Skip to main content

Verified by Psychology Today


Depression Won't Go Away? Folate Could Be the Answer

This vitamin may determine your risk and how you'll respond to antidepressants.

Folate (also known as B-9) is a vitamin that is necessary for, among other things, the formation of red blood cells, protein metabolism, cell growth and division, and prevention of neural tube defects. In addition to anemia and other health problems, folate deficiency may lead to the development of major depressive disorder (MDD). Similarly, having either a folate deficiency or problem with malabsorption is associated with poor response to antidepressant medications.

“Where Can I Find It, and Why Can’t I Use It?”

Folate is found naturally in grains, fruits, vegetables, beans, and other foods. For most people, the synthetic version, folic acid, is absorbed more rapidly than folate; however, it must be converted back to folate to be used by the body.

Although folic acid is routinely added to many processed foods, including cereals, energy bars, and breads, the inability to properly metabolize or absorb folate can result in a deficiency — even if one consumes the recommended amount (400 mcg) of folic acid.

Specifically, certain diseases, including gastrointestinal disorders like celiac disease, liver disease, and a genetic mutation (MTHFR); alcoholism or excessive alcohol consumption; taking certain medications; being on kidney dialysis; and being pregnant can lead to a deficiency. Frequent vomiting due to pregnancy or an eating disorder can also lead to deficiency.

Blood levels of folate may not accurately reflect the levels that are present in the central nervous system. In cases where a folate deficiency is pronounced or when a medical issue inhibits absorption of folic acid, the more bioavailable form, l-methylfolate, is recommended, and often at higher doses than the % Daily Value of 400 mcg.

L-Methylfolate for Treatment-Resistant Depression

Researchers first began to link folate deficiency with depression in the 1960s. Although everyone feels down or sad at some point, major depressive disorder affects roughly 6 to 7 percent of adults in a given year, and nearly twice as many women as men.

Approximately 50 to 70 percent of patients on antidepressants fail to have a remission of their depressive episode. For these patients, clinical trials and case studies suggest that l-methylfolate can improve response to antidepressants.

Furthermore, although atypical antipsychotic medications are sometimes used to augment the effects of antidepressants, these drugs are associated with side effects such as weight gain and dyslipidemia (which can cause elevated triglycerides and LDL cholesterol).

Some researchers have advocated the use of L-methylfolate supplementation for those who don’t respond well to antidepressants alone because l-methylfolate has not been shown to cause the side effects associated with antipsychotics. In general, l-methylfolate is well-tolerated and over-the-counter brands are relatively inexpensive.

How Does It Work?

L-Methylfolate is the only form of folic acid that crosses the blood-brain barrier and plays a role in neurotransmitter synthesis. It indirectly facilitates the synthesis of serotonin, dopamine, and norepinephrine, three neurotransmitters involved in mood regulation and other important functions. L-methylfolate has been shown in several studies to enhance the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), two commonly prescribed classes of antidepressants.

In two recent randomized, double-blind, placebo-controlled trials, investigators examined the effects of l-methylfolate supplementation on symptoms of depression in participants whose depression was resistant to treatment with SSRIs. In both trials, patients were assigned to receive either l-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by l-methylfolate (7.5 mg/day) for 30 days, or placebo alone for 60 days. SSRI dosages were kept constant throughout the study. In the second trial the design was identical to the first, except that the l-methylfolate dosage was 15 mg during both 30-day periods.

The team found there was no significant difference with regard to benefit across the treatment groups during the first trial. In the second trial, however, adjunctive l-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo in terms of both the response rate and degree of change in depression symptom score, as well as on two secondary measures of symptom severity. L-methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo.

The researchers concluded that adjunctive l-methylfolate at the higher dose of 15 mg/day may constitute an effective, safe, and well-tolerated treatment strategy for patients with major depressive disorder who have previously had either a partial response or no response to SSRIs.

Summary and Recommendations

Folate deficiency or malabsorption due to illness, taking certain medications, or other issues can increase the risk of developing major depressive disorder, as well as make it more difficult to treat. L-methylfolate supplementation may be beneficial for those who have major depressive disorder that has not responded adequately to treatment with antidepressant medications.

Those who have medical conditions or are on medications associated with poor absorption should consult with their physicians about whether l-methylfolate supplementation is warranted, and at what dose. A thorough inventory of symptoms should be part of the medical evaluation, as blood levels of folate may not accurately reflect levels in the central nervous system.

Finally, anyone experiencing depressive symptoms should be evaluated by a licensed mental health professional. Psychotherapy can be an invaluable part of a depression management approach whether or not someone has responded well to antidepressant medications.


Fluitt, N. (2012). L-Methylfolate: Another weapon against depression. Current Psychiatry, 11(1).

Mackey, I. (2013). Biological markers and depression: L-methylfolate as adjunctive therapy. Advance Healthcare Network for NPs & PAs.

Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, & Clain A, et al. (2012). L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. American Journal of Psychiatry. 169(12), 1267-74.

Stanger O, Fowler B, Piertzik K, Huemer M, Haschke-Becher E, Semmler A, Lorenzl S, & Linnebank M (2009). Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations. Expert Rev Neurother, 9(9), 1393-412.

Johns Hopkins: Anemia of Folate Deficiency.

National Institutes of Health

WebMD: L-Methylfolate