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Folate, Genetics & Mental Health

Micronutrients in Mental Health Series III

Folic acid has been widely researched for the treatment of depression. In this post we will continue our Micronutrients in Mental Health Series, covering the 3rd nutrient implicated in depression and anemia with our discussion of folate. The name ‘folate’ is derived from the Latin ‘folium’ which means foliage, as it is abundant in leafy green vegetables and was first isolated from spinach.  A deficiency of folate (also known as folic acid and vitamin B9) has been associated with depression, with a folate supplement being able to return one to euthymia (or a normal mood). Prescription forms of methylfolate (active folic acid (Deplin, Metanx and others)) are readily prescribed to augment the effects of antidepressant medications (improve the efficacy of antidepressant medications) and to treat ‘treatment resistant’ depression.

Symptoms of a deficiency

A holistic evaluation of a patient with depression often includes a nutritional history and may include genetic testing to determine if there are genetic polymorphisms that limit absorption and metabolism of this nutrient. A set of genetic polymorphisms that can affect folic acid absorption include those coding for an enzyme required for folate metabolism, Methylenetetrahydrofolate reductase (MTHFR). MTHFR testing can be used to determine if an individual has such a polymorphism (leads to reduced enzyme activity and an increased risk of depression, heart disease, gastrointestinal tract issues, megaloblastic anemia, birth defects, infertility, cervical dysplasia, cognitive difficulties and a number of other symptoms/conditions associated with folate deficiency). Other signs and symptoms of folate deficiency include weakness, fatigue, shortness of breath, irritability, forgetfulness, dizziness, headaches, palpitations, a sore tongue, gum disease, diarrhea, loss of appetite, weight loss and abnormal liver enzyme results on labs.

The following questionnaire, produced by Mark Hyman, MD is a helpful tool to determine if your methylation pathways (which require vitamins B12, B(folate) & Bto function optimally) are impaired due to a deficiency of one or more of these nutrients. Assign a ‘1’ beside each of those questions which you answer ‘yes’ to.


Scoring the test:

0-8; generally indicates a low-level problem with methylation

≥9; may indicate a severe problem with methylation. A visit to a skilled medical provider who works with nutrient supplementation and diet is advised.

Diagnosing deficiencies

Naturopathic physicians often evaluate patients for genetic polymorphisms and can also investigate other causes of poor folate status (including food allergies, a variety of medical conditions and medications). Those suffering from Ulcerative Colitis, Celiac disease and any condition with gastrointestinal inflammation are at increased risk of deficiency due to malabsorption.  Smokers and those with high alcohol consumption also have lower folate status. Those with liver disease and on dialysis also have lower folate status and are thus potentially more prone to deficiency and depression. Medications that adversely affect folate status include oral contraceptives (or birth control pills), anticonvulsants (which are prescribed in some cases of bipolar disorder), methotrexate, diuretics and proton pump inhibitors.

Laboratory evaluations are highly recommended prior to supplementing folic acid as folic acid supplementation can mask a vitamin B12 deficiency, causing potentially severe neurological effects. Serum folate is often measured, but this test is not a good indicator of folate status over time (it is sensitive to short-term changes in folate intake).  To get a more reliable sense of folate stores, erythrocyte (or red blood cell) folate is preferred. Other laboratory tests that may be performed to assess folate status include Homocysteine and FIGLU. Ruling out vitamin B12-deficient and iron-deficiency anemias is often a part of the work-up as well.

Treating folate deficiency & MTHFR polymorphisms

Supplements with the active form of folate (L-methylfolate, 5-MTHF or Metafolin) are preferred over most prescription forms as they do not contain potentially harmful colorings, flow agents and fillers commonly found in the prescription preparations.

Foods rich in folate include liver, asparagus, legumes, dark green leafy vegetables and whole grains. Folate is lost as vegetables are stored at room temperature and with excessive cooking. While many grains and cereals are fortified with folate, most gluten-free grains/grain products are not. Fortification is potentially harmful for those with the MTHFR polymorphism and may need to be avoided as part of their treatment regimen.

Finally, lest I get too reductionistic in discussing folate metabolism, it is helpful to take a step back and appreciate that human physiology and biochemistry is anything but simple. In its complexity we see that there is much interdependence between nutrients and synergy in absorption and metabolism in some cases. To properly process and utilize folate in our diet, we need to have a balance between dietary protein, vitamin B12 and folic acid levels. Those with deficiencies of any of these nutrients will also have imbalances in the other nutrients,.

Addressing Mental Health Concerns with Folate

If you or someone you know suffers from depression (and/or some of the deficiency symptoms listed herein), a comprehensive evaluation by a physician skilled in nutrition is advised to determine the cause(s) or factor(s) contributing to this mood disorder. Supplementation in the absence of such evaluation and testing may lack efficacy or even pose harm.

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  1. Hyman, M. (2009). The UltraMind Solution Companion Guide. Retrieved from – page 10
  2.  Herbert, V. & Kshitish, C.D. (1994). In Shils, M.E. , Olson, J.A. & Shike, M. S. (Eds.), Modern Nutrition in Health and Disease. (8th ed.). (pp. 402-423). Philadelphia, PA: Lea & Febiger.
  3. Marz, R.B. (1999). Medical Nutrition from Marz. (2nd ed.). Portland, OR: Omni-Press.
  4. Masterjohn, C. (2012). Beyond Good and Evil: Synergy and Context with Dietary Nutrients. Wise Traditions, 13 (3), 15-26.

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