TMG (Trimethylglycine)

Trimethylglycine (TMG), also called betaine, is glycine with three methyl groups attached. It occurs naturally in beets (the original source , “betaine” comes from Beta vulgaris), spinach, quinoa, wheat germ, and shellfish. It acts as both a methyl donor in biochemical reactions and an osmolyte that protects cells from osmotic and thermal stress, particularly in the liver and kidneys.

Homocysteine Reduction {#homocysteine-reduction}

TMG’s most well-established metabolic function is donating a methyl group to convert homocysteine into methionine via the betaine-homocysteine methyltransferase (BHMT) enzyme. This reaction operates in parallel to the folate-B12 remethylation cycle, providing a second pathway for homocysteine clearance.

Elevated homocysteine is an independent cardiovascular risk factor associated with endothelial dysfunction, atherothrombosis, and , at very high levels , with increased risk of stroke and dementia. A 2013 meta-analysis of randomized controlled trials (PMID 23230003) confirmed that TMG supplementation significantly reduces plasma homocysteine, with the most reliable effects at 4–6 g/day. This effect is well-replicated and mechanistically sound.

An important caveat: lowering homocysteine via B vitamins has generally not produced the expected reductions in cardiovascular events in large RCTs, suggesting that elevated homocysteine may partly be a marker of downstream dysfunction rather than a causal driver. Whether TMG-mediated homocysteine lowering translates to hard clinical outcomes in healthy adults has not been established in long-term trials.

Liver Health {#liver-health}

TMG functions as an organic osmolyte in hepatocytes, protecting liver cells against osmotic stress and supporting membrane stability. It also supplies methyl groups for phosphatidylcholine synthesis , a critical component of cell membranes and VLDL lipoprotein assembly, which is the liver’s mechanism for exporting fat.

Multiple controlled trials and reviews have found that betaine supplementation reduces liver fat accumulation, hepatic inflammation, and transaminase (ALT/AST) levels in patients with non-alcoholic fatty liver disease (NAFLD). The 2021 comprehensive PMC review (PMC8224793) concluded that betaine shows consistent hepatoprotective effects, particularly in the context of choline deficiency, alcoholic liver disease, and NAFLD/NASH. These findings are among the better-characterized clinical applications of TMG beyond homocysteine lowering.

Methylation Support {#methylation-support}

Beyond the BHMT reaction, TMG contributes broadly to the one-carbon metabolism network. The methionine produced from homocysteine remethylation is converted to S-adenosylmethionine (SAMe) , the universal methyl donor for over 200 enzymatic reactions including DNA methylation, histone modification, neurotransmitter synthesis (epinephrine, creatine, phosphatidylcholine), and detoxification conjugation reactions.

In this way, TMG supplementation can help maintain SAMe availability when dietary methyl donors (folate, choline, B12, methionine) are suboptimal. This is particularly relevant for individuals with MTHFR polymorphisms that reduce folate-cycle efficiency, or for those on diets low in choline (which is the primary dietary methyl donor). A 2015 RCT found that combining SAMe with TMG produced greater antidepressant response than SAMe alone, which is consistent with the SAMe-replenishing mechanism.

Dosing and Safety

For homocysteine reduction, 4–6 g/day is the dose range supported by meta-analysis evidence. For general methylation support, liver health, and athletic performance applications, 1–3 g/day is commonly used. TMG is generally well tolerated, with a fishy or slightly sweet taste that some people find unpleasant in powder form.

At high doses (6 g+/day), some trials have observed modest increases in LDL cholesterol and triglycerides , a genuine safety signal that partially offsets the cardiovascular benefit of homocysteine reduction. This effect appears dose-dependent and is more relevant for individuals with already-elevated lipids. Standard supplemental doses of 500 mg–2 g/day do not appear to significantly affect lipid profiles. TMG is found in meaningful amounts in beets, spinach, and whole grains, so dietary intake can supplement lower supplemental doses.