Amino Acid ·Moderate evidence ·Reviewed May 2026
Trimethylglycine (TMG), also called betaine anhydrous, is a naturally occurring amino acid derivative that serves as a methyl donor in the body. It supports the remethylation of homocysteine back to methionine and is most commonly used to lower elevated homocysteine and to maintain methylation capacity, which can be taxed when supplementing NAD precursors such as nicotinamide riboside or niacinamide.
The bottom line
Evidence rating moderate. Most-documented uses: lowers elevated plasma homocysteine, supports methylation capacity (same regeneration), may offset methyl group depletion from nad precursor supplementation. 9 sources indexed (1983–2014), with 5 interaction records on file.
Core mechanism
TMG donates one of its three methyl groups to homocysteine via the enzyme betaine-homocysteine methyltransferase (BHMT), regenerating methionine and producing dimethylglycine as a byproduct. This pathway is independent of folate and vitamin B12, providing an alternative route to the methionine synthase pathway for clearing homocysteine, particularly in the liver and kidney. By replenishing methionine, TMG indirectly supports the production of S-adenosylmethionine (SAMe), the universal methyl donor used in DNA methylation, neurotransmitter synthesis, and phospholipid formation. TMG also functions as an organic osmolyte, stabilizing protein structure and cellular hydration under osmotic stress.8,6
TMG is water soluble and well absorbed orally. Taking it with food can reduce the chance of GI upset. It is often paired with B vitamins (folate, B6, B12) since these cofactors support the complementary folate-dependent homocysteine pathway.5,1
Ranked by evidence and value.
Real-world pricing across three quality tiers. Assumes Betaine anhydrous (TMG) powder.
TMG is inexpensive in bulk powder form; cost per effective dose is calculated around a typical 1000-1500 mg daily serving. Capsules and tested/certified premium brands cost more per gram than bulk powder. Betaine HCl products are priced for digestive dosing and are not directly comparable on a methyl-donor basis. Updated 2026-06-04.
Dose: 1000-3000 mg/day (up to 6 g/day studied)3,5
Timing: Split into morning and evening doses; can be taken with or without food
Betaine reliably lowers fasting and post-methionine-load homocysteine. Doses at or above 4-6 g/day can modestly raise LDL/total cholesterol in some people, so use the lowest effective dose and pair with adequate folate, B12, and B6.
Dose: 500-1000 mg/day
Timing: Once daily, alongside the NAD precursor dose
NAD precursors increase nicotinamide methylation demand (excreted as methyl-nicotinamide), which can draw down methyl groups; TMG replenishes the methylation pool. This is supportive/mechanistic rationale rather than proven clinical benefit.
Dose: 500-1500 mg/day
Timing: Once daily in the morning, with or without food
Used to keep homocysteine in a healthy range and support overall one-carbon metabolism. Evidence for direct longevity effects in humans is limited; benefit is inferred from homocysteine and methylation surrogates.
What to test, the optimal window inside the conventional range, and how long a response takes.
Measure fasting; sample handling matters because homocysteine rises in whole blood if plasma is not separated promptly. Interpret alongside B12, folate, and vitamin B6, which also govern homocysteine metabolism. Betaine acts via the BHMT remethylation pathway, which is most relevant when folate/B12 status is adequate or when the transsulfuration pathway is impaired.
Where this appears in the symptom-to-supplement map, ranked by relevance.
TMG (betaine) donates a methyl group to homocysteine via betaine-homocysteine methyltransferase (BHMT), remethylating it to methionine and lowering plasma homocysteine. This pathway is folate-independent, complementing the folate/B12-dependent methionine synthase route.8,6
Dose-dependent homocysteine lowering is well established. Note that high doses can modestly raise LDL cholesterol and triglycerides in some individuals.
By regenerating methionine from homocysteine, betaine helps replenish S-adenosylmethionine (SAMe), the universal methyl donor for DNA, protein, neurotransmitter, and phospholipid methylation. This is especially relevant when methylation demand rises, such as during NAD precursor supplementation.6,8
Best viewed as supporting the methionine cycle rather than treating a defined clinical symptom; benefit depends on baseline methylation status.
As an organic osmolyte, betaine supports cellular hydration and may aid creatine synthesis (via methionine availability) and protein metabolism, which some trials link to improved strength and power output.2,7
Evidence for power and body composition benefits is mixed across small resistance-training studies; effects are modest at best.
Betaine supports hepatic phosphatidylcholine synthesis through the methionine/SAMe pathway, which is needed for VLDL assembly and export of triglycerides from the liver, and may reduce hepatic fat accumulation.1,2
Human data in non-alcoholic fatty liver disease are limited and inconsistent; mechanistic and animal support is stronger than clinical proof.
Evidence-based stacks that include it, with the exact dose and timing each one uses.
NAD+ precursor metabolism consumes methyl groups when excess nicotinamide is methylated and cleared; betaine (TMG) is a methyl donor that supports the methionine cycle, helping offset the methylation demand created by higher NAD+ turnover.6,8
TMG and methylfolate act on parallel homocysteine remethylation routes: TMG drives the folate-independent BHMT pathway while methylfolate (with B12) drives methionine synthase. Used together they can lower homocysteine more completely than either alone.
Recommendation: Reasonable to combine when targeting elevated homocysteine, ideally with adequate vitamin B12. Monitor homocysteine to confirm response and avoid over-supplementation.
Adequate B12 ensures the methionine synthase pathway functions, so that methyl groups from both folate and betaine are used efficiently and methionine produced by TMG is not diverted. B12 status influences the overall methylation benefit of betaine.
Recommendation: Ensure B12 sufficiency when using TMG for homocysteine or methylation support, particularly in older adults or those with low B12 intake.
Endogenous creatine synthesis consumes a large share of the body's SAMe-derived methyl groups. Supplementing creatine reduces methylation demand, while TMG helps maintain SAMe supply; together they can support methylation economy and exercise outcomes.
Recommendation: The combination is commonly used in athletic stacks and is generally safe. There is no need to separate dosing.
High-dose betaine can modestly raise LDL cholesterol and triglycerides in some people. Pairing with omega-3 fish oil, which tends to lower triglycerides, may help offset the lipid effect, but lipids should still be monitored.
Recommendation: If using higher TMG doses, check a lipid panel periodically. Fish oil is a reasonable co-supplement for those concerned about triglycerides, but it does not guarantee neutralization of the LDL effect.
Zinc is the catalytic metal cofactor for betaine-homocysteine methyltransferase (BHMT), the enzyme through which TMG donates its methyl group to homocysteine. Adequate zinc status supports the efficiency of TMG-driven remethylation.
Recommendation: Maintain adequate zinc intake when relying on TMG for homocysteine lowering. No special dose timing is required.
Numbered references. Citations throughout the page link here.
Betaine supplementation was associated with modest improvements in muscular endurance and power output in trained subjects.
Daily betaine (6 g) reduced fasting plasma homocysteine concentrations in healthy adults compared with placebo.
Betaine reduced plasma homocysteine in patients with homocystinuria by enhancing remethylation to methionine via the BHMT pathway.
Betaine donates a methyl group to homocysteine through BHMT, supporting methionine and SAMe regeneration and acting as an osmolyte.
This page is educational. Do not start, stop, or change a supplement or medication based on it without checking with a qualified healthcare professional.
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