MTHFR and Adrenal Fatigue Syndrome

MTHFR and Adrenal Fatigue Syndrome

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 23, 2025

Table of Contents

    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.

    How is Adrenal Fatigue Syndrome Different from Regular Fatigue?

    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 exist1.


    But while medical professionals are divided over whether adrenal fatigue exists, some medical societies claim that adrenal fatigue is a real and underdiagnosed disease2. 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 burnout3. 

    Other non-clinical symptoms of adrenal fatigue (as purported by web-based health practitioners) include:

    • Constant tiredness
    • Body aches and/or pain
    • Higher energy in evenings
    • Brain fog
    • Low mood
    • Increased reactivity to stress
    • Lightheadedness
    • Waking at 2-4 am
    • Anxiety
    • Cravings for high-sugar/high-sodium foods
    • Digestive problems

    These symptoms cannot be effectively improved even after sufficient sleep and can impair physical and mental health, eventually disrupting the overall quality of life.

    Testing for Adrenal Fatigue Syndrome

    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.

    • Cortisol tests: Low cortisol may indicate that the adrenal gland is either not functioning normally or not being stimulated by ACTH (Adrenocorticotropic Hormone).
    • ACTH tests: ACTH is a pituitary hormone that signals the adrenal glands to produce cortisol. High levels indicate primary adrenal insufficiency (Addison’s disease), while low levels indicate secondary adrenal insufficiency.
    • Aldosterone test: Blood or urine aldosterone levels are measured to determine the amount of ALD (Aldosterone) produced by the adrenal gland. Low levels may indicate primary adrenal insufficiency.

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

    Methylation’s Relationship to Adrenal Fatigue

    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 depression4, 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 neurotransmitters5, 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-126 are required to synthesize SAMe and have direct effects on mood and energy production. Folate is necessary for amino acid metabolism and DNA methylation7 and is an essential cofactor in the one‐carbon metabolism pathway.

    B-vitamin status

    Those with MTHFR mutations are typically low in folate8 due to poor metabolism of folic acid.


    The MTHFR C677T variant is also significantly associated with vitamin B12 deficiency9.


    Low folate and low B1210 are also associated with depression, and fatigue or lack of11 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 fatigue12.


    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 depression13.


    The B-vitamins, including B6, B9 (folate), and B12, may positively affect mood and stress. Folate levels14, 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.

    Are People with MTHFR More Susceptible to Adrenal Fatigue?

    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 SAMe15 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 levels16. Elevated homocysteine is typically associated with fatigue and is commonly seen in patients with fibromyalgia and chronic fatigue syndrome17.

    Treatment options for Adrenal Fatigue

    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 health18.


    Supplementation of folate and B619 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 fatigue20 and improvements on a multi-tasking stressor test.


    Supplementation with SAMe, as well as with methylfolate, appears to be effective in reducing depressive symptoms21.


    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 secretion22 from morning to night.

    Final Thoughts

    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.

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    References

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      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997656/

    2. Flavio A Cadegiani, Claudio E Kater; "Adrenal fatigue does not exist: a systematic review"; BMC endocrine disorders; 2016 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997656/

    3. Alain Marchand, Pierre Durand, Robert-Paul Juster, Sonia J Lupien; "Workers' psychological distress, depression, and burnout symptoms: associations with diurnal cortisol profiles"; Scandinavian journal of work, environment & health; 2014 May

      https://pubmed.ncbi.nlm.nih.gov/24469265/

    4. Helia Ghanean, Amanda K Ceniti, Sidney H Kennedy; "Fatigue in Patients with Major Depressive Disorder: Prevalence, Burden and Pharmacological Approaches to Management"; CNS drugs; 2018 Jan

      https://pubmed.ncbi.nlm.nih.gov/29383573/

    5. Asher Ornoy, Maria Becker, Liza Weinstein-Fudim, Zivanit Ergaz; "S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy"; International Journal of Molecular Sciences; 2020 May

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279375/

    6. David O Kennedy; "B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review"; Nutrients; 2016 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772032/

    7. Mami Hiraoka, Yasuo Kagawa; "Genetic polymorphisms and folate status"; Congenital anomalies; 2017 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601299/

    8. Mami Hiraoka, Yasuo Kagawa; "Genetic polymorphisms and folate status"; Congenital anomalies; 2017 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601299/

    9. Khalid M Al-Batayneh, Mazhar Salim Al Zoubi, Murad Shehab, Bahaa Al-Trad, Khaldon Bodoor, Wesam Al Khateeb, Alaa A A Aljabali, Mohammad Al Hamad, Greg Eaton; "Association between MTHFR 677C>T Polymorphism and Vitamin B12 Deficiency: A Case-control Study"; Journal of Medical Biochemistry; 2018 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294092/

    10. Prerna Sangle, Osama Sandhu, Zarmeena Aftab, Adarsh Thomas Anthony, Safeera Khan; "Vitamin B12 Supplementation: Preventing Onset and Improving Prognosis of Depression"; Cureus; 2020 Oct

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688056/

    11. G Djokic, D Korcok, V Djordjevic, A Agic, A Rankovic, Dejanovic Djukic; "The effects of S-adenosyl-L-methionine-vitamin B complex on mild and moderate depressive symptoms"; Hippokratia; 2017 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247995/

    12. Alex Ankar, Anil Kumar; "Vitamin B12 Deficiency"; StatsPearl; 2024 Sep

      https://www.ncbi.nlm.nih.gov/books/NBK441923/

    13. Marshal Folstein, Timothy Liu, Inga Peter, Jennifer Buell, Lisa Arsenault, Tammy Scott, Wendy W Qiu; "The homocysteine hypothesis of depression"; The American journal of psychiatry; 2007 Jun

      https://pubmed.ncbi.nlm.nih.gov/17541043/

    14. David A Camfield, Mark A Wetherell, Andrew B Scholey, Katherine H M Cox, Erin Fogg, David J White, Jerome Sarris, Marni Kras, Con Stough, Avni Sali, Andrew Pipingas; "David A Camfield 1, Mark A Wetherell, Andrew B Scholey, Katherine H M Cox, Erin Fogg, David J White, Jerome Sarris, Marni Kras, Con Stough, Avni Sali, Andrew Pipingas"; Nutrients; 2013 Nov

      https://pubmed.ncbi.nlm.nih.gov/24284609/

    15. George I Papakostas, Clair F Cassiello, Nadia Iovieno; "Folates and S-adenosylmethionine for major depressive disorder"; Canadian journal of psychiatry. Revue canadienne de psychiatrie.; 2012 Jul

      https://pubmed.ncbi.nlm.nih.gov/22762295/

    16. Elizabeth A. Varga, Amy C. Sturm, Caron P. Misita, Stephan Moll; "Homocysteine and MTHFR Mutations: Relation to Thrombosis and Coronary Artery Disease"; Circulation; 2005 May

      https://www.ahajournals.org/doi/10.1161/01.CIR.0000165142.37711.E7

    17. B Regland, M Andersson, L Abrahamsson, J Bagby, L E Dyrehag, C G Gottfries; "Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome"; Scandinavian journal of rheumatology.; 1997

      https://pubmed.ncbi.nlm.nih.gov/9310111/

    18. David A Camfield, Mark A Wetherell, Andrew B Scholey, Katherine H M Cox, Erin Fogg, David J White, Jerome Sarris, Marni Kras, Con Stough, Avni Sali, Andrew Pipingas; "The Effects of Multivitamin Supplementation on Diurnal Cortisol Secretion and Perceived Stress"; Nutrients; 2013 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847740/

    19. David A Camfield, Mark A Wetherell, Andrew B Scholey, Katherine H M Cox, Erin Fogg, David J White, Jerome Sarris, Marni Kras, Con Stough, Avni Sali, Andrew Pipingas; "The Effects of Multivitamin Supplementation on Diurnal Cortisol Secretion and Perceived Stress"; Nutrients; 2013 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847740/

    20. Mark A. Wetherell, Martin C. Sidgreaves; "Secretory immunoglobulin-A reactivity following increases in workload intensity using the Defined Intensity Stressor Simulation (DISS)†"; Stress and Health, Vol. 21, Iss. 2 p. 99-106; 2005 Apr

      https://onlinelibrary.wiley.com/doi/10.1002/smi.1038

    21. George I Papakostas , Clair F Cassiello, Nadia Iovieno; "Folates and S-adenosylmethionine for major depressive disorder"; Canadian journal of psychiatry. Revue canadienne de psychiatrie; 2012 Ju;

      https://pubmed.ncbi.nlm.nih.gov/22762295/

    22. M D García-Prieto, F J Tébar, F Nicolás, E Larqué, S Zamora, M Garaulet; "Cortisol secretary pattern and glucocorticoid feedback sensitivity in women from a Mediterranean area: relationship with anthropometric characteristics, dietary intake and plasma fatty acid profile"; Clinical endocrinology; 2007 Feb

      https://pubmed.ncbi.nlm.nih.gov/17223986/

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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