Methyl donors for more energy and mood, review
Feb 19 2017 by
Ray Sahelian, M.D.

Unless your major is college was chemistry, chances are you don’t remember learning about methyl donors. But if you find the field of brain nutrients and anti-aging 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, contributing to the aging process, and therefore supplementation could well be beneficial. The research in this area is still very early and no firm answers are yet available.

In chapter 9 of Mind Boosters, I mention two of the B vitamins, folic acid and B12, to be methyl donors, although I am not completely sure yet about the full role of folic acid in this capacity. Here I discuss four additional nutrients involved in methylation: TMG, DMG, SAM-e, and DMAE. SAM-e became available in the US in 1996. Interestingly, some vegetables, such as onions, garlic, and beets, contain methyl donors.

What can Methyl Donors do for You?
Methyl donors help in the production of several brain chemicals and hence improve mood, energy, wellbeing, alertness, concentration, and visual clarity. A few people notice sexual enhancement.

What conditions or diseases can methyl donors benefit?
They may be helpful in age related cognitive decline, Alzheimer’s disease, fighting depression, and overall health maintenance. They may perhaps also be helpful in Parkinson’s disease. However, the more is not necessarily better. As with most supplements, a proper balance is important since too high doses can have unpleasant side effects such as overstimulation and insomnia.

DNA methylation has been thought to be an underlying molecular mechanism that may account for the effect of dietary factors on the development and prevention of heart disease. DNA methylation is an epigenetic process that provides "marks" in the genome by which genes are set to be transcriptionally activated or silenced. Epigenomic marks are heritable but are also responsive to environmental shifts, such as changes in nutritional status, and are especially vulnerable during development. S-adenosylmethionine is the methyl group donor for DNA methylation and several nutrients are required for the production of S-adenosylmethionine. These methyl nutrients include vitamins (folate, riboflavin, vitamin B12, vitamin B6, choline) and amino acids (methionine, cysteine, serine, glycine). As such, imbalances in the metabolism of these nutrients have the potential to affect DNA methylation.

J Allergy Clinical Immunology. 2014. Asthma, allergy, and responses to methyl donor supplements and nutrients. Although environmental factors influence the development of atopic disease, dietary changes might partially explain the high burden of atopic disease. Potential mechanisms through which diet is suspected to effect asthma and allergy susceptibility are through epigenetic changes, including DNA methylation. Dietary methyl donors are important in the one-carbon metabolic pathway that is essential for DNA methylation. Findings from both observational studies and interventional trials of dietary methyl donor supplementation on the development and treatment of asthma and allergy have produced mixed results.

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A cognitive formula containing a dozen herbs and nutrients. It combines a delicate balance of brain circulation agents and neurotransmitter precursors with powerful natural brain chemicals that improve:

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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.

Benefit for depression
Behav Brain Res. 2016. Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour. In this study, maternal separation during lactation reduced body weight gain in the female adult offspring without affecting food intake, and altered total and HDL-cholesterol levels. Also, maternal separation induced a cognitive deficit as measured by NORT and an increase in the immobility time in the Porsolt forced swimming test, consistent with increased depression-like behaviour. An 18-week dietary supplementation with methyl donors (choline, betaine, folate and vitamin B12) from postnatal day 60 also reduced body weight without affecting food intake. Some of the deleterious effects induced by maternal separation, such as the abnormal levels of total and HDL-cholesterol, but especially the depression-like behaviour as measured by the Porsolt test, were reversed by methyl donor supplementation. Also, the administration of methyl donors increased total DNA methylation (measured by immunohistochemistry) and affected the expression of insulin receptor in the hippocampus of the adult offspring. However, no changes were observed in the DNA methylation status of insulin receptor and corticotropin-releasing hormone (CRH) promoter regions in the hypothalamus. In summary, methyl donor supplementation reversed some of the deleterious effects of an early life-induced model of depression in rats and altered the DNA methylation profile in the brain.

DNA methylation
J Nutr Biochem. 2012. Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. This is the most extensively studied mechanism of epigenetic gene regulation. Increasing evidence indicates that DNA methylation is labile in response to nutritional and environmental influences. Alterations in DNA methylation profiles can lead to changes in gene expression, resulting in diverse phenotypes with the potential for increased disease risk. The primary methyl donor for DNA methylation is S-adenosylmethionine (SAM), a species generated in the cyclical cellular process called one-carbon metabolism. One-carbon metabolism is catalyzed by several enzymes in the presence of dietary micronutrients, including folate, choline, betaine and other B vitamins. For this reason, nutrition status, particularly micronutrient intake, has been a focal point when investigating epigenetic mechanisms. Although animal evidence linking nutrition and DNA methylation is fairly extensive, epidemiological evidence is less comprehensive. This review serves to integrate studies of the animal in vivo with human epidemiological data pertaining to nutritional regulation of DNA methylation and to further identify areas in which current knowledge is limited.

Front Aging Neurosci. 2013 Dec 5. DNA methylation, a hand behind neurodegenerative diseases. In this review, we have reviewed and summarized recent progress regarding DNA methylation in four major neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The studies of these four major neurodegenerative diseases conclude the strong suggestion of the important role DNA methylation plays in these diseases. However, each of these diseases has not yet been understood completely as details in some areas remain unclear, and will be investigated in future studies. We hope this review can provide new insights into the understanding of neurodegenerative diseases from the epigenetic perspective.

Trimethylglycine TMG and Dimethylglycine DMG
TMG, also known as betaine, is basically the amino acid glycine attached to three methyl groups. Dimethylglycine is similar to trimethylglycine, except it has two methyl groups. You may recall that a methyl group is a carbon attached to three hydrogen atoms (CH3). Both of these nutrients are powerful methyl donors. Methylation is an important factor in many biochemical processes in the human body. In chapter 9 I mentioned that the B vitamins folic acid and B12 lower levels of homocysteine, the harmful amino acid-like substance in blood which can cause hardening of the arteries and possibly damage brain cells. By reducing homocysteine levels, the risk for heart disease can be reduced. TMG and DMG are also known to reduce homocysteine levels and therefore could be helpful in reducing the rate of heart disease. It’s possible that as we age, the process of methylation becomes less effective and supplementation with TMG or DMG may provide health and anti-aging benefits.

Methyl donors are also involved in the making of brain chemicals which accounts for their cognitive effects. My clinical experience confirms that both TMG and DMG improve mood and energy. Brian, a 29-year-old laboratory technician from Torrance, California, speaks for many when he says, “TMG gives me more energy and clearer thinking. There’s a sense of wellbeing that comes on that lasts all day.” Paul Frankel, Ph.D., co-author with Fred Madsen, Ph.D., of a book on methylation, says, “I’ve been taking TMG since 1995 at a dose of 250 mg a day. Through my interviews with individuals who have taken TMG, I have come across many who report benefits—sleeping better, having more energy, and experiencing less chronic fatigue. TMG could also jump start some people and help them fight their depression. A woman whose daughter was suffering with depression told me ‘TMG gave me my daughter back.’” Dr. Madsen adds, “ I have taken TMG for more than ten years without any side effects. People who take TMG report that their mood is enhanced.”

TMG and DMG are underutilized methyl donors that hold a great deal of promise but unfortunately, few doctors are familiar with these nutrients. At this time the clinical uses of TMG 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 of TMG or DMG 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 TMG or DMG on a daily basis until more is known about these supplements. Your dose of TMG and DMG should be reduced if you are taking B vitamins, SAMe, DMAE, or choline since all of these nutrients have overlapping functions and many have the ability to be methyl donors.

SAMe S-Adenosyl-Methionine, a compound made from the amino acid methionine, is a methyl donor involved in the synthesis of dozens of important compounds in the body. SAMe has been available by prescription in Europe for many years as an antidepressant but has been available over the counter in the US only since about 1996.

SAMe has a good potential in becoming a useful therapeutic methyl donor for depression and age related cognitive decline. Long-term studies are needed with SAMe before making widespread recommendations for its use. However, short-term human studies thus far have found it to be safe and effective. A major drawback to the long-term use of SAMe is its cost. Keep in mind, though, that TMG and DMG are also powerful methyl donors, work in a similar fashion, and are cheaper. Could TMG or DMG, taken along with B vitamins, offer similar benefits to SAMe at a fraction of the cost? It is known that TMG can help regenerate SAMe (Barak 1996). Dr. A. Barak and colleagues, from the Department of Veterans Affairs Medical Center, in Omaha, Nebraska, say, “In view of the fact that SAMe has already been used successfully in the treatment of human maladies, TMG, being a SAMe generator, may become a promising therapeutic agent and a possible alternative to expensive SAMe.”

A lot more research has to be done with SAMe to confirm some of the preliminary findings listed above. Dr. Bottiglieri and colleagues, from Baylor Research Institute, in Dallas, Texas, published a review article on SAMe and other methyl donors (Bottiglieri 1994). They summarize, “SAMe is required in numerous methylation reactions involving nucleic acids, proteins, phospholipids, amines and other neurotransmitters. The synthesis of SAMe is intimately linked with folate and vitamin B12 metabolism, and deficiencies of both these vitamins have been found to reduce central nervous system SAMe concentrations. Both folate and vitamin B12 deficiency may cause similar neurological and psychiatric disturbances including depression, dementia, and peripheral neuropathy. Studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders.”

DMAE Dimethyl-amino-ethanol
Known chemically as dimethylaminoethanol, DMAE has been known in Europe by the product name Deanol for more than three decades. DMAE has two methyl groups and is chemically similar to choline. This methyl donor has been popular for many years among those interested in improving mental alertness and clarity of thinking. DMAE can be helpful in the elderly who have cognitive decline. This nutrient can also be taken by an adult of any age who needs to be more focused and alert.

Methyl donors are very interesting nutrients with a great deal of potential, particularly as antidepressants. Since our body’s ability to methylate declines with age, it’s possible that they may someday be found to have anti-aging benefits (Cooney, 1993). These nutrients can also be taken on days when one needs to be more focused and alert.

In addition to their effects on the mind, methyl donors, along with B vitamins, can help lower homocysteine levels, thus reducing the risk for certain heart and neurological diseases.

Clin Neuropharmacol. 2013. Methyl group-donating vitamins elevate 3-O-methyldopa in patients with Parkinson disease. Levodopa (LD)/dopa decarboxylase inhibitor application increases 3-O-methyldopa (3-OMD) concentrations in association with methyl group transfers, which demand for the conversion of methionine to homocysteine. This accompanying reaction is partially reversible by methyl group-donating vitamins.OBJECTIVE:The objective of this study was to investigate of the effect of methyl group-donating vitamins on 3-OMD synthesis in LD-treated patients with Parkinson disease. We determined LD, 3-OMD, and homocysteine plasma concentrations in relation to daily LD dosage administered orally or as duodenal infusion with and without vitamins. Orally LD-treated patients with Parkinson disease had a lower LD dose compared with the ones on an LD infusion, but LD, 3-OMD, and homocysteine bioavailability was not different. The same 3-OMD and homocysteine accumulation despite the applied higher LD dosage during the infusion indicates a limited methylation capacity. Higher 3-OMD concentrations occurred during chronic vitamin supplementation, whereas the other parameters did not vary from the ones before vitamin intake. Vitamin supplementation elevated methylation of LD to 3-OMD. We suggest that, to a certain extent, plasma levels of homocysteine may reflect methyl group donation resources, whereas 3-OMD concentrations may mirror methylation capacity.

Not to be confused
There are a number of compounds with methyl groups. These include methyl salicylate, methyl benzoate, methyl alcohol, methyl bromide, methyl methacrylate, methyl orange, methyl ester, methyl paraben and others. I am not sure of the actions of some of them and do not know whether they also act as methyl donors. I guess I should have paid more attention in my college chemistry class.