Trimethylglycine supplement benefit and dosage, by Ray Sahelian, M.D.
September 12 2016

Trimethylglycine TMG (also known as betaine), and dimethylglycine DMG, are methyl donors that help in the production of several brain chemicals and hence improve mood, energy, wellbeing, alertness, concentration, and visual clarity.  

Health benefits
Unless your major is college was chemistry, chances are you don’t remember learning about methyl donors. But if you find the field of mind boosting interesting, you will certainly want to learn more about these supplements. A methyl donor is simply any substance that can transfer a methyl group [a carbon atom attached to three hydrogen atoms (CH3)] to another substance. Many important biochemical processes rely on methylation, including the metabolism of lipids and DNA. Scientists suspect that adequate methylation of DNA can prevent the expression of harmful genes, such as cancer genes. It’s quite likely that our body’s ability to methylate declines with age, potentially contributing to the aging process, and therefore supplementation is an interesting idea in terms of health benefits.

Benefit
Cell Physiol Biochem. 2013. Trimethylglycine is an important human nutrient obtained from a variety of foods and also can be synthesized from choline. It is much more abundant in kidney and liver compared to other mammalian organs. The principal role in the kidney is osmoprotection in cells of the medulla and it enters these cells via the betaine/γ-aminobutyric acid (GABA) transporter protein (BGT1), which is upregulated by hyperosmotic stress. This process has been studied in great detail. In liver, the main role is a methyl donor in the methionine cycle. However, recent studies showed that BGT1 is much more abundant in liver compared to kidney medulla. Despite this, the role of BGT1 in liver has received little attention. Entry of TMG into liver cells is a necessary first step for its action at the cellular level. Increased interest has developed because of a number of therapeutic uses. These include treatment of nonalcoholic fatty liver and hyperhomocysteinemia, a risk factor for atherosclerotic disease. Several important questions need to be addressed to better understand the potential as a therapeutic agent for other liver diseases, such as alcohol-induced injury. Heavy alcohol consumption is the most common cause for liver-related deaths and altered liver metabolism may contribute to hepatic, vascular, coronary, and cerebral diseases.

Mind Power Rx

This natural mind enhancer with trimethylglycine is a sophisticated cognitive formula. It combines a delicate balance of brain circulation agents and neurotransmitter precursors with powerful natural brain chemicals that support:

Memory and Mood
Mental clarity
Concentration 
Alertness and Focus

The beneficial herbs in the product are: Ashwagandha, Bacopa, Fo-Ti, Ginkgo biloba, Ginseng, Mucuna pruriens, and Reishi.  The nutrients and vitamins in Mind Power Rx include Acetyl-l-carnitine, Carnitine, Carnosine, Choline, DMAE, Inositol, Methylcobalamin, Pantothenic acid, Trimethylglycine, Tyrosine, and Vinpocetine. This brain supplement does not have galantamine or the club moss extract Huperzine A, nor does it have CDP-choline which raises choline levels.

Research results
Trimethylglycine lowers homocysteine levels.
Has been found to protect liver cells from toxins.
Trimethylglycine is a safe and well tolerated nutrient that leads to a significant biochemical and histological improvement in patients with nonalcoholic steatohepatitis (NASH).
May lead to sexual enhancement and enjoyment, as described in the book Natural Sex Boosters, and there are many other herbal products that have a positive influence for instance Tribulus Terrestris Extract.

Depression
Q. You have mentioned in your book, Mind Boosters that DMG and Trimethylglycine are possibly capable of providing much of the same anti-depressant actions as SAM-e, for less cost. I read somewhere that the action of a dose of SAM-e may be enhanced by taking some MSM at the same time. My guess is that would be due to an increase in methylation. Do you think that taking some MSM along with DMG or Trimethylglycine would likewise increase the effects of the DMG or Trimethylglycine?
   A. You ask a  good question. I have tried finding scientific studies on MSM but the published information on this nutrient is limited. I don't know too much about MSM's cognitive effects, although it is known that it can easily cross the blood-brain barrier. My brief personal experience with this nutrient for a few days did not indicate that it had much effect on mood--unlike DMG, Trimethylglycine, and SAM-e--but I need to emphasize that my experience was very limited. If you do try the combination of MSM with other methyl donors, please let me know if you find a synergistic effect. In the meantime, if I come across any other information, I will make sure to post it. If anyone has tried the combination, please email to me.

Int J Gen Med. 2015. Preliminary results of a randomized controlled trial carried out with a fixed combination of S-adenosyl-L-methionine and betaine versus amitriptyline in patients with mild depression. S-adenosyl-L-methionine (SAMe), a safe, endogenous, pleiotropic methyl donor well known for its antidepressant role, has been assumed to have a possible role in increasing plasma levels of compounds known to be able to raise cardiovascular risk. Although the issue is still being debated, betaine (trimethylglycine TMG), a specific methyl donor involved in the homocysteine circuit, may be able to reduce such a risk and/or, by determining a sparing effect on endogenous SAMe, may be able to improve the clinical efficiency of SAMe itself. Indeed, preliminary results have shown clinical improvement determined by an add-on therapy with betaine administered along with SAMe, versus SAMe alone, to patients affected by mild/moderate depression. This small, open-label, randomized, observational study enrolled 64 individuals with a diagnosis of mild depression. After randomization, they were treated with either Laroxyl (amitriptyline, 75 mg/day) or DDM Metile (enteric-coated SAMe, 500 mg/day, plus TMG, 250 mg/day) for 12 months. After 3 months, both treatments showed a small and not statistically significant improvement. After 6 and 12 months, both treated groups demonstrated a more noticeable improved response, although the group treated with SAMe plus betaine showed better results in terms of score, number of individuals in remission, and side effects. Compliance was overlapping in both treatments. The association of SAMe plus TMG seems to be a safe and effective tool to counteract mild depression and also when used as monotherapy in subjects with a recent diagnosis.

Additonal nutrients and herbs that help with energy levels include:
B vitamins can be used at a dosage of one to three times the RDA. A great daily multivitamin supplement is MultiVit Rx formulated by Dr. Ray Sahelian.
Bee Pollen can increase energy in many people.
Carnitine can be used at a dosage of 200 to 500 mg a day. It is best not to combine many supplements together since overstimulation can occur. Learn how each supplement works by itself.
Chromium is often used by those with blood sugar elevation.
Creatine is the best muscle booster available.
Ginseng is probably the best known Chinese herb.
Royal Jelly increases energy.
Spirulina is a form of blue green algae.
NADH is a form of the vitamin niacin and available as a supplement.

Q. I am wondering which has the more benefits as far as energy go, DMG or TMG? Also, are they to be taken with food or without for max benefits?
     A. DMG is usually available under the tongue and works quicker. They both can be taken with or without food. TMG usually provides more energy but each person is unique in their response.

Side effects, safety, risk, danger
Trimethylglycine, if taken in high dosages, such as more than 750 mg, can cause nausea, increased body temperature, restlessness and insomnia and perhaps muscle tension headache.

Prog Biophys Mol Biol. 2015. Consequences of dietary methyl donor supplements: Is more always better? Several diseases increasing in frequency are associated with altered DNA methylation. DNA methylation is accomplished through metabolism of methyl donors such as folate, vitamin B12, methionine, betaine (trimethylglycine), and choline. Increased intake of these compounds correlates with decreased neural tube defects, although this mechanism is not well understood. Consumption of these methyl donor pathway components has increased in recent years due to fortification of grains and high supplemental levels of these compounds (e.g. vitamins, energy drinks). Additionally, people with mutations in one of the enzymes that assists in the methyl donor pathway (5-MTHFR) are directed to consume higher amounts of methyl donors to compensate. Recent evidence suggests that high levels of methyl donor intake may also have detrimental effects. Individualized medicine may be necessary to determine the appropriate amounts of methyl donors to be consumed, particularly in women of child bearing age.

My son is taking a tmg supplement. Initially, in combination with b12 shots and folate it made a huge difference in his cognitive abilities. Now, when he goes to take a nap, sometimes he can't stop talking, or moving, could his body now be producing this on it's own and additional supplementation is too much? He is 2 and 4 months.
   It is easy for children to overdose on this nutrient.

My experience with trimethylglycine pills
I definitely notice a sense of wellbeing, alertness, and mental sharpness from both trimethylglycine and DMG, generally at a dose between 100 to 500 mg. One morning I took three 750 mg pills of trimethylglycine (totaling 2250 mg) on an empty stomach with an ounce of fruit juice just to see if there were any side effects. An hour later I felt the onset of mild nausea. Drinking a few ounces of milk relieved the nausea. As the day progressed, I felt more energetic and realized that my mood was enhanced. In the evening I took my routine three-mile walk and noticed that I had a great deal of energy. I kept walking and ended up covering, twice my normal distance. The drawback was that at bedtime I was still alert and couldn’t sleep at all. I got out of bed several times throughout the night. I continued feeling the alertness well into the morning of the next day. Apparently 2,250 mg is a very high dose and can have effects on the brain lasting more than twenty-four hours. A positive effect from taking DMG or trimethylglycine  that I hadn’t expected was an enhancement in libido. When I take a sublingual form of DMG, I notice the onset of alertness within a half-hour.

The Chemistry of DMG and Trimethylglycine
DMG (dimethylglycine) is basically the amino acid glycine attached to two methyl groups while TMG, also known as betaine, has three methyl groups. Commonly these methyl groups are added to homocysteine, converting it into the amino acid methionine which is then converted to SAMe, a nutrient available over the counter which has been used as a powerful antidepressant. DMG plays a crucial role in the respiratory cycle of the cells, transporting oxygen and serving as a potent methyl donor. DMG acts as a building block for the synthesis of many important substances such as choline, SAM-e, the amino acid methionine, several hormones, neurotransmitters, and DNA. The formation of the neurotransmitters norepinephrine and dopamine requires a methyl group donated by SAMe. Dopamine enhances sex drive.

Recommendations
Trimethylglycine and DMG are underutilized nutrients that hold a great deal of promise but unfortunately, few doctors are familiar with these nutrients. At this time the clinical uses of Trimethylglycine and DMG are not well defined and whether they would be helpful in the therapy of Alzheimer and Parkinson’s disease is not known. Since the body’s ability to methylate declines with age, supplements in small amounts, such as 50 to 100 mg a day, may benefit middle aged and older individuals. I recommend not exceeding 250 mg of Trimethylglycine or DMG on a daily basis until more is known about these supplements. Your dose of trimethylglycine and DMG should be reduced if you are taking B vitamins, SAMe, DMAE, or choline since all of these nutrients have overlapping functions.

Trimethylglycine Research
Trimethylglycine (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.
Betaine ( trimethylglycine ) is found in several tissues in humans. It is involved in homocysteine metabolism as an alternative methyl donor and is used in the treatment of homocystinuria in humans. In pigs, trimethylglycine decreases the amount of adipose tissue. The aim of the study was to examine the effect of trimethylglycine supplementation on body weight, body composition, plasma homocysteine concentrations, blood pressure, and serum total and lipoprotein lipids. Forty-two obese, white subjects (14 men, 28 women) treated with a hypoenergetic diet were randomly assigned to a trimethylglycine-supplemented group (6 g/d) or a control group given placebo for 12 wk. The intervention period was preceded by a 4-wk run-in period with a euenergetic diet. Body weight, resting energy expenditure, and fat mass decreased significantly in both groups with no significant difference between the groups. Plasma homocysteine concentrations decreased in the trimethylglycine group. Diastolic blood pressure decreased without a significant difference between the groups. Serum total and LDL-cholesterol concentrations were higher in the trimethylglycine group than in the control group. A hypoenergetic diet with trimethylglycine supplementation (6 g daily for 12 wk) decreased the plasma homocysteine concentration but did not affect body composition more than a hypoenergetic diet without trimethylglycine supplementation did.

questions
Q. I've just read about Trimethyglycine on your site. I recently had blood work done and everything was great except my Homocysteine, which was 11.1. I want to lower it to the 6-7 range. I've been researching and found sites with TMG protocols of up to 6 grams along with B6 (100-500 mg), B12 (1000-3000 mcg), and folic acid (800-5000 mcg). My question: Does taking these supplements at these dosages have side effects? Especially the TMG, which is very high? One site mentioned someone who had a Homocysteine number of 18. He took TMG at 6 grams and 500 mg of B6 and lowered it to 4 in 60 days. I'm just curious as to your opinion of these kind of dosages. Your thoughts are appreciated. Your site is very informative.
     A. TMG at high doses can increase body temperature and cause irritability and insomnia. My preference is not to use TMG in a dosage greater than 750 mg daily. Also, massive doses of B vitamins are not required. A fraction of the doses mentioned in your email can be effective. Each person is unique in their response, though, and some require less, others more.

I find that TMG in a high doses stimulates my brain too much. Even 500 mg seems to be too high for me.
   Yes, trimethylglycine can cause stimulation in some people even at a dose of 100 mg.

Do you know how much 2000 mg of TMG is in SAM-e supplement?
   TMG and SAM-e are different molecules even though they are both methyl donors. TMG is trimethylglycine while SAM-e is s-adenosyl-methionine. Even though they have similar actions, they are different molecules. It's hard to know what the equivalence is in terms of potency, but a very rough guess would be that sam-e is a few times (3 to 6 times?) more potent than TMG.

I take a few herbs for health and medical conditions including ahcc product for immune system, serrapeptase supplement as an antioxidant, mangosteen fruit extract, graviola fruit extract and I take trimethylglycine for sexual enhancement. Am I taking too many supplements, could these cause side effects in the long run?
    I prefer people not mix too may pills in one day unless they have tried each one separately and know the benefits and side effects quite well. It is difficult to predict interactions since that depends on the dosages used and your particular physiology and tolerance to herbs and pills.

I need to take as 2,000 much of TMG daily for mood, lower doses don't seem to work as well. I have read that if you take TMG at 2000 mg you need over 1000 mg of folic acid. Folic acid in high doses has been link to a certain cancer. Could you tell me if I only take 400 mg or 800 mg of folic (along with B6 and B12) with 2000 TMG is my homocystiene likely to be too high. I am to get a test soon so I will know. But I wanted to know what you might know.
    I am not aware that there have been any studies that say folic acid supplements are required in those who take TMG in high dosages. There are other options to treat depression naturally.

Thank you for your research and teaching on this website! I have benefitted from the information here several times. I especially appreciate the mix of your personal experience, the emperical studies, anecdotal evidence, and your analysis of the usefulness and applicability of the information from the various sources. Will TMG (375mg every other day) increase my total cholestrol or lower my HDL:LDL ratio? I am a 53yr old male with a good HDL:LDL due to much exercise and avoiding transfats, and slightly elevated total cholestrol. While I am interested in the health benefits of TMG, I really do not want to increase total cholestrol or lower my HDL:LDL ratio. While I realise that there is little science on this at the moment, what would be your guess on the typical effect of supplementation?
    Chances are low dosages of this natural supplement will not have much of an influence on cholesterol levels, it is not easy to make such predictions accurately. It is a good idea to take breaks from the use of TMG pills.

Trimethylglycine is said to be the supreme methylating compound and has been used by some in combination with other methylators e.g. folinic / folic acid, B12 to help 'lift a blockage' within the 'methylation' cycle. If however the supplimentation with trimethylglycine were to induce a headache which increased in severity with the ingestion of food, would this likely suggest a blockage due to a deficient co-factor/co-enzyme, or a state of 'over-methylation' for which supplementation with methylation agents would be detrimental?
    It is not clear to me why TMG causes headaches in higher dosages, but the simplest thing to do is reduce the dosage or use it less frequently.

First of all, thanks for all the amazing information and research on your web site. I want to ask you a few questions regarding TMG. I've read somewhere that this natural supplement is an inexpensive alternative to SAM-e, since the body can make SAM-e directly from TMG -- is this accurate? If so, how much TMG is equivalent to 200 mg of SAM-e?
    Although TMG helps with mood, it is not as effective as SAM-e to treat depression but nevertheless is of benefit. It's difficult to give equivalence ratios, but I would guess 200 mg of SAM-e would be in some ways as strong as 400 to 1000 mg of TMG but their effects are not all similar. This is a rough guess and varies among individuals.

Buy TMG supplement 500 mg Jarrow Formulas
Buy TMG trimethylglycine 500 mg

Dosage: half a tablet in the morning a few times a week
 

buy Trimethylglycine supplement, 750 mg by Source Naturals
TMG is found in a variety of plant and animal sources and is used in the conversion of homocysteine to methionine. TMG has been shown to help protect the liver and raise S-adenosylmethionine (SAM-e) levels, in animal studies.

Amount Per Serving:
Calcium- 60 mg - 6%DV
Trimethylglycine 750 mg

Dosage: a third or half tablet in the morning a few times a week. High dosages are not advised to be taken regularly.