L-Methylfolate: Augmenting Agent May Contribute to Agitation and Mania


Experts discuss the rationale and history of L-methylfolate use in patients, and then shares three cases that collectively suggest L-methylfolate may contribute to agitation and mania.

L-methylfolate is commonly presented as a safe augmenting agent to patients with antidepressant non-response in unipolar depression with virtually no side effects. Although this is likely to be true most of the time, as with any treatment, there are risks that can be significant albeit rare. Currently, there is a paucity of published literature of double-blind placebo-controlled randomized clinical trials of the efficacy and tolerability of L-methylfolate in both unipolar and bipolar depression. This article discusses the rationale and history of L-methylfolate use in such patients, and then shares three cases that collectively suggest L-methylfolate may contribute to agitation and mania.


In humans, folate (ie, Vitamin B9) is one of 13 essential vitamins. Low serum folate and low red blood cell (RBC) folate levels are independent risk factors for major depressive disorder (MDD); they also are associated with more severe depressive episodes and poor response to antidepressant treatment.1,2 Maternal folate deficiency prior to conception and throughout pregnancy has been shown to increase the risk of neural tube defects and congenital abnormalities in the developing fetus, as well as peripheral neuropathy and anemia in the mother.3

Ongoing studies in psychiatry and obstetrics support the use of oral dosing with the bioactive form of folate, L-methylfolate. L-methylfolate is FDA approved as a medicinal supplement for antidepressant augmentation.4 The use of L-methylfolate allows the clinician to bypass a critical metabolic step in folate’s transformation to L-methylfolate, specifically the reduction of methylenetetrahydrofolate to L-methylfolate by the enzyme methylenetetrahydrofolate reductase (MTHFR). MTHFR is the rate limiting step in this process, and significantly, MTHFR enzymatic activity has a wide range of function depending on its genetic polymorphisms at three nucleic acid sites, the most significant being: C677C (good activity), C677T (decreased activity), and T677T (poor activity).

L-methylfolate is the only form of folate that can cross the blood-brain barrier, where it plays an essential role in the one carbon cycle metabolic pathway that is required for the production of the monoamines serotonin, dopamine, and norepinephrine.5

Evidence for efficacy and tolerability

Papakostas and colleagues6 undertook a randomized study of L-methylfolate as adjunctive therapy in patients with MDD who had a partial response or no response to selective serotonin reuptake inhibitors. A population of 75 patients were treated for 60 days with 15 mg L-methylfolate daily. The findings indicate that L-methylfolate was significantly more effective as compared with placebo. The response rates were 32.3% in the SSRI plus 15 mg L-methylfolate group compared with 14.6% in the SSRI plus placebo group.

The number needed to treat to achieve response with the addition of 15 mg L-methylfolate to an SSRI was 6. Overall L-methylfolate was well tolerated with minimal adverse effects; manic symptoms developed in one patient in the L-methylfolate/SSRI group, which resulted in patient discontinuation.

A subset of the original acute treatment cohort was followed in a 12-month open-label continuation study during which outpatients were treated with 15 mg L-methylfolate and an SSRI.7 The researchers reported “high rates of response, remission, and recovery,” as well as overall safety, tolerability, and a good rate of retention.

Bipolar depression

Unfortunately, there is a paucity of research into the use of L-methylfolate to treat bipolar I depression (BD-I). To address this unmet need, Nierenberg and colleagues8 created an open label registry of patients with bipolar depression. The patients received treatment as usual as well as 15 mg L-methylfolate daily for 6 weeks. Pre-study medications included lithium, lamotrigine, quetiapine, valproate, lurasidone, levothyroxine, Dexedrine, and extended release methylphenidate. At week 6, there was a 50% or greater improvement on the Montgomery Asberg Depression Rating Scale, with a pre-treatment mean score of 23.4 and a post-treatment score of 13.9 in six of the 10 patients studied. Significantly, the researchers noted that one patient had “an exacerbation in YMRS (Young Mania Rating Scale) and a possible manic episode.”

With that in mind, we present three case vignettes of women with affective disorders, two with MDD and one with BD-I. All three had acute symptoms of agitation shortly after augmenting their divergent psychotropic medication regimen with 15 mg of L-methylfolate. In all 3 cases, the agitation rapidly improved upon discontinuation of L-methylfolate.

Case Vignette 1

“Jesse” was a 63-year-old married white woman who was on disability for multiple sclerosis. She struggled with treatment-resistant MDD for several years, with no evidence of a bipolar diathesis. She received numerous antidepressant medication trials, including therapeutic doses of phenelzine, fluoxetine, sertraline, nortriptyline, escitalopram, mirtazapine, venlafaxine, vilazodone, vortioxetine, and duloxetine; all of which failed.

Pharmacogenomic testing of the MTHFR gene was consistent with decreased activity of this enzyme (C677T). It was decided to augment duloxetine with 15 mg L-methylfolate daily.

After several days on this regimen, her husband called to report that she had become uncharacteristically irritable and agitated. No identifiable situational stressors, substance use, new medication, or medical illness could be identified. Her long-term medical history was significant for multiple sclerosis, hyperlipidemia, osteoporosis, neurogenic bladder, and hypertension.

Shortly after discontinuing the L-methylfolate, the irritability and agitation resolved. Upon obtaining further history, the patient reported a hypomanic-like adverse effect from previous prednisone treatment. There was no other history of bipolar spectrum symptoms.

Case Vignette 2

“Leslie” was a 43-year-old married white woman who presented with a history of treatment-resistant MDD with multiple antidepressant failures. The trials included imipramine, paroxetine, sertraline, escitalopram, duloxetine, venlafaxine, and fluoxetine. Her medical history was significant for multiple sclerosis, asthma, and migraines. She was taking venlafaxine XR 225 mg for an adequate duration, but there was a suboptimal response of her depressive symptoms when the 15 mg L-methylfolate daily was added. Upon follow up six weeks later, she reported that her experience with the L-methylfolate was horrible, describing herself as feeling “agitated and aggressive.”

Case Vignette 3

“Susan” was a 56-year-old divorced white mother with a longstanding history of bipolar disorder who presented with an episode of depression. She had had previous episodes of mania, complicated mania with psychosis, and depression as well as several inpatient psychiatric hospitalizations for repeated manic episodes and psychotic symptoms; her most recent hospitalization was more than 15 years prior to the current episode of depression. Over the previous several years, her symptoms were reasonably well-managed on a combination of carbamazepine and oral/depo injection haloperidol. Chronic residual symptoms included a notably flat affect, anhedonia, and a largely depressed mood at baseline.

Pharmacogenomic testing was performed as part of her work up, and it revealed that her MTHFR gene tested homozygous (T677T), which suggested poor enzymic activity. A trial of 15 mg L-methylfolate daily was initiated to target recalcitrant depressive symptoms.

The patient called a few days after L-methylfolate initiation and described feeling unwell, agitated, and seeming to be a bit paranoid. She was instructed to discontinue the L-methylfolate, and these symptoms resolved within a few days. She reported that she quickly felt more like herself after discontinuing the L-methylfolate. She described the brief trial as horrible and stated that she “will never take it (L-methylfolate) again.”


These case vignettes suggest that patients with unipolar or bipolar depression may be at risk for the onset of agitation shortly after beginning a trial of 15 mg L-methylfolate. In all three cases, the agitation resolved a few days after discontinuing the L-methylfolate, supporting the likelihood that it contributed to the agitation. It is interesting to note that the two patients with MDD both had a comorbid diagnosis of multiple sclerosis. This, however, may very well be coincidental.

The findings presented are preliminary and are presented with the aim of raising clinicians’ awareness that L-methylfolate may contribute to symptoms of agitation, irritability, and possibly hypomania, mixed mania, or mania in susceptible individuals. The only concrete conclusion that can be drawn is that well-designed clinical trials are needed to ferret out the rare but potentially significant adverse events associated with L-methylfolate.

There are no clinical data on the risks/benefits/adverse effects of the use of L-methylfolate off label in the treatment of bipolar depression. This is a significant lack of information, because many patients who ultimately have a diagnosis of bipolar disorder are initially treated-sometimes for years and even decades-for unipolar depression. The study by Papakostas and colleagues6 demonstrated that 7.5 mg of L-methylfolate performed no better than placebo as an augmentation agent in patients with MDD who did not respond to SSRIs, whereas 15 mg per day of L-methylfolate significantly separated from placebo. The dose response of L-methylfolate for effectiveness and adverse events in BD-I is unknown.

Future studies to assess the clinical consequences of augmenting antidepressants with L-methylfolate should include:

1. Large placebo controlled clinical trials of both unipolar depression and bipolar depression to determine the number needed to harm in the different patient populations, as well as the number needed to treat in bipolar patients.

2. Augmentation of non-SSRI antidepressants with L-methylfolate to determine if the improvement seen in MDD when SSRIs are augmented with L-methylfolate are generalizable to all antidepressants.

3. An evaluation of the L-methylfolate dosage range in patients with bipolar depression to determine which dosages (3.75 mg, 7.5 mg, 15 mg) are helpful and which are harmful.

These three cases illustrate the rare but possible adverse effects of agitation, irritability and possible onset of hypomania with adjunctive L-methylfolate. The publications reviewed report one patient who developed manic symptoms while taking L-methylfolate/SSRI for unipolar depression,6 and one patient who developed an increase in the YMRS and a possible manic episode when L-methylfolate was added to the regimen treating the underlying bipolar disorder.8 This activation by L-methylfolate is consistent with its putative mechanism of action, specifically increasing brain levels of norepinephrine, dopamine, and serotonin.


L-methylfolate, the bioactive form of folate that crosses the blood-brain barrier, has been shown to effectively augment SSRIs in patients with MDD who did not respond to SSRI monotherapy; and it also has been shown to be generally well tolerated. Its role in augmentation in bipolar depression remains to be determined. Although the current data are limited, clinicians and patients should be aware of the possibility that L-methylfolate may increase agitation and may contribute to the onset of hypomania/mania.



Ms Robinson is Psychiatric-Mental Health Nurse Practitioner, Seacoast Mental Health Center, Portsmouth, NH; and Clinical Assistant Professor, Department of Nursing, University of New Hampshire, Durham, NH; Dr Miller is Medical Director, Brain Health, Exeter, NH; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; and Consulting Psychiatrist, Insight Meditation Society, Barre, MA. Ms. Robinson and Dr Miller indicate they have nothing to disclose regarding the subject of this article.


1. Papakostas GI, Cassiello CF, Iovieno N. Folates and S-adenosylmethionine for major depressive disorder. Can J Psychiatry. 2012;57:406-413.

2. Alpert JE, Mischoulon D, Nierenberg AA, Fava M. Nutrition and depression: focus on folate. Nutrition. 2000;16:544-546.

3. Greenberg JA, Bell SJ, Guan Y, Yu Y. Folic acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol. 2011;4:52-59.

4. Mathew SJ. Treatment-resistant depression: recent developments and future directions. Depress Anxiety. 2008;25:989-992.

5. Stahl SM. Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS Spectr. 2007;12:739-744.

6. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012;169:1267-1274.

7. Zajecka JM, Fava M, Shelton RC, et al. 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;77:654-660.

8. 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.

Recent Videos
brain depression
© 2024 MJH Life Sciences

All rights reserved.