Trimethylglycine (TMG), or betaine, may lower homocysteine levels. It’s being researched for improving heart health and exercise performance. However, it can also increase cholesterol levels and its long-term safety is unknown. Read on to uncover the evidence and possible side effects of this supplement.
What is TMG?
Trimethylglycine (TMG) is a compound found in beetroot and other plants and animal foods. It was originally known as betaine because it was first discovered in sugar beets. However, TMG is one of the many betaines that have since been identified .
TMG is also known as betaine, glycine betaine, lycine, and oxyneurine. People consume TMG normally in their diet, though supplements are also available. TMG is also produced by the body from choline .
TMG supplements, commonly referred to as betaine anhydrous, have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.
Betaine hydrochloride (Betaine HCl) is made out of betaine (TMG) and hydrochloric acid. It is a supplement that allegedly increases stomach acid .
TMG has many purported health benefits. Some brands claim it protects the liver, heart, and kidneys, and can enhance physical performance. However, solid data is lacking to back up most of these claims .
Mechanisms of Action
Donates Methyl Groups
In the body, TMG can donate one of its methyl groups to homocysteine. Methyl groups are three hydrogen atoms bonded to carbon. This turns homocysteine back into methionine, which theoretically prevents homocysteine levels from getting too high .
High homocysteine levels in the blood are a risk factor for heart disease. Limited evidence suggests that TMG supplementation and dietary intake lower homocysteine levels, which may potentially protect the heart [4, 5].
Is an Osmoprotectant
Researchers call TMG an osmolyte/osmoprotectant, which means that it keeps cells hydrated and increases stress resilience. In lab settings, it can stabilize proteins and membranes when environmental conditions are bad, such as drought, low temperatures, and high salt levels .
Increases Nitric Oxide
TMG supplementation may increase blood levels of nitric oxide. Nitric oxide widens blood vessels and increases muscle blood flow during short-term exercise .
An increase in muscle blood flow can improve exercise performance by increasing nutrient delivery and waste excretion .
Purported Health Benefits
1) Exercise Performance
TMG is a common ingredient in workout supplements.
Studies indicate that TMG supplementation to improve physique may help only when accompanied by exercise .
In a meta-analysis (of 7 RCTs), two studies reported increases in power and strength. The authors concluded that additional studies are necessary to evaluate its effectiveness .
In two studies (DB-RCT) of active men, TMG supplementation increased total repetitions during exercise. Besides increasing strength, TMG might improve endurance and reduce fatigue .
2) May Improve Body Composition
In a study (DB-RCT) of 23 experienced strength-trained men, long-term TMG supplementation during an exercising training program (6 weeks) improved body composition. The men had significant increases in lean mass and decreases in body fat .
In a study (RCT) of 12 trained men, TMG supplementation alongside exercise sessions decreased cortisol levels. It also increased blood growth hormone, which helps with muscle protein synthesis. This caused their lean mass to increase [12, 10].
Large-scale, high-quality studies are needed to confirm this purported benefit.
3) May Support Heart Health
A high blood homocysteine level is a risk factor for heart disease. Limited evidence suggests that TMG supplementation lowers homocysteine levels in the blood, which can potentially protect the heart [4, 5].
In a review of 74 clinical trials, high choline and TMG intake were associated with lower blood inflammatory markers .
Because choline is a precursor to TMG, increased choline intake can lead to higher TMG blood levels. TMG then lowers homocysteine, which improves the mitochondrial membrane and protects cells from oxidative stress and inflammation .
Although TMG intake is not associated with heart attack incidence, long-term consumption has been linked with fewer heart disease-related deaths. Additional studies are needed .
4) May Help in Diabetes
In a study (RCT) of 3,000 individuals, those with lower TMG levels were more likely to have diabetes. After 2 years of lifestyle changes, higher TMG levels were associated with lower diabetes rates .
However, these studies only investigated the link between TMG blood levels and diabetes or insulin resistance. The effects of TMG supplements in humans remain unknown.
In mice, TMG supplementation:
Clinical trials are needed to determine the effectiveness and safety of TMG in people with diabetes and/or insulin resistance.
5) Has Antioxidant Effects
In rats, TMG pre-treatment reduced oxidative damage due to stress .
Clinical trials are lacking to support this purported benefit.
6) Cancer Research
In a meta-analysis of 14 trials, high TMG and choline consumption contributed to cancer prevention and lowered the risk of developing cancer. The authors emphasized that further studies are needed to verify the results .
In a study of 1,500 breast cancer patients, a higher dietary intake of TMG was associated with fewer deaths from cancer. However, it did not affect the risk of developing breast cancer .
Until large-scale studies are conducted, the effects of TMG on cancer prevention remain undetermined.
7) May Balance Mood
In 45 depressed patients who responded poorly to antidepressants, SAMe and TMG used as add-ons to conventional treatment for 90 days improved symptoms such as anxiety and feelings of helplessness and worthlessness .
However, one author of the mentioned study was the main formulator of the researched SAMe + TMG supplement. Further clinical trials are needed.
TMG administration in depressed rats changed their behavior. It helped increase serotonin and norepinephrine levels in the rats’ brains, having an antidepressant effect. Human studies have not investigated the antidepressant potential of TMG alone .
8) May Support Cognition
In a study (DB-RCT) of 193 seniors, cobalamin supplementation increased TMG blood levels. This increase in TMG was associated with better reaction time, memory, and brain function .
Additionally, the participants with the largest increase in TMG levels had the greatest memory improvement .
However, these findings have not been replicated. Additional clinical trials are needed.
9) Effects on Autism Symptoms
According to one theory, children with Autism Spectrum Disorder have abnormal methionine cycles. The methionine cycle helps with blood vessel formation and other biological pathways. Abnormal methionine cycles can cause cognitive disorders. However, the methionine-autism theory is controversial and remains unproven .
Some researchers believe that autistic children do not have high enough levels of the by-products that are needed for the cycle and are also vulnerable to oxidative stress .
In autistic children, TMG and choline deficiency contribute to low methionine and SAMe levels, which can cause abnormal gene expression .
Although scientists are unsure if TMG supplementation affects SAMe levels in autistic children, studies of healthy participants showed that TMG can increase SAMe .
Oral supplementation with folinic acid and TMG normalized the methionine cycle in a small study of autistic children. TMG also increased antioxidant levels, which protects against oxidative damage .
However, there is insufficient information about the effects of TMG on autism. Additional studies are needed to determine if TMG is safe and beneficial.
10) May Protect the Liver
TMG is being researched for improving non-alcoholic and alcoholic liver injuries, though the existing evidence is inconclusive .
In mice, TMG improved liver health by:
- Decreasing insulin resistance in the liver 
- Reducing fat buildup in the liver 
- Increasing activation of liver AMPK to help with glucose and fat (lipid) balance 
- Preventing alcohol-induced inflammation and stress 
- Protecting the liver from toxins (like chloroform, methotrexate, LPS, etc) 
- Protecting liver cells from bile-induced apoptosis 
However, human trials do not support these findings.
In a study (RCT) of 55 non-alcoholic fatty liver disease patients, TMG did not reduce fat buildup in their livers. Even though the dosage was very high (at 20 g daily), it could only stop fat buildup from worsening and could not improve the disease .
Potential synergies between SAMe, TMG, and hepatitis C treatment are being researched .
In a study of 29 nonresponders, more than half the patients responded to the addition of SAMe and TMG to conventional hepatitis C treatment. Additional research is needed .
11) Effects on the Kidneys
In the kidneys, TMG’s main role is making sure the cells stay hydrated. During cellular stress, it preserves cell volume without changing cell functions .
In mice, TMG supplementation lowered high uric acid levels, protecting the kidney from injury .
Additionally, TMG treatment protected rat kidneys from CCL4-induced toxicity. CCL4 can cause kidney cell death and cirrhosis (liver disease) .
More research is needed.
12) May Soothe Skin Irritation
In 21 healthy subjects, TMG relieved the skin irritating effects caused by detergents and decreased allergic responses .
TMG’s osmolyte properties increased skin hydration and improved skin barrier. Also, by acting as a methyl donor, it protected the cells from detergent attacks .
13) May Protect the Hair from Damage
Shampoos and other hair products can harm cells through osmotic stress. Since TMG is an osmolyte, it may keep hair cells hydrated and protect against environmental damage .
Shampoo with TMG protected hair protein structure .
Clinical studies are lacking, though.
14) May Relieve Dry Mouth
Toothpaste that contains TMG reduced dry mouth symptoms in a study (DB-RCT) of 45 individuals. The patients reported less lip dryness and difficulty eating .
Effects on Bone Health
The effects of TMG on bone health in humans are unknown.
Scientists are currently investigating TMG in human bone cells. TMG may activate pathways that increase osteoblast cell formation. Osteoblasts are cells that increase new bone formation .
TMG Side Effects/Negatives
Common Side Effects
Common side effects include :
- Sleep Disturbances
- Hair Loss
Proper safety data are lacking. The long-term side effects and risks of TMG supplementation are unknown.
Increases Cholesterol Levels
TMG may increase cholesterol levels. This potentially cancels out TMG’s benefits on heart health .
TMG doses under 6 grams may also increase LDL cholesterol and triglyceride blood levels (the main component of body fat) in obese individuals .
In another study (RCT) of 42 obese subjects, daily supplementation of 6 grams of TMG increased LDL (bad) and total cholesterol .
With this in mind, we advise people against supplementation until large-scale safety studies are carried out.
The breakdown of TMG in the body can make trimethylamine. TMG supplementation can cause a person’s urine and sweat to smell fishy .
Few human trials on TMG have been performed. Its potential to increase cholesterol and triglycerides is concerning. Until additional clinical studies are conducted, TMG supplements should be viewed as potentially dangerous products.
Fruits and Vegetables
Supplementing with TMG
A normal dietary intake of TMG from food is .5-2 grams/day .
TMG supplement doses used in clinical trials ranged from 2.5 to 6 grams per day. Although some studies suggest it is safe at an intake of 9-12 grams/day, even lower TMG doses increased blood lipids. Therefore, a safe TMG dosage cannot be established [5, 10].
Limited human studies suggest that 2.5 g/day of TMG is needed to increase blood TMG levels. This has not been confirmed by proper clinical trials .
TMG increases the expression (production) of genes that help with bone formation. In human bone cells, TMG increased RUNX2, OSX, and SOD2 gene expression. This increases the production of proteins that increase bone formation and protects against bone cell stress .
- “I have suffered from horrible anxiety/panic attacks and depression for 12 years. I read a review that this product helped someone suffering from depression and so decided to give it a shot. To my astonishment and delight, this product worked immediately!”
- “When added to folate, TMG makes a first arsenal defense against the damaging effects of high homocysteine levels. Recommended!”
- “A necessary supplement for virtually all adults nowadays, primarily as it helps the liver eliminate toxins like heavy metals.”
- “This gave me a pressure headache within minutes of ingestion.”
- “Added to my sleeping issues, unfortunately.”
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