MTHFR and Depression

If you are dealing with depression, you are not alone. It is estimated that 322 million people are suffering from depression. While there are many different causes of depression, research shows that diet and nutrient intake affects the risk of depression. A recently published study found that low levels of folate and vitamin B12 were linked to increased depression.[ref]

We are all genetically unique, and a common genetic variant in the MTHFR gene causes some people to be more susceptible to having low folate levels. This article explains the research linking MTHFR variants, folate, and depression. The information provided here is for educational purposes, and if you are under a doctor’s care, please discuss the research with your doctor before making any changes to your diet or supplements.

Why is the MTHFR gene important in mood disorders?

The MTHFR gene codes for a key enzyme in the folate cycle, which leads to the formation of methyl groups for the methylation cycle.

If all that sounds like gibberish, let me give a quick explanation of the methylation cycle (skip ahead if you know this stuff!):

How the methylation cycle works:

Methylation is the adding and removing of a methyl group (CH3) to amino acids, DNA, and other enzymes or proteins.

Most of the molecules in our body are chains of hydrocarbons — carbons plus hydrogens. So adding a methyl group stacks on one more link in a hydrocarbon chain. Sometimes it helps me to visualize it as if the molecule is made of Legos, and the methyl group just adds another Lego component to your creation.

Adding a methyl group – or an extra carbon plus three hydrogens – then changes the original molecule into something different.

Here’s an example:
a methyl group is added to neurotransmitter serotonin in the conversion to melatonin, an important circadian rhythm hormone.

Methylation can turn on and off genes, maintain and repair your DNA, and alter proteins.

It is important in the nervous system in the production and breakdown of neurotransmitters and in the detoxification of some environmental toxicants.

The key here is that both neurotransmitters and detoxification can be important in depression.

Depression and the MTHFR Gene Variants:

The MTHFR gene codes for methylenetetrahydrofolate reductase, a key enzyme needed to convert folate into methyl folate, which is used in the methylation cycle. When methyl groups are limited, a number of different reactions in the body can be constrained, including the recycling of homocysteine.[ref]

There are two main MTHFR genetic variants, known as C677T and A1298C, which decrease the functioning of the enzyme, which in turn may affect the methylation cycle. (How to check your data is down in the genetic variants section.)


  • one copy of the variant decreases the enzyme function by ~40%
  • two copies of the variant decrease enzyme function by ~70%


  • one copy of the variant decreases the enzyme function by 10-20%
  • two copies of the variant decrease enzyme function by 30-40%

Let’s take a look at what the research shows about how these MTHFR variants impact the risk of depression:

A meta-analysis that grouped the data from several different studies found that the MTHFR C677T variant increases the risk of depressive disorders. This analysis was complete in a Chinese population group.[ref]

Another meta-analysis, which included 26 different published studies, also found that the MTHFR C677T variant was associated with an increased risk of depression. This study noted that the association is stronger in Asian populations and more marginal in the Caucasian population (although still statistically significant).[ref]

Age and gender may also play a role here. Postmenopausal women who carry the MTHFR C677T variant were found to be at a 2 to 3-fold increased risk of depression. The study population group was Polish women.[ref]

I do want to point out that not all studies agree, and some researchers find that the MTHFR C677T variant has little to no impact on depression risk. This may be due to the difference that diet plays here. People who eat a diet that includes more folate (green veggies, legumes, etc) may not be at an increased risk, while people who are folate-deficient may be more susceptible to depression.[ref][ref]

What about MTHFR A1298C?
Women who were homozygous (two copies) for the MTHFR A1298C variant were found to be at twice the risk of major depressive disorder, and this risk was even higher in COMT MET allele carriers. (Check your COMT variant here)[ref]


Treating depression with high dose folate and vitamins:

A 2016 placebo-controlled clinical trial investigated the effectiveness of treating depression using methylation cycle-specific vitamins. The trial included 330 adults with major depressive disorder and an MTHFR variant. The results of the study show a marked reduction in homocysteine levels in the vitamin-treated group as well as a very impressive reduction in depression scores. The vitamin-treated group was taking high doses of three forms of folate (1mg folic acid, 2.5 mg folinic acid, and 7mg of l-methyl folate), magnesium,  zinc, phosphatidylserine, and iron, along with microgram doses of the active forms of thiamine, B6, adenosyl-B12, NADH, and TMG. The vitamin treated group saw a decrease in depression score from an average score of 27 at baseline to 15 after 8 weeks, while the placebo group only saw a 1.3 point drop.[ref — open-source article, please read for the details!]


Check your MTHFR genetic variants:

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Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):

  • G/G: typical *
  • A/G: one copy of MTHFR C677T allele (heterozygous), decreased by about 40%[ref]; somewhat increased risk of depression[ref]
  • A/A: two copies of MTHFR C677T (homozygous), decreased by 70 – 80%; increased risk of depression[ref][ref]

Members: Your genotype for rs1801133 is .

Check your genetic data for rs1801131 (23andMe v4, v5; AncestryDNA):

  • T/T: typical *
  • G/T: one copy of MTHFR A1298C (heterozygous), slightly decreased enzyme function
  • G/G: two copies of MTHFR A1298C (homozygous), decreased enzyme by about 30-40%[ref], women at 2-fold risk for depressive disorders[ref]

Members: Your genotype for rs1801131 is .

Lifehacks for MTHFR and depression:

First and foremost, if you are under the care of a physician or psychiatrist for a mood disorder, please check in with them before making any changes. Seriously. While it can be easy to think that a B-vitamin supplement is innocuous, for some people – especially combined with medications – supplements could alter your mental state.

Research does show that low folate levels correlate with higher depression scores.[ref][ref] The research, though, is on a group of people, averaging things out. You – as a unique individual – may be different than the group average.

Folate and choline-rich foods:

Getting enough folate in your diet is important with MTHFR variants. You know how your mom said to eat your green veggies – it turns out she was right.  Folate-rich foods include leafy greens, legumes, and beef liver.

Another way that your body can make methyl groups – bypassing a wonky MTHFR variant – is through getting plenty of choline.  Food rich in choline include eggs, beef, shrimp, chicken, and liver.

The website is a great place to keep track of your intake of choline and folate. Choline is not included by default, so you will need to go into your profile settings and turn it on as a nutrient. Track your food intake for a few days or a week and see whether you are regularly low on folate and choline…  then adjust accordingly.


While an argument can be made that food is your best source of vitamins and nutrients, sometimes supplements can help you to pinpoint exactly what you need and in what quantity.

Keep in mind that more is not always better when it comes to vitamins.  You can always start at a lower dose by opening up a capsule or cutting a tablet in half. The key is to pay attention, see how you feel, and adjust your intake as needed.

Supplemental TMG (betaine) is a form of choline available as a supplement.

The placebo-controlled trial referenced above included folinic acid, methyl folate, magnesium, zinc, B6, B12, B2, phosphatidylserine, and TMG (a form of choline). The high doses of folate referenced in the study should probably be taken under a doctor’s supervision. (Here’s the study again so that you can read the details)

Folic acid, a synthetic form of folate, is used as an additive in food products and in many multivitamins. To convert folic acid into the active form used by the body (methyl folate), it uses the DHFR and MTHFR enzymes. People with DHFR genetic variants (check yours here) may not be able to convert very much folic acid into methyl folate. Higher doses of folic acid may build up and circulate in the bloodstream.

Methyl folate is the active form of folate that the body uses in the methylation cycle. It is available as a supplement in various dosages. Studies do show that supplemental methyl folate helps to decrease depression scores in people with the MTHFR C677T variant.[ref] Some people report side effects, such as headaches, when they start taking methyl folate. This is one vitamin that you may want to start with low doses and see how it goes. The US RDA for folate is 400 mcg/day, so look at how much folate you regularly get in your diet as a starting point.

Related Genes and Articles:

BDNF + Serotonin Variants: Increased risk of depression and anxiety
Genetic variants in the BDNF and serotonin receptor genes combine to increase the risk of depression and anxiety. Learn more about BDNF and how these variants interact — and check your genetic data to see how this applies to you.

COMT Gene: Balancing Neurotransmitters
Wondering why your neurotransmitters are out of balance? It could be due to your COMT genetic variants. The COMT gene codes for the enzyme catechol-O-methyltransferase, which breaks down (metabolizes) the neurotransmitters dopamine, epinephrine, and norepinephrine.

Lithium Orotate + B12: The bee’s knees, for some people…
For some people, low-dose, supplemental lithium orotate is a game-changer when combined with vitamin B12. But other people may have little to no response. The difference may be in your genes.

Serotonin: How your genes affect this neurotransmitter
Serotonin… a word that brings to mind a commercial that might show our happy brain neurons bouncing serotonin between them. There is a lot more to this molecule than most of us realize! This article covers how the body makes and transports serotonin and the needed receptors to complete its pathway.

Originally published Sept. 2016. Update and revised in May 2020.

About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.