone) is obtained from products of animal origin or bacterial fermentation (e.g., cheese, natto). Vitamin K2 can also be produced by gut bacteria from vitamin K1. There are nine related vitamin K2 compounds—MK-1, MK-2 ... MK-9. The M stands for menaquinone, the K stands for vitamin K, and the n represents the number of isoprenoid side chain residues. In general, vitamin K2 is the preferred form for supporting bone and vascular health.*


Neurohacker’s Vitamin K2 (MK-7) Sourcing

Menaquinone-7 (MK-7) is a bioavailable vitamin K2, needing much lower doses than MK-4.

Produced from natto and manufactured by Japan Bioscience Labs (JBSL), a leading Japanese natto manufacturer for decades.

A clinically studied form of vitamin K2 which has been used in studies lasting up to three years. 

Non-GMO, Vegan, Gluten Free


Vitamin K2 (MK-7) Dosing Principles and Rationale

The dose of vitamin K needed will depend on the use and the form used. Of the available forms of vitamin K2, in general, shorter chain forms (MK-4, -5, and -6) require much higher doses than the longer-chain MK-7. Depending on the purpose the amount of vitamin K2 supplemented can vary (i.e., a higher dose would be used to optimize bone health, while a lower dose would be used if its an ingredient intended to support mitochondrial function).*


Vitamin K2 (MK-7) Key Mechanisms 

Supports mitochondrial structure and function*

Supports electron transport chain and oxidative phosphorylation (ATP production) [1–12]

Mitochondrial electron carrier - alternative electron acceptor/donor (complex I-III bypass) [1–3]

Supports complex I-V activity [4–9]

Supplies complex III cofactors/substrates [10–12]

Supports healthy mitochondrial function [3,4,13]

Supports mitochondrial morphology [14]

Supports AMP-activated protein kinase (AMPK) signaling 24


Supports healthy metabolic function*

Supports healthy insulin sensitivity [15–19]

Supports adiponectin levels 18,24 [18]

Supports uncoupling protein 1 (UCP-1) [18]


Supports exercise performance*

Supports endurance performance [20]

Supports resistance to muscle cramps [21]

Supports post-exercise recovery [1,2]


Supports healthy skeletal system function*

Promotes the formation of bone [22,23]


Supports healthy cardiovascular function*

Supports healthy blood coagulation [22,23]

Supports healthy vascular structure [22,23]

Supports cardiac output (during exercise) [20]

Supports healthy cardiac cells [4]


Supports cellular signaling*

Supports healthy immune signaling  [13,24,25]


Supports antioxidant defenses*

Counters the generation of reactive oxygen species [8,13,26]


Supports brain function*

Supports neuroprotective functions [8,26]


Supports a healthy gut microbiota*

Supports the production of short-chain fatty acids (SCFAs) by the gut microbiota [24]


*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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[8] N. K. Isaev, E. V. Stelmashook, K. Ruscher, N. A. Andreeva, D. B. Zorov, Neuroreport. 15, 2227–2231 (2004).
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[15] H. J. Choi et al., Diabetes Care. 34, e147 (2011).
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[18] A. G. Hussein, R. H. Mohamed, S. M. Shalaby, D. M. Abd El Motteleb, Nutrition. 47, 33–38 (2018).
[19] Y. Li, J. P. Chen, L. Duan, S. Li, Diabetes Res. Clin. Pract. 136, 39–51 (2018).
[20] B. K. McFarlin, A. L. Henning, A. S. Venable, Altern. Ther. Health Med. 23, 26–32 (2017).
[21] D. S. Mehta et al., The Indian Practitioner. 63, 287–291 (2010).
[22] T. Krueger, R. Westenfeld, L. Schurgers, V. Brandenburg, Int. J. Artif. Organs. 32, 67–74 (2009).
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[24] Y. Zhang et al., Oncotarget. 8, 24719–24727 (2017).
[25] H. Zhang et al., Oncol. Rep. 25, 159–166 (2011).
[26] J. Li et al., J. Neurosci. 23, 5816–5826 (2003).

*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.

Vitamin B12 (Methylcobalamin)

Common Names

Vitamin B12 | Methylcobalamin


Top Benefits of Methylcobalamin

Supports healthy vision*

Supports brain and nerve health* 

Supports cellular metabolism*


What Is Methylcobalamin?

Vitamin B12, or cobalamin, is unique among vitamins because it contains a metal ion, cobalt, from which the term cobalamin derived. Methylcobalamin is one of the two coenzyme forms of vitamin B12 (the other is adenosylcobalamin). These are the forms used in enzymes in the human body. Methylcobalamin is used in only one enzyme, methionine synthase, which is required to make the purines and pyrimidines needed for DNA. Methionine synthase also links the folate cycle and the S-adenosylmethionine cycle, converting methyltetrahydrofolate into tetrahydrofolate, and subsequently homocysteine into methionine (this acts to support healthy homocysteine levels). Methylcobalamin is a central player in a process called methylation or methyl donation. This process has wide spread 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. Methylcobalamin is thought to be the best form of vitamin B12 for supporting the vitamin B12-dependent enzymes that normally use this form of vitamin B12. Vitamin B12 is essential for the healthy function of nerves. In a general sense, methylcobalamin can be thought of as more of a nootropic form of vitamin B12; it’s been used extensively in research when vitamin B12 has been needed for supporting brain, nerve, and vision functions.*


Neurohacker’s Methylcobalamin Sourcing

Vitamin B12 can be found in different forms, including cyanocobalamin, hydroxocobalamin, adenosylcobalamin, and methylcobalamin. Adenosylcobalamin and methylcobalamin are considered to be the coenzyme forms, because they are what’s used in enzymes in the body.

The methylcobalamin form is selected when a biologically active form of vitamin B12 is desired and the formulation’s goal is to support methionine synthase, one of the two enzymes in the body that uses vitamin B12, or brain, nerve, and vision health.*

Methylcobalamin sourcing is focused on ensuring it is a non-GMO, gluten-free, and vegan ingredient.


Methylcobalamin Dosing Principles and Rationale

Methylcobalamin is shown to have dose-dependent benefits (see Neurohacker Dosing Principles) in the range it’s commonly dosed (up to about 1 mg), with higher doses doing a better job in normalizing functional markers of vitamin B12 status than lower doses when a person is deficient. The RDA for vitamin B12 is very low. Vitamin B12 function may not always be maintained at these low levels, with functional status sometimes requiring substantially higher doses to normalize. [1] Relative insufficiencies are more common with older age and in persons eating a vegetarian or vegan diet (vitamin B12 is found in animal products but not plants). Methylcobalamin has been the preferred form of vitamin B12 in research studies on the brain and the nervous system function dating back to the 1990's, so it's the form of vitamin B12 we include for products intended to support brain and vision health. The amount of methylcobalamin in a formula will vary depending on the intended use from an amount close to the RDA up to the 1 mg dose used in some cognitive studies.* 


Methylcobalamin Key Mechanisms


Supports methionine synthase activity*

Methylcobalamin is required as a cofactor for the activity of the cytosolic enzyme methionine synthase [2,3] 

Methionine synthase transfers the methyl group from methyltetrahydrofolate to homocysteine to form methionine and tetrahydrofolate  [2,3] 

Methionine is required for the synthesis of S-adenosylmethionine (SAMe), a methyl group donor used in many biological methylation reactions  [2,3] 

Methionine synthase is essential for the methylation of nucleic acids (DNA and RNA) for DNA synthesis and protein synthesis  [2,3] 


Supports healthy cardiovascular and cerebrovascular function*

Supports healthy homocysteine levels (healthy cardiovascular function); complementary to vitamin B6 and folic acid (vitamin B9) [4–6]


Supports healthy vision*

Supports accommodation (i.e., focusing of eyes) when using devices with screen [7,8]

Supports retinal circadian rhythms [9]

Supports healthy retinal function [10–12]

Supports healthy optic nerve function [10,13–21]

Supports retinal nerve fiber layer thickness [22,23]

Supports normal activity of ciliary muscles of the lens [8]

Supports healthy function of eye ocular surfaces and corneal nerve [24,25]


Supports a healthy gut microbiome*

Supports healthy gut microbiome flora and function [26,27]


Complementary inngredients*

Folate - Insufficient methylcobalamin slows the regeneration of tetrahydrofolate and traps folate in a form that is not usable by the body. This can often be corrected with higher doses of folate but can mask a vitamin B12 deficiency, so vitamin B12 is almost always given when folates are supplemented.

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.

Adenosylcobalamin (another coenzyme form of vitamin B12) [28]


*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]M.H. Hill, J.E. Flatley, M.E. Barker, C.M. Garner, N.J. Manning, S.E. Olpin, S.J. Moat, J. Russell, H.J. Powers, The Journal of Nutrition 143 (2013) 142–147.

[2]F. O’Leary, S. Samman, Nutrients 2 (2010) 299–316.

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

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

[5]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.

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

[7]S. Kurimoto, T. Iwasaki, T. Nomura, K. Noro, S. Yamamoto, J. UOEH 5 (1983) 101–110.

[8]T. Iwasaki, S. Kurimoto, J. UOEH 9 (1987) 127–132.

[9]N. Imamura, Y. Dake, T. Amemiya, Life Sci. 57 (1995) 1317–1323.

[10]E.M. Chester, D.P. Agamanolis, J.W. Harris, M. Victor, J.D. Hines, J.A. Kark, Acta Neurol. Scand. 61 (1980) 9–26.

[11]S.S. Reddy, Y.K. Prabhakar, C.U. Kumar, P.Y. Reddy, G.B. Reddy, Mol. Vis. 26 (2020) 311–325.

[12]J. Guo, S. Ni, Q. Li, J.-Z. Wang, Y. Yang, Neurosci. Bull. 35 (2019) 325–335.

[13]D. Stambolian, M. Behrens, Am. J. Ophthalmol. 83 (1977) 465–468.

[14]A.J. Larner, Int. J. Clin. Pract. 58 (2004) 977–978.

[15]M. Moschos, The Lancet 352 (1998) 146–147.

[16]Y. Yamazaki, F. Hayamizu, C. Tanaka, Curr. Ther. Res. Clin. Exp. 61 (2000) 443–451.

[17]X. Kong, X. Sun, J. Zhang, Yan Ke Xue Bao 20 (2004) 171–177.

[18]S.H. Chavala, G.S. Kosmorsky, M.K. Lee, M.S. Lee, Eur. J. Intern. Med. 16 (2005) 447–448.

[19]P. Enoksson, A. Norden, Acta Medica Scandinavica 167 (2009) 199–208.

[20]C. Chu, P. Scanlon, Case Reports 2011 (2011) bcr0220113823–bcr0220113823.

[21]O.P. Anand, Delhi Journal of Ophthalmology 29 (2019).

[22]S. Özkasap, K. Türkyilmaz, S. Dereci, V. Öner, T. Calapoğlu, M.C. Cüre, M. Durmuş, Childs. Nerv. Syst. 29 (2013) 2281–2286.

[23]K. Türkyılmaz, V. Öner, A.K. Türkyılmaz, A. Kırbaş, S. Kırbaş, B. Şekeryapan, Curr. Eye Res. 38 (2013) 680–684.

[24]S. Ozen, M.A. Ozer, M.O. Akdemir, Graefes Arch. Clin. Exp. Ophthalmol. 255 (2017) 1173–1177.

[25]M.R. Romano, F. Biagioni, A. Carrizzo, M. Lorusso, A. Spadaro, T. Micelli Ferrari, C. Vecchione, M. Zurria, G. Marrazzo, G. Mascio, B. Sacchetti, M. Madonna, F. Fornai, F. Nicoletti, M.D. Lograno, Exp. Eye Res. 120 (2014) 109–117.

[26]Y. Xu, S. Xiang, K. Ye, Y. Zheng, X. Feng, X. Zhu, J. Chen, Y. Chen, Front. Microbiol. 9 (2018) 2780.

[27]X. Zhu, S. Xiang, X. Feng, H. Wang, S. Tian, Y. Xu, L. Shi, L. Yang, M. Li, Y. Shen, J. Chen, Y. Chen, J. Han, J. Agric. Food Chem. 67 (2019) 916–926.

[28]E.S. Tsukerman, T.L. Korsova, A.A. Poznanskaia, Vopr. Pitan. (1992) 40–44.

Niacinamide (Vitamin B3)

Common Name

Niacinamide | Nicotinamide | Vitamin B3


Top Benefits of Niacinamide     

Supports energy metabolism*

Supports antioxidant defenses*

Supports healthy aging and longevity*

Supports neuroprotection*


What is Niacinamide?

Niacinamide (vitamin B3) is part of the B complex—a group of water-soluble vitamins that play important roles in cellular metabolism and energy production. It is called B3 because it was the third of the B complex vitamins to be discovered. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system, because of its ability to prevent pellagra, the vitamin B3 deficiency disease. Unlike the “flushing” niacin (nicotinic acid) form of vitamin B3, niacinamide does not cause flushing. Compounds with niacin activity are defined by their ability to contribute the nicotinamide (i.e., niacinamide) unit of an important molecule called NAD. NAD is found in every cell in the body. It's used to (1) make cellular energy (ATP), (2) protect cells from damage, and (3) activate processes linked to healthier aging. Research shows that as we age levels of some NAD metabolites (NAD+ as an example) decline substantially. This decline leaves us at greater risk for unhealthy aging because without sufficient NAD+ cells aren't able to do the work needed to perform at their best. Many healthy aging scientists and doctors believe maintaining higher levels of NAD+ is one of the keys to increasing the amount of time we spend in good health.*


Neurohacker’s Niacinamide Sourcing

Niacinamide sourcing is focused on identifying and purchasing from a reputable supplier and ensuring it’s NON-GMO, gluten-free, and vegan.


Niacinamide Dosing Principles and Rationale

Vitamin B3, no matter the form, is subject to a dosing threshold (see Neurohacker Dosing Principles), which means, while more might be better within a low to moderate range, very high amounts would be unlikely to add significant additional nutritional or functional benefits for most people but could increase the risk of unwanted responses. As doses of vitamin B3 increase, more gets wasted because it’s eliminated in the urine. This “wasting” increases as dose escalates. For the niacinamide (i.e., non-flushing) form of vitamin B3, we think it’s important to consider the dose where a big increase in urinary elimination starts to occur and focus on dosing in this range (as opposed to substantially above it). Rather than trying to push the pathway that produces NAD with niacinamide alone, we think a better way, and a way that fits with complex systems science, is stacking it with other ingredients that support NAD production and recycling.* 


Niacinamide Key Mechanisms 

Precursor of NADH/NAD+ (nicotinamide adenine dinucleotide)*

Supports breakdown of sugars and fats for energy [1]

Supports mitochondrial production of ATP [1]

NADH is part of complex I NADH/coenzyme Q reductase) of the mitochondrial electron transport chain [2]


Precursor of NADPH/NADP+ (nicotinamide adenine dinucleotide phosphate)*

NADPH is a key cofactor for cytochrome P450 enzymes that detoxify xenobiotics [3]

NADPH is a cofactor for glutathione reductase, which maintains the levels of reduced glutathione - confers protection against oxidative stress [4]

Essential for the functioning of a wide range of enzymes involved in redox reactions [1]


Supports healthy aging and longevity*

Influences lifespan, senescence, cell proliferation, apoptosis [1]

NAD+ is a substrate for sirtuins (SIRT-1 to SIRT-7), which promote healthspan [5]

NAD+ is a substrate for poly(ADP-ribose) polymerase-1(PARP-1), which is involved in DNA repair and essential for genome stability [5,6]

NAD+ supports mitochondrial function [7,8]

NAD+ supports stem cell function [8]

NAD+ extends lifespan (Caenorhabditis elegans and mice) [7,8]


Supports healthy brain function*

Supports neuroprotective functions [9,10]


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


REFERENCES

[1] A. A. Sauve, J. Pharmacol. Exp. Ther. 324, 883–893 (2008).
[2] N. Pollak, C. Dölle, M. Ziegler, Biochem. J. 402, 205–218 (2007).
[3] A. V. Pandey, C. E. Flück, Pharmacol. Ther. 138, 229–254 (2013).
[4] G. Filomeni, G. Rotilio, M. R. Ciriolo, Biochem. Pharmacol. 64, 1057–1064 (2002).
[5] A. R. Mendelsohn, J. W. Larrick, Rejuvenation Res. 20, 244–247 (2017).
[6] J. B. Kirkland, Nutr. Cancer. 46, 110–118 (2003).
[7] L. Mouchiroud et al., Cell. 154, 430–441 (2013).
[8] H. Zhang et al., Science. 352, 1436–1443 (2016).
[9] P. K. Shetty, F. Galeffi, D. A. Turner, Neurobiol. Dis. 62, 469–478 (2014).
[10] M. R. Hoane, D. R. Gilbert, M. A. Holland, J. L. Pierce, Neurosci. Lett. 408, 35–39 (2006).


Vitamin B12 (Adenosylcobalamin)

Common Names

Adenosylcobalamin | Cobamamide | Dibencozide | Coenzyme Vitamin B12 | Vitamin B12 | Cobalamin


Top Benefits of Adenosylcobalamin

Supports cellular metabolism*

Supports vascular function*


What Is Adenosylcobalamin?

Vitamin B12, or cobalamin, is unique among vitamins because it contains a metal ion, cobalt, from which the term cobalamin derived. Adenosylcobalamin is one of the two coenzyme forms of vitamin B12 (the other is methylcobalamin). These are the forms used in enzymes in the human body. Adenosylcobalamin is used in only one enzyme, L-methyl-malonyl-CoA mutase. This enzyme sits at a crossroads of sorts between the Krebs cycle and many amino acids. In this role, it’s important for cellular energy production and building many important molecules.*


Neurohacker’s Adenosylcobalamin Sourcing

Vitamin B12 can be found in different forms, including cyanocobalamin, hydroxycobalamin, adenosylcobalamin, and methylcobalamin. Adenosylcobalamin and methylcobalamin are considered to be the coenzyme forms, because they are what’s used in enzymes in the body.

The adenosylcobalamin form is selected when a biologically active form of vitamin B12 is desired and the formulation’s goal is to support the Krebs cycle and cellular energy production.

Adenosylcobalamin sourcing is focused on ensuring it is non-GMO, gluten-free and vegan.


Adenosylcobalamin Dosing Principles and Rationale

Adenosylcobalamin is dose-dependent (see Neurohacker Dosing Principles) in the range it’s commonly dosed (up to about 1 mg), with higher doses doing a better job in normalizing functional markers of vitamin B12 status than lower doses. The RDA for vitamin B12 is very low. Vitamin B12 function is not always maintained at these low levels, with functional status sometimes requiring substantially higher doses to normalize.[1] Relative insufficiencies are more common with older age and in persons eating a vegetarian or vegan diet (vitamin B12 is found in animal products but not plants).*


Adenosylcobalamin Key Mechanisms

L-methyl-malonyl-CoA Mutase activity*

Adenosylcobalamin is required as a cofactor for the activity of the mitochondrial enzyme L-methyl-malonyl-CoA mutase [2,3]

Methylmalonyl-CoA mutase converts methylmalonyl-CoA to succinyl-CoA [2,3]

Succinyl-CoA is an intermediate of the citric acid cycle (i.e., Krebs cycle) – supports cell energy metabolism [2,3]


Supports healthy cardiovascular and cerebrovascular function*

Downregulates homocysteine levels (protects cardiovascular function); complementary to vitamin B6 and folic acid (vitamin B9) [4–6]

 

Complementary ingredients*

Folate - Insufficient cobalamin slows the regeneration of tetrahydrofolate and traps folate in a form that is not usable by the body. This can often be corrected with higher doses of folate but can mask a vitamin B12 deficiency, so vitamin B12 is almost always given when folates are supplemented.*


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


REFERENCES

[1] M. H. Hill et al., A Vitamin B-12 Supplement of 500 μg/d for Eight Weeks Does Not Normalize Urinary Methylmalonic Acid or Other Biomarkers of Vitamin B-12 Status in Elderly People with Moderately Poor Vitamin B-12 Status. The Journal of Nutrition. 143 (2013), pp. 142–147.
[2] F. O’Leary, S. Samman, Nutrients. 2, 299–316 (2010).
[3] J. M. Berg, J. L. Tymoczko, G. J. Gatto, L. Stryer, Eds., Biochemistry (W.H. Freeman and Company, 8th ed., 2015).
[4] J. Selhub, Annu. Rev. Nutr. 19, 217–246 (1999).
[5] E. Lonn et al., N. Engl. J. Med. 354, 1567–1577 (2006).
[6] D. Serapinas et al., Reprod. Toxicol. 72, 159–163 (2017).

Niacin (Vitamin B3)

COMMON NAME

Nicotinic Acid / Niacin / Vitamin B3


TOP BENEFITS OF NIACIN

Supports energy metabolism *

Supports antioxidant defenses *

Supports healthy aging and longevity *

Supports neuroprotection *

Supports cardiovascular function *


DESCRIPTION

Nicotinic acid (vitamin B3) is part of the B complex—a group of water-soluble vitamins that play important roles in cellular metabolism and energy production. It is called B3 because it was the third of the B complex vitamins to be discovered. The term niacin is often used as a synonym for this “flushing” form of vitamin B3. In general, likelihood of flushing increases with dose; at high doses most people will experience the unpleasant flushing sensation. At doses closer to the daily value flushing is rare. Compounds with niacin activity are defined by their ability to contribute the nicotinamide unit of an important molecule called NAD. The NAD molecule sits at the crossroads of mitochondrial energy production, cellular repair and signaling, and cellular defenses. Nicotinic acid makes NAD via the Preiss-Handler pathway. NAD, once formed, is a redox molecule. It interconverts between two forms NAD+ and NADH (or the same molecules with a phosphate written as NADP and NADPH) to carry out reactions involved in cellular and mitochondrial energy production and antioxidant defenses. NAD, in the NAD+ configuration, is also an important molecule in several cellular signaling pathways involved in DNA repair and cellular stress adaptation. NAD+ levels are known to decrease with age, and raising NAD+ levels in the body has been reported to support healthy aging and to have protective effects.*


NEUROHACKER'S NIACIN SELECTION & SOURCING

Nicotinic acid is additive with other ingredients with niacin-like activity (such as niacinamide and tryptophan). Using a combination of ingredients which can be used to make NAD supports the physiological redundancy cells have to create this important molecule. Nicotinic acid sourcing is focused on identifying and purchasing from a reputable supplier and ensuring it’s NON-GMO, gluten-free and vegan.


NIACIN DOSING PRINCIPLES AND RATIONALE

Vitamin B3, no matter the form, is subject to a dosing threshold (see Neurohacker Dosing Principles), which means, while more might be better within a low to moderate range, very high amounts would be unlikely to add significant additional nutritional or functional benefits for most people but could increase the risk of unwanted responses. As doses of vitamin B3 increase more gets wasted, because it’s eliminated in the urine. This “wasting” increases as dose escalates. For the flushing form of vitamin B3, we think it’s important to consider both the amounts where (1) flushing symptoms start to occur, and (2) a big increase in urinary elimination starts to occur. Optimizing these two variables is the key to efficient and safe dosing when niacin is being used to promote better cellular function. This optimization results in a dose that is higher than the daily value, but would be considered low. Rather than trying to push the pathway that produces NAD with nicotinic acid alone, we think a better way, and a way that fits with complex systems science, is stacking it with other ingredients that support NAD production and recycling.*

 

NIACIN KEY MECHANISMS

Precursor of NADH/NAD+ (nicotinamide adenine dinucleotide)*

Supports breakdown of sugars and fats for energy [1]

Supports mitochondrial production of ATP [1]

NADH is part of complex I NADH/coenzyme Q reductase) of the mitochondrial electron transport chain [2]


Precursor of NADPH/NADP+ (nicotinamide adenine dinucleotide phosphate)*

NADPH is a key cofactor for cytochrome P450 enzymes that detoxify xenobiotics [3]

NADPH is a cofactor for glutathione reductase, which maintains the levels of reduced glutathione - confers protection against oxidative stress and is part of antioxidant defenses [4]


Supports healthy aging and longevity*

Influences lifespan, senescence, cell proliferation, apoptosis [1]

Enhances remyelination of the aging central nervous system [5]

NAD+ is a substrate for sirtuins (SIRT1 to SIRT7), which promote healthspan [6]

NAD+ is a substrate for poly(ADP-ribose) polymerase-1 (PARP-1), which is involved in DNA repair and essential for genome stability  [6,7]

NAD+ supports mitochondrial function [8,9]

NAD+ supports stem cell function [9]

NAD+ extends lifespan (Caenorhabditis elegans and mice) [8,9]


Supports healthy brain function*

Supports neuroprotective functions [10,11]


Supports healthy cardiovascular function*

Supports healthy blood cholesterol and triglyceride levels [12–17]

Supports healthy vascular function  [14–18]


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


REFERENCES

[1] A. A. Sauve, J. Pharmacol. Exp. Ther. 324, 883–893 (2008).
[2] N. Pollak, C. Dölle, M. Ziegler, Biochem. J. 402, 205–218 (2007).
[3] A. V. Pandey, C. E. Flück, Pharmacol. Ther. 138, 229–254 (2013).
[4] G. Filomeni, G. Rotilio, M. R. Ciriolo, Biochem. Pharmacol. 64, 1057–1064 (2002).
[5] A. R. Mendelsohn, J. W. Larrick, Rejuvenation Res. 20, 244–247 (2017).
[6] J. B. Kirkland, Nutr. Cancer. 46, 110–118 (2003).
[7] L. Mouchiroud et al., Cell. 154, 430–441 (2013).
[8] H. Zhang et al., Science. 352, 1436–1443 (2016).
[9] J. Chen et al., Ann. Neurol. 62, 49–58 (2007).
[10] A. Shehadah et al., Neurobiol. Dis. 40, 277–283 (2010).
[11] L.-H. Zhang, V. S. Kamanna, S. H. Ganji, X.-M. Xiong, M. L. Kashyap, J. Lipid Res. 53, 941–950 (2012).
[12] J. W. A. van der Hoorn et al., Arterioscler. Thromb. Vasc. Biol. 28, 2016–2022 (2008).
[13] Y. Si et al., Mediators Inflamm. 2014, 263786 (2014).
[14] E. Fabbrini et al., J. Clin. Endocrinol. Metab. 95, 2727–2735 (2010).
[15] F. Y. Jin, V. S. Kamanna, M. L. Kashyap, Arterioscler. Thromb. Vasc. Biol. 19, 1051–1059 (1999).
[16] M. Hernandez, S. D. Wright, T.-Q. Cai, Biochem. Biophys. Res. Commun. 355, 1075–1080 (2007).
[17] P. S. Lipszyc et al., Open Cardiovasc. Med. J. 7, 90–98 (2013).

[18] P.S. Lipszyc, G.A. Cremaschi, M. Zorrilla-Zubilete, M.L.A. Bertolino, F. Capani, A.M. Genaro, M.R. Wald, Open Cardiovasc. Med. J. 7 (2013) 90–98.

Vitamin B2 (Riboflavin)

Common Name

Riboflavin


Top Benefits of Riboflavin

Supports cellular energy production*

Supports antioxidant defenses*


What is Riboflavin?

Riboflavin (vitamin B1) is part of the B complex—a group of water-soluble vitamins that play important roles in cellular metabolism and energy production. Riboflavin is called B2 because it was the second of the B complex vitamins to be discovered. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system, because of its essential role in preventing riboflavin deficiency disorders. The “flavin” part of its name comes from the Latin word for yellow (flavus)—riboflavin in supplements is bright yellow-orange in color and is what gives B-complex vitamins their yellow color. Because of its color, persons taking high amounts of riboflavin can notice yellow-colored urine. Riboflavin exists in two main forms in cells—flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). FMN and FAD are coenzymes needed for cellular metabolism, the generation of ATP, and the metabolism and/or activation of several vitamins (folic acid, vitamin A, vitamin B3, and vitamin B6) [1–3].*

 

Neurohacker’s Riboflavin Sourcing

Riboflavin sourcing is focused on identifying and purchasing from a reputable supplier and ensuring the riboflavin is NON-GMO, gluten-free and vegan. 


Riboflavin Dosing Principle and Rationale

Riboflavin is included in formulas which include the B-complex of vitamins, since these vitamins have interrelated relationships in cellular energy production. Tissue saturation and optimization of functional markers of riboflavin status tend to occur at doses that are close to the daily values (DV) established by the institute of medicine (IOM). Because of this, we consider riboflavin to be subject to a dosing threshold (see Neurohacker Dosing Principles), which means dosing above a relatively low amount would be unlikely to add any significant additional nutritional or functional benefits for most people. Keeping this threshold idea in mind, we dose riboflavin at levels that allow a slight buffer to the DV, but would be considered low-dose compared with the high amounts often found in B complex dietary supplements.*

 

Riboflavin Key Mechanisms 


Supports mitochondrial energy (ATP) production*

Flavocoenzymes participate in redox reactions in numerous metabolic pathways critical for the metabolism of carbohydrates, lipids, and proteins [1]

Complex I (NADH dehydrogenase) of the electron transport chain requires FMN for its action [1,2]

Complex II (succinate dehydrogenase) of the electron transport chain requires FAD for its action [1,2]


Supports NAD+ production*

The kynurenine pathway requires FAD for the synthesis of the niacin-containing coenzymes NAD+ and NADP+ from tryptophan [4]


Supports vitamin metabolism*

Flavoproteins are involved in the metabolism of several other vitamins (folate, vitamin A, vitamin B6, and niacin) [1]

FAD is required as a cofactor for the folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR)  [5]


Supports antioxidant defenses*

Glutathione reductase requires FAD to regenerate two molecules of reduced glutathione from oxidized glutathione and protect against reactive oxygen species and oxidative stress [1,6,7]

Thioredoxin reductase requires FAD to reduce thioredoxin and support antioxidant defenses, redox signaling, and DNA synthesis and repair [6,7]

NADH peroxidase requires FAD to reduce hydrogen peroxide (H2O2) [7]

 

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


REFERENCES

[1] A. Saedisomeolia, M. Ashoori, Adv. Food Nutr. Res. 83, 57–81 (2018).
[2] J. M. Berg, J. L. Tymoczko, G. J. Gatto, L. Stryer, Eds., Biochemistry (W.H. Freeman and Company, 8th ed., 2015).
[3] S. O. Mansoorabadi, C. J. Thibodeaux, H.-W. Liu, J. Org. Chem. 72, 6329–6342 (2007).
[4] A. A.-B. Badawy, Int. J. Tryptophan Res. 10, 1178646917691938 (2017).
[5] C. Kutzbach, E. L. Stokstad, Biochim. Biophys. Acta. 250, 459–477 (1971).
[6] N. Couto, J. Wood, J. Barber, Free Radic. Biol. Med. 95, 27–42 (2016).
[7] R. L. Fagan, B. A. Palfey, in Comprehensive Natural Products II, H.-W. (ben) Liu, L. Mander, Eds. (Elsevier, Oxford, 2010), pp. 37–113.


Folates

Common Names

Folate | Vitamin B9 | Folic Acid | Folinic Acid | Calcium Folinate | L-5'-Methyltetrahydrofolate | 5'-Methyltetrahydrofolate | L-Methylfolate | Methyl THF | Pteroyl-L-Glutamate


Top Benefits of Folates

Supports genetic stability*

Supports production and maintenance of new cells*

Supports cardiovascular function*


What Are 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.*

 

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 Dosing 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 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]. Since the folic acid form is used to fortify many foods, an average person will be getting some exposure to folic acid in the diet. To ensure that our products do not contribute to unmetabolized folic acid in the blood, we opted to not use the folic acid form. Instead, the folate stack uses the biologically active forms (calcium folinate and L-5'-methyltetrahydrofolate) to increase DFE amount given. These active 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. Calcium folinate and L-5'-methyltetrahydrofolate accomplish this goal without the risk of increasing unmetabolized folic acid.

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 cardiovascular and cerebrovascular function*

Downregulates homocysteine levels (protects cardiovascular function); complementary to vitamin B6 and vitamin B12 [11–13]


Complementary ingredients*

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, 1790–1795 (1997).

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

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

[4] K. E. Christensen et al., Am. J. Clin. Nutr. 101, 646–658 (2015).

[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).

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

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

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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).

Benfotiamine

Scientific Name:
S-Benzoylthiamine O-monophosphate

Overview:
Benfotiamine is a synthetic S-acyl derivative of vitamin B1 (thiamine) with neuroprotective effects. By increasing vitamin B1 levels, benfotiamine can increase energy, mood and alertness.

Scientific Name:
S-Benzoylthiamine O-monophosphate

Mechanisms:

  • After ingestion, benfotiamine is converted into vitamin B1 (thiamine)[1]
  • This synthetic S-acyl derivative of thiamine has a 5-fold higher bioavailability[1]
  • Thiamine increases the production of ATP by enhancing carbohydrate metabolism[2]
  • Thiamine increases mood, energy, and alertness[2]
  • Useful for the treatment of neuropathies and chronic pain[3]
  • Can increase the activity of transketolase – reduces vascular damage associated with neuropathy and retinopathy[4]
  • Antioxidant action via NADPH oxidase[5]
  • Decreases the levels of advanced glycation end products (AGEs) – substances that contribute to neurodegeneration[6]
REFERENCES

[1] Loew D (1996). Pharmacokinetics of thiamine derivatives especially of benfotiamine. Int J Clin Pharmacol Ther, 34(2):47-50. PMID: 8929745
[2] Lonsdale D (2006). A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid Based Complement Alternat Med, 3(1):49-59. doi: 10.1093/ecam/nek009
[3] Sánchez-Ramírez GM, et al (2006). Benfotiamine relieves inflammatory and neuropathic pain in rats. Eur J Pharmacol, 530(1-2):48-53. doi: 10.1016/j.ejphar.2005.11.016
[4] Hammes HP, et al (2003). Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med, 9(3):294-9. doi: 10.1038/nm834
[5] Fraser DA, et al (2012). Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations. Genes Nutr, 7(3):459-69. doi 10.1007/s12263-011-0252-8
[6] Alkhalaf A, et al (2012). Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy. PLoS One, 7(7):e40427. doi: 
10.1371/journal.pone.0040427

Vitamin C (Ascorbic Acid)

Scientific Name:
(5R)-[(1S)-1,2-Dihydroxyethyl]-3,4-dihydroxyfuran-2(5H)-one

COMMON NAME

Vitamin C | Ascorbic acid | Ascorbate


TOP BENEFITS OF VITAMIN C

Supports antioxidant defenses *

Supports general immune health *

Supports skin health *


WHAT IS VITAMIN C?

Vitamin C, also known as ascorbic acid/ascorbate, is a vitamin naturally found in a wide variety of fruit and vegetables, particularly citrus fruit (orange, grapefruit), peppers, broccoli, brussels sprouts, and strawberries, for example. Vitamin C is an essential vitamin because, unlike most animals, the human body is unable to synthesize vitamin C and must therefore obtain it from the diet. Vitamin C is a potent antioxidant and plays an important role in cellular antioxidant defenses. Vitamin C, in the form of ascorbate, is also a co-substrate for enzymes needed to produce collagen, carnitine, and the neurotransmitter dopamine [1–3].*


NEUROHACKER’S VITAMIN C SOURCING

Vitamin C is non-GMO and vegan.


VITAMIN C DOSING PRINCIPLES AND RATIONALE

Vitamin C is an essential nutrient, which means it can’t be produced by the body and must be obtained consistently through the diet, since it can’t be stored in the body. The recommended daily allowance (RDA) for vitamin C in non-smoking healthy adults is 75 mg for females and 90 mg for males. According to 2001-02 NHANES data the average intake is about 85 mg in females and 110 mg in males. But about 3 out of 10 adults consume less than the recommended amount, while persons in the top 10% of dietary intake would consume about 200 mg on average. Neurohacker believes vitamin C follows a threshold response (see Neurohacker Dosing Principles), which means the majority of functional benefits occur in a range between the RDA amount and the highest dietary intake. Some of the evidence for this threshold response is that plasma vitamin C concentration rises steeply at intakes between 30 and 100 mg a day, and immune cells (e.g., neutrophils, monocytes, and lymphocytes) become saturated at 100 mg daily [4]. We opted for a dose of vitamin C that, when added to what would be in an average diet, comfortably places a person at the high end of this threshold response range.*


VITAMIN C KEY MECHANISMS

Supports antioxidant defenses*

Free radical scavenger [1]

Supports antioxidant defenses [5]

Counters oxidative stress and oxidative cellular damage [1,5]


Supports brain function and cognition*

Supports memory and learning [6]

Supports cognitive health [6]

Supports L-DOPA synthesis [7]

Cofactor for dopamine-β-hydroxylase (which converts dopamine to noradrenaline) [2]

Supports dopamine signaling [8]

Supports noradrenaline signaling [9]

Influences glutamate signaling [10–12]

Influences serotonin (5-HT) signaling [13]

Supports acetylcholine signaling [9,14,15]

Supports the differentiation of neuronal progenitors [16]

Supports neuronal myelination [2,17–19]

Influences neuronal calcium channel activity [20]

Supports neuroendocrine signaling [21–26] 

Supports antioxidant defenses in the brain [5,27]

Supports neuroprotective functions [5,11,27–30]


Supports healthy immune function*

Supports general immune health [31,32] 

Supports innate immunity [4,33–35]

Supports adaptive immunity [4,33,35,36]


Supports skin health*

Supports skin antioxidant defenses [37]

Supports skin in adapting to UV radiation [38–40]

Supports collagen synthesis [41]

Supports elastin synthesis [42]


Supports a healthy mood*

Supports positive affect [5,27,43–47]


Supports healthy vascular function*

Supports endothelial nitric oxide synthase activity and NO production [48–50]


*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.


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