The MTHFR Mutation and Anxiety
Anxiety and depression are two of the most common mental health disorders in the US. Anxiety disorders affect around 40 million adults aged 18 and older, and nearly half of those diagnosed with depression are also diagnosed with anxiety.
While there can be many causes for anxiety, recent research suggests that the MTHFR mutations and anxiety may be intrinsically linked. Studies have linked MTHFR gene mutations with an increased risk of mental health conditions, particularly anxiety and depression.
It is estimated that approximately 25% of the world’s population are carriers of MTHFR variant 677C>T, while another 25% have the variant MTHFR 1298A>C according to clinical genotyping. These mutations both affect the production of the critical enzyme required for metabolizing folate and breaking down the amino acid homocysteine.
So far, the most studied polymorphisms are C677T and A1298C. These have both been significantly associated with reduced MTHFR enzymatic activity and methylation.
Depending on the form of the variant, the downstream effects of an MTHFR mutation may have serious consequences for mental health. Those with certain variants may suffer symptoms for decades without knowing why.
The mutation also affects the response to standard SSRIs (Selective Serotonin Reuptake Inhibitors), which can mean that medical treatment for depression and anxiety provides little to no relief.
While it’s not possible to ‘repair’ the mutation, it is possible to manage its biological effects through supplementation and lifestyle changes. This is why a simple MTHFR gene test may be a crucial first step in finding solutions for treating anxiety and depression.
This article will explain how the MTHFR mutation can affect the biochemical pathways involved in mental health, and the symptoms it can cause when these are disrupted. We’ll also cover how to manage the symptoms of an MTHFR polymorphism—particularly anxiety and depression—by taking the right supplements.
How Does Having an MTHFR Mutation Affect Mental Health?
Many of the raw materials that we ingest through food and supplements must be processed by our body into a usable form. One of these materials is folate (Vitamin B9), which must be converted to its active form—methylfolate—before the body can use it. The MTHFR enzyme is the body’s tool for this conversion.
However, reduced function of the MTHFR enzyme leads to impaired methylation as well as a deficiency in folate. Methylation is essential for the production of DNA, metabolism of various hormones, healthy detoxification, and much more.
Each copy of the variant reduces MTHFR enzyme efficiency by approximately 35%.People who are homozygous for the T variant (this is considered to be a ‘double mutation’) have about 30% of the enzyme activity of individuals with the wild-type (CC - or ‘normal’, non-mutated) variant, while those who are heterozygous (CT - also known as a ‘single mutation’) have about 65% of the enzyme activity of CC individuals.
Because both DNA methylation and folate are crucial to mental health, reduced MTHFR activity and subsequent folate deficiency have been associated with several mental health disorders, including schizophrenia, bipolar disorder, and depression.
MTHFR’s Effects on Anxiety
Along with methylation, methylfolate is also crucial for converting the amino acid homocysteine into another amino acid, methionine. Our body needs methionine to make a range of brain chemicals that contribute to positive mood, including the neurotransmitters serotonin, dopamine, and norepinephrine.
A lack of methylfolate will lead to low levels of these neurotransmitters, which in turn is linked to a higher risk of anxiety and depression.
Methylfolate works together with vitamin B12to make S-adenosylmethionine (SAMe), an important substrate that helps produce and regulate hormones, and to maintain cell membranes. As well as generating serotonin and dopamine, SAMe is involved in making GABA (γ-aminobutyric acid), an inhibitory neurotransmitter that helps to reduce anxiety and promote feelings of calm.
Excess glutamate (an excitatory neurotransmitter) relative to GABA is common in those with methylation impairments. A lack of these methyls or an inability to use them can increase feelings of anxiety and stress.
The MTHFR mutation also affects your body’s ability to produce and use other nutrients, including B12, vitamin D, and choline, which also play a part in healthy mood regulation.
MTHFR’s Effects on Depression
Researchers have shown that MTHFR and depression are also closely related. Previous studies have indicated that around 20-30% of patients with depression are treatment-resistant and that these patients often have the MTHFR polymorphism.
This leads to low levels of L-methylfolate, and subsequently lower folate and lower levels of monoamines (dopamine, noradrenaline, and serotonin). The underlying pathophysiologic basis of depression is a depletion of these neurotransmitters in the central nervous system.
A recent meta-analysis found higher rates of depression in people with theC677T homozygous MTHFR mutation. The meta-analysis also showed an association between the MTHFR C677T variant and schizophrenia, and bipolar disorder.
Another recent study showed that an MTHFR polymorphism combined with traumatic childhood events may increase the likelihood of depression later in life. Patients with a history of recurrent depression were followed for 5.5 years. It was found that those patients with the MTHFR T allele who had been through adverse events in their early life were most likely to suffer from recurring depression.
Can an MTHFR Gene Variant Cause Other Mental Health Issues?
As both DNA methylation and folate are essential for mood and emotional health, poor MTHFR activity or folate deficiency have been associated with an onset of several psychiatric diseases, including schizophrenia, bipolar disorder, depression, autism, dementia, and ADHD (Attention Deficit Hyperactivity Disorder).
A meta-analysis of seven studies found that people with TT homozygotes (double mutation) had the greatest risk of schizophrenia, compared to people with CC wild type (no mutation) and CT heterozygous (single mutation) genotypes.
Another study reported that those with the homozygous TT genotype were also more likely to develop schizophrenia along with a higher risk of bipolar disorder. Interestingly, this association between homozygous 677TT genotypes and bipolar disorder appears to be even stronger in males than females.
It’s also been found that patients with the MTHFR T allele and COMT (Catechol-O-Methyltransferase) Met/Met homozygotes appear to have the largest increases in psychotic experiences in response to environmental stress.
Can Treating MTHFR Relieve Anxiety and Depression?
It has been well-established that there is a high incidence of folate deficiency in patients with anxiety and depression. This has often prompted the use of folic acid and folate supplements as treatment. However, these two supplements are not the same.
Those with MTHFR cannot synthesize folate in their bodies, so supplementation is essential. Low folate status may be caused by low dietary intake, low absorption of dietary folate, and faulty folate metabolism due to MTHFR genetic defects or drug interactions.
Unlike synthetic folic acid, naturally-occurring 5-MTHF (L-methylfolate) is:
- well absorbed even when gastrointestinal pH is altered
- its bioavailability is not affected by metabolic defects
- it does not mask a vitamin B12 deficiency
- can overcome metabolic defects caused by MTHFR polymorphisms
Supplementation with 5-MTHF also prevents buildup of unconverted folic acid in the peripheral circulation, which can result from folic acid supplementation.
L-methylfolate also plays an important role in the homocysteine cycle, and high levels of homocysteine have been associated with depression. People with low levels of methylfolate are also unable to manufacture the brain’s ‘happy chemicals.
L-methylfolate is the only form of folate that crosses the blood–brain barrier so that it can be immediately available for its many roles. It acts as a donor for DNA methylation, which is required for epigenetic gene silencing. Where antidepressants block the reuptake of neurotransmitters (works to keep them in your system longer), L-methylfolate allows necessary methyl donation for actually making tri-monoamines (i.e. serotonin).
Studies involving the use of L-methylfolate intreating anxiety and depression have had largely positive results. Patients have reported significant improvements in depressive symptoms and cognitive functioning, with one study showing 67.9% of patients responding and 45.7%achieving remission over 12 weeks. Patient compliance with taking methylfolate is also very high, with over 90% of patients reporting taking every dose or nearly every dose of L-methylfolate.
A case study published in the Journal of Integrative Medicine reported how an MTHFR patient with severe anxiety was treated with 5-methyltetrahydrofolate (5-MTHF) and other methylated B vitamins. After four months, her anxiety was greatly reduced, and she continued to experience improvement.
L-Methylfolate (7.5 mg and 15 mg) has been shown in retrospective and prospective studies to enhance antidepressant response, significantly improving clinical and social recovery. A double-blind multicenter study showed that adding L-methylfolate7.5 mg or 15 mg to standard psychotropic medication significantly improved clinical recovery in depressed patients with folate deficiency.
Methyl-Life® products contain the purest and most bioactive nutrient form of folate available, Magnafolate® PRO. This is the form of folate that has already been converted, so it can cross the blood-brain barrier and be immediately used by the body’s cells. 5-MethylTHF—also known as(6S)-5-methylTHF—is the predominant micronutrient form of folate that circulates in plasma and is required for numerous biological processes.
Unlike folic acid, 5-MTHF can cross the blood-brain barrier and does not mask pernicious anemia or vitamin B12deficiency. It is readily available for transport and metabolism and has no tolerable upper intake level. 5-MTHF is a better alternative because it’s a natural form of folate directly available for gastrointestinal absorption.
Those suffering from anxiety and depression are often at a loss as to why they feel the way they do. Their lives are significantly impacted by their disorder, and yet they often find no relief from medication.
The good news is that scientists now understand more about the MTHFR mutation and anxiety, particularly in terms of the impact that MTHFR has on biochemical processes within the body. The many requirements of folate are also better understood, particularly with regards to its role in creating chemicals involved in mood and brain function.
As you will have learned in this article, methylfolate is one of the most important nutrients for everyday function. It is necessary not only for healthy methylation but also reducing harmful homocysteine levels and the manufacturing of important neurotransmitters. Consequently, the depletion of these nutrients has a detrimental effect on our ability to feel calm, positive, and motivated.
Discovering that you have an MTHFR polymorphism may come as a shock, but it can also mark the beginning of your journey to better health.
The MTHFR mutation can be managed by supplementation with the right nutrients and lifestyle changes. This begins with taking a quality methylfolate supplement. Methylfolate bypasses the MTHFR mutation, providing your body with an active form of the folate it needs to carry out methylation and many other biochemical pathways. It’s the most effective way to optimize your body’s methylation processes and support a healthy mood.