MTHFR, Adrenal Fatigue and Burnout

Dr. Doni, author of The Stress Remedy, explains how MTHFR mutations are related to adrenal burnout and chronic fatigue, as well as how to get your groove back.

Part 7 of Dr. Doni’s Series on How Genetic Mutations Affect Your Health

The first six articles in this series describe genetic mutations (SNPs), how to test for them, and how they affect the methylation cycle, mood, and fertility. If you missed any of these posts and wish to catch up, here are the links:

MTHFR and Fatigue: Making the Connection

genetic mutations, adrenal distress, adrenal fatigue, adrenal exhaustion, adrenal burnout, chronic health issues, genetic health conditions, MTHFR, MTHFR mutations, SNP, single-nucleotide polymorphism, anxiety, cortisol, neurotransmitters, redefining stress, stress response, natural healthToday I am going to talk about the relationship between fatigue and the MTHFR mutation and what you can do to maintain and support your energy levels on a daily basis. Fatigue is one of the top complaints I hear from patients. It usually comes along with other concerns, such as not sleeping well, aches and pains, digestive disturbances, weight gain, menstrual or menopausal symptoms, and/or allergies. Even though the list of symptoms can be long, fatigue is the indication that your body is depleted. And, if your body is depleted, it’s because you are under stress. And, if you are stressed for long enough, that stress will eventually become adrenal distress which will have a major effect on your overall health and well-being. Adrenal distress is one of the three problem networks I describe in my book, The Stress Remedy.

Whether you are exposed to mental, emotional, and/or physical stresses, it is the job of your adrenal glands to respond. You see, our adrenal glands are constantly adapting to the stress we are exposed to and, as they adapt, the levels of cortisol and adrenaline they produce can shift away from optimal. As this occurs—whether your cortisol is low when it should be high (in the morning) or too high at times it should be low (evening)—you are more likely to feel tired.

We don’t yet know to what degree MTHFR mutations contribute to adrenal distress (also known as adrenal fatigue or adrenal burnout) but what we do know is that when we are exposed to stress, both the MTHFR enzyme and our adrenal glands are affected. We also know that when someone with an MTHFR mutation(s) is not getting enough methylfolate, they will often have lower adrenaline (norepinephrine and epinephrine) levels. This is because methylation (starting with methylfolate) is needed to produce adrenaline. Low adrenaline levels are associated with fatigue. You can read more about MTHFR here and about the methylation cycle here.

In fact, several processes that could result in fatigue are reliant on healthy methylation. The enzyme that makes serotonin and dopamine, for example, requires methylation to work well, so low serotonin and/or dopamine levels can result from not having enough methylfolate. Low methylfolate levels can also be responsible for an inability to break serotonin and dopamine down—and this is worsened when there is a mutation on MAO as well as on MTHFR. Both of these situations can affect mood and energy levels.

Another enzyme we discussed in an earlier article about mood and SNPs, called COMT, is also negatively affected by a lack of methylfolate, resulting in elevated norephinephrine and depleted epinephrine. At the same time, histamine levels can increase, making you more susceptible to allergic responses but as soon as we support methylation in the right way, all of these systems can improve.

Investigating the Cause

It is important, whenever your energy is low, to evaluate the cause by doing a number of tests including:

Blood tests:

  • Anemia, low thyroid function, blood sugar issues. All are common causes of fatigue.
  • Issues related to MTHFR function such as RBC folate, Homocysteine and Methylmalonic acid. These will tell us your folate, B6 and B12 levels.

Saliva tests:

  • Cortisol. Testing your cortisol levels will tell us how well your adrenals are functioning. If they are low in the morning then you are in adrenal distress (also known as adrenal fatigue or burnout).
  • SNPs. A simple genetic test will help us understand other mutations (SNPs) that may be playing a role in your fatigue.

Urine tests:

  • Adrenaline (norepinephrine and epinephrine). This will give us more information about the state of your adrenal glands
  • Organic Acids. This will help us evaluate your specific nutrient needs

IgA and IgG Food Panel:

  • Delayed Food Sensitivities.
  • Leaky Gut.

Both can create fatigue, stress your adrenals and disrupt methylation.

If you have a history of infections, such as mono (EBV) or Lyme Disease, or toxicity from metals, mold, or other toxins, then we also need to evaluate whether they are still playing a role in the way you feel today.

Piecing It All Together

Once you have your results back, we will be able to look at the pieces of the puzzle and see all the causes of your low energy. Then we can create a comprehensive, integrated plan that addresses each of the areas that need attention. Since all these systems in your body are inter-related, it is as we help them work well together again that you’ll start to feel better.

If you are suffering from adrenal burnout, it’s always better to get your cortisol back to optimal first before addressing any other issues (such as MTHFR and methylation) because it dictates the function of your digestion, immune system, nervous system, and hormones. If you don’t have cortisol on your side, everything else will be more difficult. Only once you have started to optimize cortisol levels would we start to introduce methyfolate.

Is There Anything I Can Do While Waiting for My Results?

While awaiting results, you can start to support your energy levels by balancing your blood sugar levels. Balanced blood sugar throughout the day helps your adrenal glands to recover and your methylation cycle to function better. Eat balanced mini-meals every 3 or 4 hours through the day (if your blood sugar levels are varying a lot, you may even need to eat every 2 hours). Always combine a healthy carbohydrate, such as colorful fruits and vegetables or a gluten-free grain (such as quinoa, millet, and rice) with a protein like free-range poultry, wild fish, or organic nuts and a healthy fat (grapeseed oil, olive oil or fats in olives or avocados).

Next, start supporting your adrenal glands and methylation cycle with nutrients.* B vitamins and electrolytes help both the adrenal glands and methylation, so starting with vitamin B1, B2, and B6 (P5P) plus magnesium bisglycinate either separately or as an electrolyte product get your body ready for methylfolate:

  • A product called B-minus, for example, contains all the important B vitamins except methylfolate and methylB12. Another similar product is called Optimal Start, which includes adrenal-supportive herbs in it.
  • Magnesium Plus contains magnesium with P5P. It can also help to have a multi-mineral product on hand as well to assist with the methylation pathways.

Once you are ready to start addressing MTHFR mutations and methylation, you could try a very low dose of methylfolate (say 400 to 800 mcg) once every three days. Here are two options: Multi-Vitamin Forte and O.N.E. Multivitamin. It’s important to keep niacin nearby in case you experience headaches, irritability, anxiety, depression, joint pain, nausea, rashes, and/or heart palpitations as these could indicate that you’ve taken too much 5MTHF at one time and need help processing it.

It can seem counterintuitive to feel worse when taking methylfolate (5MTHF), even though it would seem that your body needs it. However, it can happen because if your body is not ready for more 5MTHF, it can overwhelm your body. If you feel worse at any point, stop taking the methylfolate and contact a practitioner to assist you. This is why it is so important to work with a practitioner who can really listen to the way you feel and help you evaluate the more subtle imbalances that could be addressed with diet changes, nutrients and/or herbs.

While you are taking 5MTHF, it’s a good idea to monitor how you feel each day—perhaps with notes on your calendar or an app on your phone—this way you can tell whether a nutrient or dosage change is affecting you negatively. Start slowly with 5MTHF and other methylation-supportive nutrients, and be willing to make changes as needed.

I have put all these important tests together in one package that includes consultations with me so I can help you look at all the information and create a plan of action. I call it the MTHFR and Genetic Profiling Package. The idea is to simplify the approach for you so you don’t have to stress about the details—you’ll have me to guide you and all the benefits of a package, such as email support and discounts on supplements. You can find out about this package by clicking here.

So, for those of you experiencing fatigue, let’s look at how to know whether it’s caused by MTFHR mutations, adrenal burnout, or both.

Closing Thoughts

More than anything, I hope this article helps you to see that MTHFR mutations and adrenal distress are potentially related and/or overlapping. It is important to not overlook either of them, and instead it is imperative to address them both. You may not be able to support them at the exact same time but, over time, ensuring adequate methylation support while also optimizing your stress response, is likely to improve your energy levels and improve any other health concerns you have.

Please do share what you’ve noticed about MTHFR and adrenal fatigue. As someone with both MTHFR mutations and adrenal glands that need consistent support, I find that supporting them both is key to keeping my energy levels going all day. Do you find that too?

Thanks for your interest in these topics. Next in this series I’ll be writing about MTHFR and genetic mutations related to the other two problem networks described in The Stress Remedy, and how that can increase risk of cervical dysplasia, cancer, heart disease, and high blood pressure. To be sure not to miss it, please subscribe to my blog at the right of this page, or to my newsletter below. I’m so glad to have you join me!

–Dr Doni
29th April 2015

P.S. For more about adrenal health, please see Dr. Doni’s Guide to Adressing Adrenal Distress.


*Please keep in mind that any and all supplements—nutrients, herbs, enzymes, or other—should be used with caution. My recommendation is that you seek the care of a naturopathic doctor (with a doctorate degree from a federally-accredited program) and that you have a primary care physician or practitioner whom you can contact to help you with individual dosing and protocols. If you ever experience negative symptoms after taking a product, stop taking it immediately and contact your doctor right away.


  1. Dear Dr Doni,

    You state that you have MTHFR mutations and adrenal glands that need consistent support but I was wondering if you are able to live a full and active life (e.g sport & fitness participation) with the appropriate supplementation? Or does this inhibit your activity level?


  2. one connection to sleepiness. Folate is necessary for melatonin production. When I started supplementing with folate, I found I had a circadian rhythm for the first time in my life. Needless to say, I have a lot of sleep to catch up on. Lack of sufficient melatonin cannot be good for your health.

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