Many practitioners are aware that Betaine (aka Trimethylglycine, TMG) is the methyl donor in the BHMT pathway and as it’s alternate name suggests, possesses three chemically reactive methyl groups linked to a nitrogen atom.1
Within the BHMT pathway, Betaine is converted into Dimethylglycine (DMG) after donating one of its three methyl groups to homocysteine, to convert it to methionine and ultimately SAMe as an alternate and important route of methylation production to the well known Folate/B12 requiring MTR pathway.
What many practitioners may not be aware of, is that Betaine can be readily produced in the body through the oxidation of Choline via the choline dehydrogenase and betaine aldehyde dehydrogenase enzymes, particularly in the liver and muscles.2
For this reason Choline has also been shown to indirectly support homocysteine methylation.3
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One study of postmenopausal women showed that Choline supplementation increased plasma Betaine levels and slightly lowered plasma levels of total homocysteine (tHcy) after six weeks.4
The upper tolerable limit for Choline in adults is 3.5 g/day. Beyond the diet and supplements, the only other source of choline is via de novo synthesis from phosphatidylcholine which requires significant amounts of SAMe via the PEMT pathway (3 mole SAM to produce 1 mole choline) and produces homocysteine.
A deficiency of Choline will therefore put an increased additional burden on potentially already strained SAMe/Methylation levels, in those exhibiting insufficient methylation capacity.
Available evidence suggests that Folate deficiency can be partly compensated for when more Choline is available, and vice versa.
For example, Choline and Phosphatidylcholine were depleted in the livers of rats fed a Folate-deficient diet.5 In turn, consumption of a Choline-deficient diet decreased hepatic Folate stores6 and lowered Methionine formation in animal livers by 20%–25%,7 due to less Choline being available for conversion into Betaine. The effects of Choline deficiency on reducing liver SAMe (by 60%) and increasing liver SAH (by 50%) were pronounced.7
Supplementation with Choline can therefore prove to be an invaluable if not essential co-prescription with any methylated B vitamins in the clinical treatment of methylation insufficiencies.
Supplements that include the preferable form ‘Choline Dihydrogen Citrate’ in combination with methylated Folate and B12, such as RN Labs’s Methyl Fortify, may provide maximum utility in patients requiring comprehensive methylation support.
Alternatively if you just want to use Methyl Folate on it’s own RN Labs’s L-5MTHF provides 500 mcg per capsule.
What about how to quench excess methyl groups?
Niacinamide B3 represents an invaluable clinical tool for balancing methylation protocols.
The mechanism of action is attributed to the conversion of Niacinamide into 1-Methyl-Niacinamide after receiving a methyl group via the Niacinamide n-methyltransferase (NNMT) enzyme. NNMT shunts Niacinamide away from NAD+ formation, using S-adenosylmethionine (SAMe) as its methyl donor. Clinical observations indicate a dose of 150mg Niacinamide appears to begin quenching excess methyl groups, with 500mg or more being required to make a noticeable impact in most individuals.
1. Obeid R. The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway. Nutrients 2013; 5: 3481–3495.
2. Rogers J.D., Sanchez-Saffon A., Frol A.B., Diaz-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: Association with vascular disease. Arch. Neurol. 2003;60:59–64.
3. Wallace J.M., McCormack J.M., McNulty H., Walsh P.M., Robson P.J., Bonham M.P., Duffy M.E., Ward M., Molloy A.M., Scott J.M., et al. Choline supplementation and measures of choline and betaine status: A randomised, controlled trial in postmenopausal women. Br. J. Nutr. 2012;108:1264–1271.
4. Holm P.I., Ueland P.M., Vollset S.E., Midttun O., Blom H.J., Keijzer M.B., den Heijer M. Betaine and folate status as cooperative determinants of plasma homocysteine in humans. Arterioscler. Thromb. Vasc. Biol. 2005;25:379–385.
5. Kim Y.I., Miller J.W., da Costa K.A., Nadeau M., Smith D., Selhub J., Zeisel S.H., Mason J.B. Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver. J. Nutr.1994;124:2197–2203.
6. Horne D.W., Cook R.J., Wagner C. Effect of dietary methyl group deficiency on folate metabolism in rats. J. Nutr. 1989;119:618–621.
Zeisel S.H., Zola T., da Costa K.A., Pomfret E.A. Effect of choline deficiency on S-adenosylmethionine and methionine concentrations in rat liver.
7. Biochem. J. 1989;259:725–729.