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Betaine (trimethylglycine) is an active metabolite of Choline in the body and a component of beetroot. It serves a vital role in methylation in the body alongside folate, and is an osmoregulator like Creatine. Betaine is also a possible ergogenic aid.

Our evidence-based analysis on trimethylglycine features 137 unique references to scientific papers.

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Summary of Trimethylglycine

Primary information, health benefits, side effects, usage, and other important details

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

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How to Take

Medical Disclaimer

Recommended dosage, active amounts, other details

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).

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Human Effect Matrix

Unlocked for Examine members

The Human Effect Matrix summarizes human studies to tell you what effects Trimethylglycine has on your body, how much evidence there is, and how strong these effects are.

Full details are available to Examine members.
Grade Level of Evidence
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.
grade-b 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.
grade-b 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.
grade-b 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.
grade-b 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.
grade-b - 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).
grade-b - Very High See all 4 studies
No known alterations in fasting blood glucose concentrations or glucose concentrations during exercise seen with betaine supplementation.
grade-b - 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.
grade-b - 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.
grade-b - 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.
grade-b - 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.
grade-b - 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).
grade-b - 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.
grade-b - Very High See all 3 studies
No significant influence of betaine (acute or two weeks of supplementation) on the rate of perceived exertion.
grade-b - 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.
grade-b - 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).
grade-c Minor - See study
An increase in Apolipoprotein A1 has been noted with supplementation of betaine relative to placebo in otherwise healthy persons.
grade-c Minor - See study
Cortisol appears to be minimally (6.1%) decreased with two weeks betaine supplementation when measured after exericse in a fasted state.
grade-c 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).
grade-c 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.
grade-c 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.
grade-c 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.
grade-c 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).
grade-c 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.
grade-c 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.
grade-c 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.
grade-c - - See study
No significant influence on adiponectin concentrations in persons with fatty liver seen with betaine supplementation.
grade-c - - See study
grade-c - - See study
No significant influence of betaine supplementation on blood pressure is currently known.
grade-c - - See study
No significant influence on circulating creatinine is seen with supplementation of betaine.
grade-c - - See study
No significant alterations in fibrinogen concentrations seen with supplementation of betaine.
grade-c - - 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.
grade-c - Very High See 2 studies
No significant influence on heart rate in subjects who are rehydrated and then subject to exercise.
grade-c - Very High See 2 studies
No significant influence on hematocrit is noted with supplementation of betaine.
grade-c - 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.
grade-c - - See study
Similar to blood glucose, there is currently no known influence of betaine supplementation on fasting insulin concentrations.
grade-c - - See study
No significant alterations of kidney function in healthy persons given betaine (4g) for six months.
grade-c - Very High See 2 studies
In studies assessing lean mass, there are no apparent changes with supplementation of betaine.
grade-c - - See study
No significant alterations have been noted in circulating biomarkers of lipid peroxidation.
grade-c - - See study
No significant influence of betaine on the metabolic rate of obese persons subject to chronic supplementation.
grade-c - - See study
Betaine (2g) has failed to increase phosphocreatine levels in skeletal muscle and failed to augment the increase caused by 20g of creatine.
grade-c - - See study
No significant influence of betaine supplementation of subjective ratings of muscular soreness nor the pump relative to placebo.
grade-c - 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.
grade-c - - See study
No significant alterations in the overall oxidation of LDL cholesterol associated with supplementation of betaine.
grade-c - 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.
grade-c - 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).
grade-c - - See study
No significant influence on TNF-α concentrations following supplementation of betaine to persons with fatty liver.
grade-c - - See study
No significant influence of betaine on circulating TSH concentrations in serum.
grade-c - Moderate See 2 studies
No significant alterations in serum triglycerides are noted with prolonged supplementation of betaine supplementation.
grade-c - - 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.
grade-d 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]

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Things to Note

Primary Function:

Also Known As

Betaine, TMG, Glycine betaine, oxyneurine

Do Not Confuse With

Glycine (amino acid TMG is based off of), L-lysine (an amino acid), Choline (the molecule which produces betaine in the body)

Goes Well With

  • Folic acid (additive in reducing homocysteine)

  • Riboflavin (Vitamin B2) may reduce a fish odor in breath and body secretions if they happen to occur with supplementation of betaine (fish odor due to a genetic mutation)

  • In the case of high doses of betaine possibly causing fishy odours in the breath and in body secretions (due to trimethylamine production), supplementation of riboflavin (100mg twice daily) may eliminate the odour

  • Trimethylglycine as a hydrochloride salt (marketed as Betaine HCl) may possibly cause heartburn at high enough oral doses, thought to be related to stimulating the production of stomach acid

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