Research & Education

A Look at Overmethylation

Methylation has been a hot topic in the functional medicine community for the past decade as research has revealed the vital importance of efficient methylation pathways, and also uncovered a staggering number of individuals who are not methylating efficiently due to specific polymorphisms. In response, practitioners began testing more patients for these common genetic polymorphisms and recommending methylated forms of folate and vitamin B12 to address these inefficiencies. The discovery of undermethylation has proved to be lifechanging for many individuals who desperately needed answers to their elusive symptoms. However, the question is now arising as to whether practitioners are indiscriminately supporting methylation pathways in individuals in whom these processes are already running efficiently, and may be inadvertently contributing to the phenomenon of overmethylation.

A Review of Methylation

By way of review, methylation is the process of adding a methyl group (via the universal methyl donor, SAMe) to a molecule, which then activates a specific activity of that molecule. Methylation can modulate the stress response, detoxification, hormone regulation, gene expression, antioxidant activity, production of neurotransmitters, inflammation, energy production, fat metabolism, reproduction, and immune responses. Inadequate methyl donors can result in sluggish activity of any of these vital processes. The system that produces SAMe requires 5-MTHF (methylfolate) as a cofactor, but polymorphisms of the MTHFR (methylenetetrahydrofolate reductase) and COMT (catechol-O-methyltransferase) genes reduce the body’s capacity to produce methylfolate, leading to a deficiency in critical SAMe. Symptoms of undermethylation soon develop. Other vitamins crucial for methylation include methylcobalamin (activated B12) and pyridoxal 5’-phosphate (activated B6).


Overmethylation is an equally concerning problem in another group of individuals. Those who are overmethylators may exhibit the following symptoms:

  • Anxiety
  • Poor concentration
  • Panic disorders
  • Low motivation
  • Easily frustrated
  • Insomnia
  • Paranoia
  • Hyperactivity
  • Food/chemical sensitivities
  • High pain threshold
  • Tinnitus
  • Depression (may also be a symptom of undermethylation)
  • High energy
  • Highly creative (especially in musical ability)
  • Histamine intolerance

Those who are overmethylating have copious amounts of SAMe and easily assimilate activated forms of folate and vitamins B6 and B12. Overmethylators also seem to experience high energy levels when they consume a vegan or plant-based diet, which provides a large amount of folate. Additionally, an abundance of methionine-rich foods such as red meats, eggs, and dairy can exacerbate symptoms for overmethylators because this amino acid is also part of the process of making SAMe. Overmethylators should avoid all supplements that include SAMe and methionine.

Further, overmethylators have a high copper:zinc ratio, so copper supplements may exacerbate symptoms, while zinc supplementation may be helpful. High free copper in overmethylators is associated with disturbances in thyroid function, adrenal hormone production, and lower histamine levels. Since copper inhibits glutathione synthesis, overmethylators have higher degrees of oxidative stress and associated health risks.

While those who undermethylate tend to have low levels of neurotransmitters, causing sluggish, depressive symptoms, overmethylators produce high quantities of neurotransmitters (specifically dopamine, norepinephrine, and serotonin), resulting in anxiety. Overmethylators may also be prone to increased levels of inflammatory cytokines, further contributing to anxiety and mental health disturbances.

Like undermethylation, overmethylation can also be a result of MTHFR polymorphisms, so genetic testing alone cannot differentiate between undermethylators and overmethylators. Interpretation of testing must be accompanied by a systems review and symptomology.

Methylation is critical for the function of various biochemical pathways and optimal health. Undermethylation is the predominant condition of those with methylation polymorphisms and has appropriately received much recognition; however, overmethylation is an equally concerning condition and one that is not as well recognized. Before promoting methylation support (through supplementation with methylfolate and activated forms of B6 and B12 vitamins), it may be prudent to consider the possibility and risks of overmethylation.

By Nicole Spear, MS, CNS


Related Nutrient Roundtable: Depression and Anxiety Support

Related Webinar: Organic Acids Testing Part 3- Detoxification System: Detox, Methylation, and the Importance of Oxidative Stress