TMG and Creatine: How They Connect and Whether to Take Both

TMG and creatine are linked through methylation: your body spends a large share of its methyl groups making creatine, and TMG (trimethylglycine, also called betaine) is a methyl donor that helps refill that supply. They do different jobs, since creatine is stored in muscle as an energy reserve for short, hard efforts, while TMG supports the methionine cycle and has been studied for homocysteine and upper body power. Taking them together is a common pairing, and here is what the research shows about each one.

Key Takeaways

• TMG and creatine do different jobs: TMG donates methyl groups, and supplemental creatine raises the creatine stored in muscle (Craig, 2004; Kreider et al., 2017).
• Making creatine is one of the body's biggest uses of methyl groups, accounting for roughly 40 percent of the methyl groups supplied by S-adenosylmethionine (SAM) (Brosnan et al., 2011).
• In 76 healthy adults, 1.5, 3 or 6 g of betaine a day for 6 weeks left fasting homocysteine, a marker of methyl balance, 12 to 20 percent lower than placebo (Olthof et al., 2003).
• In 12 resistance-trained men, 2.5 g of betaine a day for 14 days raised bench throw power and isometric bench press force compared with placebo (Lee et al., 2010).
• The main caution for TMG is at high amounts: 6 g of betaine a day for 6 weeks raised LDL cholesterol in healthy adults (Olthof et al., 2005).

TMG vs Creatine: What Each One Does

The names sound alike, but TMG and creatine sit in different parts of your metabolism. TMG hands methyl groups to the methionine cycle, mainly in the liver and kidneys (Craig, 2004). Supplementing creatine raises the creatine stored in muscle, which helps your cells recycle ATP, the molecule they use for quick energy (Kreider et al., 2017).

	TMG (betaine)	Creatine
Main job	Methyl donor in the methionine cycle; also an osmolyte that protects cells	Energy reserve in muscle and brain that helps recycle ATP
Food sources	Wheat germ and bran, spinach, seafood	Mainly meat and fish
Where it works	Mainly the liver and kidneys	Stored in muscle; made in the body from arginine, glycine and methionine
Amounts	1.5 to 6 g a day in homocysteine trials; 200 mg in Enhanced NMN	5 g per scoop in our Creatine Monohydrate
What trials measured	Homocysteine, upper body power and force	Muscle creatine, high-intensity exercise and training adaptations

For more on each ingredient, see our TMG ingredient page and our creatine ingredient page.

How TMG and Creatine Are Connected: Methylation

Methylation is the transfer of a small chemical tag, a methyl group, between molecules. Most of these reactions draw on one donor, SAM, which is then recycled through homocysteine back to methionine and SAM.

Making creatine takes two steps. The kidneys join arginine and glycine to form guanidinoacetate, and the liver then adds a methyl group from SAM to finish creatine. That last step accounts for roughly 40 percent of the body's labile methyl groups from SAM (Brosnan et al., 2011).

This is where TMG comes in. TMG carries three methyl groups, and in the liver and kidneys it can hand one to homocysteine, turning it back into methionine so the cycle keeps running (Craig, 2004). Creatine synthesis draws on the methyl supply, and TMG adds to it.

The link also runs the other way. In a 2-week rat study, a creatine-enriched diet lowered plasma homocysteine by about 25 percent and reduced the kidney enzyme that starts creatine synthesis, while a guanidinoacetate diet raised homocysteine by about 50 percent (Stead et al., 2001). When creatine arrives from the diet, the body makes less of its own and spends fewer methyl groups. As a rat study, it describes the mechanism rather than a result measured in people.

Vegetarians and vegans get little creatine from food, so they make nearly all of their own (Brosnan et al., 2011).

What the Research Measured for Each

TMG and creatine have each been studied on their own. These are the studies behind the main points in this guide:

Study	Who and how much	What was measured
Olthof et al., 2003 (TMG)	76 healthy adults; placebo or 1.5, 3 or 6 g of betaine a day for 6 weeks	Fasting homocysteine 12, 15 and 20 percent lower than placebo at the three doses
Lee et al., 2010 (TMG)	12 resistance-trained men; 1.25 g of betaine twice daily for 14 days, crossover with placebo	Higher bench throw power and isometric bench press force than placebo; squat jump power and repetitions to fatigue did not differ
Kreider et al., 2017 (creatine)	Position stand reviewing creatine research in people from infants to older adults	Higher muscle creatine, linked with better high-intensity exercise performance and training adaptations

Homocysteine is a lab marker of how well the methionine cycle is keeping up, so the betaine trial shows TMG feeds that cycle in people, even at 1.5 g a day. In the strength trial, the gains showed up most in upper body tests (Lee et al., 2010). For the wider research on each, see creatine benefits and TMG benefits.

Should You Take TMG and Creatine Together?

For most healthy adults, taking both is a reasonable and common pairing. The studies above tested each ingredient on its own, so the reason to pair them comes from how they share the methyl pathway:

• Creatine supplies the finished molecule, so the body can make less of its own, which in the rat study meant fewer methyl groups spent.
• TMG adds to the methyl supply. It recycles homocysteine back to methionine, supporting every methylation reaction that draws on SAM.
• They cover different goals. Creatine is studied for muscle energy and training; TMG for methyl balance and strength.

The pairing makes most sense for people with higher methyl demands, such as vegetarians and people taking NMN. The body clears extra nicotinamide from NMN by attaching methyl groups; in 10 healthy men, these methylated breakdown products rose with the NMN dose (Irie et al., 2020). Our guide to NMN and TMG explains that pairing.

How to Take Them

• Creatine: take it every day, because creatine builds up in muscle over a few weeks and consistency matters most. See how much creatine per day for amounts.
• TMG: the homocysteine trial used 1.5 to 6 g a day and the strength trial used 2.5 g a day, split into two doses. Enhanced NMN gives a smaller supporting amount, 200 mg per serving.
• Together: both can be taken at the same time of day, with or without food. Breakfast is an easy time to build the habit.
• Follow your label. Our betaine anhydrous guide explains how TMG is labeled.

Safety and Side Effects

The International Society of Sports Nutrition describes creatine supplementation of up to 30 g a day for as long as 5 years as safe and well tolerated in healthy people (Kreider et al., 2017). Our creatine gives 5 g per scoop. See creatine side effects for more detail.

For TMG, the point to know is blood lipids at high amounts. In pooled trials in healthy adults, 6 g of betaine a day for 6 weeks raised LDL cholesterol by 0.36 mmol/l and triglycerides by 0.14 mmol/l compared with placebo, with HDL unchanged. Lower doses also raised LDL, but not significantly (Olthof et al., 2005). The 200 mg in Enhanced NMN is far below the amounts in those trials.

• Talk to your doctor before high-dose TMG if you are managing your cholesterol or take cholesterol medicine.
• Check with your clinician before creatine if you have kidney problems or take medicines that affect the kidneys.
• Ask first if you are pregnant, breastfeeding or under 18.

Where Our Products Fit

Our Enhanced NMN gives 750 mg of NMN in every 2-capsule serving with TMG 200 mg, resveratrol 200 mg, pterostilbene 100 mg and vitamin B12 as methylcobalamin 750 mcg, with ginger extract in vegan capsules. Take 2 capsules in the morning, with or without food. The TMG and methyl B12 support methyl balance while NMN supports NAD+.

Our Creatine Monohydrate gives 5 g of creatine monohydrate in every scoop. It is coming soon: join the waitlist on the product page to hear when it launches. For the bigger picture of energy at the cell level, see our guide to cellular energy and mitochondrial health.

Frequently Asked Questions

Can you take TMG and creatine together?

Yes. For most healthy adults it is a common and reasonable pairing. Creatine raises the energy reserve stored in muscle, and TMG adds methyl groups to the cycle your body uses to make its own creatine. Both can be taken at the same time of day. Check with your clinician first if you have kidney problems or manage your cholesterol.

What is the difference between TMG and creatine?

TMG, or trimethylglycine, is a methyl donor found in wheat germ, spinach and seafood that supports the methionine cycle. Creatine is an energy molecule stored in muscle and brain that helps cells recycle ATP during short, hard efforts. They are different molecules, so TMG does not replace creatine, and creatine does not supply methyl groups.

Does creatine use up methyl groups?

Making creatine does. The final step of creatine synthesis takes a methyl group from SAM, and this one pathway accounts for roughly 40 percent of the methyl groups SAM supplies. Taking creatine as a supplement is different: in a rat study, dietary creatine let the body make less of its own and lowered homocysteine.

Does TMG help creatine work better?

They have been studied separately, so the reason to pair them comes from shared biology rather than a combined trial. TMG supports the methyl supply that creatine synthesis draws on, and in its own trial 2.5 g a day for 14 days raised upper body power and force in trained men. Creatine remains the ingredient studied for muscle energy and training.

Is there a TMG and creatine supplement?

Some powders combine the two, but taking separate products lets you choose the amount of each. Our Enhanced NMN contains 200 mg of TMG per 2-capsule serving alongside NMN, resveratrol, pterostilbene and methyl B12. Our Creatine Monohydrate, with 5 g per scoop, is coming soon, and you can join the waitlist on its product page.

Should vegetarians take TMG with creatine?

Vegetarians and vegans get little creatine from food, because it comes mainly from meat and fish, so they make nearly all of their own. That puts more of the methyl load on their own metabolism, which is why some take creatine directly and add TMG for methyl support. Wheat germ, wheat bran and spinach also supply betaine.

Does TMG raise cholesterol?

At high amounts it can. In pooled trials in healthy adults, 6 g of betaine a day for 6 weeks raised LDL cholesterol and triglycerides compared with placebo, while HDL did not change. Lower doses also raised LDL, but not significantly. If you manage your cholesterol or take cholesterol medicine, talk to your doctor before high-dose TMG.

Sources

• Craig SA. Betaine in human nutrition. American Journal of Clinical Nutrition, 2004. https://pubmed.ncbi.nlm.nih.gov/15321791/
• Kreider RB, Kalman DS, Antonio J, et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. Journal of the International Society of Sports Nutrition, 2017. https://pubmed.ncbi.nlm.nih.gov/28615996/
• Brosnan JT, da Silva RP, Brosnan ME. The metabolic burden of creatine synthesis. Amino Acids, 2011. https://pubmed.ncbi.nlm.nih.gov/21387089/
• Olthof MR, van Vliet T, Boelsma E, Verhoef P. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. Journal of Nutrition, 2003. https://pubmed.ncbi.nlm.nih.gov/14652361/
• Lee EC, Maresh CM, Kraemer WJ, et al. Ergogenic effects of betaine supplementation on strength and power performance. Journal of the International Society of Sports Nutrition, 2010. https://pubmed.ncbi.nlm.nih.gov/20642826/
• Stead LM, Au KP, Jacobs RL, Brosnan ME, Brosnan JT. Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. American Journal of Physiology: Endocrinology and Metabolism, 2001. https://doi.org/10.1152/ajpendo.2001.281.5.E1095
• Irie J, Inagaki E, Fujita M, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocrine Journal, 2020. https://pubmed.ncbi.nlm.nih.gov/31685720/
• Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Medicine, 2005. https://pubmed.ncbi.nlm.nih.gov/15916468/

These statements have not been evaluated by the Food and Drug Administration. This content is for education and is not medical advice. Our products are not intended to diagnose, treat, cure or prevent any disease. Talk with a healthcare provider before starting a new supplement if you are pregnant, breastfeeding or taking medication.