Trimethylglycine (TMG): Difference between revisions

Latest revision as of 03:40, 21 January 2024

Trimethylglycine (TMG), commonly known as betaine, is an amino acid derivative that naturally occurs in various plant and animal sources. With its three methyl groups attached to a glycine molecule, TMG has garnered attention in both the dietary supplement market and the scientific community due to its role as a methyl donor in vital biochemical processes.

The story of TMG traces back to the early 20th century when it was first isolated from sugar beets, hence the name "betaine" after the Latin name for beet, Beta vulgaris. Over the years, researchers have identified its presence in numerous foods and its key functions within human metabolism. As the exploration of its potential benefits continued, TMG started to gain traction, especially in discussions related to heart health, liver function, and, more recently, longevity.

Sources in Nature

TMG is found in various organisms, both plants and animals. In plants, TMG serves as an osmolyte, helping cells retain water under stressful conditions such as high salinity. Some natural sources of TMG include:

Betaine in foods^[1]
Food	Betaine (mg/100 g)
Quinoa	630
Wheat germ	410
Lamb's quarters	330
Wheat bran	320
Canned Beetroot	260
Dark Rye flour	150
Spinach	110-130

Supplementation

TMG is also available as a dietary supplement. As a byproduct of sugar beet processing, commercial TMG supplements are usually derived from this source. Additionally, TMG can also be found in smaller amounts in certain multivitamins and specialized supplements aimed at supporting liver health or methylation processes in the body.

Nutritionally, betaine is not needed when sufficient dietary choline is present for synthesis.^[2] When insufficient betaine is available, elevated homocysteine levels and decreased SAM levels in blood occur. Supplementation of betaine in this situation would resolve these blood marker issues, but not compensate for other functions of choline.^[3]

Bioavailability and Metabolism

Once ingested, TMG is rapidly absorbed in the intestines. Inside the body, it primarily functions as a methyl donor, donating one of its methyl groups in the conversion of homocysteine to methionine, an essential amino acid. This biochemical process, which occurs in the liver and kidneys, helps maintain normal levels of homocysteine, an amino acid that, when elevated, is linked to various health risks.

Role in Cellular Osmoregulation

In addition to its role in methylation, TMG acts as an osmoprotectant. This means it helps regulate the balance of water inside and outside cells, particularly in conditions where cells might be at risk of dehydration or stress. In plants, this function is crucial for survival in high-salinity environments.

Potential Benefits

TMG has been the focus of numerous studies due to its potential health benefits. It's worth noting that while TMG has various potential benefits, individual responses can vary.

Heart Health and Homocysteine Levels

Homocysteine Reduction: TMG acts as a methyl donor in the conversion of homocysteine, a non-proteinogenic α-amino acid, back to methionine. Elevated homocysteine levels are a known risk factor for cardiovascular diseases. By helping to lower these levels, TMG can potentially contribute to reduced risks of heart diseases. The US Food and Drug Administration (FDA) approved betaine trimethylglycine (also known by the brand name Cystadane) for the treatment of homocystinuria, a disease caused by abnormally high homocysteine levels at birth. ^[4]
Endothelial Function: Some studies suggest that TMG might improve endothelial function, thus potentially benefiting cardiovascular health.

Liver Function and Detoxification

Fatty Liver Reduction: TMG has been shown to help reduce liver fat accumulation, which can be beneficial in conditions like non-alcoholic fatty liver disease (NAFLD).
Support in Detoxification: As a methyl donor, TMG can support various liver detoxification processes, assisting the body in removing harmful substances.

Stress Resistance and Cellular Hydration

Osmoprotection: TMG functions as an osmolyte, meaning it helps regulate cellular hydration. This can be particularly beneficial in conditions of cellular stress, helping cells maintain their volume and function.
Protection against Stressors: TMG may offer protective effects against certain environmental stressors, potentially aiding in resilience against some forms of oxidative stress.

Support in Metabolic Processes

Methyl Donation: As a significant source of methyl groups, TMG can support various metabolic processes in the body that require methylation. This includes the synthesis of certain neurotransmitters, DNA methylation, and other essential reactions.
Energy Production: Some evidence suggests TMG might support energy production, aiding in exercise performance and overall vitality.

Mood and Well-being

Neurotransmitter Synthesis: Through its role in the methylation process, TMG can indirectly support the synthesis of neurotransmitters such as serotonin and dopamine, which play crucial roles in mood regulation.
Potential Antidepressant Effects: Preliminary studies have shown that TMG, in conjunction with other treatments, might exhibit antidepressant properties, although more research is required in this area.

Potential Risks and Side Effects

TMG, while considered safe when taken in recommended dosages, does come with potential risks and side effects that users should be aware of.

Recommended Dosages and Overdose Implications

The typical recommended dosage for TMG supplementation is between 500 mg and 3,000 mg per day, divided into two or three doses. It can vary depending on individual health status, goals, and existing medical conditions. It is generally advisable to start with a lower dose and gradually increase it while monitoring for any adverse reactions or side effects.
Consuming TMG in excessive amounts might lead to gastrointestinal distress and may disturb the body’s metabolism of methionine and choline.

Regularly monitoring health parameters such as homocysteine levels, liver function tests, and lipid profiles can help in assessing the effectiveness and safety of TMG supplementation over time.

Side Effects

TMG supplementation may cause diarrhea, bloating, cramps, dyspepsia, nausea or vomiting.^[5] Although rare, it can also causes excessive increases in serum methionine concentrations in the brain, which may lead to cerebral edema, a life-threatening condition.^[5]

TMG supplementation lowers homocysteine but also raises LDL-cholesterol in obese individuals and renal patients.^[6]

Drug and Supplement Interactions

Anticholinergic Drugs: TMG might interact with anticholinergic medications, which reduce the effects of acetylcholine, as TMG increases levels of choline, a precursor to acetylcholine.
Choline and Folate Supplements: Concurrent use of TMG with other supplements that affect methionine metabolism, such as choline and folate, should be approached with caution, as they might synergistically increase levels of methionine, which could be detrimental.

Special Considerations

Pregnant or Breastfeeding Women: There is limited research on the safety of TMG supplementation during pregnancy and breastfeeding; thus, consultation with a healthcare professional is advised.
Pre-existing Health Conditions: Individuals with pre-existing health conditions, particularly those affecting the liver, should consult a healthcare professional before beginning TMG supplementation.

References

↑ USDA Database for the Choline Content of Common Foods, Release 2 (2008), https://data.nal.usda.gov/dataset/usda-database-choline-content-common-foods-release-2-2008
↑ Rucker RB, Zempleni J, Suttie JW, McCormick DB; "Handbook of vitamins" , ISBN: 9780849340222
↑ "Dietary reference values for choline" , https://doi.org/10.2903/j.efsa.2016.4484
↑ Holm PI et al.: Betaine and folate status as cooperative determinants of plasma homocysteine in humans. Arterioscler Thromb Vasc Biol 2005. (PMID 15550695) [PubMed] [DOI] OBJECTIVE: Two published studies have demonstrated that betaine in the circulation is a determinant of plasma total homocysteine, but none had sufficient power to investigate the possible effect modification by folate status. METHODS AND RESULTS: We measured homocysteine, betaine, folate, vitamin B(6), and related compounds in serum/plasma from 500 healthy men and women aged 34 to 69 years before (fasting levels) and 6 hours after a standard methionine loading test. Choline, dimethylglycine, and folate were determinants of plasma betaine in a multiple regression model adjusting for age and sex. The increase in homocysteine after loading showed a strong inverse association with plasma betaine and a weaker inverse association with folate and vitamin B(6). Fasting homocysteine showed a strong inverse relation to folate, a weak relation to plasma betaine, and no relation to vitamin B(6). Notably, adjusted (for age and sex) dose-response curves for the postmethionine increase in homocysteine or fasting homocysteine versus betaine showed that the inverse associations were most pronounced at low serum folate, an observation that was confirmed by analyses of interaction. CONCLUSIONS: Collectively, these results show that plasma betaine is a strong determinant of increase in homocysteine after methionine loading, particularly in subjects with low folate status. In 500 healthy subjects, postmethionine load increase in tHcy showed a stronger inverse relation to betaine than to folate and vitamin B6, whereas for fasting tHcy, betaine was a weaker determinant than folate. For both tHcy modalities, the association with betaine was most pronounced in subjects with low folate status.
↑ ^5.0 ^5.1 "Betaine" , LiverTox: Clinical and Research Information on Drug-Induced Liver Injury , National Institute of Diabetes and Digestive and Kidney Diseases , http://www.ncbi.nlm.nih.gov/books/NBK548774/
↑ Olthof MR et al.: Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Med 2005. (PMID 15916468) [PubMed] [DOI] [Full text] BACKGROUND: Betaine (trimethylglycine) lowers plasma homocysteine, a possible risk factor for cardiovascular disease. However, studies in renal patients and in obese individuals who are on a weight-loss diet suggest that betaine supplementation raises blood cholesterol; data in healthy individuals are lacking. Such an effect on cholesterol would counteract any favourable effect on homocysteine. We therefore investigated the effect of betaine, of its precursor choline in the form of phosphatidylcholine, and of the classical homocysteine-lowering vitamin folic acid on blood lipid concentrations in healthy humans. METHODS AND FINDINGS: We measured blood lipids in four placebo-controlled, randomised intervention studies that examined the effect of betaine (three studies, n = 151), folic acid (two studies, n = 75), and phosphatidylcholine (one study, n = 26) on plasma homocysteine concentrations. We combined blood lipid data from the individual studies and calculated a weighted mean change in blood lipid concentrations relative to placebo. Betaine supplementation (6 g/d) for 6 wk increased blood LDL cholesterol concentrations by 0.36 mmol/l (95% confidence interval: 0.25-0.46), and triacylglycerol concentrations by 0.14 mmol/l (0.04-0.23) relative to placebo. The ratio of total to HDL cholesterol increased by 0.23 (0.14-0.32). Concentrations of HDL cholesterol were not affected. Doses of betaine lower than 6 g/d also raised LDL cholesterol, but these changes were not statistically significant. Further, the effect of betaine on LDL cholesterol was already evident after 2 wk of intervention. Phosphatidylcholine supplementation (providing approximately 2.6 g/d of choline) for 2 wk increased triacylglycerol concentrations by 0.14 mmol/l (0.06-0.21), but did not affect cholesterol concentrations. Folic acid supplementation (0.8 mg/d) had no effect on lipid concentrations. CONCLUSIONS: Betaine supplementation increased blood LDL cholesterol and triacylglycerol concentrations in healthy humans, which agrees with the limited previous data. The adverse effects on blood lipids may undo the potential benefits for cardiovascular health of betaine supplementation through homocysteine lowering. In our study phosphatidylcholine supplementation slightly increased triacylglycerol concentrations in healthy humans. Previous studies of phosphatidylcholine and blood lipids showed no clear effect. Thus the effect of phosphatidylcholine supplementation on blood lipids remains inconclusive, but is probably not large. Folic acid supplementation does not seem to affect blood lipids and therefore remains the preferred treatment for lowering of blood homocysteine concentrations.

[usda-choline-1] USDA Database for the Choline Content of Common Foods, Release 2 (2008), https://data.nal.usda.gov/dataset/usda-database-choline-content-common-foods-release-2-2008

[ze-2] Rucker RB, Zempleni J, Suttie JW, McCormick DB; "Handbook of vitamins" , ISBN: 9780849340222

[eu-3] "Dietary reference values for choline" , https://doi.org/10.2903/j.efsa.2016.4484

[pmid15550695-4] Holm PI et al.: Betaine and folate status as cooperative determinants of plasma homocysteine in humans. Arterioscler Thromb Vasc Biol 2005. (PMID 15550695) [PubMed] [DOI] OBJECTIVE: Two published studies have demonstrated that betaine in the circulation is a determinant of plasma total homocysteine, but none had sufficient power to investigate the possible effect modification by folate status. METHODS AND RESULTS: We measured homocysteine, betaine, folate, vitamin B(6), and related compounds in serum/plasma from 500 healthy men and women aged 34 to 69 years before (fasting levels) and 6 hours after a standard methionine loading test. Choline, dimethylglycine, and folate were determinants of plasma betaine in a multiple regression model adjusting for age and sex. The increase in homocysteine after loading showed a strong inverse association with plasma betaine and a weaker inverse association with folate and vitamin B(6). Fasting homocysteine showed a strong inverse relation to folate, a weak relation to plasma betaine, and no relation to vitamin B(6). Notably, adjusted (for age and sex) dose-response curves for the postmethionine increase in homocysteine or fasting homocysteine versus betaine showed that the inverse associations were most pronounced at low serum folate, an observation that was confirmed by analyses of interaction. CONCLUSIONS: Collectively, these results show that plasma betaine is a strong determinant of increase in homocysteine after methionine loading, particularly in subjects with low folate status. In 500 healthy subjects, postmethionine load increase in tHcy showed a stronger inverse relation to betaine than to folate and vitamin B6, whereas for fasting tHcy, betaine was a weaker determinant than folate. For both tHcy modalities, the association with betaine was most pronounced in subjects with low folate status.

[:02-5] 5.0 ^5.1 "Betaine" , LiverTox: Clinical and Research Information on Drug-Induced Liver Injury , National Institute of Diabetes and Digestive and Kidney Diseases , http://www.ncbi.nlm.nih.gov/books/NBK548774/

[pmid15916468-6] Olthof MR et al.: Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Med 2005. (PMID 15916468) [PubMed] [DOI] [Full text] BACKGROUND: Betaine (trimethylglycine) lowers plasma homocysteine, a possible risk factor for cardiovascular disease. However, studies in renal patients and in obese individuals who are on a weight-loss diet suggest that betaine supplementation raises blood cholesterol; data in healthy individuals are lacking. Such an effect on cholesterol would counteract any favourable effect on homocysteine. We therefore investigated the effect of betaine, of its precursor choline in the form of phosphatidylcholine, and of the classical homocysteine-lowering vitamin folic acid on blood lipid concentrations in healthy humans. METHODS AND FINDINGS: We measured blood lipids in four placebo-controlled, randomised intervention studies that examined the effect of betaine (three studies, n = 151), folic acid (two studies, n = 75), and phosphatidylcholine (one study, n = 26) on plasma homocysteine concentrations. We combined blood lipid data from the individual studies and calculated a weighted mean change in blood lipid concentrations relative to placebo. Betaine supplementation (6 g/d) for 6 wk increased blood LDL cholesterol concentrations by 0.36 mmol/l (95% confidence interval: 0.25-0.46), and triacylglycerol concentrations by 0.14 mmol/l (0.04-0.23) relative to placebo. The ratio of total to HDL cholesterol increased by 0.23 (0.14-0.32). Concentrations of HDL cholesterol were not affected. Doses of betaine lower than 6 g/d also raised LDL cholesterol, but these changes were not statistically significant. Further, the effect of betaine on LDL cholesterol was already evident after 2 wk of intervention. Phosphatidylcholine supplementation (providing approximately 2.6 g/d of choline) for 2 wk increased triacylglycerol concentrations by 0.14 mmol/l (0.06-0.21), but did not affect cholesterol concentrations. Folic acid supplementation (0.8 mg/d) had no effect on lipid concentrations. CONCLUSIONS: Betaine supplementation increased blood LDL cholesterol and triacylglycerol concentrations in healthy humans, which agrees with the limited previous data. The adverse effects on blood lipids may undo the potential benefits for cardiovascular health of betaine supplementation through homocysteine lowering. In our study phosphatidylcholine supplementation slightly increased triacylglycerol concentrations in healthy humans. Previous studies of phosphatidylcholine and blood lipids showed no clear effect. Thus the effect of phosphatidylcholine supplementation on blood lipids remains inconclusive, but is probably not large. Folic acid supplementation does not seem to affect blood lipids and therefore remains the preferred treatment for lowering of blood homocysteine concentrations.

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