Trimethylglycine (TMG)

Trimethylglycine, commonly known as TMG or 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

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. 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.

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.
• 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. 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.

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

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.

Studies

Protective effects of TMG in experimental animal models, cell culture systems, and clinical studies.

Therapeutic Effects of TMG Administration	Experimental Model	Authors
Prevents hepatic fat accumulation in ALD	Male Wistar rats; C57BL/6 mice; Balb/c mice	[23,27,83,115,121,157,158,160]
Preserves/restores hepatic SAM: SAH ratios by regenerating SAM and lowering SAH and homocysteine levels in ALD	Male Wistar rats; hepatocytes; male C57BL/6 mice	[23,60,61,81,82,83,84,86,88,91,92,117,119,121,234,235]
Restores activities of various liver methyltransferases (PEMT, ICMT, PIMT, PRMT) to increase phosphatidylcholine levels, preventing apoptosis and accumulation of damaged proteins, and restoring proteasome activity	Male Wistar rats; hepatocytes	[23,90,91,92]
Suppresses the synthesis of DGAT2, a rate-limiting enzyme in triglyceride synthesis, by alleviating ERK1/2 inhibition in ALD	Male C57BL/6 mice	[121]
Upregulates antioxidant defense system and improves oxyradical scavenging activity in ALD	Male Wistar rats	[133]
Prevents/attenuates ER stress in ALD	Male C57BL/6 mice	[83]
Exerts hepatoprotection by preserving mitochondrial function in ALD	Male Wistar rats	[61]
Restores the serum adiponectin levels in ALD	Mice	[123]
Prevents elevations of CD14, TNFα, COX2, GADD45β, LITAF, JAK3, TLR2, TLR4, IL1β, and PDCD4 and NOS2 mRNA levels in alcoholic liver injury	Male Wistar rats	[115,133]
Prevents serum ALT and AST activity elevations in models of ALD and MAFLD	Male Wistar rats	[27,115,121]
Reduces liver oxidant stress, inflammation, and apoptosis in MAFLD	Male C57BL/6 mice	[28]
Remethylates homocysteine, protecting from oxidant stress and restoring phosphatidylcholine generation in MAFLD	C57BL/6 mice	[161]
Stimulates β-oxidation in livers of MCD diet-induced MAFLD	Male Sprague-Dawley rats	[162]
Alleviates steatosis and increases autophagosomes numbers in mouse livers with MAFLD	Male C57BL/6 mice; rats	[120,161]
Enhances the conversion of existing WAT to brown adipose tissue through stimulating mitochondrial biogenesis in MAFLD	Mice	[203]
Alleviates ROS-induced mitochondrial respiratory chain dysfunction in MAFLD	Male Sprague-Dawley rats	[163].
Attenuates different grades of steatosis, inflammation, and fibrosis in MAFLD patients	Human trials	[45,165,166,167]
Prevents adipose tissue dysfunction in ALD	Male C57BL/6 mice	[194]
Reduces the inflammatory adipokines, IL6, TNFα, and leptin in human adipocytes	Human visceral adipocytes	[204]
Inhibits lipid peroxidation, hepatic inflammation, and expression of transforming growth factor-β1 in liver fibrosis	Male chicks	[148]
Suppresses alcoholic liver fibrosis	Rats	[116]
Prevents the formation of Mallory–Denk bodies through epigenetic means by attenuating the decrease of MAT1A, SAHH, BHMT, and AMD1 expression	C3H male mice	[138]
Reverses the inhibitory effects of acetaldehyde on IFN signaling and decreases de-methylation of STAT1 by JMJD6	HCV-infected Huh7.5 CYP2E1 (+) cells and human hepatocytes	[141,143]
Enhances expression of PPARα and elevates fatty acid catabolism	Male C57BL/6 and ApoE−/− mice	[158].
Inhibits lipogenic activity in liver by activation of AMPK	ApoE−/− mice; Male C57BL/6 mice	[159,160]
Regulates colonic fluid balance	Rats	[21,200]
Improves intestinal barrier function and maintains the gut microbiota	Porcine epithelial cells; Caco-2 cells; rat small intestinal cell line IEC-18	[22,197,198]
Activates GI digestive enzymes and ameliorates intestinal morphology and microbiota dysbiosis	Male Sprague Dawley rats	[200]
Attenuates alcoholic-induced pancreatic steatosis	Male Wistar rats	[125]
Associated with resilience to anhedonia and prevention of stress-related psychiatric disorders	Male C57BL/6 mice	[218]
Treats asthma-induced oxidative stress, thus improving airway function of lung tissue	BALB/C mice	[207]
Protects against cadmium nephrotoxicity	Male Wistar rats	[206]
Protects against isoprenaline-induced myocardial dysfunction	Male Wistar rats	[205]
Anti-nociceptive and sedative role via interactions with opioidergic and GABA receptors	Male albino mice	[220]
Normalizes fetal growth and reduces adiposity of progeny from obese mice	C57BL/6J mice	[229]
Anti-cancer effect in alcohol-associated breast cancer cell growth and development	Breast adenocarcinoma cell line (MCF-7)	[213]
Reduces rectal temperature in broiler chickens	Chickens	[226,227]
Improves post-natal lamb survival	Lambs	[230]

See also

• Wikipedia article