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 it is the most popular molecule referred to as a betaine, the terms ‘trimethylglycine’ and ‘betaine’ are used interchangeably.
The main mechanisms of betaine are either its usage as a methyl donor, where it either directly donates a methyl group to reduce homocysteine into L-methionine (seen as cardioprotective) or it increases bodily levels of S-Adenosyl Methionine (SAMe) or active folate molecules, and those two can then go on to donate methyl groups to other parts of the body. Due to this, supplementation of betaine is able to indirectly support whole-body methylation, and directly support a reduction in homocysteine (which is reliably observed following moderate to high dose supplementation.
The other major mechanism is that betaine is 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 cardioprotective. It also indirectly affects folate and SAMe metabolism to support whole body methylation.
When looking at the human evidence at this moment in time, it appears that betaine is effective and reliable for reducing homocysteine concentrations when taken daily at 3g or more. A single dose of betaine reduces homocysteine levels, which remain suppressed as long as supplementation is continues. Betaine has been found to reduce homocysteine by 10% in persons with normal levels or by 20-40% in persons with elevated homocysteine levels.
Homocysteine is known to be elevated in persons with cardiovascular health issues and is a biomarker of cardiovascular complications (ie. when homocysteine is elevated then the subject is also at a higher risk for problems). Correlation does not indicate causation, however, so it is not clear whether homocysteine is merely an indicator of problems (a biomarker) or may actually promote cardiovascular dysfunction. It is thought that reducing homocysteine is protective of the heart, but a direct link between betaine supplementation and cardiovascular protection in humans has not yet been established.
Elsewhere, although the evidence is a bit confusing at this time (preliminary evidence showing amazing promise and the one controlled study failing to replicate it, but more research being needed to confirm) betaine may have a role in treating fatty liver and the associated liver fibrosis when taken at high doses(20g daily).
In regards to health, betaine shows the most promise for liver and cardioprotection. In theory it should be highly protective, but studies directly evaluating links between betaine supplementation and improved health biomarkers do not yet exist.
Finally, betaine has been recommended as a performance enhancing compound, although with quite unreliable results. When taken at 1.25g twice daily, betaine has at times been linked to increased power output (only to fail in other instances) and minor increases in workout volume and endurance (a bit more reliable than power output, but still not a consensus). The overall effect size or how much betaine benefits the subject seem to be quite small, and at this moment in time all studies finding benefit with betaine supplementation have been associated with Danisco (DuPont Nutrition) a producer of betaine.
The benefit of TMG to physical exercise, even if assumed to be present, may have little to no practical relevance since:
Serum betaine is increased to a similar degree with 1g betaine as it is with 1g of Choline supplementation, and the latter may have some centrally acting (brain related) benefits to working out while possibly being cheaper
The theory that fits most with the observed benefits to physical performance (the osmolyte actions protecting a cell) is a mechanism not only able to be repeated with choline as mentioned earlier, but is a mechanism of action of Creatine; the lone study to evaluate the combination failed to find an additive effect of betaine on creatine's benefits