By David Kiefer, MD

Clinical Assistant Professor, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona, Tucson

Dr. Kiefer reports no financial relationships relevant to this field of study.

SYNOPSIS: L-methylfolate improves some symptoms in major depression in people with type 1 bipolar disorder.

SOURCE: Nierenberg AA, Montana R, Kinrys G, et al. L-methylfolate for bipolar I depressive episodes: An open trial proof-of-concept registry. J Affect Disord 2017;207:429-433.

L-methylfolate (LMF) is surfacing as a treatment for many health conditions, but the details remain: Who would most benefit, for which diagnoses, and what is the best dose? There is a dearth of methodologically sound clinical trials to help answer these questions, but the researchers of this proof-of-concept study begin the process of adding important clinical data to the fund of knowledge.

This study was an extension of prior placebo-controlled research showing that 15 mg of LMF daily can lead to improvements in symptoms of major depression.1 This treatment approach had not been extended to depression in people with bipolar disorder, although such depression can be just as debilitating and associated with polypharmacy. Thus, although potential adjunctive therapies are necessary, they are limited. The research participants were adults who had to be on a maintenance medication (mood stabilizer or atypical antipsychotic) for type 1 bipolar disorder. The participants could not be taking antidepressant medications, yet per a scale (Mini International Neuropsychiatric Interview) had to be classified as having major depression. There was also a long list of exclusion criteria, including (interestingly) no history of multivitamin use within the last 12 weeks or dietary supplements with known central nervous system effects.

The 10 participants who satisfied the inclusion and exclusion criteria received 15 mg daily of LMF and continued on their bipolar medication for six weeks. Visits with the study clinicians occurred every two weeks for six weeks. Numerous tools were used to quantify symptoms of mania, depression, and overall functioning, as well as life satisfaction and bipolar severity. Baseline scores of these measures and final mean scores were tallied and compared using Cohen’s d statistical analysis (to establish the effect size). Of the 10 original participants, nine made it to week 4, and eight finished the six-week trial. Of all the measures, researchers highlighted that the Montgomery-Åsberg Depression Rating Scale (MADRS), a score of 9 or lower indicating remission, decreased significantly (P = 0.027) from a baseline of 23.4 to 13.9 at six weeks (effect size 1.19).

Researchers also mentioned that the Quick Inventory of Depression Symptomatology-Self Report improved by 35% with an effect size of 0.92, although no P values were provided. Also, other scales hinted at improvements in cognition, functioning, and suicidal ideation; again, P values were not indicated for the numbers provided. There was a low baseline level of mania per the Young Mania Rating Scale, but one patient showed a worsening of manic symptoms and possibly a manic episode. On this note, a large list of side effects were followed; it is unclear whether the changes noted between baseline and study endpoint were statistically significant. The most common side effects were dry mouth, headache, and fatigue. This was an open-label, uncontrolled study. Obviously, clinicians need a placebo-controlled, randomized trial to abscribe the findings here to LMF. That goes for the benefits seen and the side effects described (most alarming was the possible manic episode). I wonder about the demographic, those people with major depression associated with type 1 bipolar disorder who currently receive adequate treatment for their depressive symptoms. These patients may indeed represent a psychiatric need and, should LMF prove to be safe and effective, LMF might be able to provide such patients some relief. There is some prior clinical work on depression that would support the results seen here, and the mechanism is plausible and compelling. The researchers cited work showing that LMF modulates and increases monoamine neurotransmitters, such as dopamine, serotonin, and norepinephrine. Furthermore, it appears to freely cross the blood-brain barrier, and addresses the fact that those people suffering from depression are more likely to possess polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene, which LMF can bypass and more directly affect physiological processes. More specifically, MTHFR polymorphisms may decrease the formation of 5-methyltetrahydrofolate, a methyl donor in the formation of methionine from homocysteine.1 This irregular folate metabolism and build-up of homocysteine seems to correlate with (cause?) an expanding list of conditions, including major depression,1 multiple sclerosis,2 chronic kidney disease,3 cardiovascular disease,3 and infertility.4


  1. Cho K, et al. Methylenetetrahydrofolate reductase A1298C polymorphism and major depressive disorder. Cureus 2017;9:e1734.
  2. Dardiotis E, et al. Vitamin B12, folate, and homocysteine levels and multiple sclerosis: A meta-analysis. Mult Scler Relat Disord 2017;17:190-197.
  3. Cianciolo G, et al. Folic acid and homocysteine in chronic kidney disease and cardiovascular disease progression: Which comes first? Cardiorenal Med 2017;7:255-266.
  4. Gaskins AJ, Chavarro JE. Diet and fertility: A review. Am J Obstet Gynecol 2017; Aug; 24. doi: 10.1016/j.ajog.2017.08.010. [Epub ahead of print].