TMG Supplement: Science, Benefits, Dosage, and Picks

TMG (trimethylglycine) is a supplement used by some longevity scientists, such as Dr. David Sinclair, for its purported benefits like improving organ health and physical and mental performance. How does TMG work, and can it really prevent conditions like heart attack and stroke?

What is TMG (trimethylglycine)?

TMG, which also goes by betaine or betaine anhydrous, is a natural component found in humans, microorganisms, and some plants including beetroot. Humans consume an estimated 1–2.5 g of TMG from their diet per day. Structurally, TMG is the amino acid glycine with three methyl groups attached to it. This makes TMG a potent methyl donor. Methylation is the process by which a methyl group is added to DNA, proteins, or other molecules, playing a significant role in regulating gene expression and protein function.

Aside from being a methyl donor, TMG has been reported to possess anti-inflammatory properties and help confer greater cellular resilience against oxidative and osmotic stressors. These functions are hypothesized to help TMG influence biological processes involved in health and disease.

Potential benefits of TMG supplement

TMG is approved by the Food and Drug Administration (FDA) under the brand name Cystadane for the treatment of a rare disease called classical homocystinuria. This condition is characterized by a deficiency in an enzyme called cystathionine beta-synthase, which leads to excess buildup of the amino acid homocysteine in the blood and urine.

High homocysteine levels can cause severe developmental delays in infants and children, resulting in abnormal physical features. Some physical features of classical homocystinuria include eye abnormalities such as severe nearsightedness or dislocation of the lenses, as well as musculoskeletal problems such as unusually long limbs or scoliosis. Children with this condition may also have intellectual disability or seizures and possess a higher risk of blood clots, which can lead to stroke.

TMG is used as a treatment for classical homocystinuria. It donates a methyl group to homocysteine, thereby converting the molecule to methionine and lowering homocysteine levels to reduce the risk of complications.

Besides its sole approved medicinal use, however, research suggests that TMG may have additional health benefits.

May support liver health

TMG has been studied for its role in reducing the risk and progression of both alcohol- and non-alcohol-related liver disease. Non-alcoholic fatty liver disease (NAFLD) is caused by the buildup of fat in the liver and commonly occurs in people with metabolic syndrome. Eventually, both alcohol- and NAFLD can lead to inflammation (steatohepatitis) that progresses to cirrhosis and potentially cancer if left unchecked.

In liver cells, TMG increases the level of the molecule S-adenosylmethionine (SAM). Animal studies suggest that a relatively higher level of SAM may protect against cellular damage in alcohol-related liver disease.

Through various mechanisms, TMG is also hypothesized to decrease fatty acid synthesis and help prevent triglyceride and cholesterol accumulation in the liver caused by chronic alcohol consumption, as observed in animal studies. Furthermore, TMG has been shown to reduce oxidative liver damage in the setting of alcohol.

In mice fed a high-fat diet, TMG has been shown to suppress the expression of genes associated with NAFLD. Studies in humans, however, have been mixed. A small 2011 study involved patients with non-alcoholic steatohepatitis (NASH), which develops from NAFLD. The authors found that after taking 10 g of TMG twice a day for one year, over half of patients experienced stabilization or improvement in markers of inflammation and fibrosis.

However, a randomized controlled trial in patients with NASH showed no improvement in liver disease or fibrosis stage with the same dosage and timeline of treatment as the previous study. More clinical research is needed to clarify these differences and determine whether TMG is beneficial for liver health in humans.

May reduce homocysteine levels

High homocysteine levels in the bloodstream (homocysteinemia) contribute to atherosclerosis through the production of reactive oxygen species leading to dysfunction and hardening of the arteries. Consequently, people with higher homocysteine levels may have an increased risk of heart attacks and strokes.

Although this suggests that reducing homocysteine levels can improve cardiovascular outcomes, the research has not strongly supported this claim. A 2017 review of 15 randomized controlled trials involving 71,422 participants showed that homocysteine-lowering interventions in the form of vitamin supplements did not significantly reduce the risk of heart attacks or death compared to placebo. A small difference was seen in stroke prevention, but higher doses of homocysteine-lowering vitamins did not contribute to a more reduced stroke incidence than lower doses.

It is unclear why lower homocysteine levels are associated with a smaller risk of cardiovascular events, but interventions to reduce homocysteine levels do not seem to make much of a difference.

The role of TMG supplementation in preventing cardiovascular disease is unclear, despite its demonstrated ability to reduce homocysteine levels.

A 2013 meta-analysis of five randomized controlled trials involving healthy adult participants given at least 4 g of TMG daily showed a significant reduction in homocysteine levels after 6–24 weeks.

A separate 2022 meta-analysis further showed that TMG supplementation may reduce low-density lipoprotein (LDL) levels in addition to homocysteine. However, TMG supplementation did not appear to affect other important cardiovascular disease risk markers such as triglycerides, high-density lipoprotein (HDL), fasting blood glucose, C-reactive protein, or blood pressure.

May improve athletic performance

Multiple studies have shown a positive association between TMG supplementation and various aspects of athletic performance. Several examples include:

• A 2022 study looked at the effects of supplementing 2.5 g of TMG per day in adolescent handball players over two weeks. In a single resistance training session, those who received TMG at the end of the study period were able to perform more leg press and bench press repetitions compared to those receiving placebo.
• A 2011 study found that men taking 2.5 g of TMG daily for 14 days moderately increased the number of repetitions and volume of bench press they could perform compared to pre-supplementation.
• A 2009 study corroborated that taking 2.5 g of TMG daily for 15 days could improve muscle endurance assessed via squat exercises in healthy adolescent males.
• A 2023 study of college females receiving 2.5 g of TMG daily for 14 days experienced a higher mean power output during a sprint compared to those taking placebo.
• A 2021 study of young professional soccer players who received 2 g of TMG daily for 14 weeks, compared to placebo, had greater improvements in one-repetition maximum on the leg press and bench press, maximal oxygen uptake, and sprint ability performance.

However, not all studies show TMG to be effective for athletes. For instance, a 2020 study found that TMG supplementation did not improve cross-fit training performance.

Since studies have assessed athletic performance at one point in time following a course of TMG supplementation, further research is needed to determine whether the effects are long-lasting or must be sustained by continual TMG intake.

May prevent insulin resistance

Insulin resistance leading to chronically high blood glucose levels is the hallmark feature of type 2 diabetes. Some evidence suggests that TMG may have a beneficial impact on insulin and glucose control.

A 2018 study found that mice fed a high-fat diet experienced improved insulin sensitivity if they were treated with TMG compared to without. A review of rodent studies concluded that TMG regulates protein expression in highly metabolically active tissues such as skeletal muscles, the liver, and fat cells to help improve insulin signaling and blood glucose clearance.

Few human studies exist to confirm these effects, and results have been inconclusive.

A 2017 study found that among 2,394 adults, those who consumed higher amounts of choline and TMG in their diet had lower levels of fasting glucose and improved markers of insulin sensitivity. However, these results are confounded by the inclusion of choline. Furthermore, they only show a correlation between TMG consumption and insulin resistance, so a cause-and-effect relationship cannot be drawn.

A 2018 study involved patients with obesity and prediabetes who were randomly assigned to receive up to 4.95 g of TMG twice daily for 12 weeks or placebo. Participants in the TMG group experienced improvements in fasting glucose levels but not hemoglobin A1c levels (a marker of blood glucose on cell surfaces over the past three months). Moreover, insulin sensitivity did not improve in the TMG group after 12 weeks compared to placebo.

Further research is needed to determine whether TMG can help improve insulin sensitivity in humans. In the meantime, people with type 2 diabetes or prediabetes should rely on proven ways to manage their blood sugar by adhering to a healthy diet and exercise and by following their physician's recommendations.

Are there any side effects?

TMG supplementation is generally well-tolerated. Side effects are typically mild and may include gastrointestinal symptoms such as loss of appetite, diarrhea, bloating, cramping, indigestion, nausea, or vomiting. These may be more likely to occur at higher doses (> 6 g per day).

The manufacturer’s drug label for TMG (in the form of betaine anhydrous) notes that some individuals taking TMG have experienced the following symptoms, which are likely to be extremely rare:

• Psychiatric symptoms, including agitation, depression, irritability, and personality changes
• Sleep disturbances
• Dental problems
• Hair loss
• Hives
• Abnormal skin odor
• Urinary incontinence

Rarely, high or prolonged doses of TMG supplementation might increase methionine blood concentrations, which raises the risk of brain swelling (edema) when levels approach 1,000 micromoles/L. This risk has only been seen in children treated for classical homocystinuria who did not sufficiently restrict methionine from their diets.

The manufacturer’s drug label does not list any medical or drug contraindications to the use of TMG as a medication. However, always consult with your doctor before starting TMG as a supplement.

TMG and cholesterol levels

TMG supplementation may increase cholesterol levels when taken daily for at least several weeks. A 2021 meta-analysis explored six randomized controlled trials involving adults who received at least 4 g per day of TMG for 6–24 weeks. The authors found that those who supplemented with TMG, compared to those who took placebo, had a moderate increase in total cholesterol levels.

Based on its review of the literature, the European Food Safety Authority (EFSA) has concluded that both total cholesterol and LDL cholesterol levels may increase in individuals who have metabolic syndrome taking at least 4 g of TMG per day.

Nonetheless, it should be noted that while high cholesterol levels are associated with a greater risk of cardiovascular events, there is no available evidence that TMG intake worsens cardiovascular outcomes.

TMG and special populations

People who are pregnant or breastfeeding should not take TMG supplements as there is no substantive research on their safety in this population.

Children should generally not take TMG supplements due to the lack of safety data, except when prescribed by a physician for the treatment of classical homocystinuria.

How to use the TMG supplement

TMG supplements are taken by mouth in the form of a capsule, powder, or liquid. The powder form can be dissolved and taken with water or juice. TMG can be taken with or without meals. However, taking it with food may improve absorption and effectiveness.

There is no evidence that taking TMG at specific times of the day is more effective than others.

Dosage

In clinical studies, participants typically take TMG twice a day. The dosage used in these studies depended on the indication:

• Exercise performance: 2.5 g daily, split into two 1.25 g doses
• Homocysteine reduction: 4–6 g daily, split into two 2–3 g doses
• Liver health: 20 g daily, split into two 10 g doses

Some studies show that a daily dose of 1.5–3 g per day may be just as effective as higher doses if used for homocysteine reduction.

The duration of TMG usage ranges from two weeks in studies on athletic performance to 24 weeks in studies on homocysteine reduction.

How to choose the best TMG supplement

Several factors go into choosing the best TMG supplement depending on your individual goals and budget.

Customer feedback

The number of positive customer ratings and reviews lends credibility to the product. Unbiased reviews are more trustworthy than reviews made by consumers who were offered free or discounted products. Customer feedback on the supplement company may also be a valuable decision tool, as companies that produce higher quality supplements overall may have a better TMG supplement and better customer service.

Ingredients

Make sure that your TMG supplement contains betaine or betaine anhydrous rather than betaine hydrochloride, which is not the form used in clinical studies. Preferably, look for TMG supplements that contain no other active ingredients (such as other supplements) to better evaluate whether the supplement may work for you. Try to minimize the number of additives or fillers, as some may have unclear health consequences.

Quality

Although TMG supplements are not regulated by the FDA, the highest quality products usually have a stamp of approval from an independent laboratory that performs third-party testing to confirm the product’s strength and purity. Some companies publicize this information in the form of a Certificate of Analysis. TMG supplements are preferably produced in facilities that adhere to good manufacturing practices (GMP).

Price

Usually, the highest quality supplements are also the most expensive, but sometimes, similar products can vary in cost. Finding the right balance between quality and cost is often a personal decision.

📝Healthnews editor's top picks

1. partiQlar

• Contains 500 mg of TMG with no additives
• Designed to enhance methylation processes and support cardiovascular health
• Free from binders, fillers, preservatives and third-party tested

Try partiQlar now

2. ProHealth Longevity

• Supports cardiovascular health and may lower harmful homocysteine levels
• Contains 1,000 mg of TMG per tablet
• Third-party tested for safety and quality

Try ProHealth now

3. Vitality Pro

• Contains 500 mg of TMG per capsule
• Free from GMOs, preservatives, artificial colors or major allergens
• Packaged in 100% biodegradable materials

Try Vitality Pro now

Further information

Despite popular claims, there is insufficient evidence to recommend the use of TMG supplementation for reducing cancer risk. While there is some evidence that dietary TMG consumption may reduce the risk of certain cancers such as colorectal cancer, higher TMG levels in the blood have also been associated with an increased risk of total cancer and lung cancer. Still, other studies have shown no association between dietary TMG intake and cancer risk. Research on TMG supplementation and cancer is lacking.

Limited research suggests that TMG may play a role in helping alleviate depression. SAMe, a product of TMG methylation, has shown some promise in treating depression either when used alone or in combination with antidepressants. A small study of 46 adults with mild-to-moderate depression who are low responders to antidepressant treatment, found that the combination of SAMe with TMG demonstrated better improvements in depressive symptoms after three months than SAMe alone when used as an add-on therapy. The combination of SAMe with TMG has also been shown in a small study of 64 individuals to be more effective in treating mild depression after 6–12 months compared to the medication amitriptyline.

Final thoughts

TMG is a promising supplement with some evidence supporting its potential use for various aspects of metabolic and physical health. However, further research in humans is needed to clarify discrepancies in available studies and to determine whether TMG can lead to durable long-term outcomes in reducing disease risk and progression. In addition to a healthy diet consisting of TMG-rich foods, supplementation can be a helpful way for some people to reach their health and wellness goals.