Vitamins

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

Pantothenic Acid (as calcium pantothenate)

Scientific Name:
Calcium 3-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido]propanoate

Overview:
Calcium Pantothenate is a synthetic form and a source of vitamin B5 (pantothenic acid) with nootropic actions. Vitamin B5 can improve concentration and benefit memory and learning.

Scientific Name:
Calcium 3-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido]propanoate

Mechanisms:

  • Vitamin B5 is used in the synthesis of coenzyme A (CoA), having a key role in energy metabolism[1]
  • Vitamin B5 is necessary for the synthesis of acetylcholine – increases neuroplasticity, and improves concentration and comprehension and reduces brain fog[1,2]
  • Synergistic with cholinergic compounds[1]
References

[1] Tahiliani AG, Beinlich CJ (1991). Pantothenic acid in health and disease. Vitam Horm, 46:165-228. doi: 10.1016/S0083-6729(08)60684-6
[2] Gold PE (2003). Acetylcholine: cognitive and brain functions. Neurobiol Learn Mem, 80(3):177. doi: 10.1016/j.nlm.2003.07.002

Niacin (as Niacinamide)

Scientific Name:
Pyridine-3-carboxamide

Overview:
Nicotinamide is the amide form of vitamin B3 (nicotinic acid / niacin) that is naturally synthesized in the body with neuroprotective and anti-inflammatory effects. Experimental evidence indicates that nicotinamide can decrease age-associated cognitive impairment.

Scientific Name:
Pyridine-3-carboxamide

Mechanisms:

  • Nicotinamide is part of two essential coenzymes for energy production and DNA repair – nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP)[1]
  • Anti-inflammatory activity[2]
  • Can prevent the death of cortical neurons exposed to oxidative agents[3]
  • Can have anxiolytic effects[4]
  • Inhibits the activity of sirtuins – proteins that play important roles in aging, cell death and inflammation – can decrease neurodegenerative and age-associated memory impairment[5]
References

[1] Belenky P, et al (2007). NAD+ metabolism in health and disease. Trends Biochem Sci, 32(1):12-9. doi: 10.1016/j.tibs.2006.11.006
[2] Niren NM (2006). Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review. Cutis, 77(1 Suppl):11-6. PMID: 16871774
[3] Hoane MR, et al (2006). Nicotinamide reduces acute cortical neuronal death and edema in the traumatically injured brain. Neurosci Lett, 408(1):35-9. doi: 10.1016/j.neulet.2006.07.011
[4] Möhler H et al (1979). Nicotinamide is a brain constituent with benzodiazepine-like actions. Nature, 278(5704):563-5. doi: 10.1038/278563a0
[5] Denu JM (2005). Vitamin B3 and sirtuin function. Trends Biochem Sci, 30(9):479-83. doi: 10.1016/j.tibs.2005.07.004

Folates

Folate 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

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)


Cardiovascular and cerebrovascular function

  • Downregulates homocysteine levels (protects cardiovascular function); synergistic with vitamin B6 and vitamin B12 (11–13)


Nutrient Synergies

  • 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.

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).

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

10. S. M. Henning, M. E. Swendseid, W. F. Coulson, Male Rats Fed Methyl- and Folate-Deficient Diets with or without Niacin Develop Hepatic Carcinomas Associated with Decreased Tissue NAD Concentrations and Altered Poly(ADP-ribose) Polymerase Activity. The Journal of Nutrition. 127 (1997), pp. 30–36.

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).


*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)

Methylcobalamin Common Names

Vitamin B12 | Methylcobalamin

Top Benefits of Methylcobalamin

  • Supports cellular metabolism*
  • Supports vascular function*
  • Supports methylation*

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 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 Methylcobalamin 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 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.

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

Methylcobalamin Dosing Principles and Rationale

Methylcobalamin 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).

Methylcobalamin Key Mechanisms

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) 

Cardiovascular and cerebrovascular function

  • Downregulates homocysteine levels (protects cardiovascular function); synergistic with vitamin B6 and folic acid (vitamin B9) (4–6)

Nutrient Synergies

  • Folate - Insufficient methylcobalamin slows 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.

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).

*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.

Biotin

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 inflammation and hair loss. 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 optimal biotin status than others. Biotin is an important 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 when we are using biotin to compliment a full B complex stack. Except for subsets of the population with rare genetic disorders that affect biotin metabolism, persons eating raw egg whites, and other rare situations, this low amount of biotin is sufficient to compliment a B complex stack. 

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 (1–3)
  • Biotin-dependent enzymes have important roles in pathways associated with gluconeogenesis, lipid catabolism, and branched chain amino acid catabolism (1–3)
  • Biotin regulates chromatin structure and gene expression (1, 2)

REFERENCES

1. L. Riveron-Negrete, C. Fernandez-Mejia, Mini Rev. Med. Chem. 17, 529–540 (2017).
2. D. M. Mock, J. Nutr. 147, 1487–1492 (2017).
3. L. Tong, Cell. Mol. Life Sci. 70, 863–891 (2013).

*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 B1 (Thiamine)

Vitamin B1 (Thiamine) Common Name

Thiamine | Thiamin

Top Benefits of Thiamine

  • Supports energy metabolism*
  • Supports metabolic health*
  • Supports antioxidant defenses*
  • Supports brain 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 medicines 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 included in formulas which include the B-complex of vitamins, since these vitamins have interrelated relationships in cellular energy production.

Thiamine is additive with benfotiamine—both have vitamin B1 activity. But, because of FDA labeling regulations, only thiamine can be listed on labels as having a daily value.

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

Thiamine Dosing Principles and Rationale

Depending on the goal of a formulation, the dose of thiamine used can vary. If we are using it in combination with benfotiamine—a nutrient with vitamin B1 activity—we opt for a much lower amount of thiamine. In general, benfotiamine has increased vitamin B1 activity in peripheral tissues like the brain, heart, liver, and muscles, but wouldn’t be expected to have as much activity in the stomach or intestines. Combining a small amount of thiamine HCL to benfotiamine captures the increased bioavailability in peripheral tissues that benfotiamine offers, while also getting the stomach/intestine vitamin B1 support from the thiamine HCL.

Thiamine Key Mechanisms 

Energy metabolism

  • Supports energy generation (ATP) from carbohydrate and sugar metabolism (1)

Cofactor in the pyruvate dehydrogenase complex

  • Thiamine pyrophosphate (TPP) is required as a cofactor in the E1 subunit of the pyruvate dehydrogenase (PDH) complex (1)
  • TPP is essential for the generation by the PDH complex of acetyl-CoA, used in the citric acid cycle to generate ATP (1)
  • TPP is essential for the generation by the PDH complex of nicotinamide adenine dinucleotide (NADH), required for the production of ATP (1)
  • Cofactor in the citric acid cycle (1)
  • TPP is required as a cofactor in the alpha-ketoglutarate dehydrogenase reaction of the citric acid cycle (conversion of alpha-ketoglutarate to succinyl-CoA) (1)
  • TPP is essential in propagating the citric acid cycle to generate ATP (1)

Cofactor in the pentose phosphate pathway

  • TPP is required as a cofactor in the transketolase reaction of the pentose phosphate pathway (PPP) (1)
  • 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 (1)
  • The PPP provides ribose-5-phosphate, an essential building block in nucleic acids (1)
  • 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) (1)

Antioxidant defenses

  • Participates in the synthesis of NADPH to be used in the recycling of the antioxidant glutathione (GSH) (1)

Brain function

  • Essential for the production by the pyruvate dehydrogenase complex of acetyl-CoA used for the production of acetylcholine (1)
  • The alpha-ketoglutarate dehydrogenase reaction of the citric acid cycle reaction has a role in maintaining glutamate and gamma-aminobutyric acid (GABA) levels (1)

Other mechanisms

  • Downregulates the production of advanced glycation end-products (AGEs) (2, 3)
  • Supports healthy blood pressure (4)
  • Supports healthy blood glucose levels (5)
  • Supports healthy insulin sensitivity (5)

REFERENCES

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

*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.


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

Inositol 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 synergistic, 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 synergy, 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 synergistic at this ratio, allowing for the use of lower doses of both.(1, 2) 

Inositol Key Mechanisms

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)

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) 

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)

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) 

Female fertility

  • Inositol derivatives are second messengers in the FSH signaling pathway (25)
  • Regulates oocyte maturation (26–29)
  • Supports ovary function (2, 9, 20, 30)

Gut microbiota

  • Regulates the composition of the gut microbiota (31)

Synergies

  • Lipoic acid, N-acetyl cysteine - healthy insulin sensitivity (19)
  • Selenium - healthy thyroid function (22)
  • Resveratrol - healthy metabolic profile (32)

REFERENCES

1. M. Minozzi, M. Nordio, R. Pajalich, Eur. Rev. Med. Pharmacol. Sci. 17, 537–540 (2013).
2. M. Nordio, E. Proietti, Eur. Rev. Med. Pharmacol. Sci. 16, 575–581 (2012).
3. B. Zhang, C. Gao, Y. Li, M. Wang, J. Ethnopharmacol. 214, 83–89 (2018).
4. B. Zhang et al., Mol. Nutr. Food Res. 61 (2017), doi:10.1002/mnfr.201600710.
5. V. Unfer, F. Facchinetti, B. Orrù, B. Giordani, J. Nestler, Endocr Connect. 6, 647–658 (2017).
6. F. Corrado et al., Diabet. Med. 28, 972–975 (2011).
7. A. Santamaria et al., Climacteric. 15, 490–495 (2012).
8. D. Giordano et al., Menopause. 18, 102–104 (2011).
9. E. Benelli, S. Del Ghianda, C. Di Cosmo, M. Tonacchera, Int. J. Endocrinol. 2016, 3204083 (2016).
10. L. Pkhaladze, L. Barbakadze, N. Kvashilava, Int. J. Endocrinol. 2016, 1473612 (2016).
11. A. D. Genazzani, C. Lanzoni, F. Ricchieri, V. M. Jasonni, Gynecol. Endocrinol. 24, 139–144 (2008).
12. R. A. Haeusler, T. E. McGraw, D. Accili, Nat. Rev. Mol. Cell Biol. 19, 31–44 (2018).
13. J. Larner, D. L. Brautigan, M. O. Thorner, Mol. Med. 16, 543–552 (2010).
14. A. Yap, S. Nishiumi, K.-I. Yoshida, H. Ashida, Cytotechnology. 55, 103–108 (2007).
15. N. T. Dang, R. Mukai, K.-I. Yoshida, H. Ashida, Biosci. Biotechnol. Biochem. 74, 1062–1067 (2010).
16. Y. Yamashita, M. Yamaoka, T. Hasunuma, H. Ashida, K.-I. Yoshida, J. Agric. Food Chem. 61, 4850–4854 (2013).
17. T. E. Roche et al., Prog. Nucleic Acid Res. Mol. Biol. 70, 33–75 (2001).
18. H. K. Ortmeyer, N. L. Bodkin, B. C. Hansen, J. Larner, J. Nutr. Biochem. 6, 499–503 (1995).
19. C. Paul, A. S. Laganà, P. Maniglio, O. Triolo, D. M. Brady, Gynecol. Endocrinol. 32, 431–438 (2016).
20. J. E. Nestler, D. J. Jakubowicz, P. Reamer, R. D. Gunn, G. Allan, N. Engl. J. Med. 340, 1314–1320 (1999).
21. S. Benvenga, A. Antonelli, Rev. Endocr. Metab. Disord. 17, 471–484 (2016).
22. M. Nordio, S. Basciani, Eur. Rev. Med. Pharmacol. Sci. 22, 2153–2159 (2018).
23. S. M. Ferrari et al., Eur. Rev. Med. Pharmacol. Sci. 21, 36–42 (2017).
24. M. Nordio, S. Basciani, Int. J. Endocrinol. 2017, 2549491 (2017).
25. P. Gloaguen, P. Crépieux, D. Heitzler, A. Poupon, E. Reiter, Front. Endocrinol. . 2, 45 (2011).
26. L. Ciotta et al., Eur. Rev. Med. Pharmacol. Sci. 15, 509–514 (2011).
27. T. T. Y. Chiu, M. S. Rogers, C. Briton-Jones, C. Haines, Hum. Reprod. 18, 408–416 (2003).
28. T. T. Y. Chiu et al., Hum. Reprod. 17, 1591–1596 (2002).
29. S. G. Vitale et al., Int. J. Endocrinol. 2016, 4987436 (2016).
30. S. Gerli, M. Mignosa, G. C. Di Renzo, Eur. Rev. Med. Pharmacol. Sci. 7, 151–159 (2003).
31. Y. Okazaki, A. Sekita, T. Katayama, Biomed Rep. 8, 466–474 (2018).
32. A. Malvasi et al., Clin. Ter. 168, e240–e247 (2017).

*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 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.

Neurohacker’s Calcium Pantothenate Sourcing

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

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

Calcium Pantothenate Dosing Principle and Rationale

Vitamin B5 generally has a wide dosing range, however, 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 very high amounts would be 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 dose 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 compliment 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)

 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.

*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.

Adenosylcobalamin (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)

Cardiovascular and cerebrovascular function

  • Downregulates homocysteine levels (protects cardiovascular function); synergistic with vitamin B6 and folic acid (vitamin B9) (4–6)

Nutrient Synergies

  • Folate - Insufficient cobalamin slows 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.

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).

*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 K2 (MK-7)

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 

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)
  • Protects from complex I-V inhibition (4–9)
  • Supplies complex III cofactors/substrates (10–12)
  • Protects from mitochondrial dysfunction (3, 4, 13)
  • Supports mitochondrial morphology (14)
  • Upregulates AMP-activated protein kinase (AMPK) signaling 24

Metabolism

  • Supports healthy insulin sensitivity (15–19)
  • Upregulates adiponectin levels 18,24 (18)
  • Upregulates uncoupling protein 1 (UCP-1) (18)

Exercise performance (ergogenic effect)

  • Supports endurance performance (20)
  • Protects from muscle cramps (21)
  • Supports post-exercise recovery (1, 2)

Skeletal system

  • Promotes the formation of bone (22, 23)

Cardiovascular function

  • Regulates blood coagulation (22, 23)
  • Protects from vascular calcification and arterial stiffening (22, 23)
  • Supports cardiac output (during exercise) (20)
  • Protects cardiac cells from hypoxia (4)

Cellular signaling

  • Downregulates the expression of proinflammatory mediators – nuclear factor (NF-κB), glycogen synthase kinase 3 beta (GSK-3β), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α) (13, 24, 25)

Antioxidant defenses

  • Downregulates the generation of reactive oxygen species (8, 13, 26)

Brain function

  • Protects neurons from neurotoxic agents and oxidative damage (8, 26)

Gut microbiota

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

REFERENCES

1. S. Eleff et al., Proc. Natl. Acad. Sci. U. S. A. 81, 3529–3533 (1984).
2. Z. Argov et al., Ann. Neurol. 19, 598–602 (1986).
3. M. Vos et al., Science. 336, 1306–1310 (2012).
4. V. Shneyvays, D. Leshem, Y. Shmist, T. Zinman, A. Shainberg, J. Mol. Cell. Cardiol. 39, 149–158 (2005).
5. F. A. Wijburg, C. J. de Groot, N. Feller, R. J. Wanders, J. Inherit. Metab. Dis. 14, 293–296 (1991).
6. J. M. Cooper, D. J. Hayes, R. A. Challiss, J. A. Morgan-Hughes, J. B. Clark, Brain. 115 ( Pt 4), 991–1000 (1992).
7. F. A. Wijburg, N. Feller, C. J. de Groot, R. J. Wanders, Biochem. Int. 22, 303–309 (1990).
8. N. K. Isaev, E. V. Stelmashook, K. Ruscher, N. A. Andreeva, D. B. Zorov, Neuroreport. 15, 2227–2231 (2004).
9. T. S. Chan et al., Free Radic. Res. 36, 421–427 (2002).
10. W. W. Anderson, R. D. Dallam, J. Biol. Chem. 234, 409–411 (1959).
11. R. E. Beyer, J. Biol. Chem. 234, 688–692 (1959).
12. C. E. Horth et al., Biochem. J. 100, 424–429 (1966).
13. Y.-X. Yu et al., Acta Pharmacol. Sin. 37, 1178–1189 (2016).
14. L. M. Baldoceda-Baldeon, D. Gagné, C. Vigneault, P. Blondin, C. Robert, Reproduction. 148, 489–497 (2014).
15. H. J. Choi et al., Diabetes Care. 34, e147 (2011).
16. M. Yoshida et al., Diabetes Care. 31, 2092–2096 (2008).
17. N. Sakamoto, T. Nishiike, H. Iguchi, K. Sakamoto, Clin. Nutr. 19, 259–263 (2000).
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).
23. J. W. J. Beulens et al., Br. J. Nutr. 110, 1357–1368 (2013).
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 B6 (Pyridoxal-5-Phosphate)

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*

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 compliment a full B complex stack.

Pyridoxal 5'-phosphate Key Mechanisms

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)

Hemoglobin synthesis

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

Brain/neurotransmitter function

  • P5P is required for the activity of 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, 6)
  • Since dopamine is a precursor for noradrenaline, P5P is required for its synthesis (5)
  • Since serotonin is a precursor for melatonin, P5P is required for its synthesis (6)
  • P5P is required for the activity of the enzyme glutamate decarboxylase, which  catalyzes the synthesis of gamma-aminobutyric acid (GABA) from glutamate (7)
  • P5P also participates in the metabolism of the neurotransmitters glycine, D-serine, and histamine (8)
  • Supports executive function, memory formation, mood regulation, focus, motivation, and sleep regulation (9, 10)

Cardiovascular and cerebrovascular function

  • Downregulates homocysteine levels (protects cardiovascular function); synergistic with vitamin B12 and folic acid (vitamin B9) (11–13)

REFERENCES

1. J. M. Berg, J. L. Tymoczko, G. J. Gatto, L. Stryer, Eds., Biochemistry (W.H. Freeman and Company, 8th ed., 2015).
2. Linus Pauling Institute Oregon State University, Vitamin B6, (available at https://lpi.oregonstate.edu/mic/vitamins/vitamin-B6).
3. A. A.-B. Badawy, Int. J. Tryptophan Res. 10, 1178646917691938 (2017).
4. G. A. Hunter, G. C. Ferreira, Biochim. Biophys. Acta. 1814, 1467–1473 (2011).
5. M. E. Gnegy, in Basic Neurochemistry (Eighth Edition), S. T. Brady, G. J. Siegel, R. W. Albers, D. L. Price, Eds. (Academic Press, New York, 2012), pp. 283–299.
6. J. G. Hensler, in Basic Neurochemistry (Eighth Edition), S. T. Brady, G. J. Siegel, R. W. Albers, D. L. Price, Eds. (Academic Press, New York, 2012), pp. 300–322.
7. O. A. C. Petroff, Neuroscientist. 8, 562–573 (2002).
8. P. T. Clayton, J. Inherit. Metab. Dis. 29, 317–326 (2006).
9. J. B. Deijen, E. J. van der Beek, J. F. Orlebeke, H. van den Berg, Psychopharmacology . 109, 489–496 (1992).
10. M. Ebadi, Neurochem. Int. 3, 181–205 (1981).
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).

*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.

Niacinamide (Vitamin B3)

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. The NAD molecule sits at the crossroads of mitochondrial energy production, cellular repair and signaling, and cellular defenses. Niacinamide makes NAD via the salvage 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 have anti-aging and protective effects.

Neurohacker’s Niacinamide Sourcing

Niacinamide is additive with other ingredients with niacin-like activity (such as niacin 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.

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)

Anti-aging

  • 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)

Neuroprotection

  • Protects neuronal cells against ischemia and oxidative stress (9, 10)

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).

*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 B2 (Riboflavin)

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 in bright yellow-orange in color and is what gives B-complex vitamins there 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 is included in formulas which include the B-complex of vitamins, since these vitamins have interrelated relationships in cellular energy production.

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

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 

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)

NAD+ production

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

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)

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)

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.

*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.



Niacin

NIACIN 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 *


WHAT IS NIACIN?

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)


Healthy aging and longevity

  • Influences lifespan, senescence, cell proliferation, apoptosis (1)
  • NAD+ is a substrate for sirtuins (SIRT1 to SIRT7), 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)


Neuroprotection

  • Protects neuronal cells against ischemia and oxidative stress (9, 10)


Cardiovascular function

  • Supports healthy blood cholesterol and triglyceride levels (11–16)
  • Protects vascular function  (13–17)


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).

*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 D3 (Cholecalciferol)

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

Overview:
Cholecalciferol is a form of vitamin D (vitamin D3) with antioxidant and neuroprotective effects. Research indicates that it may contribute to delaying neurodegenerative and age-associated cognitive decline.

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

Mechanisms:

  • Cholecalciferol is an inactive form that is converted by the liver and kidneys to the active form calcitriol[1]
  • The effects of calcitriol are mediated via the vitamin D receptor (VDR)[1]
  • VDR is found in the substantia nigra, cerebellum, thalamus, hypothalamus, basal ganglia, and hippocampus[2]
  • Regulates NGF, and GDNF synthesis – neuronal survival and growth[3]
  • Upregulation of NT-3 – enhanced neuronal communication and synaptic plasticity[3]
  • Antioxidant properties – inhibits inducible nitric oxide synthase (iNOS) and increases glutathione.[4,5]
  • Facilitates calcium absorption[6]
References

[1] Christakos S, et al (2016). Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev, 96(1):365-408. doi: 10.1152/physrev.00014.2015
[2] Harms LR, et al (2011). Vitamin D and the brain. Best Pract Res Clin Endocrinol Metab, 25(4):657-69. doi: 10.1016/j.beem.2011.05.009
[3] Shirazi HA, et al (2015). 1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation. Exp Mol Pathol, 98(2):240-5. doi: 10.1016/j.yexmp.2015.02.004
[4] d’Uscio LV, et al (2003). Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res, 92(1):88-95. doi: 10.1161/01.RES.0000049166.33035.62
[5] Alvarez JA, et al (2014). Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults. Clin Endocrinol (Oxf), 81(3):458-66. doi: 10.1111/cen.12449
[6] Christakos S, et al (2011). Vitamin D and intestinal calcium absorption. Mol Cell Endocrinol, 347(1-2):25-9. doi: 10.1016/j.mce.2011.05.038

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

Overview:
Ascorbic acid is a naturally occurring essential vitamin with strong neuroprotective and antioxidant effects. Ascorbic acid is able to decrease fatigue and improve mood.

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

  • Crosses the blood brain barrier and accumulates most significantly in the hippocampus cerebellum and in the frontal and parietal cortices[1]
  • Is a cofactor for dopamine-β-hydroxylase – optimizes the production of dopamine, adrenaline and noradrenaline[2]
  • Is a cofactor in the production of the hormones oxytocin, vasopressin and α-Melanocyte-stimulating hormone[3]
  • NMDA glutamate receptor inhibition – neuroprotection against excitotoxicity[4]
  • Potent antioxidant activity by binding free radicals and increasing antioxidant enzymes’ production[5]
  • Increases blood flow by reducing NO oxidation[6]
  • Synergistic with potassium channel blockers[7]
References

[1] Spector R (1977). Vitamin homeostasis in the central nervous system. N Engl J Med, 296(24):1393-8. doi: 10.1056/NEJM197706162962409
[2] Kuo CH, et al (1979). Effect of ascorbic acid on release of acetylcholine from synaptic vesicles prepared from different species of animals and release of noradrenaline from synaptic vesicles of rat brain. Life Sci, 24(10):911-5. doi: 10.1016/0024-3205(79)90341-2
[3] Wilson LG (1975). The clinical definition of scurvy and the discovery of vitamin C. J Hist Med Allied Sci, 30(1):40-60. doi: 10.1093/jhmas/XXX.1.40
[4] Majewska MD, Bell JA (1990). Ascorbic acid protects neurons from injury induced by glutamate and NMDA. Neuroreport, 1(3-4):194-6. PMID: 1983355
[5] Figueroa-Méndez R, Rivas-Arancibia S (2015). Vitamin C in Health and Disease: Its Role in the Metabolism of Cells and Redox State in the Brain. Front Physiol, 6:397. doi: 10.3389/fphys.2015.00397
[6] Heller R, et al (2001). L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem, 276(1):40-7. doi: 10.1074/jbc.M004392200
[7] Moretti M, et al (2012). Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. 46(3):331-40. doi: 10.1016/j.jpsychires.2011.11.009