Mechanism of Action
Trimethylglycine acts as a direct methyl group donor in the liver. When it encounters homocysteine, the enzyme BHMT (betaine-homocysteine methyltransferase) transfers one of its three methyl groups to convert homocysteine back into methionine. Methionine is then transformed into SAM (S-adenosylmethionine), the body's universal methylation substrate.
SAM fuels hundreds of cellular reactions. DNA methylation, creatine synthesis, phosphatidylcholine production (a structural component of cell membranes): all depend on this substrate.
What sets this pathway apart is its independence from folate. The main homocysteine recycling route relies on vitamins B9 and B12. The BHMT pathway operates as a parallel circuit, active in the liver and kidneys. In carriers of the MTHFR C677T polymorphism (a common genetic variation that reduces folate conversion to its active form), this alternative circuit becomes especially important.
After donating a methyl group, trimethylglycine becomes dimethylglycine, then sarcosine, then glycine. Glycine is an amino acid involved in glutathione synthesis (the body's primary intracellular antioxidant) and collagen production.
Key Benefits
- Strong
Betaine contributes to normal homocysteine metabolism (effect obtained with a daily intake of 1.5 g). Several controlled trials confirm a significant reduction in plasma homocysteine with supplementation.
- Strong
A meta-analysis of 72 studies established that a 3 µmol/L reduction in homocysteine is associated with a 16% decrease in ischemic heart disease risk and a 24% decrease in stroke risk.
- Moderate
NHANES data show that a doubling of plasma homocysteine is associated with a 1.93-year acceleration on the GrimAge2 biological aging clock. One-carbon metabolism supported by betaine fuels DNA methylation.
- Moderate
A controlled trial in 23 trained men showed that betaine supplementation (2.5 g/day for 6 weeks) improves body composition by increasing lean mass and reducing fat mass.
- Moderate
The VITACOG trial showed that supplementation with one-carbon cycle cofactors reduces the rate of brain atrophy by 30% in subjects with mild cognitive impairment, and by up to 53% in those with homocysteine above 13 µmol/L.
- Moderate
In carriers of the MTHFR C677T polymorphism (8 to 10% of Europeans), the BHMT pathway activated by betaine takes on increased importance to maintain homocysteine within a favorable range.
Dosage & Forms
Several forms of betaine exist on the market. Anhydrous betaine concentrates more active substance per gram than hydrated betaine (or betaine HCl, often used as a digestive aid). Betaine HCl releases hydrochloric acid in the stomach and is not interchangeable with anhydrous betaine in a methylation context.
Dosages studied in clinical research range from 1.5 g to 6 g per day. The claim relating to homocysteine metabolism is validated from 1.5 g per day. Trials on body composition generally use 2.5 g per day. Most reviews place the optimal window between 1.5 g and 3 g per day for one-carbon cycle support.
Singular selects anhydrous betaine for its active substance concentration and metabolic versatility. The dose is calibrated in mg within the formula based on the individual profile.
In the Singular Formula
Inclusion rationale
Betaine (trimethylglycine) contributes to normal homocysteine metabolism (effect obtained with a daily intake of 1.5 g). Naturally present in beetroot, which gave it its name (Beta vulgaris), spinach and quinoa. TMG carries three methyl groups on its structure, making it one of the most concentrated methyl donors in the food kingdom. Methylation is a fundamental biochemical process: thousands of methylation reactions occur every second in the body, affecting gene expression (epigenetics), neurotransmitter synthesis, hepatic detoxification and creatine metabolism. Homocysteine is metabolized through two pathways: remethylation (dependent on vitamins B9 and B12) and transsulfuration (dependent on vitamin B6). TMG opens an alternative remethylation pathway via the enzyme BHMT in the liver, independent of folate. In the formula, TMG works in synergy with vitamin B12 (methylcobalamin), vitamin B9 (5-MTHF) and vitamin B6 (P-5-P), thereby covering the entire methylation cycle through complementary pathways. Note: a daily intake exceeding 4 g may increase blood cholesterol levels.
Selected form
Anhydrous betaine, derived from glycine carrying three methyl groups. Naturally found in beetroot, spinach and quinoa. The anhydrous form (free of crystallisation water) concentrates more active substance per gram than hydrated betaine. This molecule is a methyl group donor, essential to the methionine cycle and homocysteine homeostasis. Quality: vegan, non-GMO, no excipient.
Formula dosage
0 to 400 mg.
Synergies in the formula
Linked Biomarkers
Safety & Precautions
Anhydrous betaine has decades of use in nutrition and metabolic medicine. At doses of 1.5 g to 3 g per day, no notable adverse effects are reported in published clinical trials.
Above 4 g per day, an increase in total cholesterol and LDL cholesterol has been observed in some studies. This dose-dependent effect justifies not exceeding documented doses without professional advice.
Betaine is not recommended during pregnancy and breastfeeding due to insufficient data. Individuals on lipid-lowering medication should consult a healthcare professional before supplementation. No major interactions with common medications are documented. The gastrointestinal profile is favorable: the anhydrous form is better tolerated than betaine HCl, which can cause gastric acidity.
Scientific Studies
| Authors | Year | Type | Journal | |
|---|---|---|---|---|
| Wald DS et al. | 2002 | Meta-analysis | BMJ | View on PubMed |
Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis Meta-analysis of 72 genetic studies and 20 prospective studies showing that a 3 µmol/L reduction in homocysteine is associated with a 16% decrease in ischemic heart disease risk and 24% decrease in stroke risk. | ||||
| Smith AD et al. | 2010 | Randomised Controlled Trial | PLoS One | View on PubMed |
Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial Randomized controlled trial in 271 subjects showing that B vitamin supplementation reduces brain atrophy rate by 30%, and up to 53% in subjects with homocysteine above 13 µmol/L. | ||||
| Choi SW, Friso S | 2023 | Systematic Review | Nutr Res Pract | View on PubMed |
Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging Review showing that a doubling of homocysteine is associated with a 1.93-year acceleration on GrimAge2, and that a doubling of serum folate is associated with a 0.82-year reduction. | ||||
| Craig SA | 2004 | Systematic Review | Am J Clin Nutr | View on PubMed |
Betaine in human nutrition Reference review on betaine covering its metabolism, dietary sources, role in the methionine cycle and its supplementation potential. | ||||
| Lever M, Slow S | 2010 | Systematic Review | Clin Biochem | View on PubMed |
The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism Clinical review on betaine, its role as an osmolyte and methyl donor, and its cardiovascular, hepatic and renal implications. | ||||
| Schwab U et al. | 2002 | Randomised Controlled Trial | Am J Clin Nutr | View on PubMed |
Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects Randomized controlled trial showing that 6 g/day of betaine for 12 weeks significantly reduces plasma homocysteine in healthy subjects. | ||||
| Steenge GR et al. | 2003 | Randomised Controlled Trial | J Nutr | View on PubMed |
Betaine supplementation lowers plasma homocysteine in healthy men and women Controlled trial confirming that betaine supplementation (6 g/day for 6 weeks) reduces fasting and post-load homocysteine in healthy men and women. | ||||