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Betaine (TMG): Methylation, Cortisol, Homocysteine, & Inflammation
Trimethylglycine or TMG is also more commonly referred to as betaine (BEET-ah-een). For the chemists, as the name implies it is a trimethyl derivative of the common amino acid glycine. TMG is commonly found in our diet in beets (that’s where the name betaine came from), whole grains, spinach and shellfish.
TMG can also be made in the body naturally via oxidation of choline-containing compounds. One of its primary functions in the body is to act as an ‘osmolyte’ and increase water retention of cells. It migrates in and out of cells to preserve cellular hydration state.
Its important to point out here that in today's high stress, easily attained convenience foods, soda's, juices etc... that it is estimated the majority of the population nutritionally deficient and dehydrated.
Like creatine, a higher cellular trimethylglycine concentration can help preserve cell structure and make the cell more resilient to stress. Another important function of TMG is that it also acts as a methyl group donor in creatine synthesis as well as conversion of homocysteine to methionine. Some studies have shown that TMG supplementation may lower plasma homocysteine levels, this is important since elevated homocysteine levels can lead to blood vessel inflammation, making it a risk for heart disease.Betaine ANHYDROUS, also known by the name Trimethylglycine (TMG) is well known and utilized within the Practitioner community for its important and profound effects on methylation and Homocysteine levels.
**Note: You "may" need to support other methylation processes or amino acids/enzymes in order to the maximum benefit of Betaine (TMG). For more information concerning this please see Cycle of Illness: Methylation video and papers.
It is also known for its impact on mood and depression due to the fact when TMG helps to break down Homocysteine into Methionine, and a byproduct of this conversion is SAMe – S-adenosylmethionine, which is known to be effective in the treatment of depression, schizophrenia, demyelination diseases, liver disease, dementia, arthritis, and other conditions.
Recently, the Journal of Neurochemistry reported the brain levels of SAMe in Alzheimer’s patients are severely decreased.
Perhaps not as well-known is TMG’s significant impact on inflammation, which has significant potential anti-aging effects.
A powerful and safe methyl donor. TMG easily donates three methyl groups to the body. Methyl groups (CH3) are required in millions of biochemical reactions in human and animal bodies. Here are just a few of the best studied examples:
Lowering homocysteine.
Helping with liver detoxification.
Alleviating depression.
Reducing the chances of diabetes.
Avoiding genetic problems.
Good for those with MTHFR defect
Antioxidant and anti-inflammatory effects
Has beneficial effects on the brain, digestion, and other body systems
Supports the parasympathetic nervous system
TMG seems to help restore balance to the autonomic nervous system, especially in those who are following a complete nutritional balancing program. This may be one of its most important benefits.
Elevated Homocysteine Levels increase risk
factors for:
Cardiovascular disease
Heart Attack, Stroke
Neural Tube Defects
Cancer
Liver Disease
Depression
Peripheral Neuropathy
BIOLOGICAL BENEFITS OF TMG (Trimethylglycine)
Betaine /TMG (not to be confused with Betaine HCL) works along with Vitamin B6, folic acid and Vitamin B12 to augment the formation of SAMe, an amino acid in the brain. They are proteins and essential building blocks of all cells.
It helps with the Methylation process which is necessary for life.
TMG (Betaine Anhydrous) is a primary methyl donor with the following applications in human nutrition:
By raising level of beneficial SAMe (S-Adenosyl-Methionine).
Body building: In the animal husbandry field, TMG is used to decrease fat and increase meat yield. While human studies have just started, a 200 pound individual with 20% body fat can expect to lose as much as 5 pounds of fat and gain as much as 12 pounds of muscle.
Cardiac protection: Conversion of homocysteine to Methionine. General Health Preventative: As part of a formula for maintaining good health or disease prevention.
Glutathione Elevation: In several different studies, TMG has been shown to increase hepatic Glutathione, the body’s most important antioxidant.
Homocysteine Lowering: Specific for that purpose. The supplement of choice for lowering homocystenuria
Liver Disorders: As a part of liver-healing and protection formulas. Increases SAM levels in the liver, enables the liver to metabolize fat and protect against many challenges such as alcohol induced cirrhosis. TMG will also decrease bilirubin, alkaline phosphatase, and several other liver enzymes related to a large variety of liver disorders. Significant liver benefits have been shown in 20 studies.
Longevity Formulations: As a part of a life extension formula. TMG has shown ability to protect interrogate of cellular DNA through methyl donation.
Methyl Donor Formulations: Along with B12, Folic acid, and Choline.
: Due to its bi-polar nature, helps osmotic pressure in cells. For example it is used in salmon farming to protect fish against the problems of changing salt content. In humans, TMG maintains normal cellular electrolyte concentrations despite water and electrolyte losses during exercise. TMG also helps metabolize fats, which allows the body to burn fat rather than protein or muscle during exercise. The result is less cramping, increased endurance, and better utilization of fat stores
There have been several recent studies exploring the potential benefits of TMG supplementation, and most of them have yielded some impressive results. Nearly all studies examined a daily dosage of 2.5 grams of TMG. In many cases the dose was split with 1.25g twice per day.
While study designs varied between the clinicals, several benefits were perceived from supplementation with TMG at this level. Here’s a quick summary:
Increased muscle strength and power: Marked improvement with Weight-trained athletes taking 1.25g TMG twice daily
Increases markers of protein synthesis vs. placebo.
Enhances endurance: allowing for more bench press reps, extended sprint capacity and more cycling power.
Positive influence on anabolic environment – increased GH and IGF-1 levels, yet decreased cortisol!!
Increased muscle mass, arm size, and decreased body fat.
Many studies were 10-15 days in nature, demonstrating the potential for rapid benefits.
So what’s net effect from all these results? Whether by means of improved cellular hydration, methyl donation or improved hormonal balance, trimethylglycine supplementation works. It improves endurance and enhances your daily quality of life; along with improving pain, muscle, nerve, brain, and inflammation.
As mentioned earlier, You "may" need to support other methylation processes or amino acids/enzymes in order to the maximum benefit of Betaine (TMG). For more information concerning this please see Cycle of Illness: Methylation video and papers.
Betaine (also called trimethylglycine) is also a nutritional component of many foods, including wheat, shellfish, spinach, and sugar beets. (ref 1) It is also available as an inexpensive dietary supplement. The function it serves in the plants that make it is to protect against osmotic stresses, such as drought, high salinity, or temperature stresses.
Earlier studies hypothesized that betaine contained in red wine and whole grain may play a role in the cardiovascular protective effect of those foods. It is also an important part of a major pathway for decreasing homocysteine in humans and other animals by contributing a methyl group for remethylating homocysteine to methionine.
Betaine can be synthesized from choline, hence taking a betaine supplement is a way to spare choline for its other uses, such as to make acetylcholine and phosphatidylcholine.
Choline is also important for protecting the gallbladder (amongst other things); and the gallbladder, as well as choline, is affected by methylation impairments.
When the body is in fight or flight - which means higher cortisol levels- it creates a entire chain reaction as depicted in the slide(s) below. (slides taken from Cycle of Illness: Inflammation (Cortisol), and Cycle of Illness: Methylation.)
These chain reactions worsen your health, further hampers your methylation cycles, and increasing your inflammation, homocysteine, adipose (body fat), cortisol levels, and many other processes!!!
So you can start to see just how intricately tied all these systems, pathways, enzymes, amino acids, and proteins (etc) are.
In the slide above we review how poor methylation can incite a stress response when exposed to something the body can't metabolize. (Please see "Inflammation: Cortisol" video at end of this page for better understanding of the slide and this section of paper)
It goes into fight or flight - and it raises your cortisol levels which sets off this chain reaction which leads to:
- Gallbladder Issues (Gallbladder disease, gallbladder sludge, gallbladder stones)
- Liver Issues (Methylation impairments, Liver damage, Fatty liver)
- Pancreas and insulin issues
- Increased Bile which talks to the brain and tells body to make more metabolic changes. Some of the
changes include further methylation impairements, and the body starting to 'stash' every toxin it can't
methylate and puts it in muscle, fat - like adipose tissue (belly fat which will grow and release a
protein to tell body to create more belly fat and inflammation), and your cells.
Stashing the toxins in cells will create further cell toxicity, damage cells, damage mitochondria,
insulin issues, cortisol/adrenal issues, create more inflammation, and alter genetic expression.
Remember, genetic expression is determined by the condition the cells live in. This in turn has a
direct affect on your health, energy levels, inflammation, body weight, muscle mass, nerve, brain, and
mood.
All of which has the potential to brings on age related diseases earlier in life!!
They also note that some of the studies in which betaine supplementation lowered homocysteine concentrations and improved some clinical conditions (including heart disease and glucose tolerance in both diabetic and nondiabetic subjects) lasted for 13–16 years, and betaine dosage was typically 6 grams per day.
So with the addition of betaine, you can see where this can be extremely beneficial, but how does it work?
Betaine suppresses pro-inflammatory signaling factors
In addition to being a key ingredient for methylation and remethylating homocysteine, A new study (ref 2) now reports that betaine suppresses certain pro-inflammatory signaling factors during aging, including NF-kabbaB pathways.
NF-kappaB controls the transcription of a number of inflammatory molecules, including:
- Tumor Necrosis Factor (TNF),
- Interleukins (ILs),
- Chemokines,
- Adhesion molecules,
- Inducible enzymes
- cyclooxygenase-2 (COX-2)
- nitric oxide synthase (iNOS).
All these inflammatory signaling agents are involved in conditions such as cancer, arthritis, and atherosclerosis. They are also involved in certain conditions where inflammation is beneficial like when especially fighting infections.
Therefore, one should be cautious in using powerful drugs that block these signaling pathways—UNLESS YOU HAVE A SERIOUS MEDICAL CONDITION THAT REQUIRES THIS KIND OF INHIBITION—that’s why you need a knowledgeable doctor familiar with both prescription drugs and nutrition.
This is the reason I'm always promoting healing via food; is because drugs either stimulate, suppress or hijack certain processes or pathways in the body. This in turn is why drug use in otherwise healthy individuals can lead to further complications because these signaling pathways (as shown above / below) are responsible for so many other important biological processes. You need your NFkB to regulate many processes and to help keep you healthy from other illnesses (as shown above / below)
Therefore, mild suppression of inflammation via appropriate dietary supplements would be the way to go for those with only a non-severe degree of inflammatory pathology (such as mild arthritis).
This study was interesting because it looked at aging rats (Sprague-Dawley experiment), which, like humans, have increasing levels of NF-kappaB in association with age, as well as those with atherosclerosis, cancer, and other processes associated with oxidative stress and inflammation. (ref 2)
According to Sprague-Dawley, “Recent reviews show that upregulated NF-kappaB activity seems to be a widespread biological phenomenon in aged animals and that NF-kappaB is a critical transcription factor involved in the pathogenesis of many disorders, including inflammatory diseases.” (ref 2)
Betaine was added to regular rat chow at levels of 0.01%, 0.02%, or 0.04% and fed to 21-month-old rats for 10 days. On the basis that each rat ate on average 3 mg, 6 mg, or 12 mg of betaine, they ate 30, 60, or 120 mg/kg of body weight of betaine per day.
When is it optimal to take TMG? How much?
It’s quite evident from the consistency of the literature that the appropriate dosage of TMG is about 2.5 grams per day. Ideally it should be split in two doses 1.25g each; the first dose taken prior to training and the second either during or after your workout to replenish cellular stores.
There are no known serious side effects of trimethlyglycine supplementation, and the longer term 6 week study supports that. It is important to note that you should look closely at the source of the TMG in products you may be considering and ensure that is listed as ‘Trimethylglycine’ or ‘Betaine Anhydrous’ and NOT ‘Betaine Hydrochloride (HCl)’ which is commonly used as fish food or for low stomach acid related digestion issues.
We suggest that, if you are not already taking betaine, you may want to consider adding it to your daily regimen. Amount tends to vary for each individual. In the experiment, one individual took 500 mg four times a day, while another only needed 1 g four times a day). However, in healthy individuals 2.5 grams per day was all that was needed to optimize cellular processes.
Love and Light,
Happy Healing
Supporting Papers and Videos: I have listed them in the best "order" for information on Methylation
Methylation Video (from Cycle of Illness: Part 2)
https://www.youtube.com/watch?v=ML_RyB1cI5U&t=11s
Methylation Short Video (from Cycle of Illness:Inflammation)
https://www.youtube.com/watch?v=6DmVA0oam08
OLDER Papers on Methylation: - new updated one coming with completion of new Cycle of Illness: Methylation video.
(Pt 1) Methylation: What it is, What it Does, Why its Important
https://www.mastoqueen.com/single-post/2018/10/02/methylation-what-it-is-what-it-does-why-its-important-to-you-and-your-autoimmune-mast-cel
(Pt 2) Methylation and the MTHFR Mutation
https://www.mastoqueen.com/single-post/2018/10/05/methylation-and-mthfr-mutation
(PT 3) Balance Methylation: How to Navigate, Help and Support
https://www.mastoqueen.com/single-post/2018/10/15/balance-methylation-how-to-navigate-help-support-pt-3
Newer Papers on Methylation:
Methylation, Digestion, and Gallbladder
https://www.mastoqueen.com/single-post/2020/09/05/methylation-digestion-and-the-gallbladder
Gallbladder, Methylation and Bile Function
https://www.mastoqueen.com/single-post/gallbladder-methylation-and-bile-function
Betaine: Methylation, Cortisol, Homocysteine, & Inflammation: (this Paper)
https://www.mastoqueen.com/single-post/betaine-tmg-methylation-cortisol-homocysteine-inflammation?fbclid=IwAR1KHcztVjx5D6Ii2pN8k0GSCEh9Y6LELggQNE8poRB227huUt-FA4-jh0o
INFLAMMATION: CORTISOL (From Cycle of Illness: Inflammation)
https://youtu.be/Kje_jkYN4Xc
Signs You Need Methylation Support
https://www.mastoqueen.com/single-post/2019/07/07/signs-you-need-methylation-support
References (mentioned from Above)
Craig SA. Betaine in human nutrition. Am J Clin Nutr. 2004 Sep;80(3):539-49.
Atkinson W, et al. Dietary and supplementary betaine: acute effects on plasma betaine and homocysteine concentrations under standard and postmethionine load conditions in healthy male subjects. Am J Clin Nutr. 2008 Mar;87(3):577-85.
Steenge, GR, et al. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr. 2003 May;133(5):1291-5.
Schwab, U., et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr. 2002 Nov;76(5):961-7.
Graybiel A, et al. Use of betaine and glycocyamine… Ann West Med Surg 1951;5:863-75.
Morrison LM. Results of betaine treatment of atherosclerosis. Am J Dig Dis 1952;19:381-4.
Barak AJ, Tuma DJ. Betaine, metabolic by-product or vital methylating agent? Life Sci. 1983 Feb 14;32(7):771-4.
Barak AJ, et al. Betaine effects on hepatic methionine metabolism elicited by short-term ethanol feeding. Alcohol. 1996 Sep-Oct;13(5):483-6.
Barak AJ, et al. Dietary betaine promotes generation of hepatic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration. Alcohol Clin Exp Res. 1993 Jun;17(3):552-5.
Junnila M, et al. Reduction of carbon tetrachloride-induced hepatotoxic effects by oral administration of betaine in male Han-Wistar rats: a morphometric histological study. Vet Pathol. 2000 May;37(3):231-8.
Junnila M, et al. Betaine reduces hepatic lipidosis induced by carbon tetrachloride in Sprague-Dawley rats. Vet Hum Toxicol. 1998 Oct;40(5):263-6.
Wettstein M, et al. Betaine as an osmolyte in rat liver: metabolism and cell-to-cell interactions. Hepatology. 1998 Mar;27(3):787-93.
Zapadniuk VI, et al. Corrective effect of trimethylglycine on the nicotinamide coenzyme and adenine nucleotide content of the tissues in experimental atherosclerosis. Farmakol Toksikol. 1986 Jul-Aug;49(4):71-3.
Panteleimonova TN, Zapadniuk VI. Effect of trimethylglycine on lipid metabolism in experimental atherosclerosis in rabbit. Farmakol Toksikol. 1983 Jul-Aug;46(4):83-5.
Zahn A, et al. Effects of methionine and betaine supplementation on growth performance, carcass composition and metabolism. Poult Sci 2006, 47:576-580.
Maresh, CM, et al. The effects of betaine supplementation on strength and power performance. Medicine & Science in Sports & Exercise 39(5 suppl.): S304, 2007.
Hoffman JR, et al. Effect of betaine supplementation on power performance and fatigue. J Int Soc Sports Nutr. 2009 Feb 27;6:7.
Lee EC, et al. Ergogenic effects of betaine supplementation on strength and power performance. J Int Soc Sports Nutr. 2010 Jul 19;7:27.
Trepanowski JF, et al. The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men. J Strength Cond Res. 2011 Dec;25(12):3461-71.
Pryor JL, Craig SA, Swensen T. Effect of betaine supplementation on cycling sprint performance. J Int Soc Sports Nutr. 2012 Apr 3;9(1):12.
Czapla, R., et al. Effect of betaine on cycling sprint power. J Int Soc Sports Nutr. 2010 Apr;7(Suppl 1):P23.
Armstrong LE, et al. Influence of betaine consumption on strenuous running and sprinting in a hot environment. J Strength Cond Res. 2008 May;22(3):851-60.
Apicella JM, et al. Betaine supplementation enhances anabolic endocrine and Akt signaling in response to acute bouts of exercise. Eur J Appl Physiol. 2013 Mar;113(3):793-802.
Kraemer, W.J., et al. The influence of betaine supplementation on work performance and endocrine function in men. Annual Meeting of the National Strength and Condititoning Association, 2010.
Cholewa, J. M., et al. Effects of betaine on body composition, performance, and homocysteine thiolactone. J Int Soc Sports Nutr. 2013 Aug;10:39.
Iqbal, O. Betaine induced release of tissue factor pathway inhibitor and nitric oxide: Implications in the management of cardiovascular disease. FASEB 2006 Mar; J 20: A655.
Lever M, Slow S. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem. 2010 Jun;43(9):732-44.
Craig, S. S., et al. The betaine content of sweat from adolescent females. J Int Soc Sports Nutr. 2010 Jan;7:3.
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