Patients with MTHFR and methylation issues require a unique approach. The standard products on the

market may not be suitable for those with specific issues and therefore a more targeted programme is

required.

The ability to split your B vitamins is desirable as each patient will have a different need and this allows you

to tailor to the individual patient.

What is methylation?

Methylation or one carbon metabolism is a network of interrelated biochemical pathways for reduction or

oxidation and transfer to other compounds. This allows the transfer of a methyl group (one carbon and

three hydrogen atoms) onto amino acids, proteins, enzymes and DNA in every cell and tissue of the body.

This regulates healing, produces energy, genetic expression of DNA, synthesises neurotransmitters, liver

detoxification, immunity and hormonal clearance. So disturbances in this methylation pathway can have

significant and widespread effects on many body systems.

The key pathways are the folate pathway (of which the MTHFR gene is a crucial final step), the methionine

pathway which plays a major role in methyl group metabolism as it allows the recycling of homocysteine

back to methionine and elimination via the CBS (Cystathione beta synthase pathway). The methionine

synthase enzyme contains a cobalamin cofactor 2 which ensures that with the help of Vitamin B12 the

methyl group is transferred to homocysteine. Methionine, which is regenerated from homocysteine is then

converted to S-adenosylmethionine (AdoMET). AdoMet then donates the methyl group it obtained from 5-

MTHF to over 80 biological methylation reactions, including the methylation of DNA, RNA, proteins, lipids

and lipoproteins. The key methyltransferases are the enzyme groups that benefit from this donation of

methyl’s by AdoMET.

What is MTHFR?

MTHFR is a gene, which produces the MTHFR (methylenetetrahydrofolate reductase) enzyme and is

considered a key enzyme in one-carbon metabolism, because it catalyses the irreversible conversion of

5,10-methylene THF to 5-methyl tetrahydrofolate.1 5-MTHF is our active folate that is then used in the

methylation cycle.

Folate Metabolism

http://www.aacc.org/publications/cln/2011/january/Pages/FolateMetabolismFigure.aspx

What happens if MTHFR activity is reduced?

1. 5-MTHF levels go down 2. Transmethylation cycle slows 3. All tissues except liver and kidney show effects of decreased methylation which leads to:

- Decreased neurotransmitter production - Deficiency in glutathione

4. BHMT becomes depleted in choline which causes:

homocysteine levels to rise

methylation in the liver and kidneys decrease

phosphatidylcholine production drops causing cell membrane and myelin instability

This may then have affects for the following conditions:

Diabetes

Cancer

Pulmonary embolisms

Cleft palate

Spina Bifida

Autism

Parkinson’s Disease

Neural tube defects

Cardiovascular disease – atherosclerosis, elevated cholesterol, hypertension, fat metabolism issues

Immune deficiency

ADD/ADHD

MS

Alzheimer’s

Chemical sensitivity

Congenital Heart defects

Fibromyalgia

Chronic fatigue syndrome

Depression

Alcoholism

Addictive behaviours

Insomnia

Downs syndrome

Autism

Chronic viral infection

Thyroid dysfunction

Neuropathy

Recurrent miscarriage

Infertility

Anxiety

Schizophrenia

Bipolar

Allergies

References

1. Selhub.J Homocysteine metabolism. Annu.Rev.Nutr. 19,217,1999

2. Weissbach. H and Taylor RT. Roles of Vitamin B12 and folic acid in methionine synthesis. Vitam. Horm. 28, 415, 1970.

3.Robinson K, Mayer EL, et al. Hyperhomocysteinemia and low pyridoxal phosphate: common and independent reversible risk

factors for coronary artery disease. Circulation. 1995; 92:2825-2830.

4. Homocysteine and Risk of Ischemic Heart Disease and Stroke A Meta-analysis

Homocysteine Studies Collaboration. JAMA. 2002;288(16):2015-2022. doi:10.1001/jama.288.16.20

5. Tungtrongchitr R, Pongpaew P, Prayurahong B, et al: Vitamin B12, folic acid and haematological status of 132 Thai vegetarians.

Int J Vitam Nutr Res 1993; 63:201-207

Starter B & Methylation Support

Specific Indication: Step 1 in methylation support. Initial support for people with the MTHFR gene

mutation to aid, assist in or help support as a cofactor for key enzymes in the methylation cycle (Figure 1).

Pharmaceutical Effects: Starter B contains six B vitamins without Vitamin B12 or folate.

Clinical Benefits: The B vitamins all act as cofactors in the methylation cycle to support critical enzymes

integral to the pathway.

Thiamin (B1) and Pyridoxine (B6) are confirmed by human clinical trials to work together to cause a

decrease in DNA glycation. 1-3Human studies show that the effect of Thiamin decreasing DNA glycation

results in higher levels of methylation.2,3

Riboflavin (B2) acts as a cofactor for folate and so increases methylation. It is the limiting nutrient for

pyridoxine folate and B12 metabolism.2,3,4 It can also assist niacin in reducing excessive DNA methylation.2

It is the cofactor for the MTHFR gene.

Niacin (nicotinamide, B3) and its derivative nicotinamide are dietary precursors of nicotinamide adenine

dinucleotide (NAD). NAD functions in oxidation-reduction (redox) reactions and non-redox reactions. 11

NAD is an important cofactor for MTRR (methionine synthase reductase) enzyme.

http://lpi.oregonstate.edu/mic/vitamins/vitamin-B6

Figure 1. B vitamins & step 1 in methylation support & one-carbon metabolism.

Pantothenic acid (B5) is confirmed by human clinical trials to improve the nutritional and metabolic status

of the genome including DNA methylation,16,17 particularly for mental health in adults and psychology in

children. 18,19,20

Pyridoxine (B6) is confirmed by human clinical trials to increase DNA methylation levels and work together

with riboflavin, folate, and B12. 21,22Deficiency of Pyridoxine in animals results in reduction of DNA

methylation. 23,24 B6 is an important cofactor for the CBS pathway.

Biotin (B7) is confirmed by human clinical trials to be related to folate in its DNA methylation functions16,25.

It works with other vitamins, such as pantothenic acid, riboflavin, niacin, pyridoxine, folate and B12, to play

essential roles in maintaining mitochondrial functions including DNA methylation.2

All doses are safe according to the Australian RDI and the U. S. DRI.

References

1Polizzi FC, Andican G, Çetin E, Civelek S, Yumuk V, Burçak G. Increased DNA-glycation in type 2 diabetic patients: the effect of thiamine and pyridoxine therapy. Experimental and clinical endocrinology & diabetes, June 2012, 120(6), 329-34. PubMed PMID: 22231921

2 Schupp N, Dette EM, Schmid U, Bahner U, Winkler M, Heidland A, Stopper H. Benfotiamine reduces genomic damage in peripheral lymphocytes of hemodialysis patients. Naunyn-Schmiedeberg's archives of pharmacology, September 2008, 378(3), 283-91. PubMed PMID: 18509620

3 Schupp N, Schmid U, Heidland A, Stopper H. New approaches for the treatment of genomic damage in end-stage renal disease. Journal of renal nutrition, January 2008, 18(1), 127-33. PubMed PMID: 18089459

4 Maslinska D, Laure-Kamionowska M, Maslinski S. Methyl-CpG binding protein 2, receptors of innate immunity and receptor for advanced glycation end-products in human viral meningoencephalitis. Folia neuropathologica, 2014, 52(4), 428-35. PubMed PMID: 25574748

5 Lu W, Li J, Ren M, Zeng Y, Zhu P, Lin L, Lin D, Hao S, Gao Q, Liang J, Yan L, Yang C. Role of the mevalonate pathway in specific CpG site demethylation on AGEs-induced MMP9 expression and activation in keratinocytes. Molecular and cellular endocrinology, August 2015, 15(411), 121-129. PubMed PMID: 25916956

6 Powers HJ, Hill MH, Welfare M, Spiers A, Bal W, Russell J, Duckworth Y, Gibney E, Williams EA, Mathers JC. Responses of biomarkers of folate and riboflavin status to folate and riboflavin supplementation in healthy and colorectal polyp patients (the FAB2 Study). Cancer epidemiology, biomarkers & prevention, October 2007, 16(10), 2128-35. PubMed PMID: 17932361

7 Figueiredo JC, Levine AJ, Grau MV, Midttun O, Ueland PM, Ahnen DJ, Barry EL, Tsang S, Munroe D, Ali I, Haile RW, Sandler RS, Baron JA. Vitamins B2, B6, and B12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementation. Cancer epidemiology, biomarkers & prevention, August 2008, 17(8), 2136-45. PubMed PMID: 18708408

8Nedrebø BG, Hustad S, Schneede J, Ueland PM, Vollset SE, Holm PI, Aanderud S, Lien EA. Homocysteine and its relation to B-vitamins in Graves' disease before and after treatment: effect modification by smoking. Journal of internal medicine, November 2003, 254(5), 504-12. PubMed PMID: 14535973

9Madigan SM, Tracey F, McNulty H, Eaton-Evans J, Coulter J, McCartney H, Strain JJ. Riboflavin and vitamin B-6 intakes and status and biochemical response to riboflavin supplementation in free-living elderly people. American journal of clinical nutrition, August 1998, 68(2), 389-95. PubMed PMID: 9701198

10Premkumar VG, Yuvaraj S, Shanthi P, Sachdanandam P. Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy. British journal of nutrition, December 2008, 100(6), 1179-82. PubMed PMID: 18377693

11Penberthy WT, Kirkland JB. Niacin. In:Erdman JW, MacDonald I, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Ames: International

Life Sciences Institute;2012:293-306

12Sun WP, Li D, Lun YZ, et al. Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives. Hypertension Research. 2012 Feb; 35(2): 180-5. PubMed PMID: 21918528.

13Aoyama K, Matsubara K, Okada K, et al. N-methylation ability for azaheterocyclic amines is higher in Parkinson's disease: nicotinamide loading test. Journal of Neural Transmission (Vienna). 2000; 107(8-9): 985-95. PubMed PMID: 11041277.

14Jacob RA, Pianalto FS, Henning SM, Zhang JZ, & Swendseid ME. In vivo methylation capacity is not impaired in healthy men during short-term dietary folate and methyl group restriction. Journal of Nutrition. 1995 Jun; 125(6): 1495-502. PubMed PMID: 7782903.

15Okada K., Matsubara K., Kobayashi S., et al. 275 Abnormal N-methylation of nicotinamide in Parkinson's disease. Neurobiology of Aging, 1996, 17(4), Supplement 1, S69. Retrieved from http://www.neurobiologyofaging.org/article/S0197-4580(96)80277-6/abstract

16Fenech M, Baghurst P, Luderer W, Turner J, Record S, Ceppi M, Bonassi S. Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, beta-carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genome instability--results from a dietary intake and micronucleus index survey in South Australia. Carcinogenesis, May 2005, 26(5), 991-9. PubMed PMID: 15705599

17Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W. Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatrics, December 2011, 11, 111. PubMed PMID: 22151477

18Herbison CE, Hickling S, Allen KL, O'Sullivan TA, Robinson M, Bremner AP, Huang RC, Beilin LJ, Mori TA, Oddy WH. Low intake of B-vitamins is associated with poor adolescent mental health and behaviour. Preventive Medicine, December 2012, 55(6), 634-638. PubMed PMID: 23010437

19Rucklidge JJ, Harris AL, Shaw IC. Are the amounts of vitamins in commercially available dietary supplement formulations relevant for the management of psychiatric disorders in children? New Zealand Medical Journal, April 2014, 127(1392), 73-85. PubMed PMID: 24806250

20Uchida Y, Ito K, Ohtsuki S, Kubo Y, Suzuki T, Terasaki T. Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells. Journal of Neurochemistry, July 2015, 134(1), 97-112. PubMed PMID: 25809983

21Pirouzpanah S, Taleban FA, Mehdipour P, Atri M. Association of folate and other one-carbon related nutrients with hypermethylation status and expression of RARB, BRCA1, and RASSF1A genes in breast cancer patients. Journal of molecular medicine (Berlin, Germany), August 2015, 93(8), 917-34. PubMed PMID: 25805039

22Maruti SS, Ulrich CM, White E. Folate and one-carbon metabolism nutrients from supplements and diet in relation to breast cancer risk. American journal of clinical nutrition, February 2009, 89(2), 624-33. PubMed PMID: 19116331

23Martinez M, Cuskelly GJ, Williamson J, Toth JP, Gregory JF 3rd. Vitamin B-6 deficiency in rats reduces hepatic serine hydroxymethyltransferase and cystathionine beta-synthase activities and rates of in vivo protein turnover, homocysteine remethylation and transsulfuration. Journal of Nutrition, May 2000, 130(5), 1115-23. PubMed PMID: 10801907

24Eloranta TO, Kajander EO, Raina AM. A new method for the assay of tissue. S-adenosylhomocysteine and S-adenosylmethione. Effect of pyridoxine deficiency on the metabolism of S-adenosylhomocysteine, S-adenosylmethionine and polyamines in rat liver. Biochemical journal, November 1976, 160(2), 287-94. PubMed PMID: 1008858

25Xue J, Zempleni J. Epigenetic synergies between biotin and folate in the regulation of pro-inflammatory cytokines and repeats. Scandinavian journal of immunolog, November 2013, 78(5), 419-25. PubMed PMID: 24007195

26Depeint F, Bruce WR, Shangari N, Mehta R, O'Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chemico-biological interactions, October 2006, 163(1-2), 94-112. PubMed PMID: 16765926

Hydroxocobalamin & Methylation Support

Specific Indication: Step 2 in methylation support.

Pharmaceutical Effects: Precursor to Active B12's – methylcobalamin & adenosylcobalamin

Clinical Benefits:

Provides a stable and naturally occurring form of Vitamin B12 Converts to both methylcobalamin and adenosylcobalamin. May support the methylation cycle without causing side effects

Particularly important for those with adenosylcobalamin SNP’s – MMAB, MUT

Chewable form for better absorption Easily taken by children

Hydroxocobalamin is a naturally occurring form of Vitamin B12. It is a precursor molecule for

methylcobalamin and adenosylcobalamin. In the human body, hydroxocobalamin is converted to

cobalamin that is readily absorbed in the gut. One of the important functions of hydroxocobalamin in the

body is conversion of homocysteine into the essential amino acid methionine2 . It is also required for

proper functioning in of the nervous system and energy generation for cellular activities.

Role of Hydroxocobalamin as a Cofactor

The cobalamin or Vitamin B12 is one of the essential nutrients required for integral functions. It usually

works with folate to carry out chromosomal replication and DNA synthesis in myeloid cells and bone

marrow. Similarly, its role is also well established in maintaining the integrity and stability of the myelin

sheath on nerve cells4 . Vitamin B12 deficiency directly impacts the nerve cells impairing cognitive and

psychological capabilities. It also coverts methymalonic acid to another compound namely succinate.

Succinate further helps in linking carbohydrate and lipid metabolism in the body for energy generation5. In

the cytosol, due to methylation processes hydroxocobalamin is converted into methylcobalamin. But in

many instances, the reduction reaction in the presence of ATP results in the generation of

adenosylcobalamin.

Prescription as a Therapeutic Agent

Hydroxocobalamin has shown high affinity for the cyanide molecule and reacts with any cyanide molecules

by pulling them out of the mitochondria. The reaction of cyanide and hydroxocobalamin results in

production of cyanocobalamin which can easily be excreted through urine resulting in detoxification .

One very important function of hydroxocobalamin is its role as a scavenger of nitric oxide and its

derivatives. Many studies have indicated that hydroxocobalamin is in fact the only form of Vitamin B12

that reduces the cellular toxicity of nitric oxide by neutralizing its damage and toxicity of cellular functions.

The core atom of hydroxocobalamin, Cobalt (III) interacts with nitric oxide neutralising the toxicity.

Nitric acid functions as a muscle regulator but due to a number of circumstances increases in levels leads

to discomfort and swelling in the neural cells. In one study, the utilization of hydroxocobalamin was seen

to significantly reduce the occurrence, frequency and severity of migraines .

References:

1Hall CA, Begley JA, Green-Colligan PD. The availability of therapeutic hydroxocobalamin to cells. Blood. 1984 Feb; 63(2): 335-41. PMID: 6692038.

2Andrès E, Fothergill H, Mecili M. Efficacy of oral cobalamin (vitamin B12) therapy. Expert opinion on pharmacotherapy. 2010 Feb; 11(2): 249-56. PMID:

20088746.

3Carrillo-Carrasco N, Sloan J, Valle D, Hamosh A, Venditti CP. Hydroxocobalamin dose escalation improves metabolic control in cblC. Journal of inherited

metabolic disease. 2009 Oct; 32(6): 728-31. PMCID: PMC3479241.

4Hamel J. A review of acute cyanide poisoning with a treatment update. Critical care nurse. 2011 Feb; 31(1): 72-82. PMID: 21285466.5Seetharam B, Yammani RR.

Cobalamin transport proteins and their cell-surface receptors. Expert reviews in molecular medicine. 2003 Jun; 5(18): 1-18. PMID: 14585166.

6Andrès E, Fothergill H, Mecili M. Efficacy of oral cobalamin (vitamin B12) therapy. Expert opinion on pharmacotherapy. 2010 Feb; 11(2): 249-56. PMID: 20088746. 7Bhattacharya R. Antidotes to cyanide poisoning: present status. Indian Journal of Pharmacology. 2000; 32(2): 94-101. 8Shepherd G, Velez LI. Formulary Forum: Role of Hydroxocobalamin in Acute Cyanide Poisoning. Annals of Pharmacotherapy. 2008 May; 42(5): 661-9. PMID: 18397973. 9Sauer SW, Keim ME. Hydroxocobalamin: improved public health readiness for cyanide disasters. Annals of emergency medicine. 2001 Jun; 37(6): 635-41. PMID: 11385334. 10DesLauriers CA, Burda AM, Wahl M. Hydroxocobalamin as a cyanide antidote. American journal of therapeutics. 2006; 13(2): 161-165. 11Greenberg SS, Xie J, Zatarain JM, Kapusta DR, Miller MJ. Hydroxocobalamin (vitamin B12a) prevents and reverses endotoxin-induced hypotension and mortality in rodents: role of nitric oxide. Journal of Pharmacology and Experimental Therapeutics. 1995 Apr; 273(1): 257-265. PMID: 7714773. 12DesLauriers CA, Burda AM, Wahl M. Hydroxocobalamin as a cyanide antidote. American journal of therapeutics. 2006; 13(2): 161-165.

Methylcobalamin & Methylation Support

Specific Indication: Step 2 in methylation support.

Pharmaceutical Effects: Active B12

Clinical Benefits:

Critical coenzyme required for methylation through methionine Synthase4 Plays an important role in developing cognitive ability by regulating the myelin sheath and basic structure of nerve cells Only cobalamin compound that regulates the sleep wake cycle. Is directly utilised by enzymes that are dependent on Vitamin B12 for their functioning i.e.: methionine synthase.4 Chewable form for better absorption Easily taken by children

Methylcobalamin also referred to as MeB12 and MeCbl is another compound of the cobalamin family. It is

one of the naturally occurring coenzyme forms of cobalamin found in the human body.1-3

Hydroxocobalamin is metabolised into adenosylcobalamin and methylcobalamin. According to estimates,

almost 80% of cobalamin present in body is in the form of methylcobalamin.

Important Functions of Methylcobalamin

Plays an important role in developing cognitive ability by regulating the myelin sheath and basic structure

of nerve cells.

Only cobalamin compound that regulates the sleep wake cycle. It improves the overall quality of sleep and

helps in developing nerve cells by maintaining the circadian rhythms. Due to its deficiency, the sleep wake

cycle is greatly disturbed leading to symptoms such as agitation, anxiety, restlessness and distress.

Methylcobalamin is one of the coenzymes that is directly utilized by enzymes which are dependent on

vitamin B12 for their functioning. Methionine synthase specifically utilises methylcobalamin as a cofactor

in their reactions4

Acetyl-CoA is one of the basic compounds required by a number of organisms to produce complex organic

derivatives for different reactions and pathways. A reduced level of methylcobalamin can prompt subacute

spinal cord degeneration and megaloblastic iron deficiency4.

Analgesic Effect of Methyl Cobalamin

a. Neuropathic Pain in Diabetic Neuropathy

One of the important clinical benefits of methylcobalamin is inhibiting pain connected with diabetic

neuropathy. The neuropathic pain has been described as burning and aching irritation which increases the

sensitivity of the skin7.. The clinical trials have indicated that methylcobalamin may reduce the occurrence

and frequency of neuropathic pain associated with diabetes8. The oral use of methylcobalamin reduces

intensity of pain by improving overall velocity of nerve impulses and conduction. The studies have

observed the reduction in overall pain scale score in neuropathic pain after consumption of methyl

cobalamin. After four weeks of injectable methylcobalamin, 73% reduction in pain symptoms were

observed through Likert-type pain intensity scale. The researchers identified improved sensory and motor

nerve impulses and velocity through consumption of methylcobalamin indicating its significant role as

analgesic9.

b. Neuralgia

The action of methylcobalamin has also been reported to ease pain associated with different neuralgia.

Considerable reduction in pain values was observed in trigeminal neuralgia, facial neuralgia, sub-acute

herpetic neuralgia and glossopharyngeal neuralgia10. Intravenous injection of methylcobalamin greatly

reduces the symptoms of pain in trigeminal neuralgia11. It not only reduces the pain symptoms but may

also improves quality of life13. It may also improve the velocity of nerve conduction thus acting as an

analgesic in many neuropathies8.

References

1 Rossi M, Glusker JP, Randaccio L, Summers MF, Toscano PJ, Marzilli LG. The structure of a B12 coenzyme: methylcobalamin studies by X-ray and NMR methods. Journal of the American Chemical Society. 1985 March; 107(6): 1729-38. 2Xu G, Lv ZW, Feng Y, Tang WZ, Xu GX. A Single‐Center Randomized Controlled Trial of Local Methylcobalamin Injection for Subacute Herpetic Neuralgia. Pain Medicine. 2013 Jun; 14(6): 884-94. PMID: 23566267. 3Okada K, Tanaka H, Temporin K, Okamoto M, Kuroda Y, Moritomo H, Murase T, Yoshikawa, H. Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model. ). Experimental neurology. 2010 Apr; 222(2), 191-203. PMID: 20045411. 4Okada K, Tanaka H, Temporin K, Okamoto M, Kuroda Y, Moritomo H, Murase T, Yoshikawa, H. Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model. ). Experimental neurology. 2010 Apr; 222(2), 191-203. PMID: 20045411. 5Xu G, Lv ZW, Feng Y, Tang WZ, Xu GX. A Single‐Center Randomized Controlled Trial of Local Methylcobalamin Injection for Subacute Herpetic Neuralgia. Pain Medicine. 2013 Jun; 14(6): 884-94. PMID: 23566267. 6Jensen KP, Ryde, U. Conversion of homocysteine to methionine by methionine synthase: A density functional study. Journal of the American Chemical Society. 2003 Nov; 125(46): 13970-71. PMID: 14611228. 7Li G. [Effect of mecobalamin on diabetic neuropathies. Beijing Methycobal Clinical Trial Collaborative Group]. Zhonghua Nei Ke Za Zhi. 1999 Jan; 38(1): 14-7. PMID: 11798619. 8Devathasan G, Teo WL, Mylvaganam A. Methylcobalamin (CH3-B12; Methycobal) in chronic diabetic neuropathy. A double-blind clinical and electrophysiological study. 1986. 9Dongre YU, Swami OC. Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience. International Journal General Medicine. 2013 May; 6. 413-7. PMID: 23761981. 10Singh PM, Dehran M, Mohan VK, Trikha A, Kaur M. Analgesic efficacy and safety of medical therapy alone vs. combined medical therapy and extraoral glossopharyngeal nerve block in glossopharyngeal neuralgia. Pain Medicine. 2013 Jan; 14(1): 93-102. PMID: 23279193.

11Xu G, Lv ZW, Feng Y, Tang WZ, Xu GX. A Single‐Center Randomized Controlled Trial of Local Methylcobalamin Injection for Subacute Herpetic Neuralgia. Pain Medicine. 2013 Jun; 14(6): 884-94. PMID: 23566267. 12Singh PM, Dehran M, Mohan VK, Trikha A, Kaur M. Analgesic efficacy and safety of medical therapy alone vs. combined medical therapy and extraoral glossopharyngeal nerve block in glossopharyngeal neuralgia. Pain Medicine. 2013 Jan; 14(1): 93-102. PMID: 23279193. 13Teramoto J. Effects of Methylcobalamin on neuralgia. Neurological Therapeutics. 1984; 1(2): 315. 14Okada K, Tanaka H, Temporin K, Okamoto M, Kuroda Y, Moritomo H, Murase T, Yoshikawa, H. Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model. ). Experimental neurology. 2010 Apr; 222(2), 191-203. PMID: 20045411. 15Watanabe T, Kaji R, Oka N, Bara W, Kimura J. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. Journal of the neurological sciences. 1994 Apr; 122(2): 140-3. PMID: 8021696. 16Jensen KP, Ryde, U. Conversion of homocysteine to methionine by methionine synthase: A density functional study. Journal of the American Chemical Society.

2003 Nov; 125(46): 13970-71. PMID: 14611228.

Total B (methyl) & Methylation Support

Specific Indication: Step 3 in methylation support. Multi B with active methyl folate and methyl B12

support and assist in methylation reactions (Figure 1).

Pharmaceutical Effects: Total B contains eight B vitamins with methylcobalamin and methyl folate.

Clinical Benefits:

Supports critical enzymes in the methylation cycle Contains Metafolin form of L-5MTHF for superior absorption and stability Low excipients Vegan and vegetarian friendly No corn, soy, gluten, dairy, egg, GMO

Thiamin (B1) and Pyridoxine (B6) are confirmed by human clinical trials to work together to decrease DNA

glycation,1-3 which increases higher levels of methylation.4,5

Riboflavin (B2) enhances the effect of low-dose folate by increasing methylation reactions of other

vitamins such as pyridoxine, folate and B12.6,7,8,9

Niacin (nicotinamide, B3) and its derivative nicotinamide are dietary precursors of nicotinamide adenine

dinucleotide (NAD). NAD functions in oxidation-reduction (redox) reactions and non-redox reactions. 11

NAD is an important cofactor for MTRR (methionine synthase reductase) enzyme.

Pantothenic acid (B5) is confirmed to improve DNA methylation,15,16 particularly for mental health.17,18,19

Pyridoxine (B6) increases DNA methylation levels and works together with riboflavin, folate, and B12.20,21

Deficiency causes reduced DNA methylation.22,23

Biotin (B7) is related to folate in its DNA methylation functions.16,24 It works with other vitamins on

mitochondrial functions and DNA methylation.25

Folate (L-5-MTHF) increases genome and other DNA methylation in healthy patients26-29.

Oral folate will not cause excessive DNA methylation.30 The folate effect of increasing DNA methylation can

reduce homocysteine levels31. 5-MTHF, works faster, more efficient, is safer, crosses the blood brain

barrier and does not mask a Vitamin B12 deficiency.32,34,35

Methylcobalamin (Methyl B12) maintains a desirably high degree of genome DNA methylation.36,37. B12

deficiency can reduce genome DNA methylation in the body up to 2 folds.38-40It works with folate to reduce

homocysteine level.41,42

Metafolin (L (6S)-5-MTHF) is a calcium. As a crystalline type I form it has solid stability, is soluble in water.33

All doses are safe according to the Australian RDI and the U. S. DRI

Figure 1. B vitamins & step 3 in methylation support & one-carbon metabolism.

References

1 Polizzi FC, Andican G, Çetin E, Civelek S, Yumuk V, Burçak G. Increased DNA-glycation in type 2 diabetic patients: the effect of thiamine and pyridoxine therapy. Experimental and clinical endocrinology & diabetes, June 2012, 120(6), 329-34. PubMed PMID: 22231921

2Schupp N, Dette EM, Schmid U, Bahner U, Winkler M, Heidland A, Stopper H. Benfotiamine reduces genomic damage in peripheral lymphocytes of hemodialysis patients. Naunyn-Schmiedeberg's archives of pharmacology, September 2008, 378(3), 283-91. PubMed PMID:18509620

3Schupp N, Schmid U, Heidland A, Stopper H. New approaches for the treatment of genomic damage in end-stage renal disease. Journal of renal nutrition, January 2008, 18(1), 127-33. PubMed PMID:18089459

4Maslinska D, Laure-Kamionowska M, Maslinski S. Methyl-CpG binding protein 2, receptors of innate immunity and receptor for advanced glycation end-products in human viral meningoencephalitis. Folia neuropathologica, 2014, 52(4), 428-35. PubMed PMID:25574748

5Lu W, Li J, Ren M, Zeng Y, Zhu P, Lin L, Lin D, Hao S, Gao Q, Liang J, Yan L, Yang C. Role of the mevalonate pathway in specific CpG site demethylation on AGEs-induced MMP9 expression and activation in keratinocytes. Molecular and cellular endocrinology, August 2015, 15(411), 121-129. PubMed PMID:25916956

6Powers HJ, Hill MH, Welfare M, Spiers A, Bal W, Russell J, Duckworth Y, Gibney E, Williams EA, Mathers JC. Responses of biomarkers of folate and riboflavin status to folate and riboflavin supplementation in healthy and colorectal polyp patients (the FAB2 Study). Cancer epidemiology, biomarkers & prevention, October 2007, 16(10), 2128-35. PubMed PMID:17932361

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B3 – Niacin (Nicotinamide) and Excessive Methylation Inhibition

Specific Indication: Assists in the reduction of excessive DNA methylation reactions.

Excessive methyl side effects may include:

Increased anxiety

Decrease in mood

Headaches or migraines

Muscle aches and pains

Rash

Nausea

Acne

insomnia

Pharmaceutical Effects: The randomized and single blinded clinical trial conducted by Premkumar et al.

from India in 2008 confirmed that 50 mg niacin (nicotinamide) intake daily can reduce excessive DNA

methylation in human patients effectively.1 No patient drop off or adverse effects were reported.

Clinical Benefits:

Reduces methylation reactions Eases side effects within hours No gluten, soy, corn, egg, dairy, GMO, fish, shellfish, nuts or prebiotics Vegan and vegetarian friendly

Another five clinical studies from Japan, China and the U.S. support the evidence that niacin (nicotinamide)

can reduce DNA methylation significantly in healthy humans, and humans with diseases.2-6 In addition, the

five studies in humans support the evidence that 50 to 100 milligram niacin (nicotinamide) oral intake daily

can effectively reduce excessive DNA methylation levels.

Warning: Any niacin may cause flushing. Flushing is caused by the activation of phospholipase A2, an

enzyme that stimulates the production of specific lipids called prostanoids. These molecules can induce

the dilation of blood vessels in the skin and trigger a flushing response. This flushing is not dangerous and

is no reason for alarm.

Figure 1. Dietary niacin inhibits DNA and other metabolite methylation.

http://www.nature.com/nchembio/journal/v9/n5/full/nchembio.1234.html?message-global=remove

References

1 Premkumar VG, Yuvaraj S, Shanthi P, & Sachdanandam P. Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy. Br J Nutr. 2008 Dec; 100(6): 1179-82. PubMed PMID: 18377693 2Tian YJ, Li D, Ma Q, et al. Excess nicotinamide increases plasma serotonin and histamine levels. Sheng Li Xue Bao. 2013 Feb 25;65(1):33-8. PubMed PMID: 23426511. 3Sun WP, Li D, Lun YZ, et al. Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives. Hypertension Research. 2012 Feb;35(2):180-5. PubMed PMID: 21918528. 4Aoyama K, Matsubara K, Okada K, et al. N-methylation ability for azaheterocyclic amines is higher in Parkinson's disease: nicotinamide loading test. Journal of Neural Transmission (Vienna). 2000;107(8-9):985-95. PubMed PMID: 11041277. 5Jacob RA, Pianalto FS, Henning SM, Zhang JZ, & Swendseid ME. In vivo methylation capacity is not impaired in healthy men during short-term dietary folate and methyl group restriction. Journal of Nutrition. 1995 Jun; 125(6): 1495-502. PubMed PMID: 7782903. 6Okada K., Matsubara K., Kobayashi S., et al. 275 Abnormal N-methylation of nicotinamide in Parkinson's disease.

Neurobiology of Aging, 1996,17(4), Supplement 1, S69.