L-Methylfolate for Depression: The Real Deal?

L-Methylfolate for Depression: The Real Deal?You may have already seen journal advertisements for Deplin (, a formulation of L-methylfolate produced by a company called Pamlab LLC. Touted as an “antidepressant food,” Pamlab claims it is “a first choice in depression augmentation.” Response rates to antidepressants are suboptimal, so any treatment that helps to improve symptoms without causing troublesome side effects would be a welcome addition. But can a nutritional supplement really relieve depression?

L-methylfolate is metabolized from dietary folate, and is necessary for the synthesis of serotonin, norepinephrine, and dopamine. Given that nearly all antidepressants target one or more of these neurotransmitters, L-methylfolate seems like a rational option for augmenting antidepressants. Both dietary folate and folic acid normally undergo an enzymatic transformation process to become L-methylfolate, so the obvious first question is why would anyone need to buy Pamlab’s pricey L-methylfolate preparation (Deplin) if their own bodies can produce it naturally? The company points to studies indicating that in about 50% the population, genetic variations impair the function of the enzymes required to transform folate to L-methylfolate. However, a recent review of the data on one of these genetic polymorphisms (called “C677T”) found that overall, it did not put people at any higher risk of depression (Gaysina D et al., Am J Med Gen B Neuropsychiatr Genet 2008;147B: 699-706). Thus, it is unclear whether less efficient enzymatic transformation of folate truly has any clinical relevance.

A more important question is whether there is any established link between low folate levels and depression. A recent meta-analysis of 10 epidemiological studies found a statistically significant but small relationship between low folate levels and increased risk for depression (Gilbody S et al., J Epidemiol Community Health 2007;61:631-637). However, the authors noted that most of the studies they reviewed were cross-sectional, meaning that they took a snapshot of the link between folate levels and depression at a single point in time. In such studies, it is impossible to identify a cause-effect relationship. For instance, low folate levels in depressed patients could simply be a byproduct of lower folate consumption due to decreased appetite.

One study used a more sophisticated strategy by collecting data on folate intake from 2313 nondepressed Finnish men, then examining their incidence of hospitalization for depression approximately 13 years later. After controlling for variables such as alcohol intake and education level, patients with lower than average folate intake were about 2.5 times as likely to be hospitalized for depression at follow-up compared to patients with higher than average folate intake (Salonen et al., Psychother Psychosom 2004;73:334-339). Another study examined how blood levels of folate (rather than folate intake) were related to depression in a sample of over 7000 British women aged 20-34. At baseline, there was a significant relationship between low folate levels and increased depressive and anxious symptoms. Women with significant symptoms of anxiety and depression were then excluded from a two-year follow-up analysis, which found there was not a significant relationship between initial blood folate levels and subsequent incidence of depression. This suggests that depression may lead to low folate levels rather than vice versa (Kendrick et al., 2008 J Epidemiol Community Health 2008; 62:966-972).

Does folate supplementation relieve symptoms of depression? A ten-week trial of 127 participants compared 0.5 mg/day folic acid (standard folate, not Deplin) augmentation of fluoxetine to placebo augmentation, and found that folic acid significantly outperformed placebo in terms of treatment response rate (38% vs. 18%) and overall improvement on the Hamilton Depression Rating Scale (Coppen A and Bailey J, J Affect Disord 2000; 60:121-130). However, the advantages for folic acid were not seen until ten weeks into treatment.

In a smaller trial, patients with depression or schizophrenia were given either 15 mg methylfolate (equivalent of 7.5 mg L-methylfolate) or placebo in addition to their existing medication regimen. Though hampered by a small sample size (24 depressed patients and 17 patients with schizophrenia), there was a statistically significant benefit on a general clinical outcome scale and there were trends toward a significant benefit on other outcome measures in the six-month study (Godfrey PSA et al., Lancet 1990; 336:392-395). A third trial compared 50 mg methylfolate (equivalent of 25 mg L-methylfolate) plus placebo to 50 mg trazodone twice daily in the treatment of depression. The study included 96 participants, all of whom also had a diagnosis of mild to moderate dementia. Both groups improved across the eight-week trial, with no significant differences emerging between the treatments (Passeri M et al., Aging 1993;5:63-71). Across these clinical trials, adverse events appeared to occur infrequently with folate.

The bottom line is that there is some limited support for the efficacy of both standard folic acid and L-methylfolate as an augmentation agent for depression. The recommended dose of Deplin, according to the manufacturer, is 7.5 mg daily. The cost of their formulation is about $60 per month at this dose, though Pamlab currently offers a coupon on their website which lowers the cost to $47 monthly. By contrast, the usually recommended dose of folic acid (400 micrograms) costs only about 50 cents per month – 1% the cost of Deplin. At this point, since there have been no trials comparing the less expensive folate supplementation with L-methylfolate, it is not clear that there is any advantage to using Pamlab’s formulation.

TCPR VERDICT: Folate: Might be effective for depression, but we recommend that patients try the cheap stuff (folic acid) before springing for Deplin (L-methylfolate).

L-Methylfolate for Depression: The Real Deal?

This article originally appeared in:

The Carlat Psychiatry Report
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This article was published in print 6/2009 in Volume:Issue 7:6.