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  • Kate Alsop, ND

MTHFR and Depression | Individualizing Natural Wellness Series - Part 1

Depression is a serious condition with wide ranging symptoms that affect every aspect of a person’s life. Effects are commonly seen as cognitive and physical manifestations, in addition to depressed mood. Between 1994 and 2008, the rate of antidepressant use in the US increased nearly 400% and is still climbing. As of 2008, one in ten American’s over 12 years of age takes antidepressants! (1)

While many factors are known to influence depression (e.g. stressful and adverse life events, genetic predisposition, vitamin D levels, overall diet and exercise), in this post I will focus on the role that the gene MTHFR plays in this condition, and along with the methylation cycle it is a part of.

This gene and the system it takes part in is now proving to play a very important role in depression after being overlooked for decades (2–10). It is now known to affect mood in two distinct and significant ways: depletion of SAM and accumulation of homocysteine.

Meet SAM

SAM Functions

MTHFR codes for an enzyme that processes the B vitamin folate which is crucial to the production of SAM, S-adenosylmethionine, which you may have seen on health food store shelves. SAM is used by over 200 enzymes in the human body, therefore the inability to produce it in sufficient amounts can cause many different problems. Specific to depression, SAM is used in both the production and degradation of neurotransmitters (chemical messengers produced by your brain cells to talk to one another) (11). Without it, the availability of neurotransmitters within the body becomes dysregulated, leading to changes in both mood and cognition.

Too much Homocysteine

Part of the cycle which produces SAM is actually responsible for the metabolism of another compound that has recently gained fame, homocysteine. When MTHFR is working too slowly, Homocysteine levels in the body begin to rise. This was first studied to have an effect on cardiovascular health, but has more recently been associated with a significantly increased risk of depression. While excess homocysteine can be used in a positive way, to drive the production of glutathione, your body’s chief antioxidant, only so much can be used in this way.

When there is too much homocysteine for the road to glutathione to handle, it begins to travel down other pathways, producing 2 new neurotoxic compounds: homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which have neurotoxic effects on dopaminergic neurons (i.e. neurons that make the neurotransmitter dopamine) (12). Imbalances of this neurotransmitter are associated with many symptoms of depression (e.g. depressed mood, attention deficit, pain, nausea).

These contributions to depression symptoms are so significant that in a recent randomized, double-blind, placebo controlled trial of patients with major depressive disorder, 42% of patients receiving the appropriate forms of the involved B-vitamins (including methylfolate) achieved remission from depression by week 8 of the trial!(13)

I should also take the time to note that MTHFR is not the only gene in this methylation pathway known to have defects. There are a number of others that can be affected (e.g. MTR, MTRR, BHMT) therefore for many clients, testing for the MTHFR SNPs is not enough information to give us the full picture of where the roadblocks are in the pathway. In these cases, it is helpful to have a full genome report from 23andMe to enable us to look at all of the involved genes.

How can we overcome our DNA??

Most healthcare providers will simply recommend supplementing with 5-methylfolate when they find a defect in MTHFR, but because we as human beings are more than just our genes, this isn’t the right approach for many people. Additionally, most people do not want to feel like they must take any pill every day for the rest of their lives, no matter if it is a drug or a supplement. Everything you do (diet, supplementation, environmental exposures, stress, mental and emotional state) affects how your genes and enzymes function!


To learn more about how you can effect tremendous change in your methylation status through diet and lifestyle modifications:

Register for my upcoming webinar! On Monday, Oct 24th at 7 pm I will be presenting Naturopathic Genetic Analysis – Individualizing Natural Wellness where I will go in depth into Naturopathic strategies for overcoming these genetic defects and their associated conditions. You can register on our Homepage.

Like us on Facebook! be sure to like our Facebook page to be the first to see new posts in this series and learn more about your genes and your health!

Visit our webpage dedicated to our Naturopathic Genetic Analysis service!

References (links included)

1. CDC/National Center for Health Statistics. FastStats - Depression. (2016). Available at: (Accessed: 12th October 2016)

3. Wu, Y.-L. et al. Association between MTHFR C677T polymorphism and depression: An updated meta-analysis of 26 studies. Prog. Neuro-Psychopharmacology Biol. Psychiatry 46, 78–85 (2013).

8. Arinami, T., Yamada, N., Yamakawa-Kobayashi, K., Hamaguchi, H. & Toru, M. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am. J. Med. Genet. 74, 526–528 (1997).

9. Yang, Y. et al. Genetic epidemiology of migraine and depression. Cephalalgia 36, 679–91 (2016).

11. Zhang, Y. et al. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLoS One 11, e0146797 (2016).

12. Bhatia, P. & Singh, N. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression. Fundam. Clin. Pharmacol. 29, 522–8 (2015).

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