Trimethylglycine

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 Beet Root) 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

The lowest active dose of betaine is 500mg taken throughout the course of the day. This is a dose that appears to be minimally active in reducing homocysteine and may be healthy to take, and doses of this up to 1,000mg seem to be in the range of being minimally active but also able to be gained through food consumption (so supplementation may not be needed).

The standard doses that seen to be used for dietary supplementation are in the range of 2,500-6,000mg taken in two divided doses daily, and taking said doses alongside a meal does not appear to be required. This is the dosage range which reliably reduces homocysteine, and is the dosage range where (unreliable and minimal) benefits to physical performance have been noted.

Studies on liver fat and fibrosis, and in some clinical settings on homocysteine reduction where the subject appears to be resistant to the 6g dose, the dosage can be increased up to 20g daily; this does appears to be moderately well tolerated (like any osmolyte, it may cause diarrhea in this high of a dose).

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects trimethylglycine has on your body, and how strong these effects are.

Grade	Level of Evidence [show legend]
	Robust research conducted with repeated double-blind clinical trials
	Multiple studies where at least two are double-blind and placebo controlled
	Single double-blind study or multiple cohort studies
	Uncontrolled or observational studies only

Level of Evidence ? The amount of high quality evidence. The more evidence, the more we can trust the results.	Outcome	Magnitude of effect ? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.	Consistency of research results ? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.	Notes
	Homocysteine	Strong	Very High See all 9 studies	Betaine (3g or more) appears to potently and reliable reduce homocysteine concentrations following a single dose and maintaining this reduction for as long as supplementation is continued. The magnitude is around 10% in persons with normal homocysteine levels, and greater (20-40%) in those with high homocysteine, and (unlike folate) works in instances of methionine loading tests. 500mg betaine can reduce homocysteine after a methionine load, but it too low to influence fasting homocysteine.
	LDL-C	Minor	High See all 3 studies	Similar to total cholesterol, one study noted a stasis in LDL when placebo decreased (a relative increase). Reasons for this unknown and the data needs to be replicated, and HDL was unaffected.
	Liver Enzymes	Minor	Low See all 5 studies	Similar to liver fat and damage, the levels of liver enzymes in serum appears to be reduced potently in preliminary evidence with the currently largest trial showing no significant influence; there may be a role, but it needs to be further elucidated.
	Total Cholesterol	Minor	High See all 3 studies	One study noted a stasis in total cholesterol when placebo decreased (a relative increase). Reasons for this unknown and the data needs to be replicated.
	Anaerobic Running Capacity	-	Very High See all 3 studies	Studies assessing distance, time, or other parameters of performance during cycling tests have failed to find any significant benefit with betaine supplementation (one positive study measuring power output is pooled in that parameter).
	Blood Glucose	-	Very High See all 4 studies	No known alterations in fasting blood glucose concentrations or glucose concentrations during exercise seen with betaine supplementation.
	Fat Mass	-	Very High See all 3 studies	Fat mass does not appear to be significantly influenced with either short term (2 week) or long term supplementation.
	Fatigue	-	High See all 3 studies	One study noted a reduced rate of change in fatigue (no overall differences in fatigue outright though) seen with betaine, whereas the other two studies have failed to find benefit with betaine.
	HDL-C	-	Very High See all 3 studies	No significant alterations in circulating HDL-C are seen with prolonged supplementation of betaine in persons with metabolic impairment.
	Lactate Production	-	High See all 3 studies	An attenuation in the rise of lactate seen in more endurance based exercise may need to be replicated, since two other studies (majority of evidence) have failed to find an interaction with betaine ingestion and lactate.
	Muscular Endurance	-	High See all 3 studies	There may be a small benefit in prolonged and exhaustive resistance training with betaine relative to placebo, but at this moment in time most evidence assessing muscular endurance has failed to find a statistically significant increase (trends to improve do seem apparent).
	Power Output	-	High See all 7 studies	There appear to be isolated cases of power output being increased which fail to be replicated elsewhere under similar experimental conditions, and the majority of evidence suggests that the power output increase seen is no greater than placebo; a potential ergogenic effect is either due to a currently unknown prerequisite (ie. parameter of the study population) or is not present.
	Rate of Perceived Exertion	-	Very High See all 3 studies	No significant influence of betaine (acute or two weeks of supplementation) on the rate of perceived exertion.
	Serum Folate	-	Very High See all 4 studies	Chronically there are no changes to serum folate due to the body normalizing folate levels, but acute supplementation can reduce folate concentrations in serum sharply for a short time.
	Weight	-	Very High See all 4 studies	No significant alterations in weight are seen with supplementation of betaine, which is different than what is seen with another popular sports osmolyte (creatine).
	Apolipoprotein A	Minor	- See study	An increase in Apolipoprotein A1 has been noted with supplementation of betaine relative to placebo in otherwise healthy persons.
	Cortisol	Minor	- See study	Cortisol appears to be minimally (6.1%) decreased with two weeks betaine supplementation when measured after exericse in a fasted state.
	Dry Mouth	Minor	Very High See all 4 studies	Symptoms of dry mouth either caused by a disease state (Sjögren's syndrome) or as a side-effect of pharmaceuticals appears to be significantly reduced when betaine is formulated into a toothpaste at 4%. Studies currently have a potential industry influence (financing).
	IGF-1	Minor	- See study	IGF-1 appears to be minimally increased relative to placebo (7.8%) following two weeks supplementation of betaine and when tested after exercise in a fasted state.
	Liver Damage	Minor	- See all 3 studies	Preliminary evidence showed a large decrease in fibrotic area and inflammation in the livers of persons with NAFLD given high dose (20g) betaine, but the best evidence failed to find a significant influence. An interaction is apparent, but the exact role is not known as this time.
	Liver Fat	Minor	Very High See all 3 studies	Preliminary evidence showed a major decrease in liver fat (normalization in over half of persons with fatty liver) but currently the best evidence suggests that this does not occur as potently; there may still be a role, but this requires more research.
	Muscle Oxygenation	Minor	- See study	There appears to be a minor increase in overall oxygen consumption during physical training (anaerobic) to fatigue associated with betaine supplementation, although this was alongside increased work volume (which may be the causative factor).
	Plasminogen Inhibitor 1	Minor	- See study	An increase in PAI-1 concentrations has been noted with 4g of betaine supplementation daily over the course of six months in otherwise healthy adults.
	Serum Methionine	Minor	Moderate See 2 studies	Secondary to reducing homocysteine (since betaine gives a methyl group to homocysteine to convert it into L-methionine) there is an increase in serum methionine seen with supplementation acutely; this is normalized somewhat after prolonged supplementation.
	Training Volume	Minor	- See study	One study noted an increase in overall training volume (6.5%) when the whole workout was assessed, and this was without any apparent changes in the volume conducted in any individual set or any changes in the rate of perceived exertion.
	Adiponectin	-	- See study	No significant influence on adiponectin concentrations in persons with fatty liver seen with betaine supplementation.
	Blood Flow	-	- See study
	Blood Pressure	-	- See study	No significant influence of betaine supplementation on blood pressure is currently known.
	Creatinine	-	- See study	No significant influence on circulating creatinine is seen with supplementation of betaine.
	Fibrinogen	-	- See study	No significant alterations in fibrinogen concentrations seen with supplementation of betaine.
	Growth Hormone	-	- See study	The minor increase in growth hormone seen with betaine (6.1%), relative to placebo, failed to reach statistical significance and is too low of magnitude to consider it practically appreciable.
	Heart Rate	-	Very High See 2 studies	No significant influence on heart rate in subjects who are rehydrated and then subject to exercise.
	Hematocrit	-	Very High See 2 studies	No significant influence on hematocrit is noted with supplementation of betaine.
	Hydration (Total Body Water)	-	Very High See 2 studies	Betaine supplementation does not appear to be significantly beneficial in improving hydration status of users either outright or after prior dehydration relative to water alone.
	Insulin	-	- See study	Similar to blood glucose, there is currently no known influence of betaine supplementation on fasting insulin concentrations.
	Kidney Function	-	- See study	No significant alterations of kidney function in healthy persons given betaine (4g) for six months.
	Lean Mass	-	Very High See 2 studies	In studies assessing lean mass, there are no apparent changes with supplementation of betaine.
	Lipid Peroxidation	-	- See study	No significant alterations have been noted in circulating biomarkers of lipid peroxidation.
	Metabolic Rate	-	- See study	No significant influence of betaine on the metabolic rate of obese persons subject to chronic supplementation.
	Muscle Creatine Content	-	- See study	Betaine (2g) has failed to increase phosphocreatine levels in skeletal muscle and failed to augment the increase caused by 20g of creatine.
	Muscle Soreness	-	- See study	No significant influence of betaine supplementation of subjective ratings of muscular soreness nor the pump relative to placebo.
	Nitric Oxide	-	Very High See 2 studies	A potent increase in nitric oxide seen in a pilot study has failed to be replicated in a controlled intervention.
	Oxidation of LDL	-	- See study	No significant alterations in the overall oxidation of LDL cholesterol associated with supplementation of betaine.
	Oxygen Uptake	-	Moderate See 2 studies	A minor increase in oxygen uptake was noted in selective testing (final sprint of one, but not both, betaine conditions) which did not manifest over the whole study period and is likely practically insignificant.
	Serum Cobalamin	-	Moderate See all 3 studies	Mixed evidence as to whether B12 is influenced with supplementation of betaine, but the higher quality study appears to show no effect (since the other study noted a decline in B12 in placebo).
	TNF-Alpha	-	- See study	No significant influence on TNF-α concentrations following supplementation of betaine to persons with fatty liver.
	Thyroid-Stimulating Hormone	-	- See study	No significant influence of betaine on circulating TSH concentrations in serum.
	Triglycerides	-	Moderate See 2 studies	No significant alterations in serum triglycerides are noted with prolonged supplementation of betaine supplementation.
	VO₂ Max	-	- See study	Although a minor increase in oxygen uptake was noted in certain situations (final sprint of testing), overall VO2 max is not significantly affected.
	Salivation	Minor	Very High See all 3 studies	Betaine containing toothpaste, in persons with xerostomia (dry mouth), can reduce symptoms of dry mouth possibly related to an increase in salivation (basal salivation, not in response to stimuli)

Studies Excluded from Consideration

• Confounded with the inclusion of diethanolamine glucuronate and nicotinamide ascorbate^[1]