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MTHFR and Overmethylation


MTHFR and Overmethylation

Methylation is a process that’s constantly occurring in your body. It’s essential to life - your body can’t function without it.


Methylation involves adding a methyl group -- one carbon atom and three hydrogen atoms -- to a chemical compound, giving it the power it needs to be utilized by the body.


The methyl group is provided by a donor known as S-adenosylmethionine (SAMe). The donor will only do its job effectively if the body is producing methylfolate, which acts as a switch for the system that makes SAMe available.


Due to our busy lifestyles and poor eating habits, it’s quite common to experience complications with the methylation process. When your body isn’t properly adding these methyl groups to the nutrients you consume, there’s a good chance those nutrients can’t be used effectively by your body.


This article will explain overmethylation, its symptoms, and how it compares to undermethylation. We will describe how methylation issues develop and how they can be managed through diet and supplementation.


What is Overmethylation?

As explained above, methylation is a crucial biochemical process in which one carbon atom and three hydrogen atoms are added to a molecule to create a methyl group. Methyl groups are required for numerous cellular functions[1] such as DNA methylation, phosphatidylcholine synthesis, protein synthesis, and many more. The methyl group can be delivered via dietary methyl donors[1], such as methionine, folate, betaine, and choline.


Methyl groups turn on many crucial processes, including the body’s stress response, detoxification, the synthesis of neurotransmitters, and glutathione production[2].


However, variations in the MTHFR gene can reduce the function of the MTHFR enzyme. This can have a range of downstream effects on the body.


According to some health practitioners, impaired function of the MTHFR enzyme[3] can result in undermethylation due to a deficiency of methyl groups in the body. This can then lead to a range of health issues.


Overmethylation is much less common. It is believed to occur when the body has more methyl groups than it needs or can use. This can upset the proper function of the body’s normal biochemical processes. Also known as hypermethylation, overmethylation can result from a range of factors and may be linked to MTHFR single nucleotide polymorphisms (SNPs). It can lead to poor concentration, anxiety, panic attacks, sleep disorders, and sensitivities to environmental toxins, among other symptoms.


It’s important to note that there is currently very little scientific research regarding undermethylation and overmethylation, and that sources should be checked carefully.


What Causes Overmethylation?

There is currently a lot of speculation about the causes of overmethylation, but some studies have linked “hypermethylation” or methylation alterations to various genetic and environmental factors.


Some research has indicated that toxicity from Bisphenol A may cause DNA hypermethylation.[4] BPA is an industrial chemical used to make certain plastics and resins. It has also been suggested that high levels of estrogen exposure over a woman’s lifetime can lead to changes in DNA methylation.[5]


There is also some evidence that excess intake of folate and other B vitamins may cause disruption in DNA methylation. One study found that male offspring of mice fed a high-folate diet had a decreased sperm count, altered methylation in key genes, increased postnatal mortality in offspring, and reduced litter size.


Disturbances in folate levels - due to either low or high folate status - can lead to hypo- or hypermethylation, resulting in epigenetic instability and dysregulation of gene expression.


One study found that people who were homozygous for MTHFR 677TT had an elevated copper-to-zinc ratio and a higher risk of over-methylation. High levels of free copper are also noted in those shown to be over-methylating, which may lead to irregularities in thyroid function, adrenal hormone production, and lower histamine levels.


Researchers suggested that the reduced function of the MTHFR enzyme results in elevated homocysteine, so the body tries to metabolize the homocysteine via an alternative channel using a flavin cofactor (flavin adenine dinucleotide).


Hyperactivation of this pathway may result in excessive SAMe production and low histamine.

Other research has also linked low histamine (histapenia) to overmethylation, as histamine and methyl groups are inversely related. Low histamine levels might indicate overmethylation, while high levels might indicate undermethylation.

Overmethylation Symptoms

Symptoms of overmethylation* are said to include


  • Anxiety
  • Adrenal fatigue
  • Depression
  • Inability to concentrate
  • Hyperactivity
  • Panic attacks
  • Poor motivation
  • Easily frustrated
  • Sleep disorders, insomnia
  • Paranoia
  • Sensitivities to foods/chemicals
  • High pain threshold
  • High energy levels
  • Low histamine

Anxiety, restlessness
Higher levels of DNA methylation have been found in patients experiencing anxiety, along with elevated levels of inflammatory cytokines (interleukin-6) and an increased risk for inflammatory diseases.

Depression
A systematic review showed that most studies found BDNF (Brain-derived neurotrophic factor) and SLC6A4 (the serotonin transporter gene) hypermethylation to be associated with MDD or depression in general.

*Many symptoms associated with overmethylation are similar to undermethylation, which highlights the importance of the methylation cycle.

Possible Methylfolate Side Effects

Remember, methylfolate & B12 are vitamins, so any side effects are typically going to be much less severe than they would be with a pharmaceutical drug. But if you’re very sensitive to drugs, vitamins and supplements, it’s advisable to start low and increase slowly.

If you are starting methylfolate or have changed your dosage and are experiencing the following symptoms, you may be over-methylating:

  • You feel “amped-up” or jittery
  • Your heart is racing/pounding/palpitating
  • You feel like you've had too much caffeine
  • You are agitated/aggravated/irritable
  • You feel overwhelmed
  • Your anxiety levels have increased

This could be an "over-methylation" reaction, which simply means your body has more methyl donors than it can deal with at once. Over-methylation can throw normal bodily functions out of balance.

Dealing with Overmethylation Issues: What to do if you’re overmethylating

If you suspect that your body is overmethylating, the first step is to seek help from a qualified health practitioner. Everyone is different, and the right treatment for you must cater to your unique needs. This will require a comprehensive assessment of your symptoms and health history.

Managing overmethylation may involve changes to your diet and lifestyle, and supplementing with specific nutrients.
It may be possible to counter an over-methylation reaction with N-acetyl cysteine (NAC) at a dosage range of 600-3,000 mg, as NAC has been discovered to increase intracellular glutathione levels. Glutathione (200-500 mg) is also recommended, preferably in sublingual form for effective uptake in the body.

Nicotinic acid or niacin (not niacinamide) can be beneficial in reducing over-methylation side effects. According to naturopath Ben Lynch, taking 50 mg of niacin every 30-60 minutes until symptoms subside may help to reduce over-methylation.

Note: Most overmethylation reactions will be temporary, as B-vitamins are water-soluble and are not stored in the body. However, we highly recommend seeking the advice of a qualified health practitioner before experimenting with methylfolate dosage. We also recommend starting with a low dose and increasing slowly in order to find the dosage range that works best for you. It may help to check out our Dosage page to learn more about how much methylfolate to take as well as our Methylation Protocols to better understand how to supplement according to your specific needs.


What about Undermethylation?

Undermethylation is another example of imbalanced methylation. It is believed to occur when the body is lacking in the methyl groups (CH3) it needs to carry out normal biological processes. Insufficient methyl groups can affect numerous bodily functions, such as neurotransmitter production, DNA regulation, and detoxification.

While those who overmethylate may experience anxiety and mental health imbalances due to increased levels of inflammatory cytokines and neurotransmitters (such as dopamine, norepinephrine, and serotonin), those who undermethylate are associated with the opposite. Undermethylation tends to result in low levels of neurotransmitters, which can then lead to low mood and other depressive symptoms, as well as feelings of sluggishness and low energy.

Other characteristics of undermethylation include high levels of oxidative stress, low vitamin B6, D, and folate levels, and low levels of unbound copper. There is also a tendency for higher histamine.

As mentioned above, the symptoms of overmethylation can be similar to those of undermethylation, which makes it even more important to seek the advice of a qualified health practitioner who can assess your symptoms.


  • Fatigue
  • Depression
  • Insomnia
  • Headaches
  • Obsessive-compulsive behaviors
  • Poor memory
  • Allergies
  • Digestive disorders

Getting Support for Methylation Issues

Proper methylation is critical for numerous biochemical pathways in the body.
Overmethylation and undermethylation can both lead to complications with daily function, increasing the risk of physical and mental health issues.

Undermethylation is most commonly treated with supplements that assist with methylation, including methylfolate and vitamin B12. Choosing a high-quality methylfolate supplement such as Methyl-life’s® Methylfolate range and eating a diet high in methylation-supporting nutrients is also recommended.

In addition to the advice above, treating overmethylation may involve managing your body’s histamine levels to avoid the elevated levels of serotonin, dopamine, and norepinephrine. High levels of copper may be reduced by supplementing with zinc, manganese, Vitamin C, niacinamide, Vitamin B12, and methylfolate. 

References

1. https://www.mdpi.com/2072-6643/5/9/3481
2. https://methyl-life.com/blogs/mthfr/glutathione-and-mthfr
3. https://www.ncbi.nlm.nih.gov/books/NBK66131/
4. https://www.sciencedirect.com/science/article/pii/S2468227619306969
5. https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0664-7
6. https://pubmed.ncbi.nlm.nih.gov/18950248/
7. https://pubmed.ncbi.nlm.nih.gov/28535307/
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648405/

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    Written By,
    - Katie Stone


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