Trimethylglycine (TMG) is a molecule which, structurally, is the amino acid glycine with three methyl groups attached to it. It is known as a "betaine" molecule ("betaine" being a category of molecules), but because it was the first dietary betaine discovered (from beetroot) and is the most popular molecule referred to as a betaine, the terms "trimethylglycine" and "betaine" are used interchangeably.

One of betaine's major mechanisms is its role as a methyl donor. Betaine either directly donates a methyl group to reduce homocysteine into L-methionine or it increases bodily levels of S-adenosyl methionine (SAMe) or active folate molecules, both of which can go on to donate methyl groups to other parts of the body.

Evidence in humans indicates that betaine effectively and reliably reduces homocysteine levels in both healthy people and people with various conditions.^[2][1] However, betaine also appears to increase total and LDL-cholesterol at high doses (> 4 g per day).^[1]

Elevated homocysteine levels have been associated with an increased risk of cardiovascular disease and cardiovascular events in several observational studies. However, correlation does not indicate causation. Although it is thought that reducing homocysteine levels is cardioprotective, interventions that lower homocysteine levels don’t seem to prevent cardiovascular events in people with cardiovascular disease.^[3]

Betaine's other major mechanism is it acts as an osmolyte, or a molecule that is shuttled in and out of a cell to affect its hydration status. Similar to creatine, increased intracellular concentrations of betaine promote cell hydration and resilience to stressors.

Betaine (also known as TMG) is an "osmolyte", a molecule that regulates water balance in cells. Betaine can directly methylate homocysteine, which is potentially cardioprotective. It also indirectly affects folate and SAMe metabolism to support whole-body methylation.

Elsewhere, mechanistic evidence demonstrates that betaine is effective for preventing and improving nonalcoholic fatty liver disease,^[4] but there is a lack of studies in humans. Two 1-year trials in participants with nonalcoholic steatohepatitis (NASH) observed an improvement in liver fat, inflammation, and fibrosis with a dosage of 10 g of betaine twice per day (20 g total), but there was no control group in either study.^[5][6]A more recent 1-year randomized controlled trial in participants with NASH reported no improvement in liver fat, inflammation, or fibrosis with a dosage of 10 g of betaine twice per day.^[7]

Finally, there is mixed evidence on the efficacy of betaine as a performance-enhancing compound. Most studies report that supplementation with betaine does not enhance maximal strength or power.^[8] Betaine also doesn’t seem to enhance resistance exercise performance when low volumes (1–3 sets) are performed.^[9][10] However, there is evidence to suggest that betaine enhances resistance exercise performance in protocols that challenge muscular endurance with high levels of metabolic stress.^[11][12]

The mechanism by which betaine may improve resistance exercise performance in this specific context is unclear, but it may be due to betaine’s ability to attenuate increases in lactate levels during exercise.^[11][12][13] It’s also hypothesized that betaine’s osmolytic effects help to enhance resistance exercise performance during high-volume training. Even so, this may be of no practical relevance because creatine shares this mechanism of action, and the lone study to evaluate supplementation with betaine and creatine failed to find an additive effect of betaine on creatine’s benefits.^[14]