What Is TMG? A Deep Dive Into Trimethylglycine and Its Role in Health

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A hand holding a TMG supplement between 2 fingers

Trimethylglycine (TMG), also known as betaine, is a naturally occurring compound first identified in sugar beets in the 19th century.1  Chemically, TMG is the amino acid glycine bound to three methyl groups, making it a quaternary ammonium molecule. This structure gives TMG a positive charge on its nitrogen and a negative charge on its carboxyl group, classifying it as a zwitterion. In the body, TMG plays vital roles as an osmolyte (helping cells maintain fluid balance) and as a methyl donor in key metabolic pathways.2.

Given these functions, TMG has attracted attention for its potential health benefits – from liver and heart health to exercise performance and beyond – as well as for any risks or side effects it may carry. In this comprehensive post, we’ll explore what TMG is, where it’s found, its evidence-based benefits, therapeutic applications, possible risks (including considerations for conditions like heart disease and cancer), recommended dosages, and its regulatory status.

TMG is an organic osmolyte and methylated amino acid derivative. It’s essentially the amino acid glycine with three methyl groups attached, hence “tri-methyl-glycine.” This compound was originally discovered in sugar beets (Beta vulgaris), which is why it’s commonly called betaine.3.  TMG is present widely in nature – found in many plants, animals, and even microorganisms – and is non-toxic and stable in the body.4. In human metabolism, TMG can be made internally from choline (another dietary nutrient) or obtained directly from foods.5

Biologically, what does TMG do?
Its two primary roles are:

Osmolyte function: TMG accumulates in cells to protect against osmotic stress (dehydration or high salinity conditions).

Because it carries both a positive and negative charge in its structure, TMG helps balance intracellular osmotic pressure similar to electrolytes.6. Unlike some ions, betaine doesn’t strongly bind to proteins, which allows it to stabilize proteins and enzymes under stress without disrupting their function7. For example, in kidney cells – which face high osmotic pressure – betaine helps protect proteins and maintain cell volume.8.

  • This osmolyte role means TMG supports cell hydration, integrity of cell membranes, and overall cellular resilience in the face of stress or dehydration.

Methyl donor function: TMG is a crucial player in one-carbon metabolism, the network of reactions that transfer methyl (-CH₃) groups. Specifically, TMG can donate one of its methyl groups to convert homocysteine (a potentially harmful amino acid) into methionine (an essential amino acid).9. This reaction is catalyzed by the enzyme betaine-homocysteine methyltransferase (BHMT), which is highly active in the liver and kidneys, and also present in other tissues like adipose tissue and the intestine.10. By remethylating homocysteine, TMG helps reduce homocysteine levels and generates methionine, which can then form S-adenosylmethionine (SAM) – the body’s universal methyl donor for DNA, proteins, neurotransmitters, and more. In short, TMG helps maintain proper methylation processes and amino acid balance. This not only supports cardiovascular health (since high homocysteine is a risk factor) but also influences gene expression and cellular function through methylation.

Key Point: TMG is an amino acid-derived nutrient that acts as both a cellular hydrator and a methyl donor. These dual roles underlie many of its health effects, as we’ll discuss.

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TMG is obtained in the diet from a variety of foods, especially those of plant origin. Most people get about 0.5 to 1 gram of betaine per day from a typical diet, but intake can reach ~2 g or more in individuals who eat a lot of TMG-rich foods.11

Notable dietary sources include:

  • Beetroot and sugar beets: As the name betaine suggests, beets are a top source. Beetroot juice and beet-derived products contain high levels of TMG.                                              
  • Wheat bran and germ: Whole grains, particularly wheat bran and wheat germ, are naturally rich in betaine.12A whole-wheat diet can significantly increase daily TMG intake.
  • Spinach and other leafy greens: Spinach and certain other vegetables accumulate TMG and contribute to dietary intake.13        
  • Shellfish and seafood: Some aquatic animals concentrate betaine. Diets high in shellfish (like shrimp, mussels, or crab) have been associated with higher betaine intake, up to ~2.5 g/day in some cases. 14                                                                                               
  • Other sources: Quinoa, amaranth, and legumes provide some betaine. Additionally, foods high in choline (e.g. eggs, liver, soybeans) indirectly support TMG levels because the body oxidizes choline into betaine as needed.15. It’s worth noting that choline and betaine are nutritionally connected. Up to a certain point, choline from food (such as egg yolks or soy) can be converted by our cells into betaine.16.

Thus, a diet rich in choline-containing foods will also help maintain betaine levels. That said, getting betaine itself from foods (like the ones above) is an efficient way to ensure this nutrient’s availability for its roles in the body.

How stable is betaine from food? TMG in foods is quite bioavailable. Research indicates that betaine consumed from food or as a supplement is absorbed similarly and ends up being metabolized in the liver and kidneys to smaller methyl donors (dimethylglycine and sarcosine).17.

In other words, your body can effectively utilize betaine whether it comes from a bowl of spinach or a dietary supplement, with most of it being taken up by the liver for metabolic processes.

Beyond diet, TMG is available as a dietary supplement, usually derived from natural sources like sugar beets. There are a couple of forms and uses to be aware of:

Betaine Anhydrous (Trimethylglycine)

This is the purified form of TMG with no water molecules attached (anhydrous). It’s typically sold in capsules or powder labeled “TMG.” Betaine anhydrous supplements are often taken for cardiovascular support (homocysteine management) or sports performance. A common serving size is on the order of 500 mg to 2,000 mg (2 g) per day, depending on the intended use. For instance, athletes might use ~2.5 g per day based on studies suggesting performance benefits (more on that later), whereas individuals aiming to support homocysteine metabolism might take 500–1500 mg, sometimes alongside B-vitamins like folate and B₁₂ for synergistic methylation support.

Betaine HCl (Betaine Hydrochloride)

This is a form where betaine is bound to hydrochloric acid. Betaine HCl is marketed as a digestive aid because the HCl can increase stomach acidity. Each capsule typically contains a few hundred milligrams of betaine bound to HCl. While Betain HCl does release TMG upon digestion, its primary use is to support digestion in people with low stomach acid, rather than to provide methylation benefits. If someone is specifically looking for TMG’s systemic benefits, betaine anhydrous is the preferred form since it delivers higher doses of pure betaine without excess acid. Caution: Betaine HCl should be taken with meals (to avoid stomach upset or heartburn from the acid) and is not advised in conditions like active ulcers.

Prescription form (Cystadane®)

In the United States and some other countries, high-dose betaine anhydrous is actually an FDA-approved orphan drug for a rare metabolic disorder. Under the brand name Cystadane, betaine anhydrous is prescribed to patients with homocystinuria, a genetic condition that causes extremely high homocysteine levels. In these patients, betaine is given at medical doses (often 6–9 grams per day, split into multiple doses) to dramatically lower homocysteine by converting it to methionine.18

  • Cystadane has been in use since the 1990s for this purpose and exemplifies how powerful TMG’s methyl donation can be in a therapeutic context. (We’ll discuss homocystinuria more in the therapeutic applications section.)

No matter the form, one reassuring fact is that TMG is generally well-tolerated and non-toxic at typical doses. It’s a natural component of our diet and body, so supplementing in reasonable amounts is considered safe for most people (with certain caveats discussed under Risks). Later, we’ll detail recommended dosages for various goals and what authorities say about TMG’s safety.

TMG has been studied for a range of health and performance benefits. Below, we delve into several key areas where evidence (from scientific studies or clinical trials) suggests beneficial effects:

One of the most well-researched areas for TMG is liver health, especially fatty liver conditions. The liver is a hub for methylation reactions and fat processing, and TMG’s activities in the liver have significant metabolic impacts.

Preventing Fatty Liver

Research has shown that betaine supplementation can protect liver cells from accumulating fat (steatosis) in various contexts. In alcohol-induced liver disease models, TMG has been observed to prevent fat buildup and liver injury.19. Similarly, in non-alcoholic fatty liver disease (NAFLD), betaine helps support the methionine-homocysteine cycle in the liver, which is crucial for exporting fat from the liver. By donating methyl groups, TMG aids the production of phosphatidylcholine, a molecule needed to package and ship fat out of the liver. In doing so, it may reduce the risk of fat accumulation in liver cells. Animal studies and some clinical investigations suggest that betaine can prevent or reduce fatty liver progression.20. For example, betaine has been seen to preserve liver function and prevent oxidative stress in rodents on high-fat diets, effectively attenuating fatty liver disease progression.21

Nonalcoholic Steatohepatitis (NASH) trials

Early human trials gave hope that high-dose betaine might improve NASH, an aggressive form of fatty liver disease. A small pilot study found improvements in liver enzymes and histology with betaine therapy, leading to a larger placebo-controlled trial.22. In that trial, patients with NASH were given a sizeable dose (20 g of betaine daily) for one year. The results were mixed: there was a decrease in liver fat content in the betaine group, suggesting TMG helped reduce steatosis, but there was no significant improvement in liver inflammation or fibrosis compared to placebo.23. In other words, betaine did not significantly improve the overall NASH pathology, though it might have protected some patients from worsening steatosis. Researchers noted that betaine failed to reduce certain inflammatory and metabolic markers in NASH patients (like S-adenosylhomocysteine and cytokines).24. So, while betaine is not a proven cure for NASH, it may have modest benefits in fatty liver management. Ongoing research is evaluating if TMG could be combined with other therapies to better help NAFLD/NASH.25

Supporting Liver Function

Beyond fat metabolism, TMG may help the liver by maintaining a healthy ratio of SAM (S-adenosylmethionine) to SAH (S-adenosylhomocysteine) inside liver cells.26. A high SAH (a byproduct when methyl groups are used up) can inhibit crucial methylation reactions. TMG, by removing homocysteine (and thereby lowering SAH), helps restore the liver’s methylation capacity.27. This supports numerous methylation-dependent processes, including the synthesis of important molecules and antioxidants in the liver. Some studies also indicate betaine can reduce liver oxidative stress and inflammation, further contributing to hepatoprotection.28

Therapeutic potential

Due to its low cost and good tolerability, researchers have argued that betaine “is worth revisiting” as a therapy for liver diseases.29. Especially for conditions like alcoholic liver disease or as an adjunct in metabolic fatty liver, TMG could offer benefits by correcting methylation imbalances and oxidative stress at a relatively low risk.30. Indeed, a comprehensive 2021 review concluded that betaine shows significant therapeutic promise in alleviating alcohol-induced liver injury and metabolic-associated fatty liver disease, by mechanisms like preserving gut integrity, supporting adipose (fat tissue) function, and regulating methionine metabolism.31

Summary: TMG aids the liver in processing fats and preventing fat buildup by supplying crucial methyl donors. It has shown protective effects in many liver studies, although large human trials in NASH did not fully meet expectations. Still, evidence suggests that betaine supports liver health, particularly in the context of fatty liver and possibly as a complementary approach to liver disease management.

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TMG’s influence on the heart and blood vessels centers largely on its ability to lower homocysteine. Homocysteine is an amino acid that, at high levels, has been implicated as an independent risk factor for cardiovascular disease (it can damage blood vessel linings and promote clots). TMG offers a way to remethylate and neutralize homocysteine, which could translate into heart protection:

Homocysteine Reduction

Supplementing with TMG has been shown to significantly reduce plasma homocysteine concentrations. For example, a study in healthy adults who took betaine (typically 6 g per day) found about a 10% reduction in fasting homocysteine levels over several weeks.32   In obese individuals, similar dosing lowered homocysteine by roughly 9%.33  These effects are meaningful because even moderate homocysteine lowering might reduce cardiovascular risk over the long term. In patients with certain genetic or renal conditions that cause high homocysteine, betaine can lower levels even more dramatically (often in combination with B-vitamins). In the genetic disorder homocystinuria, extremely high homocysteine can be cut by ~20–30% on average with high-dose betaine therapy34 – a life-saving intervention for that condition.

Blood Lipids – A Double-Edged Sword

While homocysteine reduction is beneficial, some studies noted a trade-off when using high-dose TMG. Notably, a 2005 analysis of multiple trials reported that betaine supplementation (6 g/day) for six weeks led to a rise in LDL (“bad”) cholesterol and triglycerides in healthy individuals.35 

Specifically, LDL increased by about 0.36 mmol/L (≈14 mg/dL) on average relative to placebo, and triglycerides by ~0.14 mmol/L.36  The ratio of total:HDL cholesterol also worsened slightly.37

These changes could potentially counteract some benefits of homocysteine lowering.38 It’s important to highlight that this lipid-raising effect was dose-dependent – lower doses (e.g. 3 g/day) did not significantly affect lipids in healthy subjects,39 and the effect was more pronounced in overweight individuals with metabolic syndrome.40 

In fact, EFSA’s review noted no adverse lipid changes at 3 g/day in healthy people, but at 4 g/day some increases in total and LDL cholesterol were observed in susceptible groups.41  The mechanism isn’t fully understood, but it might relate to TMG influencing liver fat metabolism or gene expression in ways that raise LDL production.

Bottom line: TMG reliably lowers homocysteine (good for the heart), but at high doses it might unfavorably raise LDL cholesterol in some people (bad for the heart). More research is needed, but if you have high cholesterol or are at risk, it’s wise to monitor blood lipids if you embark on high-dose TMG supplementation.

Blood Pressure and Vascular Health

On a more positive note, some population studies link higher dietary betaine with better cardiovascular markers. In one analysis, individuals (especially obese subjects) with higher combined intake of choline and betaine had lower blood pressure and lower LDL cholesterol compared to those with low intake.42  Moreover, long-term diets rich in betaine have been associated with lower markers of inflammation and improved blood vessel function.43  

These findings suggest that getting betaine from foods (or moderate supplementation) could support heart health beyond homocysteine effects – possibly through anti-inflammatory pathways. Additionally, betaine’s role in maintaining normal homocysteine metabolism is officially recognized: the European Food Safety Authority (EFSA) approved a health claim that “Betaine contributes to normal homocysteine metabolism,” which food producers can use if a product provides at least 500 mg of betaine per serving.44   This reflects scientific consensus that betaine at nutritional doses helps keep homocysteine in a healthy range, indirectly benefiting cardiovascular well-being.

TMAO and Atherosclerosis – The Gut Connection

A discussion of betaine and heart health isn’t complete without addressing trimethylamine-N-oxide (TMAO), a molecule gaining attention in cardiology. TMAO is produced when gut bacteria digest certain nutrients like choline, carnitine, and yes, betaine. Gut microbes can convert TMG into trimethylamine (TMA), which the liver then oxidizes to TMAO.45  High TMAO levels in blood have been linked to a greater risk of atherosclerosis (plaques in arteries) and heart events in some studies.46  This raises the question: Could taking betaine inadvertently raise TMAO and thus heart risk? It appears that while betaine is a potential precursor to TMAO, its impact is relatively modest. Research in mice found that a high-betaine diet produced far less TMAO (by about 100-fold) compared to an equivalent high-choline diet.47

 Betaine tends to be efficiently absorbed in the small intestine, leaving less for gut bacteria to feast on, whereas unabsorbed choline is readily converted to TMA by microbes. Moreover, some rodent studies showed that adding extra betaine did increase TMAO levels, but did not accelerate atherosclerosis development in the absence of other risk factors.48  These nuances suggest that moderate betaine supplementation is unlikely to drastically spike TMAO in most people, especially if one’s gut flora doesn’t favor that conversion. Nonetheless, individuals concerned about TMAO (such as those with existing cardiovascular disease) should be aware of this possible connection. Maintaining a healthy gut microbiome and moderation in dosing can help mitigate any TMAO-related concerns.

Summary: TMG contributes positively to heart health by lowering homocysteine and possibly reducing blood pressure and inflammation. However, high doses may raise LDL cholesterol in some cases, and there’s a complex interplay with gut-derived metabolites like TMAO. On balance, dietary or supplemental betaine at reasonable levels appears heart-friendly – indeed, it’s officially recognized for supporting normal homocysteine metabolism – but ultra-high doses for homocysteine lowering are not widely recommended without medical supervision, given mixed effects on lipids.

Betaine has gained popularity in the fitness and sports nutrition world as a potential ergogenic aid (a substance that enhances physical performance). TMG is often included in pre-workout formulas or taken on its own by athletes. What does the science say? A growing body of research indicates that betaine supplementation (typically around 2–3 g per day) can impart modest yet meaningful benefits for strength, power, and body composition:

Muscle Endurance and Power

Several studies have found improvements in muscular performance with betaine. For instance, a trial in active young men showed that two weeks of betaine supplementation significantly improved muscle endurance in lower-body exercises, allowing more repetitions to failure compared to placebo.49 

In another study, college-aged strength athletes who took ~2.5 g/day of betaine for 6 weeks were able to increase their bench press power and total weight lifted more than those on placebo.50 

Similarly, betaine has been reported to enhance peak power output – meaning athletes can generate a bit more explosive force during short, intense efforts. The mechanism isn’t fully pinned down, but hypotheses include betaine’s role as an osmolyte (helping muscle cells stay hydrated and voluminized), as well as its influence on creatine synthesis and methylation of muscle proteins.

Strength Gains

Longer-term studies give a clearer picture of strength benefits. In one 14-week, placebo-controlled trial with resistance-trained young athletes (youth soccer players), those who took 2 g/day of betaine experienced greater increases in their 1-RM strength (one-rep max on leg press and bench press) and improved repeated sprint performance compared to the placebo group.51  They also saw improvements in aerobic fitness (VO₂max) over the season.52 

This suggests TMG helped the athletes train harder or recover better, leading to measurable performance gains. Other research in resistance training contexts has noted betaine supplementation can improve body composition – reducing fat mass while increasing lean muscle mass – when combined with a consistent exercise regimen.53

Mixed Findings

It’s important to note that not all studies find a benefit – some report no significant changes in performance with betaine, especially in untrained individuals or at lower doses.54  However, when looking at the trend across studies, a review concluded that in several studies, 2–3 g/day of betaine has enhanced resistance training performance and improved body composition in young adults.55

The consistency of positive findings in trained populations suggests that betaine may be more effective when the individual is engaging in high-intensity training that challenges methylation and osmolyte pathways (for example, betaine might help buffer lactate or modulate hormones like cortisol during heavy training).

Possible Mechanisms

Betaine’s ergogenic effects are thought to come from a combination of factors. As an osmolyte, betaine can increase the water retention within muscle cells (cellular hydration), which may positively affect muscle fiber integrity and anabolism (this concept is similar to how creatine works as a cell volumizer). Additionally, TMG’s methyl donation could influence the synthesis of creatine (our muscles’ quick energy reservoir) – in fact, the body uses methyl groups to create creatine, so ample betaine might support higher creatine phosphate stores in muscle. There’s also evidence TMG might raise the testosterone-to-cortisol ratio and reduce inflammation in athletes,56 potentially aiding recovery and adaptation to training. All these small effects can add up to better performance over weeks of training.


Summary: For athletes and fitness enthusiasts, betaine is an emerging supplement that can boost exercise performance. Benefits like improved muscle endurance, slightly greater strength gains, and favorable body composition changes have been reported with ~2–2.5 grams daily over periods of a few weeks to months.57 

While it’s not a miracle supplement, TMG appears to be a safe and useful addition to a training program, especially for those looking to gain an edge in power or high-intensity endurance activities.

 

 

Because TMG is intimately involved in methylation (alongside nutrients like folate, vitamin B₁₂, and B₆), it can have wide-reaching effects on biochemical pathways, including those related to the brain and nervous system. Proper methylation is essential for neurotransmitter production, myelin sheath maintenance, and even mood regulation. Here’s what we know about TMG in this context:

SAMe Production: By converting homocysteine to methionine, betaine indirectly boosts levels of S-adenosylmethionine (SAMe). SAMe is a compound that donates methyl groups to over a hundred reactions in the body, including the synthesis of dopamine, serotonin, and other neurotransmitters. Higher SAMe availability has been associated with improved mood and has even been used therapeutically as a supplement for depression and osteoarthritis. While TMG itself is not a known antidepressant, by sustaining SAMe levels it may support a healthy mood and cognitive function. For instance, individuals with suboptimal folate/B₁₂ status (which leads to low SAMe and high homocysteine) might experience brain fog or low mood – TMG can help compensate by remethylating homocysteine and restoring the methylation cycle58  Some anecdotal reports from users and integrative physicians suggest TMG supplementation improves mental clarity and energy, likely due to its role in these fundamental pathways.

Neuroprotective Aspects: Research is emerging on betaine’s potential neuroprotective effects. Betaine has been noted to protect against neurological stress in certain models, possibly by reducing oxidative stress and inflammation in the nervous system.59  The 2021 review on betaine mentioned a “neuroprotective role” for the compound.60

This could be connected to TMG ensuring the maintenance of membrane lipids (through phosphatidylcholine synthesis) and preventing the accumulation of toxic metabolites. However, hard evidence in humans is limited. Some observational data indicate that higher plasma betaine correlates with better cognitive health in older adults, but causality isn’t established. It stands to reason that keeping homocysteine low via betaine (as high homocysteine is a known risk factor for cognitive decline and Alzheimer’s) would be beneficial for the brain.61  In summary, we can say TMG supports normal methylation in the brain, which is foundational for neurological health, even if direct cognitive benefits need further study.

  • Possible “Nootropic” Use: You might see TMG mentioned in the context of nootropics (substances that improve cognitive function). While TMG isn’t a stimulant or a classic nootropic, its general support of cellular metabolism and blood flow (through homocysteine reduction) could indirectly aid cognitive function. Additionally, by contributing to the production of acetylcholine (a neurotransmitter involved in memory, since choline can be freed up when some is converted to betaine), it might aid memory circuits. This is speculative, but some supplement formulations for brain health include TMG along with B-vitamins and other methyl donors to ensure the brain’s methylation capacity is optimal. At the very least, ensuring one has enough betaine/choline, folate, and B₁₂ can prevent the kind of methylation-related cognitive issues that arise with deficiencies.

Summary: TMG’s benefit for the mind is largely behind the scenes, helping maintain the biochemical environment needed for brain and nerve cells to function. By producing SAMe and keeping homocysteine in check, it contributes to brain health, potentially supporting mood and cognition. Those with high homocysteine or methylation impairments may notice improved mental clarity when using TMG as part of a methylation-supportive regimen.

  • Kidney Protection: The kidneys accumulate betaine to protect their cells in the face of high osmolarity (since urine concentration processes could dehydrate cells). There’s interest in whether extra dietary betaine can help kidney function or protect against kidney injury. Some animal studies suggest betaine may reduce kidney oxidative stress and fibrosis. In humans, this is not well-studied, but ensuring adequate betaine might be beneficial for overall renal health due to osmolyte support. (Individuals with kidney impairment should consult a doctor before supplementing, however, as their handling of methylated compounds can differ.)

     

Body Composition and Metabolism: We touched on this under exercise – betaine might help reduce fat mass and increase lean mass when combined with exercise.62  Some mechanistic research also indicates betaine can enhance metabolism in the liver and adipose tissue. For example, in animal models of obesity, betaine supplementation improved insulin sensitivity and reduced blood triglycerides and liver fat.63  Betaine-treated mice had better glucose tolerance and less insulin resistance, partly by normalizing the insulin signaling pathways in the liver.64  

This raises the possibility that betaine could be helpful in metabolic syndrome or pre-diabetes, by improving how the body handles fats and sugars. Small human studies have had mixed results on insulin resistance, so more research is needed.65  Still, betaine’s role in lipid metabolism suggests a potential preventative benefit against metabolic disorders.


Pancreas and Other Organs: Interesting findings have shown betaine may prevent fat accumulation in the pancreas and preserve pancreatic function in animal studies.66 

  • A fatty pancreas (pancreatic steatosis) can be a problem related to metabolic syndrome, and betaine’s fat-exporting assistance might extend there too. Furthermore, by reducing systemic inflammation, betaine could indirectly benefit other organs like the heart (discussed), joints, and possibly even the skin (some skincare products include betaine for its moisturizing properties). These areas are less documented but hint at the broad protective roles of this molecule.

     

In summary, TMG’s health benefits are multi-faceted. From safeguarding the liver and tuning up heart risk factors, to boosting athletic performance and supporting methylation throughout the body, betaine is a valuable nutrient. It acts at a fundamental level in cells, which is why its benefits seem to span so many systems. However, as with any bioactive compound, there are also potential risks and side effects to consider, especially when used in high doses or certain populations. Let’s examine those next.

 

Before diving into the risks, it’s worth highlighting specific therapeutic contexts where TMG is used or being explored:

Homocystinuria (Genetic Homocysteine Disorder)

We mentioned this earlier – homocystinuria patients lack certain enzymes to properly process homocysteine, leading to extremely high homocysteine levels that can cause cardiovascular and neurological damage. Betaine anhydrous (Cystadane) is an FDA-approved treatment for this condition.67  By providing an alternate pathway to convert homocysteine into methionine, betaine can dramatically lower homocysteine in these patients. Long-term registry data on patients (including children) treated with betaine showed a ~29% average drop in plasma homocysteine and good tolerance over many years.68  

This use of TMG showcases its powerful methylation effect. While homocystinuria is rare, some physicians also use betaine “off-label” in milder cases of hyperhomocysteinemia (e.g. in patients who can’t normalize homocysteine with B-vitamins alone). It’s a targeted therapy under medical supervision in such cases.

Nonalcoholic Fatty Liver Disease (NAFLD/NASH)

As discussed, betaine has been tested in clinical trials for NASH with mixed results.69   It’s not an approved therapy, but it remains a supplement of interest. Some doctors might recommend a trial of a few grams of TMG per day for patients with NAFLD, given its low cost and plausible benefits, provided the patient is monitored. TMG could especially be considered in fatty liver patients who also have high homocysteine or low SAMe levels.

Alcoholic Liver Disease

Chronic alcohol use disrupts the liver’s methylation cycle (alcohol metabolism consumes methyl groups and raises homocysteine). Betaine has shown protective effects in alcoholic liver injury models by restoring the SAM:SAH ratio and preventing fat accumulation in the liver.70  While not a mainstream treatment, some research suggests betaine could be an adjunct to improve liver function in recovering alcoholics or in alcohol-related liver steatosis. Its anti-inflammatory effect in the liver and gut (helping maintain gut barrier function) could reduce the cascade of damage alcohol.71

Potential Cancer Therapies (Adjunctive)

Interestingly, betaine might have a role in cancer prevention or therapy. It has been observed to suppress the development of certain cancers in animal models, possibly by normalizing DNA methylation patterns and reducing oxidative stress.72.  For example, some studies found betaine stabilized the expression of tumor suppressor genes via methylation, thereby slowing cancer cell growth.73. Betaine has also been noted to increase oxidative stress within cancer cells, which can inhibit their proliferation.74. That said, this is not a green light to take betaine as a cancer treatment – the relationship between methyl donors and cancer is complex (as discussed below in Risks). However, populations with higher dietary betaine intake have shown lower incidence of certain cancers in epidemiological studies (notably breast and colorectal cancer).75. This might be due to overall healthier diets or betaine’s effect on keeping DNA methylation stable, thereby preventing the inappropriate activation of oncogenes. Research in this area is ongoing.

Other Therapeutic Ideas

There’s exploration of betaine for conditions like metabolic syndrome, diabetes, and polycystic ovary syndrome (PCOS), because of its effects on liver fat and insulin. Also, since betaine can reduce homocysteine, researchers have looked at whether it might help in chronic kidney disease (where homocysteine often rises) or in improving circulation (homocysteine can impair endothelial function). No definitive clinical guidelines exist for these uses yet, but they represent areas of future investigation. Betaine’s inclusion in medical foods or functional foods for these conditions could be on the horizon if evidence solidifies.

In summary, TMG is not just a supplement; it’s verging into medicinal territory for specific uses. Its role in homocystinuria is well-established, and its potential in liver disease and other metabolic disorders is promising, though not fully proven. As with any therapeutic agent, appropriate dosing and medical oversight are key when using TMG for specific health conditions.

Despite being a natural compound that our bodies are familiar with, TMG supplementation – especially at high doses – can have undesirable effects for some individuals. It’s important to be aware of these potential risks and side effects:

Gastrointestinal Upset

The most common side effects of betaine supplementation are digestive. Some people experience nausea, upset stomach, diarrhea, or cramps when taking TMG, particularly at higher doses (e.g. several grams at once). For instance, in one registry of patients on high-dose betaine (median 6–9 g/day), a few reported mild side effects like “bad taste” in the mouth and nausea, and one patient on very high doses developed gastritis (stomach inflammation).76  Splitting the dose throughout the day and taking it with meals can minimize GI discomfort. Starting with a low dose and gradually increasing also helps your system adjust.

Fishy Odor (Trimethylamine issue)

 A notorious but rare side effect is the development of a fishy body odor. This happens when TMG (or choline) is metabolized to trimethylamine (TMA) faster than your body can clear it. Normally, TMA is quickly converted to odorless TMAO in the liver, but if someone has a lot of TMA production or a genetic issue called trimethylaminuria (fish-odor syndrome), they might build up TMA which smells like rotting fish. High doses of betaine could, in theory, contribute to this in susceptible individuals.77. It’s not common, but if you or others notice a strong fishy odor in sweat or breath after starting TMG, you should reduce the dose or discontinue use. Maintaining good gut flora (perhaps with probiotics) might reduce TMA production as well.

Allergic Reaction

True allergic reactions to betaine are extremely rare (given it’s a simple amino acid derivative found in common foods). There are no significant reports of allergic responses in the literature. Betaine is generally considered non-allergenic, gluten-free, and lactose-free as a supplement.78. However, as with any supplement, there could be sensitivities to other ingredients (like fillers) or idiosyncratic reactions in isolated cases.

Interactions with Medications

TMG itself doesn’t have many known direct drug interactions. It does not significantly affect cytochrome P450 enzymes or common drug pathways. However, one area of caution is in individuals on anticholinergic medications or acetylcholinesterase inhibitors (like some Alzheimer’s medications) – since betaine relates to choline metabolism, there’s a theoretical interaction if huge doses alter choline availability. This is more theoretical than observed. Another consideration is for those on folate-dependent chemotherapy drugs (e.g. methotrexate): betaine provides an alternative methylation route, but it’s unclear if that could undermine certain chemotherapies that rely on disrupting folate/methylation in cancer cells. It’s best to consult a healthcare provider if you’re on any prescription meds and plan to take high-dose TMG regularly. In practice, many cardiologists or doctors are fine with patients taking a gram or two of betaine for homocysteine support, even alongside medications, as no acute interactions have been documented.

Cancer and Methylation Concerns

One complex issue is whether taking extra methyl donors like TMG is safe in individuals with active cancer or a history of cancer. Methylation can be a double-edged sword in oncology. On one hand, betaine might protect DNA from damage and suppress tumor initiation (as some studies suggested, betaine was associated with lower risk of certain cancers due to maintaining normal gene methylation).79. 

On the other hand, once a cancer is established, rapidly dividing tumor cells have high demands for methyl groups to synthesize DNA and RNA. There’s a theoretical concern that loading up on methyl donors (like folic acid, B12, betaine, etc.) could potentially fuel tumor growth or interfere with treatments that intentionally induce methylation stress on cancer cells. Some oncology nutrition guidelines advise against high-dose supplemental methyl donors during active chemotherapy (unless needed for deficiency) for this reason. While no direct clinical evidence shows betaine causes cancer to worsen, prudence is advised. 

If you have a history of cancer or pre-cancerous conditions, talk to your doctor before using TMG supplements. They may recommend avoiding high doses or monitoring certain markers. Interestingly, some cell studies indicate betaine actually slows cancer cell proliferation by restoring normal methylation of tumor suppressor genes.80. so the relationship is not straightforward. In summary, betaine is likely safe from a cancer standpoint for the general population (and may even be preventive), but those with cancer diagnoses should use it only under medical advice.

Elevated Cholesterol in Susceptible Individuals

As discussed earlier, a known effect of high-dose betaine is the potential rise in LDL cholesterol and total cholesterol.81. If you have hypercholesterolemia or familial tendencies toward high LDL, be cautious. Monitor your lipid profile a few months after starting betaine, especially if taking ≥3 grams daily. In overweight or insulin-resistant individuals, 4+ grams of TMG per day caused a significant uptick in LDL in a controlled study.82. However, this effect was not seen at 2–3 g doses in healthy persons,83 and interestingly, dietary choline+betaine intake correlates with lower LDL in some observational studies.84. So the risk appears context-dependent. Regardless, it’s wise to keep an eye on your cholesterol markers and discuss with a healthcare provider if they worsen after starting TMG.

Contraindications

There are not many official contraindications for betaine, but here are some scenarios to be careful with:

Pregnancy and breastfeeding: TMG is naturally present in food and the body, so normal dietary amounts are certainly fine. For supplementing, there isn’t much research in pregnant/breastfeeding women. It’s probably safe at low doses, but high doses should be avoided unless medically indicated, as we don’t know the effects on the fetus/infant in large amounts.

Kidney disease: Those with severe kidney impairment should consult a doctor. Since betaine and its metabolite dimethylglycine are excreted a bit in urine,85and kidney patients often have altered one-carbon metabolism, professional guidance is needed. Interestingly, betaine might help lower homocysteine in kidney patients, but again, individual supervision is key.

Trimethylaminuria: As mentioned, if someone has this rare genetic condition (where TMA accumulates and causes body odor), taking betaine or choline supplements is contraindicated – it will worsen the odor issue.

Major depression on medication: There’s no direct contraindication, but since high homocysteine is common in depression, some psychiatrists use TMG as an adjunct. If you’re on meds, just loop in your provider. TMG could theoretically change SAMe levels which interact with monoamine metabolism, but generally it’s considered supportive, not harmful, in mood disorders.

Summary of Safety: For most people, betaine is safe and well-tolerated at doses found in foods and moderate supplement levels (say, 500 mg up to 2 g per day). Side effects tend to be mild if they occur. The main precautions involve high doses (3+ grams) and individuals with certain health conditions or sensitivities. Always start with a low effective dose and increase gradually if needed. And if you have any complex medical conditions or take multiple medications, it’s prudent to seek medical advice before making TMG a daily regimen.

How much TMG should one take? The answer depends on the context – are you aiming for general health maintenance, targeting a specific health outcome, or addressing a medical condition? Below are some guideline ranges derived from research and clinical use:

General Health/Methylation Support

For a basic nutritional/top-up effect, doses in the range of 500 mg to 1,000 mg (1 gram) per day are commonly used. This level is similar to what a high-betaine diet might provide, and can help ensure optimal homocysteine metabolism. Many multivitamins or B-complex supplements that include TMG contain about 500 mg of betaine as a supportive nutrient. If you have moderately elevated homocysteine (say in the 12–15 µmol/L range) and adequate B-vitamin status, adding 500–1000 mg of TMG daily may help bring it down towards the normal range. Always pair methyl donors with sufficient B₁₂, B₆, and folate, since they work synergistically to recycle homocysteine.

Cardiovascular/Homocysteine Lowering

In cases of high homocysteine or for cardiovascular prevention, 2–3 grams per day of betaine is a typical supplemental dose used in studies. For example, trials in healthy people often used 1.5 g twice a day (3 g total) to achieve homocysteine reductions.86. At 3 g/day, as noted, no significant adverse lipid effects were seen in healthy subjects.87  It’s a kind of middle-of-the-road dose that can yield a 10% or greater drop in homocysteine. If someone does not respond to folate/B₁₂ supplementation alone, doctors might add betaine in this range. However, if you’re doing this on your own, it’s wise to have your homocysteine levels and cholesterol levels rechecked in a couple of months to ensure it’s having the desired effect.

Fatty Liver Support

Although one large trial used 20 g/day for NASH (which is extraordinarily high and not generally recommended), some practitioners suggest 10–15 g/day split into multiple doses for a limited period under supervision, especially in severe cases. But for a more conservative approach, 3–6 g/day might be tried for NAFLD. For instance, 1 g with each meal (3 g total) or 2 g with each meal (6 g total). This should be done in consultation with a doctor, as it’s above typical supplement levels. Lifestyle changes (diet, exercise) remain key for fatty liver; betaine is an adjunct. Signs of improvement (like lower liver enzymes or imaging changes) would be monitored over months.

Sports Performance

The sweet spot for ergogenic effects seems to be around 2.5 g per day. Many sports studies used precisely 2.5 g/day (often split into two 1.25 g doses) and saw benefits in power and body composition. Some protocols use a slightly lower chronic dose (e.g. 2 g/day) but even that showed improvements over 14 weeks.88. It’s common for athletes to mix 2–3 grams of betaine anhydrous in their pre-workout shake or take it with a meal prior to training. It does not need to be cycled and is not a stimulant. There’s no evidence that going above ~3 g yields further performance gains (and it could invite side effects), so mega-dosing is not practiced here.

Homocystinuria (Medical Use)

Prescription guidelines for homocystinuria typically recommend 6 g per day for children and up to 6–9 g per day for adults, divided into 2–3 doses.89. Some patients even require higher doses (10–12 g) if tolerated, to reach target homocysteine levels, but such dosing is strictly under metabolic specialist care. If you ever come across the notion of taking 6+ grams of betaine, realize this is usually in a medical context for a serious genetic disorder – not something the average person should do without medical reason.

Betaine HCl for Digestion

This form is dosed differently. Typically, 300–650 mg betaine HCl per capsule, taken at the start of a meal. People with low stomach acid might take 1–3 capsules with major meals (equaling ~0.6 to 2 g betaine HCl). However, the goal in that scenario is the HCl (to aid digestion), not the betaine’s systemic effects. You wouldn’t count this toward, say, a homocysteine-lowering regimen because most of it assists digestion locally. If someone is using both betaine HCl and betaine anhydrous, be mindful of total betaine intake to avoid unexpected high doses.

Practical Tips

  • Time of Day: TMG can be taken any time, but many take it with meals to avoid stomach upset. Taking it earlier in the day might be preferable for some, as very large doses late at night could, in theory, be stimulating (due to SAMe production). However, most don’t report any energizing effect – it’s quite neutral feeling for most people.

  • Powder vs Pills: Betaine anhydrous often comes as a slightly sweet, soluble powder (since it’s a type of amino acid, it dissolves in water). This powder can be mixed into water, juice, or protein shakes. Pills are more convenient for some but can be large if you’re taking grams. The powder form allows easy titration of dose.

  • Storage: TMG is hygroscopic (attracts moisture), so keep it in a tightly sealed container; otherwise, the powder can clump. Store in a cool, dry place.

  • Stacking: For homocysteine control, betaine is often “stacked” with B₁₂, B₆, and folate (5-MTHF) to comprehensively tackle homocysteine via all pathways. For athletic use, betaine can stack with creatine (complementary osmolytes) and protein. No known adverse interactions with common supplements (like it’s fine alongside vitamins, amino acids, etc.).

Finally, remember that more is not always better. Once you saturate the methylation capacity and osmolyte needs, excess betaine will just be broken down or excreted. Sticking within evidence-backed ranges maximizes benefit and minimizes any risk.

When considering any supplement, it’s good to know how it’s viewed by regulators and health authorities. Here’s a rundown for TMG/betaine:

United States (FDA)

Betaine is not assigned a Recommended Dietary Allowance (RDA) or Daily Value, since it’s not deemed an essential nutrient (our bodies can make some from choline). However, it is widely available as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA). 

This means as long as it’s marketed as a supplement (not claiming to cure diseases), it can be sold over-the-counter. In terms of food additives, betaine is considered Generally Recognized as Safe (GRAS) in the U.S. for specific uses. The Flavor and Extract Manufacturers Association (FEMA) lists betaine as GRAS for use as a flavoring or flavor enhancer up to 0.5% in foods.90. 

Additionally, the FDA’s GRAS Notice Inventory includes betaine as a GRAS ingredient for use as a humectant (moisture-retainer) and nutritional additive in certain foods.91. For example, a major ingredient supplier (Danisco/DuPont) self-affirmed GRAS status for its betaine product to be added to beverages and health foods, which the FDA had no objections to.92. All this essentially means that at moderate levels found in fortified foods or supplements, betaine is viewed as safe by U.S. authorities.

FDA-Approved Drug (Orphan Status)

As noted, Cystadane (betaine anhydrous) is an FDA-approved drug for homocystinuria, receiving approval in 1996.93. This was an orphan drug designation due to the rarity of the condition. The drug form is simply high-purity betaine powder with dosing instructions for patients. The existence of an approved drug version underscores that the FDA acknowledges betaine’s potent physiological effects in certain contexts, even though for the general public it’s treated as a supplement.

European Union (EFSA)

The European Food Safety Authority has evaluated betaine on a couple of fronts. Firstly, as part of the EU health claims process, EFSA’s Panel on Nutrition approved the claim that “Betaine contributes to normal homocysteine metabolism,” as mentioned earlier.94. This claim is now authorized in the EU, with the condition that a food must provide at least 500 mg of betaine per serving to use it.95. This indicates a recognized beneficial effect at that intake. Secondly, betaine was assessed as a Novel Food ingredient a few years ago for its addition to sports nutrition products. 

EFSA concluded that betaine added to sports drinks or bars (at about 2.5 g/day intake for adults) is safe.96. They calculated a margin of safety and even set a guidance level: they considered an additional 400 mg/day (approximately 6 mg/kg body weight) on top of normal dietary intake as a level that definitely poses no risk.97. However, they also acknowledged that even up to ~3 g/day added has been used without ill effect in adults.98. 

The somewhat conservative 400 mg number was derived by taking a no-adverse level of 4 g and adding a large safety factor. In practice, the EU approved betaine’s use in certain fortified foods aimed at athletes, reflecting a consensus of safety for a few grams per day.99

Elsewhere

Betaine is accepted in many countries as a supplement. For instance, Japan and Korea have approved betaine as a functional food additive or ingredient.100  It’s also used in animal nutrition (poultry and swine feed) as a performance and carcass-quality enhancer, which has a long history of safe use in that industry – indirectly reassuring for human use.

No Upper Limit Defined

There is no formally defined Tolerable Upper Intake Level (UL) for betaine by bodies like the U.S. Institute of Medicine, likely because it’s not considered essential and adverse effects in healthy populations are minimal at normal intakes.

That said, the data about LDL increase at 6 g/day provides a practical upper threshold to be cautious about for self-supplementation.101. Many supplement labels will suggest not exceeding 3 g or so daily unless directed by a healthcare professional.

Quality and Purity

Regulatory oversight for supplements means ensuring what’s on the label is in the bottle. Reputable brands that do third-party testing (NSF, USP, etc.) are recommended to ensure you’re getting pure betaine anhydrous without contaminants. Betaine itself is a stable molecule; the concern would mainly be quality of manufacturing.

In summary, betaine/TMG enjoys a reputation as a safe, naturally-derived compound with approval for use in foods and supplements globally. Health authorities acknowledge its role in homocysteine metabolism and have given it a green light for various applications, provided it’s used at sensible levels. As always, “safe” does not mean “everyone should take it” – it just means it has a wide margin of safety for the general population. People with specific health conditions should heed the earlier risk discussions and personalized medical advice.

Trimethylglycine (betaine) is a fascinating example of a nutrient that blurs the line between food and medicine. Biochemically, it serves as a key methyl donor and osmoprotectant, underpinning processes that affect our cardiovascular health, liver function, muscular performance, and more. Research to date paints a generally positive picture: TMG can support liver health by reducing fat buildup and oxidative stress, improve cardiovascular risk factors by lowering homocysteine (while we remain cautious about high-dose effects on lipids), and even enhance athletic performance through better endurance and strength adaptation. It helps “grease the wheels” of methylation pathways, which has downstream benefits for DNA repair, neurotransmitter production, and cellular detoxification.

From a therapeutic standpoint, betaine is already an approved treatment for homocystinuria, highlighting its potent physiological action in the right context. Its potential uses in fatty liver disease, metabolic syndrome, and other conditions are still being explored, with some promising findings. At the same time, we must approach TMG supplementation with a balanced view of safety and risks. It is not free of side effects – gastrointestinal upset can occur, and those with certain metabolic sensitivities or health conditions need individualized guidance. The interplay with TMAO and long-term heart outcomes is an area of active research, reminding us that nutrients can have complex effects.

If you’re considering TMG, here are a few takeaway points:

Diet first: Many people can obtain enough betaine through a healthy diet rich in beets, whole grains, and greens. Dietary betaine (and choline) are part of a heart-healthy, liver-friendly eating pattern.102

Targeted supplementation: If you have specific needs – like moderate hyperhomocysteinemia, non-alcoholic fatty liver concerns, or you’re an athlete looking for a performance edge – betaine supplementation in the range of 1–3 grams per day might be beneficial, and studies support its use in these scenarios.103

Watch and adjust: Pay attention to your body’s response. Check relevant blood markers (homocysteine, lipid profile, liver enzymes) after a few months on TMG to ensure it’s moving things in the right direction. Each individual may respond differently; for example, if LDL creeps up, you might adjust the dose or ensure your diet and other supplements (like omega-3s or fiber) are counterbalancing that.

Safety is high: Regulatory bodies regard betaine as safe and have even approved claims about its health role.104. Just stick to reasonable dosages and avoid extremely high intakes unless under medical supervision.

Consult if in doubt: As with any supplement regimen, it’s wise to consult a healthcare provider, especially if you have complex conditions or take medications. They can provide personalized insight – perhaps checking your baseline homocysteine or advising on dose – to integrate TMG into your health strategy effectively.

In conclusion, trimethylglycine is a valuable tool in nutritional and functional medicine. It exemplifies how a simple molecule from beets and spinach can influence the sophisticated pathways in our bodies for the better. By understanding its benefits and respecting its risks, one can harness TMG to support a range of health goals, from a healthier heart and liver to better workouts. As science progresses, we’ll continue to learn more about the nuances of this compound, but it’s safe to say that betaine has earned its place in the pantheon of evidence-backed supplements for holistic health support.

🔒 Medical and Affiliate Disclosure

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This post is for general informational and educational purposes only and does not provide medical or health advice. The information presented here is not a substitute for professional advice, diagnosis, or treatment. Always seek the guidance of your physician, pharmacist, or other qualified healthcare provider with any questions you may have regarding your health, medications, or supplements.

We do not provide any form of medical advice. The use or reliance on any information contained in this post is solely at your own risk.

Michael Brown in Lab Coat with arms crossed

Michael J. Brown, RPh, BCPS, BCPP

Mr. Brown is a Clinical Pharmacist specializing in pharmacotherapy and psychiatry.

Read Michael’s story here.

Feel free to send Michael a message using this link.

 

 
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