MTHFR and Adrenal Fatigue Syndrome

By: Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM

MTHFR could be the reason for many things in your bodyMethyl-tetrahydrofolate reductase (MTHFR), is an enzyme that is responsible for methylation in every single cell in your body. If you have a history of multiple miscarriages, chronic migraines, irritable bowel syndrome, depression, or a family history of heart attack or stroke, this little enzyme might be the cause of your illness.

Methylation 101

MTHFR’s function in your body is to methylate your cells, but what is this exactly and how does it work? Methylation is the process of adding a methyl group, one carbon and three hydrogens, to a compound. By doing so, MTHFR can help create, convert, and alter compounds within your cells. Methylation has its hands in many processes. It is involved in cellular repair, where it plays a major role in the synthesis of nucleic acids and the production of DNA and mRNA. It helps with neurotransmitter production and detoxification by converting amino acids from one form to another. It is vital in the formation and development of red blood cells, white blood cells, platelets, and the maintenance of a healthy immune system.

MTHFR has more than fifty variants; the most common are 677T, 1298C, or a combination of both.

Some of these variants cause a decrease in methylation, and as a result, can lead to disease. For example, the variant 677T is most commonly associated with cerebral vascular accident (stroke), elevated homocysteine, cardiovascular disease risk, peripheral neuropathy, deep vein thrombosis, early onset heart disease, stillbirth, neuro-tube defect, cleft lip, and preeclampsia. Conditions associated with variant 1298C include fibromyalgia, chronic fatigue, schizophrenia, chronic migraines, and irritable bowel syndrome.

MTHFR can be either heterozygous or homozygous. People with a heterozygous MTHFR have one normal gene and one altered gene. This will cause your enzyme activity to decrease by forty percent.

If you are homozygous, meaning both your MTHFR genes are anomalies, your enzyme activity can drop by as much as ninety percent and your system will only be methylating at a rate of ten percent to twenty percent of normal.

Aggravating factors for MTHFR include heavy metals exposure from amalgam, vaccines, mercury laced fish, aluminum cookware and occupational hazards as well as a diet high in processed and hydrogenated foods. Anesthesia, diabetes, lymphoma can also be factors that aggravate MTHFR.

MTHFR sufferers also in general have problems clearing metals, including lead, mercury and aluminum. This is due to the body’s inability to clear toxins on a timely basis. Symptoms seem to progress with time.

Screening for MTHFR Mutations

If you fall under any of the following categories, screening for potential MTHFR mutation may be considered.

  • Patients suffering from several mental conditions such as depression, anxiety, schizophrenia.
  • Relatives of someone with known MTHFR mutations.
  • Increased folate, homocysteine, cobalamin levels for no apparent reason.
  • Patients with severe neurological disorders such as multiple sclerosis, Alzheimer’s, epilepsy, autism.
  • Strong family history of heart disease and stroke.
  • Infertility.
  • Patients with birth defects.
  • Drug sensitivities to anesthesia, nitrous oxide, methotrexate.

Laboratory Testing for MTHFR

Testing for MTHFRA blood test can include common laboratory serum tests such as liver enzymes, ferritin and homocysteine levels. The genetic testing can include the MTHFR profile. Glutathione is usually found low. The B12 level may be high, because the body is unable to utilize the unmethylated form. A urine analysis can be helpful; it may show heavy metal challenges to be positive and urine organic acid may be present. A Toxic Screening test may show excessive amounts of toxins present.

MTHFR Treatment

Just because you have the mutation does not mean you will show symptoms or develop conditions associated with MTHFR. Not all MTHFR sufferers need to be treated. Many have a marginal expression of MTHFR and lead a normal life.

If you learn that you do have significant MTHFR variants that are symptomatic, supplementation with the activated form of folate (vitamin B9) and B12, also known as methylfolate and methylcobalamin respectively, is recommended.

Methylcobalamin, more commonly referred to as vitamin B12, is naturally found in foods such as meat, seafood, and dairy products. As long as the dosage is properly titrated methylated vitamin B12 is safe for most people and may be taken as a nutritional supplement. Methyl B12 is best taken as an intramuscular shot, nasal spray, or sublingually in high doses.

Excessive vitamin B12 supplementation can cause anxiety, jitters, rapid heart rate, heart palpitation, and fatigue. Most of these side effects are mild, but medical evaluation is recommended because some of the possible side effects can be serious and should only be treated under supervision. Each person requires specific nutrients tailored to his or her own body and titration is necessary to obtain the optimal dosage with minimal side effects.

Methyl folate is taken orally. Physician supervision is best as the dosage needed is high. Methylfolate side effects include: severe anxiety, irritability, palpitations, acne, rash, sore muscles, achy joints, insomnia, nausea, headaches, and migraines.

On top of oral supplementation, prescription medications are also available. Drugs such as MetanX, Deplin, and CerefolinNAC contain methylfolate and may be beneficial.

Treatment of MTHFR also needs to be directed towards toxin control if the body is strong enough to handle it. This is important because the body’s toxic load and toxin clearance capability is reduced. Household chemicals, such as artificial scents, cleaners, and pesticides should be avoided. Chronic chemical exposure should be curtailed as much as possible. Use safe chemicals and organic pest control chemicals whenever possible.

From a diet perspective, it is important to avoid hydrogenated fats and processed foods. Increased consumption of fruits and vegetables are vital to alkalize the body and help the liver metabolize normally.


A frustrated man that may have MTHFRAFS represents the neuroendocrine deregulation of the body under excessive physical and emotional stress. Common symptoms include fatigue, insomnia, and lethargy. Symptoms in advanced stages can include hypoglycemia, heart palpitation, depression, anxiety and loss of libido. Sufferers usually have a wide variety of non-specific complaints that seem to defy conventional medical wisdom because laboratory tests are usually totally normal.

It is unknown whether MTHFR is associated with AFS or not. If it is indeed associated the degree of correlation is also unknown. Much more research is necessary.

Due to the concurrent hypersensitivity of AFS sufferers to nutritional supplementation, paradoxical reactions can occur frequently. The use of methylated folate and B12 for MTHFR should proceed with care. Those that have mild AFS with moderate symptoms can have a trial of this supplementation under proper supervision. If MTHFR variant is indeed the culprit, relatively quick resolution and improvement of symptoms is expected. The failure of significant improvement is an alert that MTHFR may not be the dominant cause of fatigue even if MTHFR testing is positive. Over aggressive use of methylated folate and methylated B12 is a common recovery mistake in those with AFS as they can mask the underlying problem and worsen AFS. Energy output may be up, but the underlying adrenal weakness is overlooked.

Those with advanced stages of AFS need to be very cautious because they usually fare quite differently. Because of their already highly sensitized bodies and low threshold of stimulatory excitation response, any product including methylated folate or methylated B12 can further increase an excitation response and trigger an adrenal crash. The more advanced the AFS the higher the risk. Using such compounds should only proceed under the guidance of a health care professional.


© Copyright 2014 Michael Lam, M.D. All Rights Reserved.