TMG

• Methylation support
• Homocysteine reduction
• Liver health
• Cardiovascular support

• Exercise performance
• Protein synthesis
• Digestive health
• Detoxification support
• Mood regulation
• Cellular hydration

Trimethylglycine (TMG) exerts its diverse biological effects through two primary mechanisms: as a methyl donor in biochemical reactions and as an osmolyte that protects cells from environmental stress. As a methyl donor, TMG plays a crucial role in the methionine cycle, a fundamental biochemical pathway involved in methylation reactions throughout the body. TMG donates one of its methyl groups to homocysteine, converting it to methionine in a reaction catalyzed by the enzyme betaine-homocysteine methyltransferase (BHMT). This reaction is particularly active in the liver and kidneys.

The newly formed methionine can then be converted to S-adenosylmethionine (SAM), the body’s primary methyl donor, which provides methyl groups for numerous biochemical reactions including DNA methylation, neurotransmitter synthesis, hormone metabolism, phospholipid production, and detoxification processes. Through this pathway, TMG supports methylation reactions that are essential for gene expression regulation, cellular energy production, nervous system function, and detoxification. The conversion of homocysteine to methionine also explains TMG’s ability to reduce elevated homocysteine levels, which are associated with cardiovascular risk and other health concerns. This homocysteine-lowering effect is particularly important in individuals with genetic polymorphisms affecting the MTHFR enzyme or other components of the methylation cycle, as these can lead to impaired homocysteine metabolism and elevated levels.

TMG provides an alternative pathway for homocysteine metabolism that can compensate for these genetic variations. As an osmolyte, TMG helps maintain cellular hydration and stability under stress conditions. It acts as an organic osmolyte that protects cells from dehydration, excessive heat, and high salinity by stabilizing protein structure and maintaining cell volume. This osmolyte function is particularly important in the liver, kidneys, and other tissues exposed to osmotic stress.

In the liver, TMG’s osmolyte function helps protect hepatocytes from various stressors, including alcohol, environmental toxins, and metabolic stress. This protective effect contributes to TMG’s hepatoprotective properties and its potential benefits for conditions like non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease. TMG also influences lipid metabolism in the liver through multiple mechanisms. It can increase phosphatidylcholine synthesis via the PEMT (phosphatidylethanolamine N-methyltransferase) pathway, which requires adequate methylation capacity.

Phosphatidylcholine is essential for VLDL (very low-density lipoprotein) formation and export from the liver, helping prevent hepatic fat accumulation. Additionally, TMG may influence lipid metabolism through its effects on gene expression via DNA methylation. In muscle tissue, TMG may enhance protein synthesis and exercise performance through several mechanisms. Its osmolyte properties can improve cellular hydration in muscle cells, potentially enhancing protein synthesis and reducing protein breakdown.

TMG may also support creatine synthesis, as it can be converted to glycine, a precursor for creatine. Furthermore, by supporting methylation reactions, TMG may influence energy metabolism in muscle tissue. In the digestive system, TMG has been shown to support intestinal barrier function and may help protect against inflammation. It can influence the gut microbiome composition and may help reduce the production of trimethylamine (TMA), a bacterial metabolite that can be converted to trimethylamine N-oxide (TMAO) in the liver, which has been associated with cardiovascular risk.

TMG also plays a role in epigenetic regulation through its support of DNA methylation. By providing methyl groups for DNA methylation reactions, TMG can influence gene expression patterns, potentially affecting various aspects of health and disease risk. This epigenetic role may be particularly important during development and in conditions associated with altered DNA methylation patterns. Through these diverse mechanisms, TMG influences numerous physiological processes, explaining its wide range of potential health benefits from cardiovascular support to liver health to exercise performance.

No official Recommended Dietary Allowance (RDA) has been established for trimethylglycine (TMG), as it is not considered an essential nutrient. The body can synthesize TMG from choline, and it is also present in various foods. The average dietary intake of TMG from food is estimated at 100-300 mg per day, though this varies significantly based on diet composition. Based on clinical research, effective supplemental doses typically range from 500-6,000 mg per day, depending on the specific health goal.

For general methylation support and modest homocysteine reduction, 500-3,000 mg per day appears effective for most individuals. For more significant homocysteine reduction, particularly in those with hyperhomocysteinemia or MTHFR polymorphisms, higher doses of 3,000-6,000 mg per day have been used in clinical studies. For liver support and NAFLD, doses of 1,500-3,000 mg per day have shown benefits in research. For exercise performance, 2,000-2,500 mg per day is commonly used in studies showing ergogenic effects.

TMG is often taken in divided doses (e.g., 500-1,000 mg 2-3 times daily) to maintain more consistent blood levels, though single daily doses have also shown efficacy in studies.

Trimethylglycine (TMG) demonstrates good oral bioavailability, with approximately 80-90% of an oral dose being absorbed in the small intestine. Absorption occurs primarily through active transport systems, including specific betaine transporters and possibly amino acid transporters. After absorption, TMG enters the portal circulation and is transported to the liver, where a significant portion is utilized due to the liver’s high expression of betaine-homocysteine methyltransferase (BHMT), the enzyme that uses TMG to convert homocysteine to methionine. The remaining TMG enters the systemic circulation and is distributed throughout the body, with particularly high concentrations in the kidneys, liver, and brain.

TMG can cross the blood-brain barrier, though at a relatively slow rate compared to some other nutrients. Plasma concentrations of TMG typically peak within 40-60 minutes after oral ingestion, with a relatively short plasma half-life of approximately 14-18 hours. However, the biological effects of TMG can persist longer due to its incorporation into the methylation cycle and its effects on gene expression and protein function. TMG is not extensively metabolized in humans beyond its role as a methyl donor.

After donating a methyl group to homocysteine (converting it to methionine), TMG becomes dimethylglycine (DMG), which can be further metabolized to sarcosine and eventually to glycine. Excess TMG is primarily excreted unchanged in urine.

Taking with meals containing protein may enhance utilization through complementary effects on methylation pathways, Combining with cofactors like vitamin B12, folate, and vitamin B6 supports overall methylation cycle function, Dividing into multiple smaller doses throughout the day may improve overall effectiveness when using higher total daily doses, Using powder form dissolved in water or liquid for potentially faster absorption compared to capsules or tablets, Taking consistently at the same times each day helps maintain steady methylation support, Ensuring adequate hydration, as TMG functions as an osmolyte and its effects may be enhanced with proper hydration, Consuming adequate protein to ensure availability of amino acids involved in related metabolic pathways, For exercise performance, timing dose approximately 30-60 minutes before activity

For general methylation support, TMG can be taken with meals at any time of day. Dividing the daily dose into 2-3 administrations (typically with meals) helps maintain more consistent blood levels and methylation support throughout the day. When using TMG specifically for homocysteine reduction, taking it with meals containing protein may theoretically enhance its effectiveness, as protein provides amino acids involved in the methylation cycle. For those using TMG to support exercise performance, taking it approximately 30-60 minutes before exercise allows for peak plasma levels during the activity.

Some research suggests this timing provides optimal ergogenic effects. When using TMG for liver support, morning dosing with breakfast may align with the body’s natural detoxification rhythms, though research specifically examining timing effects for liver health is limited. For those taking multiple supplements, TMG can generally be taken alongside most other supplements without significant interaction concerns. However, separating TMG from supplements or medications that might compete for absorption (such as other amino acids or amino acid derivatives) by at least 30-60 minutes may theoretically enhance absorption.

For individuals with MTHFR polymorphisms or other methylation challenges, consistent daily dosing is particularly important to maintain methylation support. Some practitioners recommend taking TMG earlier in the day rather than in the evening, based on the theory that enhanced methylation activity might be stimulating for some individuals. However, this effect varies greatly between individuals, and many people can take TMG in the evening without sleep disturbances. Consistency in daily supplementation is generally more important than specific timing for many of TMG’s benefits, particularly for supporting methylation pathways and homocysteine reduction.

• Generally well-tolerated with minimal reported side effects at recommended doses
• Mild gastrointestinal discomfort (nausea, diarrhea, stomach upset)
• Fishy body odor (rare, primarily in individuals with genetic variations in FMO3 enzyme)
• Headache (uncommon)
• Mild nausea (particularly when taken on an empty stomach)
• Potential for increased TMAO (trimethylamine N-oxide) levels, though clinical significance is debated
• Temporary mood changes in sensitive individuals (both positive and negative reported)
• Mild insomnia or sleep disturbances (rare, primarily with evening dosing in sensitive individuals)

• Trimethylaminuria (Fish Odor Syndrome) – may exacerbate symptoms
• Caution advised in patients with bipolar disorder (theoretical concern based on effects on methylation and neurotransmitter metabolism)
• Caution in patients with certain cancers (theoretical concern based on methylation effects, discussed further below)
• Pregnancy and breastfeeding (insufficient safety data for high-dose supplementation)
• Caution in patients with severe kidney disease (TMG is primarily excreted by the kidneys)
• Known hypersensitivity to TMG or related compounds

• Potential interaction with medications affecting homocysteine metabolism
• Theoretical interaction with medications affecting methylation pathways
• Possible interaction with certain antidepressants (due to effects on neurotransmitter metabolism)
• Potential interaction with methotrexate and other antifolates (TMG may affect their mechanism of action)
• Theoretical interaction with DNA methyltransferase inhibitors used in cancer treatment
• Caution with medications metabolized through methylation pathways

No official Tolerable Upper Intake Level (UL) has been established for trimethylglycine. Based on available research, doses up to 15 grams per day have been used in short-term clinical studies without serious adverse effects, though such high doses are not typically recommended for regular use. For general supplementation, doses of 500-3,000 mg daily appear to be well-tolerated by most healthy adults for extended use. A note of caution regarding cancer: Some theoretical concerns have been raised about methyl donors like TMG potentially promoting the growth of existing cancer cells through epigenetic mechanisms, particularly in certain hormone-sensitive cancers.

However, other research suggests TMG may have anti-cancer effects through improved methylation and cellular function. The current scientific consensus is that there is insufficient evidence to conclude that TMG supplementation increases cancer risk in humans, but those with active cancer should consult healthcare providers before supplementing. Another consideration is TMAO (trimethylamine N-oxide) production. TMG can be metabolized by gut bacteria to trimethylamine (TMA), which is then converted to TMAO in the liver.

Elevated TMAO has been associated with cardiovascular risk in some studies. However, the clinical significance of TMG supplementation on TMAO levels and cardiovascular outcomes remains unclear, with some research suggesting that the benefits of homocysteine reduction may outweigh potential concerns about TMAO. As with any supplement, it’s prudent to use the lowest effective dose for the intended purpose, particularly for long-term use. Those with pre-existing health conditions, on medications, or with specific sensitivities should consult healthcare providers before using TMG.

Trimethylglycine (TMG) is Generally Recognized as Safe (GRAS) by the FDA for use as a food ingredient and animal feed additive. As a dietary supplement ingredient, TMG falls under the regulations of the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under DSHEA, manufacturers are responsible for determining that their products are safe before marketing, but do not need FDA approval. The FDA has not approved specific health claims for TMG supplements.

In the context of food additives, TMG (listed as betaine) is permitted for use as a flavor enhancer, humectant, and texturizer with no specific limitations other than Good Manufacturing Practices. TMG has been used in medical foods for the management of homocystinuria, a rare genetic disorder affecting methionine metabolism. These medical foods are regulated differently from conventional dietary supplements and require greater oversight.

Eu: In the European Union, TMG (betaine) is approved as a food additive (E number not assigned) and as a feed additive for animals. As a food supplement ingredient, TMG is regulated under the Food Supplements Directive (2002/46/EC). The European Food Safety Authority (EFSA) has evaluated TMG and found it to be safe for use in foods and supplements at typical doses. EFSA has rejected health claims related to TMG and homocysteine reduction, liver function, and physical performance due to insufficient evidence meeting their standards. However, TMG is approved as an orphan medicinal product in the EU for the treatment of homocystinuria, a rare genetic disorder.

Canada: Health Canada has approved TMG as a Natural Health Product (NHP) ingredient with authorized claims related to its role as a methyl donor and support for liver function and homocysteine metabolism. TMG is listed in the Natural Health Products Ingredients Database with a proper name of ‘Betaine’ and is classified as a Type 1 ingredient (safe for use in NHPs).

Australia: The Therapeutic Goods Administration (TGA) regulates TMG as a listed complementary medicine ingredient. It is included in the Australian Register of Therapeutic Goods (ARTG) as an active ingredient for various formulations. TMG is generally considered safe for use in complementary medicines at appropriate doses.

Japan: In Japan, TMG is recognized as a food ingredient and is permitted for use in various food categories. It is not specifically approved as a Food for Specified Health Uses (FOSHU) ingredient, but is allowed in general food supplements.

China: In China, TMG is approved as both a food additive and a nutritional supplement ingredient. It is included in the Chinese Pharmacopoeia and is permitted for use in health foods with certain functional claims, though specific approved claims may vary.

Low to moderate

$0.10-$0.50 per day for powder (500-3,000 mg); $0.30-$1.00 per day for capsules/tablets; $0.50-$1.50 per day for specialized formulations

Trimethylglycine (TMG) offers good value compared to many other supplements, providing multiple evidence-based benefits at a relatively modest cost. Pure TMG powder represents the most economical option, typically costing $0.05-$0.15 per gram, making even higher doses (3,000-6,000 mg daily) affordable at $0.15-$0.90 per day. The powder form has the additional advantage of flexible dosing, allowing users to adjust amounts based on individual response and specific health goals. However, TMG powder has a distinctly sweet taste that some users find unpleasant, which may make capsules or tablets worth the premium for many people despite the higher cost per gram.

Capsules and tablets typically cost 2-3 times more than powder on a per-gram basis but offer greater convenience and mask the taste. For homocysteine management, TMG’s cost-effectiveness is particularly notable when compared to other methylation support supplements. At approximately $0.20-$0.60 per day for an effective dose (1,500-3,000 mg), TMG is among the most affordable evidence-based options for supporting healthy homocysteine levels, especially for those with MTHFR polymorphisms who may not respond optimally to folate alone. For liver support, comparing TMG to other hepatoprotective supplements is informative.

While milk thistle and NAC are popular for liver health, TMG offers a different and complementary mechanism of action at a similar or lower price point, making it a valuable addition to liver support protocols. For exercise performance, TMG (2,000-2,500 mg daily) costs approximately $0.10-$0.40 per day as a powder or $0.30-$0.80 per day in capsule form. This compares favorably to many pre-workout supplements and performance enhancers, though the effects may be more subtle than stimulant-based products. When comparing products, calculate the cost per gram of TMG rather than per serving, as serving sizes vary widely between brands.

Some manufacturers provide higher-purity pharmaceutical grade TMG at a premium price, but for most applications, food-grade TMG (typically 99%+ pure) offers better value with negligible practical differences. For those seeking to maximize value, buying in bulk (500g-1kg containers) typically offers significant savings over smaller packages, with the added benefit that TMG is highly stable when properly stored. For specific therapeutic applications, such as homocysteine management or methylation support, the value should also consider potential cost savings from reduced need for other interventions or supplements. For example, TMG may reduce the amount of other methyl donors needed, potentially offsetting some of its cost.

Trimethylglycine (TMG) is a highly stable compound with an excellent shelf life when properly stored. Pure TMG (anhydrous betaine) typically maintains its potency for 3-5 years or longer under appropriate storage conditions. TMG in capsule or tablet form generally has a manufacturer-assigned shelf life of 2-3 years, though this is often conservative and the actual stability may be longer. The stability is primarily limited by the potential for moisture absorption rather than chemical degradation, as TMG itself is not prone to oxidation or breakdown under normal conditions.

TMG is hygroscopic (attracts water molecules from the environment), which can affect its physical properties but not necessarily its chemical potency. However, prolonged exposure to moisture can potentially lead to degradation over time. TMG in solution (liquid formulations) has reduced stability compared to dry forms, with a typical shelf life of 1-2 years when properly preserved.

Store in a cool, dry place away from direct light and heat (below 25°C/77°F). Keep containers tightly closed to prevent moisture absorption, as TMG is hygroscopic and can absorb moisture from the environment. While refrigeration is not necessary, it may extend shelf life, particularly in humid environments. Avoid storing in bathrooms or other high-humidity areas.

For powder forms, using the included scoop or a clean, dry utensil is recommended to prevent introducing moisture into the container. Some manufacturers include desiccant packets in TMG containers to maintain dryness – these should be left in place but not consumed. Once opened, TMG powder should ideally be used within 1-2 years for optimal freshness, though chemical stability remains longer. For capsules and tablets, storage in the original container is recommended as these are designed to protect from light and moisture.

If transferring to another container, ensure it is airtight and include a desiccant if possible.

Moisture (primary concern; can cause clumping and potential degradation over time), Extreme heat (temperatures above 80°C/176°F can cause degradation), Strong acids or bases (can cause chemical modification in solution), Prolonged exposure to very high humidity, Microbial contamination (if moisture is introduced), Note: TMG is remarkably stable compared to many other supplements, with minimal concerns about oxidation or light degradation, Note: The anhydrous form of TMG is more stable than hydrated forms

Synthesis Methods

Natural Sources

Quality Considerations

Trimethylglycine (TMG) has a rich scientific history dating back to the 19th century, though its use as a specific supplement is relatively recent. TMG was first isolated from sugar beets (Beta vulgaris) in 1860 by German chemist Karl Heinrich Leopold Ritthausen, who named it ‘betaine’ after the plant genus. This discovery marked TMG as one of the earliest identified plant-derived nitrogenous compounds. While TMG itself wasn’t used as a specific supplement historically, foods rich in TMG have long been valued in various cultures.

Beets, in particular, have been used medicinally across many traditional healing systems. In ancient Roman and Greek medicine, beets were prescribed for blood disorders, digestive issues, and as a general tonic. In traditional European folk medicine, beet juice and preparations were used to support liver health and blood formation. The scientific understanding of TMG’s biological roles began to expand significantly in the early 20th century.

By the 1930s, researchers had identified TMG’s role as a methyl donor in biological systems, though the full significance of methylation processes was not yet understood. In the 1950s and 1960s, the importance of TMG in liver metabolism was established through research on ‘lipotropic factors’ – compounds that help prevent or reduce fat accumulation in the liver. TMG, along with choline and methionine, was identified as a key lipotropic agent. This led to early clinical applications for liver disorders, particularly alcoholic liver disease.

The connection between TMG and homocysteine metabolism was elucidated in the 1970s and 1980s, as researchers mapped out the methionine cycle and identified the enzyme betaine-homocysteine methyltransferase (BHMT). This discovery laid the groundwork for TMG’s later use in managing hyperhomocysteinemia, a risk factor for cardiovascular disease. The commercial development of TMG as a specific supplement began in the 1980s, initially for veterinary applications in animal feed, where it was used to improve growth and reduce fat in livestock. TMG’s use as a human dietary supplement gained momentum in the 1990s, coinciding with growing scientific interest in homocysteine as a cardiovascular risk factor and the recognition of methylation’s importance in human health.

The identification of genetic polymorphisms affecting methylation pathways, particularly the MTHFR gene variants discovered in the 1990s, further increased interest in TMG as a supplement. TMG offered an alternative methylation pathway that could potentially compensate for reduced function in the folate-dependent pathway affected by these genetic variations. In the early 2000s, research into TMG’s effects on exercise performance began to emerge, with studies suggesting benefits for power output, endurance, and body composition. This led to TMG’s inclusion in sports nutrition products and increased its popularity among athletes and fitness enthusiasts.

More recently, the growing understanding of methylation’s role in epigenetics, gene expression, and various aspects of health has further expanded interest in TMG as a supplement. Research into TMG’s potential benefits for conditions ranging from fatty liver disease to cognitive function continues to evolve. Today, TMG is widely available as a dietary supplement in various forms, used for purposes ranging from homocysteine management to liver support to exercise performance enhancement. It is often included in comprehensive methylation support formulas alongside other nutrients like folate, B12, and B6.

Unlike many traditional herbal supplements with centuries of concentrated extract use, TMG’s history as a specific supplement spans only a few decades, though the foods containing it have been consumed throughout human history.

TMG supplementation for non-alcoholic fatty liver disease (NAFLD), Effects of TMG on cognitive function in older adults, TMG as adjunctive therapy for depression in patients with MTHFR polymorphisms, TMG supplementation for cardiovascular risk reduction, Effects of TMG on muscle protein synthesis and recovery in athletes, TMG for homocysteine reduction in patients with kidney disease, Combination of TMG with other methyl donors for comprehensive methylation support, TMG’s effects on gut microbiome composition and TMAO production, Long-term TMG supplementation for healthy aging biomarkers, TMG for supporting methylation in individuals with genetic polymorphisms affecting methylation pathways