Folate and Depression
Folate is the general term for vitamin B9, which includes synthetic folic acid, folinic acid and methylfolate. As a vitamin, folate is key for moving around single carbon units or “methyl groups.” When a methyl group is added to a substance, the process is called methylation. Methylation reactions are critical for the production of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), cell membrane compounds called phospholipids, neurotransmitters and the reduction of the inflammatory amino acid homocysteine (Shulpekova 2021). The vitamin is also critical during pregnancy to prevent birth defects.
Nutritionally, folate is found naturally in a number of different foods, including leafy greens, beans and whole grains (Subar 1989). It’s also commonly added to grain products as folic acid. Unfortunately, folate consumption in the United States is often low with between 5% and 20% of individuals not meeting their recommended intake (Bailey 2010).
Folate and Mental Health
As a nutrient, folate plays a critical role in supporting brain function. First, folate is required for the production of neurotransmitters, including serotonin, dopamine and norepinephrine. Neurotransmitters are signaling molecules that allow brain cells to communicate with each other. These same neurotransmitters are often targeted by standard antidepressant medications.
In addition, folate plays a key role in reducing the harmful effects of homocysteine by transforming it back into the essential amino acid methionine. Elevated homocysteine is associated with heart disease, Parkinson’s disease and dementia. Homocysteine also interferes with brain function by damaging DNA, inducing free radical damage and causing inflammation (Moradi 2021). Studies have found higher levels of homocysteine in patients with depression, although further research is needed to fully understand the correlation (Moradi 2021).
Folate and Depression
Deficiencies in folate have been linked to depression and poor responses to antidepressant medications (Fava 1997). And it makes sense, since folate is necessary for the synthesis of serotonin. If a medication raises serotonin, but the body is struggling to produce it, the efficacy of the medication would likely be reduced. A more recent meta-analysis also suggests that low levels of folate are associated with depression (Bender 2017).
Studies using folate for treating depression, however, are somewhat mixed based on the form of folate used for treatment. Generally, benefits have somewhat favored the use of the active form of folate, methylfolate. An early study on high-dose methylfolate found improvements in depression in patients that were deficient (Godfrey 1990). Improvements appeared to increase with longer supplementation, although benefits were modest, with a 15% reduction in depression scores. In elderly patients with both depression and mild to moderate dementia, high dose methylfolate reduced depression scores 22% while improving cognitive function (Passeri 1993). A separate study of depressed elderly patients found that 81% of them responded to treatment with high-dose methylfolate.
A study on the addition of folinic acid (the natural precursor to methylfolate) in patients not responsive to standard antidepressant medication found benefits with the combination. Depression scores dropped by one-third on average over the course of eight weeks (Alpert 2002).
A study on major depression combining methylfolate with antidepressant medication found the combination twice as effective for improving depression symptoms as medication alone (Papakostas 2012). One-third of patients with methylfolate plus medication had depressive symptoms decreased by half. However, in the trial, high doses were needed for efficacy, as 7.5 mg of methylfolate had no benefits, while 15 mg was effective. Side effects were comparable to placebo, even with high doses of methylfolate. A separate trial on high-dose methylfolate found the treatment worked best in those depressed patients that were overweight, had higher levels of inflammation or higher homocysteine (Papakostas 2014). Long-term use in conjunction with medications also showed benefits, with one trial finding 38% of patients achieving complete remission with the combination after a year of treatment (Zajecka 2016).
Interestingly, a meta-analysis of all studies on folate, including studies on folic acid which were not highlighted above, found no effect of folate for treating depression (Trincado 2018). Studies with folic acid have been more mixed and likely contributed to the negative findings. However, a more recent meta-analysis found both methylfolate and folic acid to be effective for reducing depressive symptoms, although overall, the effects were quite modest (Altaf 2021). A separate analysis on just methylfolate for adjunctive treatment with antidepressants also found small, but significant benefits (Maruf 2022).
Is the Synthetic Form, Folic Acid, Toxic?
Some concerns have been raised around the toxicity of the synthetic form of folate, folic acid. Studies do consistently show that folic acid can build up in the blood stream since it is so poorly metabolized (Kelly 1997, Pfeiffer 2015). There is concern that high levels of folic acid in the blood may contribute to cancer, and high folate levels of any type are known to exacerbate vitamin B12 deficiencies which can cause nerve damage (Maruvada 2020). With the available data, it’s worth being cautious. Methylfolate and folinic acid are preferred over folic acid supplementation. In addition, when supplementing folate, vitamin B12 should always be included to mitigate any risks from a vitamin B12 deficiency.
Overall, folate appears to be helpful for depression with modest benefits. Higher doses of the active form methylfolate appear to be more effective and patients with a greater need for folate may also respond better. Data on its use without concomitant antidepressant medication is sparse. As a treatment for depression, it is worth considering folate, especially since side effects are rare and generally mild in nature. When supplementing, methylfolate or folinic acid are preferred over folic acid and vitamin B12 should be included to avoid vitamin B12 deficiency risks.