MTHFR and Adrenal Fatigue Syndrome

In recent years, adrenal fatigue syndrome has been a popular topic despite not being accepted as a medical diagnosis.

However, many health practitioners still use the term to describe a set of symptoms relating to constant exhaustion, particularly neurological conditions. Fatigue is often linked to poor sleeping patterns, immune dysfunction, digestive issues, hormonal imbalances, and/or food sensitivities and allergies. These symptoms are often similar to those associated with MTHFR genetic mutations and may come from nutritional deficiencies affecting methylation.

This article will explain adrenal fatigue syndrome, how it differs from ‘regular’ fatigue, and the available tests. We will also discuss how adrenal exhaustion may be linked to methylation dysfunction associated with MTHFR polymorphisms and how these can be treated through supplementation.

Regular fatigue is usually a one-off or short-term feeling of tiredness that we can attribute to a known cause, such as a late-night, disturbed sleep, temporary stress, or other circumstances. In most cases, regular fatigue can be remedied by a good night’s rest.

Adrenal fatigue is not an accepted medical diagnosis, and a major systematic review in 2016 concluded that it does not exist.

But while medical professionals are divided over whether adrenal fatigue exists, some medical societies claim that adrenal fatigue is a real and underdiagnosed disease. The original theory—created by the chiropractor and naturopath James L. Wilson in 1998—is that the adrenal glands become overtaxed by excess cortisol release and can no longer produce cortisol levels necessary for optimal body function. Adrenal fatigue is most often described as a steep decline in cortisol secretion from morning to evening, followed by a peak at night (which causes insomnia).

Patients with symptoms of adrenal fatigue may be tested for salivary cortisol rhythm and serum basal cortisol levels. Those with results suggesting dysfunctional cortisol production may then be treated with corticosteroids.

Poor cortisol concentrations at different diurnal time points have been associated with psychological distress, depression, and burnout. Other non-clinical symptoms of adrenal fatigue (as purported by web-based health practitioners) include:

Laboratory testing is available to assess for adrenal insufficiency, which may indicate Addison’s disease. Addison’s disease is a rare disorder in which the adrenal glands cannot produce enough of the steroid hormones cortisol and aldosterone. Tests generally include electrolyte balance, glucose level, and kidney function.

Alternative health practitioners may offer specific testing for adrenal fatigue, such as salivary or urinary cortisol tests and/or DHEA (Dehydroepiandrosterone) tests.

There are several ways in which an impaired methylation cycle may lead to fatigue. It should also be noted that fatigue is a common symptom of depression, occurring in over 90% of patients.

SAMe insufficiency

The methylation process is required to produce SAMe (s-adenosyl methionine). SAMe acts as a methyl donor and plays a vital role in the synthesis and function of monoamine neurotransmitters, including noradrenaline, adrenaline, dopamine, serotonin, and histamine. These neurotransmitters are essential for healthy mood and motivation and have potential antidepressant effects. SAMe deficiency has been reported in major depression and other neuropsychiatric conditions.

Folate and B-12 are required to synthesize SAMe and have direct effects on mood and energy production. Folate is necessary for amino acid metabolism and DNA methylation and is an essential cofactor in the one‐carbon metabolism pathway.

B-vitamin status

Those with MTHFR mutations are typically low in folate due to poor metabolism of folic acid.

The MTHFR C677T variant is also significantly associated with vitamin B12 deficiency.

Low folate and low B12 are also associated with depression, and fatigue or lack of energy is one of the key identifying symptoms of major depressive disorder.

In B12 deficiency, homocysteine cannot be converted to methionine, which impairs the conversion of methyl-THF to THF. This results in increased levels of homocysteine, poor DNA synthesis, and megaloblastic anemia. Anemia is often associated with fatigue.

B vitamins are also required for the clearance of homocysteine. Homocysteine is produced in the human body due to methionine metabolism, a process necessary for the methylation of a wide range of substances, including DNA. High homocysteine levels are associated with low levels of monoamine neurotransmitters and depression.

The B-vitamins, including B6, B9 (folate), and B12, may positively affect mood and stress. Folate levels, in particular, are found to be significantly correlated with the cortisol awakening response, which may suggest that those with low folate levels due to MTHFR are more prone to impaired cortisol levels.

People with MTHFR are at higher risk of low B-vitamins, particularly folate and B12. These two nutrients play significant roles in both mood and adrenal function. Folate and SAMe are both required for the proper function of the one-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. As a group, the B vitamins are also essential for carbohydrate metabolism and energy production.

Genetic mutations in MTHFR are the most common risk factor for elevated homocysteine levels. Elevated homocysteine is typically associated with fatigue and is commonly seen in patients with fibromyalgia and chronic fatigue syndrome.

A holistic approach to treating adrenal fatigue symptoms should begin with an assessment for nutritional deficiencies, particularly B-vitamins. The effect of specific dietary nutrients on diurnal cortisol secretion patterns has been linked to diet and nutritional status. Multivitamin supplementation containing B-vitamins has been found to have many positive effects on mood, cognition, and general health.

Supplementation of folate and B6 increased the cortisol awakening response in patients after 16 weeks. Studies have shown that stress may be significantly improved following supplementation with a vitamin B complex, with one study reporting nine weeks of supplementation with a multivitamin in younger women led to reductions in fatigue and improvements on a multi-tasking stressor test.

Supplementation with SAMe, as well as with methylfolate, appears to be effective in reducing depressive symptoms.

Diet may also help. One study reported that women with a higher intake of monounsaturated fats and a lower saturated fat intake showed a steeper decline in cortisol secretion from morning to night.

Fatigue and low mood are often linked. Both may be a result of inadequate nutritional status. Supplementation with multivitamins may help to fill in any gaps in the diet and assist with metabolic dysfunctions (such as MTHFR insufficiency) that may contribute to nutritional deficiencies.

A multivitamin that contains methylated folate and other bioavailable nutrients is highly recommended. Methylated folate is the only form of folate that can bypass MTHFR polymorphisms and is recommended over synthetic folic acid. As a crucial nutrient in the methylation cycle, folate may also benefit those with symptoms of adrenal fatigue.

Vitamins B12 and B6 are also essential components of the methylation cycle and production of neurotransmitters and the conversion of homocysteine.

Methyl-Life® offers a comprehensive multivitamin range to support optimal methylation and healthy mood. Each multi contains pure methylfolate and highly bioavailable B12, along with other energy-supporting vitamins and minerals. This makes them ideal for those struggling with MTHFR, fatigue, depression, and other related health concerns.