Trimethylglycine

Trimethylglycine (commonly referred to as betaine) 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; possible ergogenic aid as well.

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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 it seems that the two terms (trimethylglycine and betaine) are used interchangeably.

The main mechanisms of TMG 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 TMG is an osmolyte compound, or a molecule that is shuttled in and out of a cell on demand to preserve the size of the cell and its hydration status. A high TMG concentration in a cell, similar to Creatine, can preserve cellular structure and make it more resiliant to stressors.

Trimethylglycine or TMG (informally, and somewhat incorrectly, known as betaine) is a molecule that mediates water balance of a cell due to it being an 'osmolyte', and is also able to support methyl donation in the body by directly methylating homocysteine (cardioprotective) or indirectly supporting folate and SAMe metabolism which also then support whole body methylation

When looking at the human evidence at this moment in time, it appears that betaine is very effective and reliable in reducing homocysteine concentrations when taken at 3g daily or more. The reduction occurs within a single dose and maintains a reduction for as long as supplementation is continues; the magnitude being around 10% in persons with normal homocysteine levels and 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), but homocysteine is known to both be merely an indicator for problems (a biomarker) as well as possibly having a causative role. 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) TMG may have a role in treating fatty liver and actually improving the fibrotic state of the liver when taken at very high (20g) dosages daily.

In regards to health, at this moment in time most promise appears to be related to cardioprotection or the liver. In theory TMG should be highly protective, but the studies directly evaluating a link between TMG supplementation and improved health biomarkers do not yet exist

Finally, TMG appears to be recommended as a performance enhancing compound with quite unreliable benefits. TMG, when 1.25g is taken twice daily, 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 it benefits the subject seen to be quite small, and at this moment in time all studies finding benefit with TMG supplementation have been associated with Danisco (DuPont Nutrition) a producer of TMG.

The benefit of TMG to physical exercise, even if assumed to be present, may have little to no practical relevance since:

  • Serum TMG is increased to a similar degree with 1g TMG 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 TMG on creatine's benefits

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Also Known As

Betaine, TMG, Glycine betaine, oxyneurine, lycine


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)


Things to Note

  • 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

Is a Form of


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)

Caution Notice

Examine.com Medical Disclaimer

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).


In regards to physical performance, right now the theory which seems to be 'most correct' in estimating how betaine increases physical performance is the osmolyte theory where (secondary to water retention in a cell) a cell is not as easily damaged and can perform better in periods where cells would normally be damaged, but not inherently.

If this is the case, then studies need to be conducted on creatine and betaine coingestion since creatine also has this property and is probably potent enough to fully wash out any potential osmolytic benefit of betaine. Furthermore, creatine is reliable whereas betaine is not.


Kurtis Frank

The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Trimethylglycine has in your body, and how strong these effects are.
GradeLevel of Evidence
ARobust research conducted with repeated double blind clinical trials
BMultiple studies where at least two are double-blind and placebo controlled
CSingle double blind study or multiple cohort studies
DUncontrolled or observational studies only
Level of Evidence
EffectChange
Magnitude of Effect Size
Scientific ConsensusComments
BLactate production

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... show

BBlood Glucose

No known alterations in fasting blood glucose concentrations or glucose concentrations during exercise seen with betaine supplementation.

BHomocysteine

Strong

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... show

BSerum Folate

Chronically there are no changes to serum folate due to the body normalizing folate levels, but acute supplementation can reduce folate concentrations in serum... show

BWeight

No significant alterations in weight are seen with supplementation of betaine, which is different than what is seen with another popular sports osmolyte (creatine).

BFat Mass

Fat mass does not appear to be significantly influenced with either short term (2 week) or long term supplementation.

BHDL-C

No significant alterations in circulating HDL-C are seen with prolonged supplementation of betaine in persons with metabolic impairment.

BLDL-C

Minor

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,... show

BTotal Cholesterol

Minor

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.

BLiver Enzymes

Minor

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... show

BPower Output

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... show

BMuscular Endurance

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... show

BFatigue

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... show

BAnaerobic Running Capacity

Studies assessing distance, time, or other parameters of performance during cycling tests have failed to find any significant benefit with betaine supplementation (one... show

CGrowth Hormone

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... show

CIGF-1

Minor

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.

CCortisol

Minor

Cortisol appears to be minimally (6.1%) decreased with two weeks betaine supplementation when measured after exericse in a fasted state.

CInsulin

Similar to blood glucose, there is currently no known influence of betaine supplementation on fasting insulin concentrations.

CDry Mouth

Minor

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... show

CSerum Methionine

Minor

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... show

CSerum Cobalamin

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... show

CMetabolic Rate

No significant influence of betaine on the metabolic rate of obese persons subject to chronic supplementation.

CBlood Pressure

No significant influence of betaine supplementation on blood pressure is currently known.

CTriglycerides

No significant alterations in serum triglycerides are noted with prolonged supplementation of betaine supplementation.

CCreatinine

No significant influence on circulating creatinine is seen with supplementation of betaine.

CThyroid-Stimulating Hormone

No significant influence of betaine on circulating TSH concentrations in serum.

CNitric Oxide

A potent increase in nitric oxide seen in a pilot study has failed to be replicated in a controlled intervention.

CTraining Volume

Minor

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... show

CLipid Peroxidation

No significant alterations have been noted in circulating biomarkers of lipid peroxidation.

CHeart Rate

No significant influence on heart rate in subjects who are rehydrated and then subject to exercise.

CRate of Perceived Exertion

No significant influence of betaine (acute or two weeks of supplementation) on the rate of perceived exertion.

CMuscle Oxygenation

Minor

There appears to be a minor increase in overall oxygen consumption during physical training (anaerobic) to fatigue associated with betaine supplementation, although this... show

CMuscle Soreness

No significant influence of betaine supplementation of subjective ratings of muscular soreness nor the pump relative to placebo.

CHydration

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.

CHematocrit

No significant influence on hematocrit is noted with supplementation of betaine.

CLean Mass

In studies assessing lean mass, there are no apparent changes with supplementation of betaine.

CMuscle Creatine Content

Betaine (2g) has failed to increase phosphocreatine levels in skeletal muscle and failed to augment the increase caused by 20g of creatine.

CLiver Damage

Minor

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... show

CLiver Fat

Minor

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... show

CAdiponectin

No significant influence on adiponectin concentrations in persons with fatty liver seen with betaine supplementation.

CTNF-Alpha

No significant influence on TNF-α concentrations following supplementation of betaine to persons with fatty liver.

CRate of Percieved Exertion

No significant influence on the rate of perceived exertion is seen with supplementation of betaine in rehydrated athletes.

CVO2 max

Although a minor increase in oxygen uptake was noted in certain situations (final sprint of testing), overall VO2 max is not significantly affected.

COxygen Uptake

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... show

CPlasminogen Inhibitor 1

Minor

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.

CKidney function

No significant alterations of kidney function in healthy persons given betaine (4g) for six months.

COxidation of LDL

No significant alterations in the overall oxidation of LDL cholesterol associated with supplementation of betaine.

CApolipoprotein A

Minor

An increase in Apolipoprotein A1 has been noted with supplementation of betaine relative to placebo in otherwise healthy persons.

CFibrinogen

No significant alterations in fibrinogen concentrations seen with supplementation of betaine.

CBlood Flow
DSalivation

Minor

Betaine containing toothpaste, in persons with xerostomia (dry mouth), can reduce symptoms of dry mouth possibly related to an increase in salivation (basal salivation,... show


Studies Excluded from Consideration

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

Disagree? Join the Trimethylglycine Discussion

Table of Contents:


Edit1. Sources and Structure

1.1. Summary

Trimethylglycine (TMG) is a betaine molecule, and the first betaine to be discovered as a component of beetroot sugars but later found to be a component of the body under standard conditions.[2] It is simply the Glycine molecule with three additional methyl groups added to it, which gives the name of trimethyl- (three methyl groups) glycine.

Due to its origin, the terms trimethylglycine and betaine are commonly used interchangeably despite betaine technically being a category of molecules of which TMG belongs to. For the purpose of this article the terms will be used interchangeably, and if betaine (as a category of molecules) or any specific betaine molecule that is not trimethylglycine is referred to it will be made note of.

Trimethylglycine (TMG) is molecule in the 'betaine' class of molecules. It was the first discovered betaine and the entire category of betaine was named after its initial source (beets), and due to this this molecule is commonly (but incorrectly) referred to as betaine itself; it can correctly be referred to as 'glycine betaine' though

The term 'betaine' refers to any molecule with a cationic (positively charged) group not bearing any free hydrogens (in the case of TMG, this is the nitrogenous ammonium group) connected to an anionic (negatively charged) group. TMG has the amino acid Glycine as the negatively charged functional group, and on the nitrogen of glycine (which forms the core of the ammonium group) are three methyl groups; hence the name trimethylglycine.

The term 'glycine betaine' is commonly used to refer to dietary TMG, and other betaines include 'proline betaine' (trimethylproline) found in fruits;[3] and technically trigenolline (found in Coffee[4] and alfalfa[5]) as well as dimethylsulfoniopropionate (DMSP; mostly in microalgae[6]) are dietary betaines.

Whereas DMSP is structurally similar to TMG except for a sulfur replacing the nitrogen, trigenolline and proline betaine are both cyclical betaine structures. Other names for trimethylglycine beyond glycine betaine include lycine[2] (not to be confused with the amino acid L-lysine) and oxyneurine.[2]

Beyond being the first discovered betaine molecule, it is also the one that appears to be most involved in human metabolism and most present in the food supply

1.2. Sources

Betaine can be found in the following foods (dry weight unless otherwise specified for solid foods):

Grains

  • Wheat bran (13,390µg/g[2][7])
  • Wheat germ (12,410µg/g[2][7])
  • White bread (360-520µg/g[3])
  • Wholemeal bread (670-790µg/g[3])
  • Wholegrain (560-620µg/g[3])
  • Bran cereal (2,300-7,200µg/g) with trace levels in corn flakes[3]
  • Muesli (270-440µg/g[3])
  • Biscuits of wheat (1,900-2,500µg/g), chocolate (160µg/g), or plain (290-430µg/g)[3]
  • Fettucini pasta (1,300-1,400µg/g[3])
  • Instant noodles (990-1,400µg/g[3])
  • Plain crackers (1,000-1,300µg/g[3]) with trace levels in rice crackers
  • Cakes (170-270µg/g[3])
  • Muffin (120-160µg/g[3])
  • Scone (440-500µg/g[3])

Vegetables

  • Spinach (6,000-6,450µg/g[2][7])
  • Beets (1,140-2,970µg/g[2][7])
  • Asparagus (33-45µg/g[3])
  • Potatoes (26-39µg/g[3])
  • Bell peppers including green (24-31µg/g), orange (10-11µg/g), and yellow (10-26µg/g) with limited in red (12µg/g or trace)[3]
  • Trace levels in corn, baked beans, onions, and tomatoes[3]

Fruits

  • Avocadoes (3-35µg/g[3]), with the best sources of betaines in fruits being proline betaine in mandarins (920µg/g[3]) and orange juice (700-780µg/g[3]) with all other fruits essentially devoid of betaines
  • Wine (processed from grapes) at an average 10-11mg per liter of wine (range of 21-211µM; no difference between white and red apparent)[8]

Meat and Alternatives

  • Shrimp (2,190µg/g[2][7])
  • Salmon (20-23µg/g[3])
  • Tuna (33-45µg/g[3])
  • Fish (battered product) at 71µg/g[3]
  • Corned beef (76-140µg/g[3])
  • Mutton (62-180µg/g[3])
  • Bacon (49-97µg/g[3])
  • Ham (81-95µg/g[3])
  • Sausage (320µg/g[3])
  • Meat pie (240µg/g[3])
  • Peanut butter (9-10µg/g[3])

Dairy

  • Milk (Homo) at 7-28µg/g[3]
  • Milk (Soy) at 11µg/g or less[3]
  • Brie (Cheese) at 54-67µg/g[3]
  • Blue (Cheese) at less than 1µg/g[3]
  • Edam (Cheese) at 33-35µg/g[3]
  • Feta (Cheese) at less than 1µg/g[3]

The New Zealand diet appears to have a daily intake of 298+/-4mg of TMG daily, mostly via grain products.[3]

1.3. Structure

Betaine is frequently referred to as a zwitterionic molecule (or an inner salt) due to it possessing both a positive and negative charge on different parts of the same molcule; this zwitterionic property dose not apply to its parent molecule (choline) which possesses only a positive charge.

1.4. Physicochemical Properties

Boiling food products appears to result in a significant loss in betaine concentrations.[9]

1.5. Biological Significance

The human body can convert dietary Choline into betaine in the liver, initially due to choline being metabolized into betaine aldehyde (via mitochondrial choline oxidase) and then again in the mitochondria by betaine aldehyde dehydrogenase to form betaine.[10][11] This conversion is largely seen as irreversible, and is the principle metabolic rate of choline in the body[2][12] with the remainer of choline being used towards synthesis of acetylcholine and phospholipids (such as phosphatidylcholine).[2]

Betaine is the major active metabolite of choline (although choline itself can influence more than just what betaine influences)

The synthesis of Phosphatidylcholine in the human body required to conversion of three molecules of S-Adenosyl Methionine (SAMe) into S-adenosylhomocysteine[11] via the PEMT enzyme (phosphatidylethanolamine N-methyltransferase) and this appears to be quantitatively the most important usage of SAMe in the body and the major contributor of de novo synthesis of homocysteine.[13]

Betaine is thought to be relevant to this process since, via the betaine-homocysteine methyltransferase (BHMT) enzyme, it reduces homocysteine into methionine which is one of the two pathways homocysteine can be reduced (the other being a folate dependent mechanism);[11] deficiencies of dietary choline or betaine cause a greater need for dietary folate to compensate.[14][15] This enzyme is also suppressed in instances of high salt intake[16] thought to be due to preventing excessive cellular swelling.

Alongside folate, dietary choline (via the metabolite betaine) or betaine itself are able to reduce homocysteine back into methionine and preserve whole-body methyl donation processes


Edit2. Molecular Targets

2.1. Cellular Hydration

Similar to some other molecules (such as Taurine, Creatine, glycerol, and trehalose[17]) TMG is an osmolyte and positively influences the hydration status of a cell.[17] Although its synthesis (from choline) is not altered by the tonicity of a cell,[18] it seems that the uptake of choline into the mitochondria (required to produce betaine) is[19] suggesting an intracellular role in osmoregulation.

Similar to other osmolytes, trimethylglycine concentrations in a cell can change the hydration status and tonicity of a cell which implicates TMG in a regulatory position; it can be effluxed and influxed into a cell to maintain hydration status, and increasing its cellular concentrations (with supplementation) is met with a swelling of the cell


Edit3. Pharmacology

3.1. Absorption

Trimethylglycine (TMG) is absorbed in the intestines via a sodium and chloride dependent mechanism[2] mostly in the duodenum (chick studies[20][21]).

Absorption of TMG appears to be very rapid[22] and has an absorption half-life of around 17 minutes following oral ingestion in humans[23] and peaks after 40-60 minutes;[23][22][24] based on the circulating concentrations following a single dose peaking in the range of 933-1014μM (from a basal concentration of less than 100μM) it seems to be very well absorbed during this time.

Trimethylglycine is taken up in the intestines quite rapidly and peaks in the blood similarly rapidly, with the absorption of betaine being near complete

3.2. Serum

Under normal dietary (without extra supplementation) fasting trimethylglycine TMG concentrations tend to be in the range of 20-70μM[25][23][26][2][23] with no significant differences in insulin resistant (type II diabetic) patients despite higher urinary excretion rates[23] but in the lower range of normal in persons with elevated fasting homocysteine concentrations.[23]

Fasting TMG concentrations in serum (independent of supplementation) do not appear to be perturbed in states of insulin resistance of type II diabetes, but appear to be lower when homocysteine is higher

The absorption of TMG appears to be rapid as, following an acute dose of 50mg/kg, it appears in the blood with an absorption half-life of 17 minutes[23] and this remained unchanged following repeated dosing.[23] This dose reached a Cmax of 940+/-190μM at a Tmax of 54 minutes, and while the Tmax remained unchanged following repeated doses the Cmax progressively rose thought to be due to accumulation of betaine.[23]

Elsewhere, dosing in the range of 1-6g TMG has been noted to have a similar Tmax of 40-60 minutes but a dose-dependent Cmax increasing serum TMG from a baseline of 47+/-10μM to 284+/-131µM, 599+/-190μM, and 1015+/-231μM.[22] This has been noted elsewhere in athletes given betaine, where the increase in serum betaine (reaching 933μM) was not different between consumption of betaine with water or TMG with a 6% carbohydrate/electrolyte solution.[24]

Supplementation of 1,000mg TMG in otherwise healthy persons appears to increase serum TMG (steady state levels) from a baseline concentration of 31.4+/-13.6µM to 52.5+/-26.5µM (67%)[27] whereas in this same population 3,000mg TMG increased serum betaine from 31.4+/-13.6µM to 109+/-41µM (247%) and 6,000mg from 31.4+/-13.6µM to 255+/-136µM (712%).[27]

In otherwise healthy humans, serum TMG dose-dependently increases in response to oral TMG supplementation up to 6,000mg betaine both acutely (when measuring the Cmax value) and when measuring steady state levels

3.3. Distribution

It seems that tissue levels of trimethyglycine (TMG) are higher than plasma levels in all measured tissues except for skeletal muscle and brain, where they tend to be comparable to and lower than plasma respectively.[28] Intestines, lungs, the heart, and spleen showed high dependence on and correlation with plasma TMG[28] whereas other tissues that were less dependent (liver, testes and kidneys) tended to be sites of synthesis and have highest concentrations of TMG.[28]

Elevations in tissue TMG (in rats) are known to be dietary rather than due to endogenous synthesis[29] and when rats (already consuming TMG at 0.9% of the diet) are measured TMG has been noted to accumulate mostly in the liver (1.6-9.5mM per liter of tissue water; 3.21-3.22µM/g tissue wet weight), kidneys (2.0-5.4mM; 2.78-3.24µM/g) and testes (2.4-3.4µM; 2.63µM/g) while the brain contained lowest levels of betaine (190µM or less; 0.02-0.04µM/g);[28] the female reproductive tract does not appear to possess a TMG content when at normal dietary levels in rats.[28]

Orally ingested TMG, due to increasing serum TMG, can increase TMG accumulation into tissues. TMG appears to be at higher levels in tissue than in plasma for all measured tissues except muscle and the brain and tissues with low synthetic capacities or lower TMG concentrations can more readily accumulate it from plasma

3.4. Cytology

On the cytoplasmic level, TMG is taken up into a cell mostly by the betaine/GABA transporter designated BGT-1[30] (similar to rat BGT-1, but 97% homologous[31] to mouse mGAT2[32]) and has two other less specific transporters it can be taken up by (although not specifically expressed in humans, suggesting that BGT-1 is the only one of concern at this moment in time[33][18]). BGT-1 (SLC6A12[34]) is in the same receptor superfamily as the Creatine transpoters (major one is SLC6A8[35] and the testicle specific one is SLC6A10[36]), and similar to the Taurine transporter (SLC6A6) which also has low affinity for GABA as well[37] BGT-1 doesn't appear to have too much affinity for GABA[38] and may (practically speaking) be predominately a betaine transporter.

BGT-1 appears to be regulated by hypertonicity, designed to take up betaine from outside of a cell when said cell requires the osmolytic properties of betaine[30] and it should be noted that the other GABA transporters (GAT1-3) are not known to mediate betaine uptake.

Trimethylglycine (TMG) can readily be taken up by a cell from the plasma via the BGT-1 transporter, which is more active in periods of cellular hypertonicity in order to preserve cellular hydration status

On the intracellular level, it appears that choline has its synthesis into betaine controlled due to uptake into the mitochondria (where it produces TMG) since the influx into the mitochondria responds to cellular tonicity (specifically, in a hypertonic state[19]) although synthesis per se is unaffected.[18]

The transportation of choline into the mitochondria for synthesis of TMG responds readily to a hypertonic state in order to preserve the cellular hydration status

3.5. Metabolism

The first stage of choline metabolism (the one stage not highly relevant to TMG supplementation) is the irreversible conversion of choline into TMG via mitochondrial oxidation.[2][12] Beyond that, metabolism of trimethylglycine (TMG) involves its methyl donation process, since in the process of converting homocysteine into methionine TMG itself is degraded into N,N-dimethylglycine (DMG) via the enzyme betaine homocysteine methyltransferase (BHMT).[2]

DMG itself can be subject to the dimethylglycine dehydrogenase enzyme, a folate binding protein (protein that can bind folate, which serves as a coenzyme in this process),[39][40] which converts DMG to N-methylglycine;[41] N-methylglycine is more commonly referred to as Sarcosine, and metabolism of sarcosine via sarcosine dehydrogenase will produce free Glycine since the last methyl group is removed.[42][43] Both of these stages, which lose a methyl group, donate it to the active folate molecule known as tetrahydrofolate which then becomes 5,10-methylenetetrahydrofolate and is itself a methyl donor.[41]

The general metabolic pathway goes from choline which produces (via an irreversible two step oxidation) TMG, which produces (via methyl donation to homocysteine) DMG followed by producing (removing yet another methyl group) sarcosine and finally (removing the final remaining methyl group) the amino acid glycine

Both TMG directly and the newly synthesized 5,10-methylenetetrahydrofolate can convert homocysteine into L-methionine, which is how they both influence the same end point in interventions (homocysteine reduction).[44][41] Specifically, 5,10-methylenetetrahydrofolate is substrate to the MTHFR enzyme to create 5-methyltetrahydrofolate (Levomefolic acid or Metafolin)

5,10-methylenetetrahydrofolate can also donate a methyl group to glycine if need be, to synthesis serine (the racemic amino acid mixture of D-Serine) via serine transhydroxymethylase[45] or it can be oxidized to form 10-formyltetrahydrofolate and support purine synthesis via thymidylate synthase;[46] administration of pure 5-methyltetrahydrofolate (Levomefolic acid) circumvents these two options.

The methyl groups 'lost' during the metabolism of DMG into glycine are actually given to the bioactive form of folate known as tetrahydrofolate (THF), and THF then goes off to donate these methyl groups to other processes

3.6. Elimination

The elimination half-life for TMG supplementation (50mg/kg oral intake) has been noted to be 14.38+/-7.17 hours after a single dose, and this was significantly increased to 41.17+/-13.50 after repeated dosing.[23]

There appears to be a very long elimination half-life with trimethylglycine, in accordance with its high bodily retention

Urinary elimination of trimethylglycine (TMG) supplementation tends to be in the form of dimethylglycine (DMG), which is the methylation byproduct of trimethylglycine; overall urinary excretion appears to be low as it has been measured at around 4% of oral intake (50mg/kg)[23] and in the dosage range of 1,000-6,000mg in otherwise healthy persons when measured over the next 24 hours the urine accounts for 3.2-7.4% of orally ingested TMG (and excreted in the form of TMG, which increased with dose as DMG excretion was fairly stable).[22]

Both TMG and DMG are found in the urine, and DMG excretion rates seem to not be too responsive to changes in dietary supplementation (perhaps due to a limit on methylation) whereas TMG elimination goes up linearly with supplementation. It seems urinary excretion consists of a small amount of overall excretion when measured acutely, perhaps due to high bodily retention or fecal elimination


Edit4. Neurology

4.1. Pharmacokinetics

Out of all organs which tend to hyperaccumulate trimethylglycine (TMG) to levels higher than observed in serum (and skeletal muscle which is approximately equal), the brain tends to have nearly undetectable levels of TMG[28] which may be related to how, at least in mice, the transporter that mediates TMG uptake (BGT-1 in humans and rats, mGAT2 in mice) is present at the blood brain barrier[31] and in the brain at quite low concentrations (at least relative to other GABA transporters).[34] While high levels of inhibitors for other GABA transporters (0.5mM) can reduce GABA uptake across the blood brain barrier by around 81.4-89.1%,[31] high levels of TMG only suppress uptake by 22.2% in vitro.[31]

mGAT-2 colocalizes with P-glycoprotein (a known efflux protein) at the blood brain barrier[31] and does have high affinity for GABA,[47] but due to GABA not readily be taken up from the periphery into the brain (rather, most GABA is synthesized locally[48][49]) and the low accumulation in the brain relative to serum TMG,[28] it suggests that this transporter is mostly an efflux transporter (removing GABA from the brain into the periphery) rather than an influx transporter.

Finally, the enzyme of synthesis for TMG from choline known as betaine-homocysteine methyltransferase (BHMT) is not appreciably localized in the brain[50] and there only appears to be a minor expression of a secondary gene for its transcription;[51] this suggests minimal local production of TMG from choline, which is in accordance with the measured brain tissue measurements (rats) being 0.02-0.04µM per gram wet weight.[28]

The transporter to mediate TMG uptake into the brain does exist, but TMG does not accumulate in the brain to a large degree when peripheral (blood not in the brain) levels increase; this may be because the transporter that mediate betaine is thought to be more involved in its efflux rather than influx

Despite the above, the transporter still has a role (astrocytes) in regulating osmotic balance to a degree[52] although other osmolytes that are known to accumulate in the brain (Taurine and Creatine, for example) may play a more relevant role than TMG.

The transporter, within the brain, still can have a role in osmoregulation (maintaining hydration status of a cell in response to its environment) although practical significance of this related to oral supplementation of betaine is not known yet unlikely (under normal conditions)

4.2. Glutaminergic Neurotransmission

Homocysteine is known to be an agonist of NMDA receptors at the 10-100μM range[53] which is a concentration seen in some instances of blood brain barrier disturbances (ie. stroke[54]). It is thought reducing serum homocysteine can alleviate glutaminergic neurotoxicity in these states, but the hypothesis has not been tested.

4.3. Epilepsy and Convulsion

The BGT-1 transporter appears to be involved in seizures in the medial entorhinal cortex (mEC) as its inhibition reduces the seizure threshold,[55] but it is unsure what this means for dietary supplementation of trimethylglycine (TMG) due to the brain being nonresponsive to changes in serum TMG.

The betaine transporter has a role in epilepsy and convulsions (in which its inhibition is desired to reduce convulsions), but practical significance to TMG supplementation is not known


Edit5. Cardiovascular Health

5.1. Cardiac Tissue

The heart tissue of rats appears to accumulate trimethylglycine (TMG) to the concentration of 224-372µM per liter of tissue water (78% water content in the heart) or to the level of 0.19-0.32µM per gram wet weight of the heart at the serum level of 101-186µM; it appears to be highly responsive to changes in serum TMG.[28]

250mg/kg of TMG daily for a period of 30 days in rats then subject to cardiotoxicity (isoprenaline) was able to greatly attenuate the damage as assessed by preventing changes in LDH (prevented 83.2% of the increase) and CPK (90.6%) while fully preventing the rise in homocysteine;[56] TMG without cardiotoxicity showed nonsignificant protective effects as assessed by enzyme leakage (indicative of cellular membrane damage)[56] and has been replicated elsewhere where lysozymal enzymes and lipid peroxidation were normalized to the same degree in heart tissue.[57]

Preliminary evidence shows a cardioprotective effect, and since it appears to be similar to Creatine in a way it is possible this is secondary to the osmolyte properties of TMG; more research is needed to evaluate the mechanisms and see if this is relevant to human ingestion

5.2. Blood Flow

A meeting abstract (preliminary evidence) has made note that trimethylglycine (TMG) supplementation, at 6g daily in a pilot study of 12 subjects, has increased nitric oxide levels in the blood from 28.8+/-3.4µM to 82.3+/-13.2µM (185% increase) after one week of supplementation.[58] A later study using a lower dose (2.5g TMG in two divided doses) in otherwise healthy persons failed to replicate any influence on nitric oxide metabolism in otherwise healthy subjects.[59]

Preliminary evidence suggesting a large increase in nitric oxide has failed to be replicated in otherwise healthy subjects who were exercising; more research is needed to see under what conditions an increase in nitric oxide may occur

5.3. Atherosclerosis

Betaine does not actually appear to be correlated with homocysteine in a fasted state (while folate is)[27] and despite low betaine plus choline intake (ie. low methylation) is thought to promote atherogenesis via reduced methylation of DNA[60][61] and betaine insufficienct being a risk factor for acute cardiovascular complications in those with metabolic syndrome[62] typical dietary betaine plus choline intake does not appear to be associated with reduced risk of coronary heart disease.[63]

A relative deficiency of betaine appears to be a risk factor for acute cardiovascular complications in those with metabolic impairments, but there does not appear to be a dose-dependent protective association seen with betaine when looking at persons not in betaine insufficiency

High doses of betaine (6g or more) have been frequently used for the treatment of homocysteine[11][64][65] since it appears that patients with high homocysteine levels (hyperhomocysteinemia) due to a genetic defect in homocysteine metabolism only respond to such a high level of intake.[66][67][68] Homocysteine may work in reducing homocysteine after a single dose[69] and time-dependently increases in potency up until day five[27] where it then persists in magnitude for as long as supplementation is continued.

Both folic acid and betaine are known to decrease fasting homocysteine concentrations, with more potency coming from the former[70][71] although in response to a methionine load betaine is effective whereas folic acid is not.[72]

High dose betaine supplementation, similar to folic acid (folate), is usually used to lower homocysteine concentrations in pathological conditions characterized by high homocysteine concentrations

In otherwise healthy adults (fasting plasma homocysteine of 8.4-22.2μM), supplemental betaine (1,500-3,000mg daily) is able to reduce plasma homocysteine after six weeks by 12-15% (slightly less than 6,000mg daily which reached 20%) which was of similar magnitude to when homocysteine was measured after two weeks.[69] Elsewhere, 3,000mg was confirmed to be effective (10% reduction) while 1,000mg failed in otherwise healthy persons (baseline homocysteine of 10.4-13.2μM),[27] 6,000mg was noted to reduce homocysteine by 8% (pilot study)[73] and 9% in obese humans,[74] and one study noted an 11% decrease relative to placebo after six weeks.[72]

In response to a methionine load in otherwise healthy humans, a single dose of betaine in the range of 1,500-6,000mg is able to reduce the increase in homocysteine by 16-35% which persisted in magnitude when tested again after two and six weeks.[69] This has been noted to the degree of 40% (AUC) or 49% (increment after six hours) following 6g over six weeks of supplementation, where 800μg of folic acid was ineffective.[72]

Finally, low doses of betaine (500-800mg) appear to also be able to reduce homocysteine concentrations in otherwise healthy men but only after an L-methionine load;[75] the dose appears to be too low to influence fasting homocysteine concentrations.[75]

Betaine supplementation appears to acutely reduce plasma homocysteine in otherwise healthy persons in a dose-dependent manner, and appears to persist in magnitude when measured over the course of six weeks. It is nonsignificantly less potent than the active dose of folic acid at doing this, but appears to be significantly more effective when measuring increases in homocysteine following an L-methionine load

The donation of a methyl group from betaine towards homocysteine results in L-methionine being produced (as L-methionine is methylated homocysteine, and homocysteine is demethylated L-methionine), and an increase in L-methionine is seen with supplementation of 6,000mg of betaine (not 1,500-3,000mg) over six weeks in otherwise healthy humans by 60% (fasting) and 12% (post methionine load).[69] Betaine also appears to increase L-methionine oxidation as well[76] due to increasing methionine-mediated methylation.[76]

As evidence of the direct methyl donation in plasma, betaine supplementation increases plasma L-methionine in accordance with the decrease in plasma homocysteine

Genetically speaking, persons who are homozygotes for the T-allele of methylenetetrahydrofolate reductase (MTHFR) respond more to betaine supplementation, and even in healthy persons without any problems in homocysteine levels in serum the whole-group decrease (10.4-14.2%) is increased when only looking at these persons (15.4-21.9%).[27]

5.4. Cholesterol

Trimethylglycine (TMG) supplementation has been noted to, in animal studies (rodent and swine), increase cholesterol relative to control.[77][78]

Supplementation of betaine at 6g daily for 12 weeks has once been associated with stasis (no change) in total cholesterol and LDL cholesterol levels in obese subjects where the placebo experienced a decline, causing a relative increase.[74] In this scenario, HDL-C was unaffected in both groups.[74]

One study conducting three trials on TMG supplementation at 6g daily[79] noted that there was a significant increase in total cholesterol in otherwise healthy humans (0.36mM: 8%) which was almost solely accounted for by an increase in LDL cholesterol (0.14mM; 11%) detectable within two weeks of supplementation;[79] this increase in cholesterol was not seen in the trials on folic acid, appears to increase in magnitude from the 1,500-6,000mg dosage range, and did not influence HDL-C production.[79]

5.5. Triglycerides

Trimethylglycine (TMG) supplementation is proposed[79][77] to increase triglyceride levels in serum due to an increased synthesis of vLDL cholesterol and efflux of triglycerides from the liver into peripheral circulation (tissue outside of the liver and not inclusive of the brain), since TMG can contribute to local synthesis of Phosphatidylcholine (PC).

PC synthesis in the liver will stimulate vLDL synthesis and efflux per se[80][81] as PC is a component of vLDL cholesterol, and the process of converting phosphatidylethanolamine into PC is initiated by the BHMT enzyme[82] and finalized by S-Adenosyl Methionine which TMG also supports[83].

Methylation from TMG appears to be able to stimulate phosphatidylcholine synthesis, and it is thought that production of phosphatidylcholine in the liver stimulates vLDL production which then causes efflux of triglycerides from the liver into the blood (good in reducing liver triglycerides, potentially negative for serum triglycerides)

Supplementation of 6g trimethylglycine (TMG) to obese individuals over the course of 12 weeks has failed to significantly influence triglyceride concentrations in serum despite an increase in LDL and total cholesterol (as the decrease seen in placebo was not present with TMG supplementation);[74] this study did note a nonsignificant trend to increase triglycerides which reached 12% in magnitude relative to placebo.[74]

One study conducting three trials[79] each with TMG at 6g daily for six weeks of which measured confirmed an increase of 0.14mM (95% confidence interval of 0.04–0.23mM) or 13% relative to baseline in otherwise healthy subjects, evident within two weeks of supplementation.[79] This was also seen with dietary supplementation of 2.6g of supplemental Phosphatidylcholine (PC) over the course of two weeks, where an 8% increase was noted.[79]

At this moment in time, it appears that supplementation of the therapeutic dosage of TMG (6g) to reduce homocysteine by around 10-20% is also met with an increase in triglycerides of around 10% in otherwise healthy human subjects


Edit6. Fat Mass and Obesity

6.1. Metabolic Rate

Supplementation of 6g trimethylglycine (TMG) daily for 12 weeks in obese persons has failed to significantly influence the metabolic rate.[74]

At this moment in time, there does not appear to be an increase in the metabolic rate seen with high doses of TMG supplementation in obese humans

6.2. Fat Mass

Supplementation of 6g betaine daily for 12 weeks in obese individuals has failed to significantly influence weight loss nor fat mass as assessed by calipers.[74]


Edit7. Skeletal Muscle and Physical Performance

7.1. Mechanisms

Although preliminary evidence suggested a possible role for trimethylglycine (TMG) supplementation in increasing nitric oxide concentrations in serum[58] supplementation of 2.5g TMG (via 500mL gatorade) in two divided doses daily for two weeks prior to fasted exercise training in otherwise healthy subjects has failed to modify circulating NOx levels (biomarker for nitric oxide) and failed to influence the perception of a pump,[59] there was a higher muscle tisssue oxygen saturation (StO2) before training and lower levels after indicative of more oxygen consumption during training.[59]

This was hypothesized[59] to be due to increased cellular swelling with TMG, which is known to protect from urea-induced inactivation of muscle myosin adenosine triphosphatase (ATPase)[84] and generally protect the cell from stressors (well established with Creatine[85]); this was thought to then enhance the overall work capacity seen (6.5% in the fasted state as assessed by bench press[59]) to promote more muscle cell metabolism.

One of the hypothesized mechanisms for TMG's ergogenic effects are secondary to cellular swelling and causing a more robust cellular survival in the presence of damaging stimuli such as exercise; this appears to work well with the observations that there is increased muscle oxygen consumption alongside the increased workload, and less biomarkers of damage (lactate) but not alongside an increase in nitric oxide which could be another explanation for increased oxygen consumption

Another possible hypothesis[86] is that provision of TMG as a methyl donor favors Phosphatidylcholine (PC) synthesis (known to require a lot of methylation from TMG[13]). Similar to PC, methyl donation can promote the synthesis of Creatine since S-Adenosyl Methionine (SAMe) is required to synthesize creatine and SAMe is replenished when TMG methylates homocysteine into L-methionine (although the one trial to investigate phosphocreatine stores in muscle with 2g betaine failed to find any effecti[87]).

The ability of TMG to act as a methyl donor is thought to possibly play a role vicariously through phosphatidylcholine synthesis, and this exact same role is thought to play another role in promoting the synthesis of creatine

7.2. Hypertrophy

Trimethylglycine (TMG) is detectable in rat skeletal muscle at the concentration of 124-217µM per liter of tissue water (0.10-0.18µM per gram wet weight, due to a 76% water content of skeletal muscle) at the serum level of 101-186µM; it is one of the few organs that does not hyperaccumulate betaine above serum concentrations.[28]

TMG is found in skeletal muscle, and under normal conditions (standard dietary conditions) it appears to be at levels comparable to that seen in serum

Supplementation of TMG at 1,250mg twice daily (dissolved in gatorade) for two weeks prior to an acute exercise session (in the morning in a fasted state) failed to alter resting Akt and p70S6K phosphorylation, but after exercise Akt phosphorylation dropped in placebo and was maintained in the betaine group (resulting in a significant relative increase).[88]

Phosphorylation of AMPK, which is reduced during exercise, is not affected by TMG supplementation at the aforementioned dosage of 1,250mg twice daily.[88]

The Akt/mTOR signalling pathway, involved in protein synthesis, appears to be increased to a greater degree following exercise when the subject consumes TMG supplementation. This was found in a fasted state, and it is not known if it applies to a fed state

7.3. Resistance Training

In studies using the standard supplemental protocol (1.25g of trimethylglycine (TMG), usually in 250mL of carbohydrate solution like gatorade, to be taken twice daily for two weeks) there has been an increase in total work conducted over the course of a bench press workout (6.5%) despite no significant increase in the volume conducted in any individual set; this study was conducted in a fasted state in resistance trained men while leg exercises saw not benefit.[59] Similar to that, one study reported a lesser chance in fatigue state during exercise with TMG relative to placebo yet failed to find any whole group differences in fatigue[86] suggesting minimal practical benefits.

For exercises where near maximal weight was used, one study noted that two weeks supplementation increased the amount of training volume conducted by the legs at 90% average power until fatigue;[89] exercises at 90% peak power to fatigue saw benefit at week one but became nonsignifcant after two weeks, and the chest was not benefitted[89] and elsewhere in minimally trained men given TMG there was no benefit to exercises (bench and squat) conducted at 85% of their one rep maximum until fatigue relative to placebo.[90]

There appears to be an antifatigue effect when looking at the workout as a whole, but since many parameters of fatigue measurement also come back negative and (when fatigue reduction does occur) the magnitude of fatigue reduction is minor and may not be practically relevant

7.4. Power Output

In response to the standard supplemental protocol (1.25g of trimethylglycine (TMG), usually in 250mL of carbohydrate solution like gatorade, to be taken twice daily for two weeks) betaine has failed to increase power output in the bench or leg press exercises in resistance trained men exercising in the fasted state,[59] no changes in eccentric or concentretic power in weight training (recreationally active men in a nonfasted state),[86] and no changes to peak power on leg or chest exercises in college aged men at one or two weeks (nor changes in power on a wingate test).[89] One study conducted in sedentary men given 2g TMG for 10 days either in isolation or alongside 20g of creatine failed to note any power enhancement either inherently with betaine or an enhancement of the creatine-induced increase in power output.[87]

The two positive tests using the standard protocol (2.5g TMG in two divided doses over two weeks) in minimally active men where an increase in power output occurred as assessed by an isometric (but not jump) squat test and both isometric and bench throw tests[90] and a study where power output was assessed by sprinting tests on a cycle erogmeter in recreationally active persons (four 12 second sprints against resistance) noted improvements in the average and maximum peak power output (3.4% and 3.8%) and average and maximum mean power output (3.3% and 3.5%) in the TMG group relative to placebo.[91]

One study has noted an increase in power output in a gym setting and one on a cycle ergometer, while the latter test has failed to be replicated and two other studies in a gym setting have failed to find any significant improvement relative to placebo. At this moment in time possible power enhancement from TMG supplementation seems unreliable

7.5. Heat Tolerance

One study has been conducted in trained runners who were dehydrated to 2.7% reduced bodyweight (exercise for 90 minutes in a heated environment) and then were allowed a rehydrating beverage of either a carbohydrate/electrolyte solution (or water) with or without additional trimethylglycine (TMG) at 5g/L until they reached less than 1.4% of a deviation from normal bodyweight, and then they were subject to a performance test.[24] This study noted a serum level of TMG at the peak levels (933μM) which somewhat similar to supplementation of 50mg/kg (940+/-190μM)[22] or 6g (1015+/-231μM)[23] TMG elsewhere.

TMG supplementation alone (relative to water alone) or TMG with carbohydrates (relative to carbohydrate) failed to significantly improve sprinting to volitional fatigue although a nonsignificant trend was evident[24] and there appeared to be increased whole body oxygen uptake in the carbohydrate plus TMG (relative to carbohydrate) of 5% when measured during the final sprint only.[24]

There was no significant influence on the rate of percieved exertion of any biomarker of hydration between betaine groups and their respective controls.[24]


Edit8. Interactions with Hormones

8.1. Growth Hormones

Supplementation of trimethylglycine (TMG) at 1,250mg twice daily (dissolved in gatorade) for two weeks prior to an acute exercise session (in the morning in a fasted state) was noted to be associated with nonsignificantly higher growth hormone (6.1%; P=0.089) while IGF-1 was significantly increased (7.8%) concentrations after exercise.[88]

May be able to increase IGF-1 in a fasted state, with the increase in growth hormone being very minor (significantly less than Arginine and Creatine) and only measured acutely rather than over 24 hours; weak evidence to support practically relevant increases in growth hormones

8.2. Cortisol

Supplementation of trimethylglycine (TMG) at 1,250mg twice daily (dissolved in gatorade) for two weeks prior to an acute exercise session (in the morning in a fasted state) was noted to be associated with reduced cortisol levels (6.1%) after exercise.[88]

Minor reductions in cortisol with supplemental TMG when measured around fasted physical training


Edit9. Inflammation and Immunology

9.1. Virology

Compounds that enhance methylation (via SAMe) are thought to be able to augment the anti-viral efficacy of interferon A (IFNα) therapy. This is in part due to how protein phosphatase 2A (PP2Ac; overexpressed in hepatitis C infected cells[92][93]) is known to negatively regulate the signalling of IFNα[93] by reducing levels of a protein known as protein arginine methyltransferase 1 (PRMT1) which methylates (positively influences) PIAS1[94] and STAT1[95] using SAMe as substrate, and it is though that superloading methyl donating molecules can circumvent this reduction in methylation and preserves IFNα signalling.

At least when looking at in vitro evidence, SAMe can inhibit hepatitis C (HCV) replication[96] and potentiate and/or preserve IFNα signalling in isolated Huh-7 cells infected with HCV.[97]

It is thought that hepatitis C viral replications is 'preserved' in part by a mechanism involving reduced methyl donation to a few proteins, resulting in a weakining of interferon alpha (IFNα) signalling and less antiviral effects from IFNα. Supporting methylation appears to preserve the potency of IFNα signalling

The combination of trimethylglycine (TMG; 3g twice daily) paired with S-adenosylmethionine (SAMe; 400mg thrice daily) in addition to standard antiviral therapy (pegylated IFNα and ribavirin) appeared to enhance the early virological response but failed to significantly improve sustained virological response.[98]

Preliminary evidence supports limited efficacy for TMG supplementation, but is confounded with the inclusion of SAMe supplementation as well


Edit10. Peripheral Organ Systems

10.1. Oral Cavity

Betaine is thought to be beneficial for dry mouth symptoms due to its inclusion in toothpaste (by itself) appears to reduce dry mouth symptoms at 4% of the toothpaste by weight in subjects with chronic dry mouth (usually Sjögren's syndrome) when used twice daily over two weeks (pilot study) with more potency in those with worse symptoms of dry mouth.[99] It also seems effective when paired with sodium lauryl sulfate (SLS)[100][101] but less so than betaine by itself.[101]

Brushing of the teeth with a betaine containing toothpaste does not appear to significantly alter the microbiotica (bacterial colonies) or the mouth nor the appearance of the mucosa.[99]

Sodium lauryl sulfate (SLS) is a common detergent in mouthwashes and toothpastes that may irritate the mucosa of the dry mouth, and betaine has been noted to reduce SLS induced mucosal irritation (1.0%)[102] with a second study failing to note an inhibition of SLS (1.2%) induced irritation[100] and one of the previous studies noting benefit against 1% also noting a failure against 0.5% and 2.0% SLS concentration.[102] Another irritant used in some oral cosmetics, cocoamidopropylbetaine or CAPB, at a concentration of 2.0% was not protected against with betaine.[102]

Betaine by itself in a toothpaste at around 4% concentration appears to alleviate dry mouth symptoms, and while it has the potential to also reduce irritation by SLS (a detergent that is also a mucosal irritant) it is unreliable in its protection and its efficacy against dry mouth may be reduced in the presence of SLS

A mouthwash containing betaine (1.33% betaine solution alongside olive oil and xylitol, the latter at 3.30%) over the course of four weeks in persons with dry mouth induced by medications (xerostomia) when 12mL is used for 30s thrice daily after meals appears to be effective in reducing symptoms as assessed by OHIP‐14 scores where 63% of persons reported improvement from baseline to a small (40%) or moderate (23%) degree;[103] this has been noted previously within a week of supplementation in an unblinded pilot study,[104] and other minor constituents of this mouthwash (Vitamin E and B5) may also be active.

Betaine containing mouthwash (1.33%) also appears to reduce symptoms of dry mouth, but at the same time all the studies conducted on this product include other potential confounds which may add to the clinical efficacy

10.2. Liver

TMG is detectable in the rat kidney at a concentration of 1.6-9.5mM (per liter of tissue water) and 3.21-3.22µM/g (per gram of organ wet weight), and due to its high concentration relative to plasma (101-186µM) and other organs under resting conditions is not highly responsive to changes in serum.[28]

Betaine is readily synthesized in the liver and is present in high but variable levels, it does not appear to readily respond to plasma alterations of betaine in otherwise normal conditions

Oral supplementation of betaine glucuronate at 150mg (alongisde diethanolamine glucuronate and nicotinamide ascorbate at 30mg and 20mg respectively) twice daily over eight weeks in persons with fatty liver (non-alcoholic steatohepatitis) was able to reduce liver fat by 25% whereas placebo saw a 3% reduction whereas liver enzymes were reduced by 11% (ALT), 14% (AST) and 15% (γ-GT).[1] There was also a reduction in liver size seen with supplementation, and while there was significantly less reported pain in the upper left quadrant of the torso (45-57%) dyspepsia was not different between groups and supplementation was well tolerated.[1]

A pilot study using betaine in isolation (3,000mg twice daily) over the course of a year in persons with fatty liver noted significant reductions in ALT and AST where three (out of seven) patients had normalized values and another three had over a 50% reduction; the three dropouts had a 38-39% reduction in those two enzymes and there was one nonresponders.[105] This study also noted significant reductions in liver necrosis area (assessed by necroinflammatory grade), fibrosis, and fat buildup.[105] These benefits were later seen in a study on a larger sample (n=23) in a cohort design where 10g twice daily reduced liver fat and inflammation in over 90% of subjects (and four subjects reporting a reduction in liver fibrosis of over two stages) alongside reductions in homocysteine.[106]

Despite the aforementioned preliminary evidence, the large trial has been conducted on this topic[107] failed to note a reduction in S-adenosylhomocysteine (the methylation target of betaine) or in fibrosis, and while the betaine group actually underperformed relative to placebo in improving steatosis by over one grade (29% vs 61%) there was less overall changes with betaine (71% vs 22%) suggesting a possible role in stasis of disease progression.[107] There was an increase in plasma L-methionine and SAMe noted however, with all other serum inflammatory biomarkers and adiponectin unaffected, and subject self-reported health and well being was not different between groups.[107] It was noted elsewhere[108] that this study had some limitation such as a high dropout rate (associated with intestinal distress from high dose betaine) and high levels of persons with advanced fibrosis.

Preliminary evidence for betaine in the treatment of nonalcoholic steatohepatitis (NASH) noted remarkable benefits with high dose supplementation, but the most recent and well controlled trial has failed to note many of the benefits although a reduction in liver fat still appeared to exist. There does appear to be a role for betaine in this disease state, but its exact role requires more research to pinpoint

10.3. Kidneys

TMG is detectable in the rat kidney at a concentration of 2.0-5.4mM (per liter of tissue water) and 2.78-3.24µM/g (per gram of organ wet weight), and due to its high concentration relative to plasma (101-186µM) and other organs under resting conditions is not highly responsive to changes in serum.[28]

TMG is one of the major osmolytes of the kidneys alongside sugars (Inositol and sorbitol[109]), Taurine,[110] and glycerophosphocholine (GPC)[111] with TMG and GPC (the methylamines) being known to counteract the protein destabilizing effects of urea in renal cells without perturbing cellular function.[112]

It appears that urinary TMG excretion is increased in the type II diabetic state despite plasma levels remaining stable[113] which has been known to correlated with plasma retinol binding protein (RBP) and glucose[114] (although acute spikes in glucose in nondiabetics do not increase urinary TMG[115]). This elevation is also noted in patients with kidney diseases not associated with diabetes[113] and is thought to be a biomarker for proximal tubular dysfunction.[114]

10.4. Intestines

TMG is known to accumulate in the intestines to the level of 524-920µM per liter of tissue water (75% water content of tissue) or 0.43-0.75µM/g tissue wet weight under normal rat dietary conditions (serum TMG at 101-186µM), and appears to be responsive to changes in serum TMG.[28]

10.5. Lung

TMG is known to accumulate in the skin to the level of 290-500µM per liter of tissue water (79% water content of tissue) or 0.25-0.43µM/g tissue wet weight under normal rat dietary conditions (serum TMG at 101-186µM), and appears to be responsive to changes in serum TMG.[28]

10.6. Skin

TMG is known to accumulate in the skin to the level of 305-412µM per liter of tissue water (65% water content of tissue) or 0.22-0.30µM/g tissue wet weight under normal rat dietary conditions (serum TMG at 101-186µM), and appears to be responsive to changes in serum TMG.[28]

10.7. Testes

TMG is detectable in the rat testes at a concentration of 2.4-3.4mM (per liter of tissue water) and 2.63µM/g (per gram of organ wet weight), and due to its high concentration relative to plasma (101-186µM) and other organs under resting conditions is moderately responsive to changes in serum (less than other organs, more than the liver and kidneys).[28]


Edit11. Other Medical Conditions

11.1. Alzheimer's Disease

Betaine is thought to be beneficial for the treatment of Alzheimer's disease due to correlations with elevated homocysteine and risk of Alzheimer's Disease.[116][117] A causative or biomarker role is not known for homocysteine, as since it does potentially have excitotoxic roles via the NMDA receptors[53] there are also reduced S-adenosyl methionine levels in the brain of those with Alzheimer's[118] and their cerebrospinal fluid[119] suggesting impairments in overall methylation in general.

Betaine is not known to accumulate in the brain following oral ingestion[28] nor does its enzyme of synthesis (BHMT) seem to be located in the brain at high levels[51][50] but it is hypothesized[120] that reductions in peripheral homocysteine may play a protective role assuming homocysteine is playing a causative role.

On the assumption that homocysteine plays a causative role in Alzheimer's pathology, it is hypothesized that reductions in peripheral homocysteine (perhaps resulting in less homocysteine influx into the brain) could reduce symptoms of Alzheimer's disease

In a small 24-week pilot study, supplementation of betaine (3g twice daily for a total of 6g) to seven persons with Alzheimer's Disease concurrently using an acetylcholinesterase inhibitor, but results were too variable and the sample too small to come to any conclusions on treatment efficacy relative to baseline; Homocysteine levels were not measured in this study.[120]

The evidence at this point in time in humans cannot be used to evaluate the efficacy of betaine supplementation

11.2. Angelman Syndrome

Supplementation of betaine with other factors thought to improve methylation in the body (Creatine, B12, and levomefolic acid) to subjects with angelman syndrome has failed to exert therapeutic effects.[121]


Edit12. Nutrient-Nutrient Interactions

12.1. Choline

2,400mg choline bitartrate (1g choline) daily for twelve weeks in postmenopausal women (may have higher requirements for dietary choline[122]) has been noted to not only increase plasma choline at weeks six and twelve (from a medium value of 7.33µM to 11.1-11.7µM) but also plasma TMG (from a median value of 30.7µM to 54.6-65µM, or 77-111%) and dimethylglycine (from 3.53µM to 3.92-4.63µM) under steady state conditions.[123]

Interestingly, 1g of betaine itself has increased plasma steady state concentrations from 31.4+/-13.6µM to 52.5+/-26.5µM (67%)[27] suggesting that choline and betaine are actually equipotent in increasing plasma betaine in a resting state.

Oral supplementation of choline appears to be sufficient in increasing plasma betaine concentrations, and at least at the 1,000mg dosage it appears to be just as potent as betaine at increasing plasma betaine concentrations

12.2. S-Adenosyl Methionine (SAMe)

In rats supplemented with an additional 0.5% betaine in their feed, it appears that SAMe production in the liver is increased two-fold relative to control; this is increased to five-fold if the rats were pretreated with ethanol (which normally impairs this pathway)[124] and injections of betaine have demonstrated dose-dependent increases in red blood cell concentrations of SAMe in rats.[125]

12.3. Creatine

Creatine is perhaps the most well renowned ergogenic aid (performance enhancer) known as a dietary supplement, and it appears that the synthesis of creatine requires methyl donation; supplementation of betaine to a diet without supplemental creatine can accelerate creatine synthesis in the rat[126] probably just via increasing SAMe concentrations (which are directly required for creatine synthesis).[127]

Supplementation of betaine at 2g to otherwise healthy adults over the course of ten days has failed to increase muscle phosphocreatine content (the active form of creatine)[87] and the addition of 2g betaine to supplementation of 20g creatine failed to augment the increase noted with creatine.[87] Alongside the failure to increase intramuscular phosphocreatine levels was a failure of betaine to augment the power enhancement seen with creatine supplementation.[87]

12.4. Folate

Folate and betaine are interrelated as both molecules are known to improve methylation status of the body, and betaine can preserve methylation in periods of low folate status while a reduction in bioavailable betaine (via reduced dietary choline intake) increases requirements for folate.[14][128]

Supplementation of betaine (1,000mg) appears to be able to acutely suppress folic acid concentrations in serum by 23-28% after the first week of supplementaton, but this is readily normalized back to baseline levels within a week afterwards.[27] Similar to that, when folic acid supplementation is added to betaine there is an increase in serum folic acid due to its supplementation (41-59%) which is then normalized to control within a week[27] and other studies measuring serum folic acid levels after prolonged supplementation fail to note any significant changes.[72][129]

When 1mg folic acid is added to 6,000mg betaine, the reduction in homocysteine seen with betaine (14.2%) is added upon by the folic acid (an additional 5.1%).[27]

Folic acid appears to be additive with betaine in reducing plasma homocysteine

12.5. Vitamin B12

Cobalamin (Vitamin B12) does not appear to have its serum concentrations altered with ingestion of betaine at doses of 1,000mg up to 6,000mg, even if the highest dose has an additional 1mg of folic acid added to it of periods of up to six weeks of supplementation.[27][129]

One study noted an increase in plasma B12 relative to placebo, but there was a decrease noted in placebo which may have caused the relatively significant increase.[72] Similar to this, a relative increase has been noted with TMG relative to folic acid in one study[129] where B12 nonsignificantly decreased with folic acid supplementation (800µg).

12.6. Alcohol

It seems that chronic alcohol ingestion (rats) impairs the function of the methionine synthetase enzyme, but liver concentrations of SAMe are not affected acutely since the liver pool of betaine is used up when the betaine:homocysteine methyltransferase (BHMT) enzyme is upregulated;[124] supplementation of betaine at 0.5% of the rat diet, normally enough to two-fold increase SAMe, increases it five-fold in rats subject to ethanol.[124]


Edit13. Safety and Toxicology

13.1. Side-Effects

Trimethylamine (TMA) is a metabolite that is known to have a fishy odour, which is normally at low levels and undetectable unless the person has high levels in their urine and body secretions (Trimethylaminuria) which is a condition known as "Fish Odour Syndrome";[130] it is caused by either a mutation in the liver enzyme flavin containing mono-oxygenase type 3 (FMO3[131]) which metabolizes TMA known as 'Primary trimethylaminuria' or from excess production of TMA in the intestinal tract from bacteria known as 'Secondary trimethylaminuria'.[132][133] It is medically benign (ie. not a medical concern), but adherence to supplementation goes down since many subjects would rather not smell like fish and it mild trimethylaminuria could affect anywhere between 1 in 20 or 1 in 100 of persons.[134]

The main cause of trimethylaminuria is high dietary choline intake, but it appears that betaine administration may also be capable of inducing Fish Odour Syndrome or at least the scent of fish in bodily secretions when used in therapeutic doses of 20g.[135] Although one study has noted that dimethylglycine (DMG) was associated with a fishy smell[136] it is thought that this isn't the factor since it was later found to not be correlated, and an increase in TMA was noted in its place.[135]

It is possible that, similar to choline, that betaine can cause a fishy smell in the breath and bodily secretions when taken at high therapeutic doses in some persons who are genetically susceptible to it

It appears that oral ingestion of riboflavin (Vitamin B2) at the dose of 100mg taken twice daily has, at least in one case study where fishy odor was a side-effect of 16-20g betaine ingestion, been able to reduce nearly abolish the fishy odour in breath and body secretion within a few days and to reduce TMA in the urine when measured after 30 days;[135] this was thought to be due to increased FMO3 activity, of which riboflavin is a cofactor for.

At least one case study has supported the usage of riboflavin (Vitamin B2) at 100mg twice daily in eliminating the fish odour associated with betaine supplementation

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