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MTHFR and Depression: Is Folate Deficiency to Blame?

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MTHFR and Depression: Is Folate Deficiency to Blame?

Despite the advances in science and medicine, research has still not identified the exact cause of depression, the most prevalent mental health disorder worldwide. According to recent statistics in the United States, 7.1% of all adults and approximately 13% of adolescents aged 12 to 17 had at least one major depressive episode in 2017. 1

See also: Genes that have been linked to depression

Depression has been described as a symptom of a brain that is unable to act fast enough. Functional MRI studies that have compared healthy brain scans to depressed brain scans found that people with depression simply have a brain that is unable to activate at the normal rate.  In other words, depression is a neurological system that is slowed down. 2

We hear often about having a genetic predisposition to certain diseases, is it possible that the MTHFR gene plays a role in mental health?

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What is the MTHFR gene and how does it increase your risk for depression?

The MTHFR gene provides instructions for making the MTHFR enzyme. This enzyme forms part of an important pathway that converts homocysteine to methionine in the blood. It also converts folate, also known as Vitamin B9, into the useable, active form known as methyl folate.

If MTHFR activity is impaired, a build-up of homocysteine in the blood occurs together with a methionine deficiency.

Why would your MTHFR enzyme not be functional?

Well, common mutations in the MTHFR gene can pose a risk to our body’s ability to convert homocysteine in the blood to bioactive Vitamin B9. These mutations are the C677T variant and the A1298C variant. Individuals with MTHFR C667T have problems with their folate metabolism and are at a higher risk of low serum folate.

There is a complex relationship between MTHFR genes and depression, but essentially, research suggests that folate deficiency can contribute to depression.

MTHFR is required for neurotransmitter production in the brain

The MTHFR enzymes are vital to healthy functioning neurotransmitters. These are chemical signals in your brain that regulate your mood. If the enzyme is not functioning properly, this can lead to low serotonin and dopamine levels, which may lead to the development of depressive symptoms.

A 2017 meta-analysis of 43 studies examined if there was an association between folate and depression.3 The meta-analysis looked at studies that measured folate levels in people with depressive symptoms or depression and compared these levels to individuals without depression. Folate levels were measured based on red blood cell folate, serum folate, or dietary folate intake.

The study conclusion was that individuals with depression had lower serum levels of folate and dietary folate intake than individuals without depression. The authors also stated that future research looking at folate supplementation in depression is the next step and that clinicians may wish to consider folate supplementation for patients with depression.

There is accumulating evidence that low folate status is associated with depression.


If you are depressed and have found that you don’t carry the MTHFR gene variants, you could have folate deficiency that occurs due to other factors.

Additional causes of low folate can include:

  • Cancer or inflammatory conditions
  • Chronic and excessive alcohol consumption reduces absorption
  • Pregnancy
  • Malabsorption associated with gastrointestinal illnesses such as inflammatory bowel disease and celiac disease
  • Smoking
  • Lactose intolerance
  • Drug-induced deficiencies (e.g. phenytoin, methotrexate, sulfasalazine, triamterene, NSAIDs), and genetic variations that affect folate absorption, or transport.

Folate Therapy and 5-MTHF

Folate supplementation options for depression include folic acid, folinic acid, and 5-MTHF (L-methyl folate).

  • Supplementation with 5-MTHF has advantages over using synthetic folic acid.
  • This is because 5-MTHF is absorbed well even when there are changes in gastrointestinal pH (such as elevated gastric pH from proton pump inhibitors), as opposed to folic and folinic acid. Additionally, 5-MTHF overcomes metabolism defects even though you may have MTHFR variants.
  • Another positive factor for using 5-MTHF is that it’s the only form of folate that can cross the blood-brain barrier. Once in the brain, 5-MTHF is a cofactor that is involved in the production of the neurotransmitters serotonin, dopamine, and norepinephrine which are essential for mood regulation.

The effects of 5-MTHF on depression were assessed in a trial on patients with major depressive disorder. They were supplemented with 7.5 mg or 15 mg 5-MTHF(Deplin).4 Participants had to rate their experiences before and after three months of supplementation.

The trial involved 502 patients supplemented with 5-MTHF in addition to their antidepressants, while 52 patients were supplemented with 5-MTHF alone. The study found that the satisfaction of taking antidepressant medication supplemented with 5-MTHF was higher than before supplementation. They also found that overall, 67.9% of patients responded to therapy with significant improvements in depressive symptoms and function, with 47.5% achieving remission over 12 weeks. Also, those taking 5-MTHF as monotherapy (meaning alone) had similar response rates compared to those patients taking it as adjuvant therapy (meaning together with their anti-depressants).

Alternative sources of folate

If you’re not a fan of taking supplements, you can always modify your diet to include folate-rich foods. High folate food sources include:

  • Spinach
  • Liver
  • Asparagus
  • Brussels sprouts
  • Dark green leafy vegetables
  • Fruit and fruit juices
  • Nuts
  • Beans
  • Peas
  • Seafood
  • Eggs
  • Dairy products
  • Meat
  • Poultry
  • Grains

The emergence of nutraceuticals for the treatment of depression

The most common therapy for the treatment of major depressive disorder is a combination of pharmacotherapy (antidepressants) and psychotherapy as this combination currently provides the quickest and best-sustained response. However, research has shown that 60% of patients with depression are not treated effectively with psychotherapy and medication.5

As I mentioned previously, there is emerging evidence of the effect of the administration of nutraceuticals, such as folate supplementation, for the treatment of depression. It has the added benefit of working well alone, or in combination with antidepressants. So if you’re amongst the 60% of these patients, consider nutraceuticals as an alternative or complementary therapy.

If you do decide to switch over to folate therapy, consult with your health care practitioner first to ensure that your supplementing with the correct dosage-too little may have no effect, and too much may have adverse effects.

Dr. Gina Leisching

Dr. Gina Leisching holds a BSc in Functional Human Biology, and Honours degree in Physiological Sciences, as well as a doctorate in human physiology from Stellenbosch University, South Africa. At Gene Food, Dr. Gina uses her expertise to provide evidence-pieces that readers may find helpful and informative.

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