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Undermethylation: Is this the cause of your fatigue?

Methylation is essential for healthy cells and organs, immune function, cognitive function, and prevention and treatment of cancer. It is also implicated in many common complaints seen by practitioners on the daily such as fatigue. This article will focus on what methylation is, why it is important, how to optimize your methylation status, and tests you can have done to evaulate your methylation status.

What is methylation?

Methylation is part of phase 2 detoxification and cell expression. Detoxification happens in 2 phases (well 3 really with phase 3 happening prior to phase 2). Phase 1 of detoxification happens in the liver and involves the cytochrome P450 enzymes. Phase 2 happens in the gut and involves conjugation of toxins. Methylation, which is part of phase 2 detoxification, is a main biochemical process that turns biological switches on and off for a host of reactions within the body. In other words, methylation regulates gene expression in the body by turning genes on and off. That's a big deal! DNA methylation is a major component of epigenetic health regulating genes, cell differentiation and conditions like cancer prevention and treatment (Moore, et al). Methylation aids in:

  • Detoxification

  • Neurotransmitter production

  • Hormone metabolism

  • The breakdown of histamine

  • Immune system regulation

  • DNA/genetic expression

  • Growth and development

How does methylation happen?

DNA methylation involves addition of a methyl group to the carbon 5 position of the cytosine ring - a carbon atom attached to three hydrogens (CH3) (Moore, et al). This process occurs billions of times per second! Basically the amino acid methionine with the help of SAMe donates a methyl group to form homocysteine. With the help of vitamin B12 and folate ( in the form of methyltetrahydrofolate) homocysteine is turned back into methionine or is converted to glutathione with the help of cystathionine, cysteine and vitamin B6. Magnesium is also an important player as well as the enzymes that are bolded in black in the above schematic. Any SNP's (single nucleotide polymorphisms) in these enzyme pathways (MTHFR, CBS, BHMT, MTR) could impair ones methylation capacity and require some individuals to supplement key nutrients through diet and/or neutraceutical to help over-ride these SNPs.

SAMe (S-adenosylmethionine), which is the bodies major methyl donor, gives away its methyl groups to other organ systems in the body such as the cardiovascular, neurological, and reproductive systems as well as aids in detoxification throughout the body.


An important end product of an effective methylation cycle is our mega antioxidant glutathione. Glutathione aids in the detoxification of heavy metals like mercury and lead, mycotoxins, POPs (persistent organic pollutants), protection from alcohol, and protection from oxidative stress (Pizzorno, J). The methylation cycle is dependent of the production of SAMe to produce the methyl donors so other organ systems can function and detoxification can happen throughout the body. To little SAMe from inadequate intake of methione, b-vitamins, magnesium, choline and methylation cannot happen and the impacts can be seen throughout the body in wide array of symptoms as the body cannot function the way it needs and detoxification is impaired.

How do I know if I am methylating adequately?

There are simple blood tests that can be done to evaluate for proper methylation. These tests, for the most part, can be run through insurance and include:

  • Homocysteine

  • Vitamin B12

  • Folate (vitamin B9)

  • MMA (methylmalonic acid)

  • Vitamin B6

  • Reduced and Oxidized glutathione levels

  • RBC magnesium

You can also have other tests run that are likely an additional cost such as:

  • Plasma amino acids

  • Organic acid testing

  • Methylation panel

  • Genetic testing: MTHFR, COMT

Factors that affect methylation