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Editor’s Note: Methylation and the MTHFR gene (which pardon my language I’ve dubbed “the motherfucker gene,”) is a very hot topic these days. The functional medical community is all abuzz about its implications, as many of us, including myself, contend with this gene variation and what it personally means to us. A gene does not dictate an illness. Rather it’s the gene variation that can put a predisposition on an individual. Remember knowledge is power.

Do you or someone you know have a history of heart disease, depression, Alzheimer’s disease, , diabetes, or ? These are just some of the conditions that have been linked to faulty methylation. If you are pregnant, or thinking of becoming pregnant, then supporting methylation to prevent neural tube defects (and actually lots more!) is super-important, too. It’s the reason your doctor tells you to make sure you’re getting enough folate (or folic acid).

Methylation is a process that happens in every cell of our body. It is essentially an attachment or creation of a methyl group (one carbon plus three hydrogens) on an existing molecule. This simple change, however, is enough to alter the function or action of that molecule. It’s a form of biochemical governance.

Here are some of the ways we use methylation:

  • Cell division and renewal
  • Healthy immune cells
  • Synthesizing and clearing adrenaline
  • Detoxification in the liver (and elsewhere)
  • Producing energy for cells to use in chemical reactions
  • Clearing out excess estrogen and histamine
  • Regulating how our genes get expressed

Don’t miss that last one. Methylation is one of the ways that the body makes sure the right genes are turned on, and the ones that we don’t want get turned off. This has really far reaching implications for just about everything that happens in the body. It also means that even if we have a gene that predisposes us to a disease like Alzheimer’s, we can help that gene to stay silent by supporting healthy methylation.


You may have heard about the MTHFR gene. MTHFR stands for methylenetetrahydrofolate reductase, an enzyme that converts folate into the active form (5-mTHF) that can be used to make S-adenosylmethionine (SAMe). SAMe is a fantastically versatile compound and used in most methylation reactions because it has a readily-donatable methyl group.

A well-functioning MTHFR gene also helps to keep homocysteine within normal levels. Homocysteine is a compound that may have come onto your radar if you have heart disease, since higher levels have been associated with worse outcomes.

If you already know what the MTHFR gene is, perhaps you know that you have a variant of this gene such as C677T or A1298C. If you have two copies of the C677T gene (this means you are homozygous for this variant), then the MTHFR enzyme’s activity can drop by 70-75 percent. If you have one copy of this gene (heterozygote), then activity can be reduced by 33-35 percent. If you have two copies of the A1298C variant you may lose 39 percent of MTHFR gene activity.

Treating Methylation Deficits

Most often, treating methylation deficits involves adding supplemental nutrients such as natural folates (5mTHF), B-12, and betaine to help overcome the lagging enzyme activity. We know that this approach can work well.

However, this doesn’t work for everyone, nor is it an ideal long-term approach. Many individuals can actually experience an increase in symptoms, especially those related to anxiety, nervousness, and depression. If this has happened to you, then you may be wondering where to go from there.

If you don’t tolerate methylation supplements, and actually even if you do, it is really important to get your diet and lifestyle dialed in, too. With supplementation, we can run the risk of pushing methylation activity too far the other way and actually promote a state of excess methylation, which research is showing can be detrimental, too.  Alzheimer’s disease, autoimmune disease, and cancer are some of the conditions associated with aberrant methylation.

What we want is balance — not too much, not too little. Just right. And there is actually a way to do that with food-based nutrients, superfood methylation adaptogens, specific eating patterns, sleep hygiene, stress management, and exercise. Your functional medicine practitioner should also be looking at areas of excessive SAMe drain, which can reduce the amount of SAMe available for healthy functions. , , , and poor gut health can all have negative effects on methylation activity and must be considered as well.

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mthfr gene

Screening And Methylation Deficits?

Supporting healthy methylation is actually a good since we tend to lose methylation capacity as we age. Methylation should therefore be on all of our radars. It’s certainly on mine.

More specifically, I recommend that anyone with the following conditions (or with a family history of these concerns) ask their practitioner to order the MTHFR genetic test, or have your full genetic profile done through 23andme.

  • Addiction
  • Allergies
  • Alzheimer’s disease
  • Anxiety
  • Asthma
  • Autism
  • Behavioral disorders
  • Bipolar disorder
  • Cancer
  • Chemical sensitivity
  • Chronic fatigue
  • Cleft palate
  • Dementia
  • Depression
  • Diabetes
  • Downs syndrome
  • Fertility issues
  • Fibromyalgia
  • Heart disease
  • High blood pressure
  • Insomnia
  • Multiple sclerosis
  • Neuropathy
  • Parkinson’s disease
  • Pre-pregnancy and pregnancy
  • Schizophrenia
  • Thyroid disease

High levels of homocysteine, or low levels of folate and vitamin B-12 are other flags to potentially-impaired methylation. If you’re working with a functional medicine practitioner, they will be able to order additional tests that provide an in-depth look at methylation activity such as SAMe, SAH and SAMe:SAH ratios, expanded nutrient status, and genome analysis.

You can find out more about our full program for correcting and optimizing your methylation capacity in our eBook Methylation Diet and Lifestyle. Use coupon code mymdl15  for 15 percent off.

Dr. Kara FitzgeraldDr. Kara Fitzgerald received her doctorate of naturopathic medicine from National College of Natural Medicine in Portland, Oregon. She completed the first CNME-accredited post-doctorate position in nutritional biochemistry and laboratory science at Metametrix (now Genova) Clinical Laboratory under the direction of Richard Lord, Ph.D. Her residency was completed at Progressive Medical Center, a large, integrative medical practice in Atlanta, Georgia. Dr. Fitzgerald is lead author and editor of Case Studies in Integrative and Functional Medicine, a contributing author to Laboratory Evaluations for Integrative and Functional Medicine and the Institute for Functional Medicine’s updated Textbook for Functional Medicine. She has been published in numerous peer-reviewed journals. Dr. Fitzgerald is on faculty at the Institute for Functional Medicine, and is an Institute for Functional Medicine Certified Practitioner. She was formerly on faculty at University of Bridgeport in the School of Human Nutrition and the School of Naturopathic Medicine. She is a clinician researcher for The Institute for Therapeutic Discovery. Dr. Fitzgerald regularly lectures internationally for several organizations and is in private practice in Sandy Hook, Connecticut.

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