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Methylation is a process where a methyl group (a carbon and three hydrogens) is attached to another substance.   Current research estimates that 30 to 40 percent of the population has abnormalities in one or two of the genes for the enzyme methyltetrahydrofolate reductase (MTHFR).  This enzyme converts folic acid to 5-methylfolate, which is the active form of folate; abnormalities in this enzyme’s activity can lead to decreased methylfolate production, which can have profound biochemical effects in the body.  However, methylation is an extremely complex process involving multiple enzymes and pathways, not just the MTHFR, and abnormalities can occur in other genes/enzymes as well.   Abnormalities anywhere in the methylation cycle can result in overall under- or over-methylation, and as such, just testing for this one gene may not show the entire picture of methylation.

Functions of Methylation: Why Should We Care?

The methylation process can affect every cell and process in the human body.

Gene Regulation

Methylation and acetylation are the two major chemical gene regulators.  Not all genes are active at all times and methylation appears to be one of the major methods by which cells lock genes in the “off” position.  This is particularly important for turning off cancer genes, but all genes need to have a balance of activity; no gene should be active constantly.  Because of this, proper DNA methylation is essential for cell growth and division, and research is indicating links between abnormal methylation with aging, cancer development and progression, and birth defects. Abnormal cell growth can affect any cell that naturally has a rapid turn-over-rate, such as skin, red and white blood cells, and the intestinal lining.

Vitamin Activation

Methylation is required to activate vitamin B12 and folate; without the addition of that methyl group, those vitamins are inactive.  If a person has abnormal methylation, the levels of B12 and folate measured in the blood could be normal, but the body could be functioning at a deficiency because those vitamins aren’t in the active form.   Vitamin B12 and folate are cofactors in many processes and are essential in red blood cell production and therefore, energy metabolism.

Protein Metabolism and Homocysteine

Methylation is also essential for overall protein metabolism and specifically, the conversion of the amino acid homocysteine to methionine or cysteine. Homocysteine is highly inflammatory and a major and independent risk factor for coronary artery disease and heart disease.  Homocysteine levels can be measured in the blood and can be used to evaluate both inflammation levels but also methylation status.  Most labs use a reference range that has a normal level just below a cutoff value (e.g., < 15).  I evaluate a patient’s result using both upper and lower values to provide a balanced range since either too much or too little methylation may be problematic.



Neurotransmitter Synthesis and BH4 Recycling

Synthesis of neurotransmitters, including serotonin, and dopamine, is dependent on methylfolate, which acts as an enzyme cofactor. If the methylation process is defective, a lower amount of methylfolate may be available, reducing the production of these neurotransmitters.

Methylfolate is also essential for the recycling of tetrahydrobiopterin (BH4), which is an essential cofactor for the production of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine, and epinephrine.  BH4 is also required for the production of nitric oxide, which is a strong vasodilator.   There is some research that indicates a lack of BH4, and therefore, nitric oxide, may be responsible for circulation-related diseases.


One of the other major roles of methylation is detoxification, as it is one of the major Phase 2 detoxification pathways in the liver.  Detoxification occurs in two phases; the first phase occurs by enzymes in the liver cells and it serves to break down a substance so that in Phase 2, another group can be added to it to make it easier for the body to eliminate.  There are a number of different phase 2 pathways, and different substances, including hormones, neurotransmitters, and chemicals, are detoxified through different pathways.  The challenge in this system lies in the fact that often the product of Phase 1 detoxification is more toxic than the original substance and if there are problems with its Phase 2 pathway, that more toxic substance will remain active in the body for a longer time period.

One particular issue with methylation as a detoxification route is that estrogen is one of the main substances that are detoxified by methylation.  Estrogen gets converted to hydroxyl-estrogen via Phase 1, and this form of estrogen is highly toxic, causing DNA damage and contributing to breast cancer risk.  Through Phase 2 methylation, that hydroxyl-estrogen is converted to the much less active and safer methyl-estrogen; this form of estrogen actually appears to have some beneficial cardiovascular effects.  Understanding the role of methylation becomes exceptionally important in looking at a woman’s estrogen exposure and breast cancer risk, separate from her total estrogen level or her breast cancer genetic status.

Impaired methylation can also decrease glutathione production; glutathione is the primary antioxidant in the human body and one of the major detoxification routes, especially for heavy metals.  Methylation is also the breakdown pathway for histamine, and elevated levels of histamine are associated with allergies and brain inflammation.  Blood levels of histamine can be evaluated along with homocysteine to give a window into a person’s actual methylation status.

Cellular energy

Methyl group donation is essential for the synthesis of carnitine and CoQ10.  These two nutrients are required to produce cellular energy in the mitochondria.  Without them, the mitochondria cannot produce energy (ATP), which is the biochemical energy source for every process in the body.

Symptoms of Methylation Abnormality

Many different symptoms can be associated with methylation abnormalities, and patients can be overmethylators or undermethylators.  Not every patient with a methylation abnormality will have all of these symptoms and some of these symptoms can also be associated with other causes besides methylation.  Additionally, there may be overlap between the two patterns.

Symptoms of those two patterns can include:

Overmethylation Undermethylation
Anxiety/ panic attacks Low pain tolerance
ADHD, Hyperactivity, restless legs Frequent headaches
Sleep disorders Perfectionism, rumination about past
Food and chemical sensitivities Fewer food allergies
Lack of respiratory allergies Environmental/respiratory allergies
Dry eyes and mouth Easy tears, saliva
Low libido High libido
Depression but usually  worse on SSRIs Depression better with SSRIs, antihistamines


Methylation Support

Normal methylation and methylfolate levels in particular clearly profoundly affect our health.  The question becomes, if a person has one or more of those genetic abnormalities, has evidence of abnormal homocysteine and/or blood histamine levels, and/or has symptoms associated with abnormal methylation, how can we support that process?

There are several supplements we can use to support methylation both directly and indirectly.  These include:

  • 5 MTHF and methylcobalamin (B12): these may act more directly as enzyme cofactors than methyl donors to the entire methylation cycle.
  • Choline, TMG (trimethylglycine or betaine), and DMG (dimethylglycine): Choline is metabolized into TMG, which is involved in SAM(e) synthesis.  DMG is formed when TMG loses one of its methyl groups.  All three provide sources of methyl groups.
  • S-adenosyl methionine [SAM(e)] and methionine: SAM(e) is produced in the liver from the amino acid methionine and is one the best methylating agents available. The challenge is that SAM(e) can be expensive to maintain appropriate dosing levels.  Therefore, supplementing with methionine and supporting liver function may be an alternative solution.

Other nutrients that indirectly support methylation and may be considered include zinc, phosphatidylserine, inositol, calcium, magnesium, B complex, and Vitamins B2, B6, A, C, D and E.  Glutathione or N-acetylcysteine supplementation may be needed because of the effect methylation has on glutathione production.

It is important to note that some patients who undermethylate do not tolerate methylfolate, especially in high doses.  For those patients, other methyl donors may be a better way to support methylation.  Additionally, the dose of methyl supports may need to be titrated up slowly to allow for other enzymes time to upregulate.  For example, the COMT enzyme breaks down the catecholamine neurotransmitters (serotonin, dopamine, and norepinephrine).  If a patient starts a high dose of methyl support and production of those neurotransmitters significantly increases, the COMT enzyme may not be able to keep up with the breakdown, leading to a state of catecholamine excess.  Therefore, methylation support may need to be started slowly to reach a relatively high dose to replete deficiencies, and then decreased down to a maintenance level.

Methylation clearly plays a significant role in human health.  However, this is definitely one situation where one size does not fit all.  Patients need to be evaluated for their methylation status and different methylation supports may need to be used in different doses at different times to support optimal health.

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