Trimethylglycine (TMG), also known as betaine or glycine betaine, is a derivative of the amino acid glycine. The compound was originally discovered in sugar beets. It also occurs in such foods as quinoa, wheat bran and spinach. Trimethylglycine is made in the bodies of most organisms from the nutrient choline.
Clinical Significance of Trimethylglycine
Trimethylglycine is a methyl donor, which, by definition, donates methyl groups that consist of 1 carbon and 3 hydrogen atoms in a process known as methylation. Remethylation of homocysteine, a toxic amino acid formed from the essential amino acid methionine, can be accomplished via a pathway that involves TMG as a cofactor. (Another pathway requires B vitamins.) By lowering homocysteine levels, the risk of cardiovascular and cerebrovascular disease can be reduced.
An early double-blind, cross-over study involving patients with elevated levels of homocystine (a metabolite of homocysteine) who received 3 grams oral betaine twice per day resulted in a significant decrease in average plasma homocysteine levels.1
Impact of TMG on Liver, Kidney and Heart Health
In a pilot study of patients with non-alcoholic steatohepatitis (NASH), betaine given twice per day for one year improved liver enzymes, degree of steatosis, necroinflammatory grade and stage of fibrosis in the majority of patients.2 A subsequent randomized study in which NASH patients received 20 grams TMG daily or a placebo for a year resulted in a lower steatosis grade among those who received TMG.3
In a crossover trial involving chronic renal failure patients, treatment with TMG, folic acid and vitamin B6 for three months was associated with 18% lower homocysteine levels after a methionine load test than levels associated with folate and vitamin B6 alone.4 A randomized study involving obese men and women who consumed a low calorie diet for 12 weeks found that those who received 6 grams per day of TMG experienced an average reduction in plasma homocysteine of 8.76 micromoles per liter after four weeks and 7.93 micromoles per liter at 16 weeks in comparison with a placebo group.5
A study involving 90 patients undergoing coronary angiography found that the postmethionine load increase in total plasma homocysteine was inversely related to plasma betaine and the postmethionine load betaine.6 In a double-blind trial involving 308 men and postmenopausal women, fasting total homocysteine levels were inversely related to plasma TMG levels. Plasma TMG observed to increase following 12 weeks of folic acid supplementation.7 The authors concluded that “Plasma betaine concentration is a significant determinant of fasting total homocysteine concentrations in healthy humans.”
In a study involving four groups of healthy men and women who were given 1.5 grams (g), 3 g, or 6 g of TMG, or a placebo daily for six weeks, fasting plasma homocysteine levels among those who received TMG were a respective 12%, 15% and 20% lower at the end of the treatment period in comparison with the placebo.8 Methionine loading tests conducted after one day of supplementation resulted in increases in homocysteine that were 16%, 23% and 35% lower, respectively, than in the placebo group, and tests conducted at the end of the six-week period resulted in increases that were 23%, 30% and 40% lower. “Thus, doses of betaine in the range of dietary intake reduce fasting and postmethionine loading plasma homocysteine concentrations,” authors Margreet R. Olthof and colleagues conclude. “A betaine-rich diet might therefore lower cardiovascular disease risk.”
In a double-blind, crossover study, 10 men and women were randomized to receive 1, 3 or 6 grams betaine after an overnight fast.9 Blood samples collected immediately before the participants received the compound, and at 2, 7 and 24 hours were analyzed for serum betaine and plasma homocysteine levels. Three and 6 gram doses were associated with a reduction in plasma homocysteine after 2 hours in comparison with baseline levels and homocysteine remained low during the 24 hours of monitoring following the 6 gram dose.
In a study that included eight healthy men, a high betaine meal that contained approximately 517 milligrams (mg) betaine or a meal that contained the same amount of betaine plus 622 mg choline resulted in decreases in plasma homocysteine 6 hours later.10 Participants who were given the high betaine and choline meal, as well as those who received a 500 mg betaine supplement experienced an attenuation of increased plasma homocysteine associated with a methionine loading test in comparison with receiving a low betaine and choline control meal.
Brain Health and Beyond
In addition to cardiovascular disease, homocysteine levels have also been associated with cognition. A double-blind, placebo controlled trial in which older Dutch participants received vitamin B12, B12 plus folic acid, or a placebo for 24 weeks resulted in a reduction in total homocysteine concentrations of 36% and an increase in TMG of 38% in the group that received vitamin B12 plus folic acid.11 While higher plasma TMG levels at the beginning of the study were associated with better performance in several cognitive domains, participants whose increase in betaine after the treatment period was among the top one-third of subjects had better memory performance in comparison with those whose change in betaine was among the lower two-thirds.
Supplementation with TMG for 15 days has been associated with a reduction in fatigue in response to exercise in a study of active college-aged men.12 In a double-blind, crossover study involving resistance trained men, 14 days of 2.5 grams TMG supplementation was associated with an increase in total repetitions and volume load during bench presses in comparison with preintervention values.13 In another crossover study involving trained men, two weeks of TMG supplementation was associated with a decrease in circulating cortisol and an enhanced anabolic endocrine profile, suggesting increased protein synthesis.14
Recently, a placebo-controlled study involving 76 premenopausal women who received 6 months of a combination of boswellia, myoinositol and TMG resulted in a 60% reduction in breast density after 6 months, while those who received a placebo experienced a 9% reduction.15 The combination was also associated with clinical improvement in a trial that tested its effects on women with fibroadenomas of the breast.16
In an investigation reported in JAMA Neurology that identified 36 infants and children with a severe deficiency of methylenetetrahydrofolate reductase (MTHFR, an enzyme encoded by the MTHFR gene that plays a role in the remethylation of homocysteine to methionine), revealed only 2 deaths out of 26 who received treatment with TMG, while 9 out of 10 untreated patients died.17 No deaths occurred among those who received early treatment with TMG. “The results clearly indicate that betaine treatment improves survival, prevents further cerebral damage, and allows normal development if treatment is initiated early,” the authors conclude.
The Bottom Line
“Betaine has been shown to protect internal organs, improve vascular risk factors, and enhance performance,” concludes Stuart A. S. Craig in a review published in the American Journal of Clinical Nutrition. “Databases of betaine content in food are being developed for correlation with population health studies. The growing body of evidence shows that betaine is an important nutrient for the prevention of chronic disease.”18
- Gahl WA et al. J Inherit Metab Dis. 1988;11(3):291-8.
- Abdelmalek MF et al. Am J Gastroenterol. 2001 Sep;96(9):2711-7.
- Abdelmalek MF et al. Hepatology. 2009 Dec;50(6):1818-26.
- McGregor DO et al. Kidney Int. 2002 Mar;61(3):1040-6.
- Schwab U et al. Am J Clin Nutr. 2002 Nov;76(5):961-7.
- Holm P et al. Arterioscler Thromb Vasc Biol. 2004 Feb;24(2):301-7.
- Melse-Boonstra A et al. Am J Clin Nutr. 2005 Jun;81(6):1378-82.
- Olthof MR et al. J Nutr. 2003 Dec;133(12):4135-8.
- Schwab U et al. J Nutr. 2006 Jan;136(1):34-8.
- Atkinson W et al. Am J Clin Nutr. 2008 Mar;87(3):577-85.
- Eussen SJ et al. Br J Nutr. 2007 Nov;98(5):960-8.
- Hoffman JR et al. J Strength Cond Res. 2011 Aug;25(8):2235-41.
- Trepanowski JF et al. J Strength Cond Res. 2011 Dec;25(12):3461-71.
- Apicella JM et al. Eur J Appl Physiol. 2013 Mar;113(3):793-802.
- Pasta V et al. Eur Rev Med Pharmacol Sci. 2015 Nov;19(22):4419-26.
- Pasta V et al. Eur Rev Med Pharmacol Sci. 2016 May;20(9):1860-5.
- Diekman EF et al. JAMA Neurol. 2014 Feb;71(2):188-94.
- Craig SAS. Am J Clin Nutr. 2004 Sep;80(3):539-49.