MTHFR, depression, anxiety, symptoms and treatment

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, low folate, vitamin B12, and depression.[ref]

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How does the MTHFR mutation affect mood?

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 the 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 neurotransmitter synthesis, DNA repair, and turning on or off genes  can be important in depression.

Here’s how one study sums up the possible ways MTHFR variants can impact mood:

doi: 10.1038/s41398-018-0276-6

Depression and Mood Swings with MTHFR

The MTHFR gene codes for methylenetetrahydrofolate reductase, a key enzyme needed to convert folate into methylfolate, 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. (see genotype report below)


  • 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.[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 ancestry and more marginal in Caucasians (although still statistically significant).[ref]

Age and gender may also play a role here. Postmenopausal women who carried the MTHFR C677T variant were found to be at a 2 to 3-fold increased risk of depression.[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]

Depression treatment clinical trial:  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]


MTHFR Genotype Report

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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:

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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 also 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.

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