• Karla Benzl, M.D.

Folate and Depression

Updated: Jun 1, 2020



What is Folate?

Folate, also known as Vitamin B9, is a term that refers to a group of naturally occurring micronutrients such as 5-methyltetrahydrofolate (5-MTHF), folinic acid, and other tetrahydrofolate derivatives. Folate is an essential micronutrient, which means that the body does not produce it naturally, and must obtain it from the diet. Folate is important for cell division, red blood cell production, protein metabolism, and nucleic acid production. In addition, folate has been linked to mental health, as it is important for brain function and other processes of the nervous system. Three well-known neurotransmitters that affect mood and cognition include serotonin, dopamine, and norepinephrine. These neurotransmitters are made via chemical processes involving folate. Studies have found low levels of folate in depressed patients (Fava, 2009). In addition, depressed patients with low folate levels are more likely to have a suboptimal response to antidepressant medication, and higher chance of relapsing symptoms (Fava, 2009 and Papakostas, 2012).




Folate levels can be impacted by poor diet, gastrointestinal disease, or certain medications. Specific populations at risk for low folate levels include women of childbearing age, individuals with poor nutrition, individuals with eating disorders, elderly individuals, and individuals with excessive alcohol intake or tobacco use (Stahl, 2008).

Folate intake and absorption are important for health, but genetics also influence how the body utilizes it. Genetic polymorphisms (altered gene copies) of the MTHFR gene are associated with less efficient folate metabolism. The two most common MTHFR gene mutations occur at alleles C677T and A1298C. A certain percentage of the population will have one or two copies of these mutations, although it is more common to have just one mutation.

The MTHFR gene codes for MTHFR enzyme, which is involved in converting or “reducing” folate (and folic acid) during cellular processes involving methylation or one carbon transfer of compounds. Genetic polymorphism of MTHFR genes leads to less efficient methylation reactions. This can interfere with cellular processes, including but not limited to: function of DNA synthesis and repair, neurotransmitter synthesis, heavy metal detoxification, antioxidant activity (Friso, 2013). With regards to mental health, this is may be important. Suboptimal neurotransmitter synthesis has been linked to mood and cognitive symptoms. Indeed, C677T polymorphisms have been associated with increased severity of depression, poor response to antidepressant medications, and more sensitivity to stress (Bousman, 2014). This is why folate supplementation has been the focus of mental health research.


L-methylfolate supplementation verus folic acid?

As mentioned previously, folate is a term for Vitamin B-9, and refers to various derivates of this vitamin. A common form of folate is folic acid. Folic acid is an oxidized version of folate. Although it is typically a synthetic vitamin, folic acid can occur naturally in cooked or store foods. Folic acid is added to foods in many countries, and is the predominant form of folate in many vitamin supplements. It is metabolized through the liver and requires enzymatic processes to make it bioactive. You are probably familiar with folic acid as a prenatal supplement, as taking this vitamin has been associated with decreased risk of neural tube deficits in developing fetuses. Dihydrofolate is the naturally occurring form of folate, found in foods such as leafy greens, legumes, egg yolks, and liver.

L-methylfolate, on the other hand, is a bioactive form of folate. Folic acid and dihydrofolate are converted to L-methylfolate by the MTHFR enzyme (Stahl, 2008). Taking L-methyfolate bypasses the need for enzymatic conversion, and is readily used by the body regardless of genetic polymorphisms of the MTHFR gene. Also, it readily crosses the blood –brain-barrier (the sheath of membranes and vessels that enclose the brain). Compared to folic acid, L-methylfolate is better absorbed by the gastrointestinal tract. In addition, it has less potential for drug interactions than folic acid.



Can L-methyfolate help treat depression?

L-methylfolate has been explored as a potential treatment for depression, particularly as an add-on treatment to antidepressants. Several studies have shown a positive impact when adding L-methylfolate supplementation to SSRIs/SNRIs in depressed persons who have not fully responded to antidepressant medication. Adding L-methylfolate to antidepressant medication can both increase their onset of action and their effectiveness. In fact, two randomized, placebo-controlled trials have demonstrated that L-methylfolate is both an effective and tolerable treatment for major depressive disorder when taken in conjunction with an antidepressant (Papakostas, 2012 and Papakostas, 2014). Additionally, the use of L-methylfolate as a stand-alone treatment has been observed to have an antidepressant effect as well. L-methylfolate is labeled as a prescription medical food by the FDA, and some insurance companies will cover it as a treatment for depression.

Typical dosing for antidepressant augmentation with L-methylfolate is 15mg once a day, however, this may vary per individual. Some clinicians report “over-methylation” concerns at higher doses, however, this experience is poorly defined (Oberg , 2015). Typical side effects include nausea. Therapeutic benefit may not be observed until 2-4 weeks. As with any psychiatric intervention, positive results occur sooner, later, or may not observed.


What populations can benefit from L-methylfolate as an antidepressant?

Generally speaking, L-methylfolate supplementation is an option if you have tried antidepressants without a full response. You may also benefit from an L-methylfolate supplement if you have a genetic polymorphism of the MTHFR gene. Lab analysis does exist to determine if you have a genetic polymorphism. You can request genetic analysis from your doctor (such as Genomind), or obtain from direct-to-consumer genetic tests. Always discuss the risks and benefits with your doctor before trying new supplements. Dietary sources of folate include green leafy vegetables, legumes, egg yolks, grains, nuts. These foods are typically recommended in a healthy diet, sans any food allergies.




Selected References

1. Bousman C, Potiriadis M, Everall IP, Gunn JM: Methylenetetrahydrofolate reductase (MTHFR) genetic variant and major depressive disorder prognosis: a five-year prospective cohort study of primary care attendees. Am J Med Genet B Neuropsychiatr Genet 2014; 165B:68-76.

2. Fava M, Mischoulon D: Folate in depression, efficacy, safety, differences in formulations and clinical issues. J Clin Psychiatry 2009; 70; 12-17

3. Friso S, Udali S, Guarini P, Pellegrini C, Pattini P, Moruzzi S, Girelli D, Pizzolo F, Martinelli N, Corrocher R, Olivieri O, Choi SW: Global DNA hypomethylation in peripheral blood mononuclear cells as biomarker of cancer risk. Cancer Epidemiol Biomarkers Prev 2013; 22: 348-355.

4. Zajecka J, Fava M, Shelton R, Barrentine L, Young P, Papakostas G. Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study. J Clin Psychiatry. 2016 May;77(5):654-60.

5. Martone G. Enhancement of recovery from mental illness with l-methylfolate supplementation. Perspect Psychiatr Care. 2018 Apr;54(2):331-334.

6. Oberg E, Givant C, Fisk B, Parikh C, Bradley R. Epigenetics in Clinical Practice: Characterizing Patient and Provider Experiences with MTHFR Polymorphisms and Methylfolate. J Nutrigenet Nutrigenomics. 2015;8(3):137-50.

7. Papakostas G, Shelton R, Zajecka J, Temad B, Rickels K, Clain A, Baer L, Dalton E, Sacco G, Schoenfeld D: L –methylfolate as adjunctive therapy for SSRI-resistant major depression: results from two randomized, double-blind, parallel-sequential trials. AM J Psychiatry 2012; 169:1267-1274

8. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014 May;44(5):480-8.

9. Stahl S.L-methylfolate: a vitamin for your monoamines. J Clin Psychiatry. 2008 Sep;69(9):1352-3.

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