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NMU 291 – Folic Acid Supplementation Improves Efficacy of Anti-Depression Drugs

Nutrition/Natural Medicine Update No 291 (June 6, 2023)

with Dr. James Meschino

Topic: Folic Acid Supplementation Improves Efficacy of Anti-Depression Drugs

Source:  Journal of Clinical Psychiatry (2023)


On May 9 2023 the Journal of Clinical Psychiatry published a review paper of relevant studies that tested the B-vitamin, folic acid, as an adjunctive treatment for major depressive disorder. More specifically the researchers looked at a special form of folic acid known as methylfolate, which the study showed improved the efficacy of anti-depressant drugs in patients who were previously shown to be unresponsive to the use of anti-depressant drugs alone. In other words, there is a population of patients who suffer from depression who do not respond to anti-depressant drugs, but when methylfolate supplementation is added to antidepressant drug therapy, the response rate improves significantly. We have seen studies like this over the years, but this is the first review paper that has integrated the findings of all relevant previous studies into one overall review, which also included recommendations for psychiatrists to consider. These findings are not surprising as anti-depressant drugs generally work by slowing down the breakdown of the brain neurotransmitter known as serotonin, which helps to raise brain levels of this feel-good brain chemical. But there are no drugs that increase the synthesis of serotonin. We know that folic acid is required to synthesize various neurotransmitters, including serotonin. The same is true for vitamin B12, which has been shown to help improve cognition and mood in people suffering from low vitamin B12 levels. The supplement known as 5-hydroxytryptophan (5HTP) has also been shown to raise serotonin levels and improve certain types of depression. Omega-3 fats also play a role in preventing and reversing depression to some degree by improving nerve cell fluidity and reducing brain inflammation, as two of the purported mechanisms.

But this paper only reviewed the studies using methylfolate, a special form of folic acid. The researchers commented that methylfolate is required to make a cofactor known as tetrahydrobiopterin that is required to synthesize various neurotransmitters, including serotonin. They also noted that methyfolate supplementation was particularly useful in patients with drug-resistant major depression, who were overweight and/or had high levels of inflammatory blood markers. In concert with these findings, overweight patients are known to secrete higher amounts of inflammatory chemicals, called cytokines, which are known to interfere with the synthesis of certain neurotransmitters, including serotonin. Thus, overweight patients with depression are often unresponsive or less responsive to anti-depressant drugs due to higher inflammatory chemicals (prostaglandins and cytokines) in their body, and thus, in these cases, are shown to benefit by the addition of methylfolate supplementation to their treatment plan. The researchers suggest that the addition of methylfolate supplementation to the treatment regime helps the brain overcome the adverse effects of inflammatory cytokines, enabling the brains of these individuals to resume more normalized synthesis of serotonin. This is something that drugs cannot do.

They explain to their psychiatric colleagues that the effective dosage of methylfolate in major depressive patients who are unresponsive to anti-depressant drug therapy is 15 mg per day.  The recommendation is to add methylfolate to standard anti-depressant drug treatment in cases where patients are unresponsive to anti-depressant drug treatment alone.It should be noted that a number of common vitamins and minerals are essential to the synthesis of brain neurotransmitters, such as serotonin, dopamine and other important brain chemicals. More specifically, the B-vitamins, folic acid, vitamin B12, vitamin B6, vitamin B3, and pantothenic acid, along with vitamin C and magnesium are required for the synthesis of many brain neurotransmitters, as well as enabling the brain cells to generate the energy required for normal brain function. This is one more reason why I think people should consider taking a high potency multi-vitamin and mineral each day that includes a B-50 complex as well increased antioxidant dosages, such as vitamin C and vitamin E. Regarding methylfolate supplementation, if you have suffered from depression and antidepressant medications have not been effective or provided only a partial response, then you may want to discuss with your doctor adding 15 mg/d of methylfolate as an adjunctive treatment, especially if your blood homocysteine level is high, or your blood ESR and/or your CRP blood levels are elevated (these are markers of inflammation). As a final comment, the review paper published in the Journal of Clinical Psychiatry in May 2023 underscores our growing understanding that certain natural supplements can cross the blood-brain-barrier and produce important effects on brain function and brain health and even help to slow and reverse important aspects of brain aging.

I have provided a link to the methylfolate review paper in the text below.



Maletic V et al. A review of L-methylfolate as adjunctive therapy in the treatment of major depressive disorder. J Clinical Psychiatry. May 9 2023.


B-vitamin may help boost anti-depressant efficacy. Medscape (June 2, 2023) Batya Swift Yasgur.


Eat Smart, Live Well, Look Great,
Dr. Meschino

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