What is MTHFR and why is it important?

MTHFR is an enzyme required to convert folic acid into an active form called L-methylfolate that is usable by our bodies. L-methylfolate plays an important role in making neurotransmitters such as serotonin, dopamine, and norepinephrine, which help regulate mood.

Some people carry a mutation in the MTHFR gene, which limits their ability to create L-methylfolate.

What is folate and L-methylfolate?

“Folate is a form of B vitamin that occurs naturally in many foods,” according to an article on the University of Michigan’s (U-M) health library website. “Folic acid is the man-made form of folate that is added to processed foods or vitamin and mineral supplements. Folate is needed in the human body for production of red blood cells.”

Some people have a genetic mutation that limits their ability to convert folic acid and dietary folate into its active form (l-methylfolate).

Does the MTHFR test help people with depression?

The GeneSight MTHFR test shows whether or not a person has genetic variation in MTHFR. Knowing this information could be used by a healthcare provider if they are interested in using folate supplementation as a treatment strategy for depression. The GeneSight MTHFR test shows whether or not a person has genetic variation in MTHFR by evaluating the C677T polymorphism.

How do doctors treat people with reduced MTHFR activity?

There are two possible treatment options for people with reduced MTHFR activity; both are oral supplements:

  • L-methylfolate: Studies have shown that using L-methylfolate alone3-6 or in addition to an antidepressant6-8 can help reduce depressive symptoms. Only one study evaluated the MTHFR C677T genotype in depressed patients taking l-methylfolate supplementation. While the findings were not significant, this study showed that there was a trend for depressed patients with variation in MTHFR benefitting more from taking L-methylfolate.9
  • Folic acid: While this is a possible treatment option, healthcare providers and researchers are split on whether it is an effective one. Studies evaluating the effect of folic acid alone on depression response have produced mixed results.10-12 Some studies show that folic acid in addition to an antidepressant helps improve depression13-15, while other studies show no benefit16-18. There are currently no studies evaluating the MTHFR C677T genotype in depressed patients taking folic acid supplementation.

Should patients take L-methylfolate or folic acid?

Patients should talk with their doctor before taking any medication or supplement. L-methylfolate is available over the counter or as a prescription. Folic acid is generally available in 400 mcg in a multivitamin or 800 mcg in a prenatal vitamin. Note: Myriad Neuroscience does not make dosing recommendations; your healthcare provider must determine if this is right for you.

There are some things you may want to discuss with your doctor. First, if you are allergic to L-methylfolate, you should not take it. Further, you should tell your doctor if you have “seizures or epilepsy; a history of vitamin B12 deficiency or pernicious anemia; or a history of bipolar disorder (manic depression),” according to the U-M health library website. Additionally, you should tell your doctor if you are pregnant or nursing, as they may consider adjusting your dosage. Finally, make sure you follow all directions on the label and do not take this medicine in larger or smaller amounts or for longer than recommended.

Are there any risks to taking folic acid supplements?

There may be some potential risks with high doses of folic acid. Although studies have produced mixed results19–25, high doses of folic acid may mask symptoms of vitamin B12 deficiency (i.e., anemia). Some studies have also shown that high intake of folic acid may intensify the neurologic effects of vitamin B12 deficiency (i.e., cognitive impairment).19,26,27

While more research needs to be conducted, folic acid and L-methylfolate dietary supplements may help with depressive symptoms. Please talk to your healthcare provider to find out if this is right for you.


For more information on how the GeneSight test can help you or your healthcare provider, email us at medinfo@genesight.com, or phone 855.891.9415.

This document is for educational purposes related to pharmacogenomics and personalized medicine only and should not be considered medical advice. The information is based on scientific opinion from industry experts and is intended to provide additional information to healthcare providers. These materials may be changed, improved, or updated without notice. Myriad Neuroscience is not responsible for any errors or omissions contained in third party content. We encourage you to contact us for specific scientific advice regarding our GeneSight® tests. You may print a copy of this document for your own personal noncommercial use. You may not copy any part of this document for any other purpose, and you may not modify any part of this document without the permission of Myriad Neuroscience. “GeneSight,” “Myriad Neuroscience” and associated logos are registered trademarks of Myriad Neuroscience. © 2021 Myriad Neuroscience. All rights reserved.


  1. Frosst, P. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10, 111–113 (1995).
  2. Chango, A. et al. The effect of 677C—>T and 1298A—>C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr 83, 593-596 (2000).
  3. Guaraldi, G. P., Fava, M., Mazzi, F. & La Greca, P. An Open Trial of Methyltetrahydrofolate in Elderly Depressed Patients. Ann. Clin. Psychiatry 5, 101–105 (1993).
  4. Passeri, M., Cucinotta, D., Abate, G. & Senin, U. Oral 5’­methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging Clin. Exp. Res. 5, 63–71 (1993).
  5. Di Palma, C., Urani, R., Agricola, R., Giorgetti, V. & Dalla Verde, G. Is methylfolate effective in relieving major depression in ceronic alcoholics? A hypothesis of treatment. Curr. Ther. Res. – Clin. Exp. 55, 559–568 (1994).
  6. Shelton, R. C., Manning, J. S. & Barrentine, L. W. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. Prim Care Companion CNS Disord 15, 1–9 (2013).
  7. Godfrey, P., Toone, B., Carney, M., Flynn, T. & Bottiglieri, T. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336, 392–395 (1990).
  8. Papakostas, G. I. et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am. J. Psychiatry 169, 1267–74 (2012).
  9. Papakostas, G. I. et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J. Clin. Psychiatry 75, 855–63 (2014).
  10. Loria-Kohen, V. et al. A pilot study of folic acid supplementation for improving homocysteine levels, cognitive and depressive status in eating disorders. Nutr. Hosp. 28, 807–15 (2013).
  11. Adhikari, P. M. et al. Effect of vitamin B12 and folic acid supplementation on neuropsychiatric symptoms and immune response in HIV-positive patients. J. Neurosci. Rural Pract. 7, 362–367 (2016).
  12. de Koning, E. J. et al. Effects of Two-Year Vitamin B 12 and Folic Acid Supplementation on Depressive Symptoms and Quality of Life in Older Adults with Elevated Homocysteine Concentrations : Additional Results from the B-PROOF Study, an RCT. (2016). doi:10.3390/nu8110748
  13. Coppen, A. & Bailey, J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J. Affect. Disord. 60, 121–30 (2000).
  14. Resler, G. et al. Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes. Neuroimmunomodulation 15,145–152 (2008).
  15. Venkatasubramanian, R., Naveen, C. & Pandey, R. S. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. J. Affect. Disord.150, 644–648 (2013).
  16. Basoglu, C. et al. Adjuvant folate treatment to escitalopram and serum homocysteine, folate, vitamin B-12 levels in patients with major depressive disorder. [Turkish]. Bull. Clin. Psychopharmacol. 19, 135–142 (2009).
  17. Bedson, E. et al. Folate augmentation of treatment – evaluation for depression (FolATED): randomised trial and economic evaluation. Health Technol. Assess. (Rockv). 18, (2014).
  18. Sarris, J. et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am. J. Psychiatry appiajp201615091228 (2016). doi:10.1176/appi.ajp.2016.15091228
  19. Morris, M. S., Jacques, P. F., Rosenberg, I. H. & Selhub, J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 85, 193–200 (2007).
  20. Mills, J. L. et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am. J. Clin. Nutr. 77, 1474–1477 (2003).
  21. Ray, J. G., Vermeulen, M. J., Langman, L. J., Boss, S. C. & Cole, D. E. C. Persistence of vitamin B12 insufficiency among elderly women after folic acid food fortification. Clin. Biochem. 36, 387–391 (2003).
  22. Metz, J., McNeil, A. R. & Levin, M. The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate. Clin. Lab. Haem. 26, 323–325 (2004).
  23. Liu, S. et al. A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects. BMC Pregnancy Childbirth 4,(2004).
  24. Wyckoff, K. F. & Ganji, V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post-folic acid fortification period than in the pre-folic acid fortification period. Am. J. Clin. Nutr. 86, 1187–92 (2007).
  25. Qi, Y. P. et al. The prevalence of low serum vitamin B12 status in the absence of anemia or macrocytosis did not increase among older U.S. adults after mandatory folic acid fortification. J Nutr 144, 170–176 (2014).
  26. Morris, M., Selhub, J. & Jacques, P. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham Heart Study. J Am Geriatr Soc 60, 1457–1464 (2012).
  27. Moore, E. M., Ames, D., Mander, A. G., Carne, R. P. & Brodaty, H. Among Vitamin B12 Deficient Older People, High Folate Levels are Associated with Worse Cognitive Function: Combined Data from Three Cohorts. J. Alzheimer’s Dis.39, 661–668 (2014).