March 14, 2023

Undermethylation: Is this the cause of your fatigue?

Check out our blog post on undermethylation

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




  • Stress

  • Ability to digest and absorb the key nutrients involved in the methylation process i.e. GET YOUR GUT RIGHT!

How do I know if hypomethylation is an issue for me?

First of all, a in-depth biomarker analysis on routine, yearly labs can help to treat poor methylation before the symptoms start. Ask your provider to run additional markers on your yearly exam. Symptoms of poor methylation:

  • fatigue

  • insomnia

  • frequent skin cancer

  • headaches

  • IBS

  • addiction

  • depression

How do I optimize methylation?

What can you do at home to insure that you are methylating properly? First of all, having an in-depth biomarker analysis is helpful but making sure your diet is good! Get in lots of color to assure you are getting the vitamins and minerals needed for methylation co-factor support and optimize your gut function for digestion and absorption of the nutrients needed for methylation to occur. It is also important to clean up your environment from toxic chemicals, incorporate stress management into your daily routine, and decrease consumption of alcohol. If you are looking for a provider to dig a little deeper for you for health optimization schedule a consult!


Moore, L.D., Thuc, Le. & Guoping, F (2013). DNA Methylation and It’s Basic Function. Neuropsychopharmacology volume 38, pages 23–38 (2013

Pizzorno J. Glutathione! Integr Med (Encinitas). 2014 Feb;13(1):8-12. PMID: 26770075; PMCID: PMC4684116.

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