Can a Special Form of Folic Acid Treat Depression?

Maylin Rodriguez-Paez, RN

Depression afflicts about 10% of Americans1 and it is estimated that one fourth of the US population will experience depression at some point during their lives3.

Many people find no relief whatsoever. In fact, about 30% don’t respond to conventional treatments, leaving many feeling pretty hopeless2.

If you’re one of these people, please pay close attention. Below, we’ll explain how L-methylfolate, a special type of folic acid, could help treatment-resistant cases of depression.

Hopefully, you’ll be as encouraged by this as we are.

When SSRI Drugs Don’t Work

SSRIs (selective serotonin re-uptake inhibitors) are the first line of treatment for depression, but they don’t work in up to 60% of people who take them.3

In an effort to help such patients, many traditional doctors will simply increase the dose or switch them to another class of drugs. However, based on new research, better options may be on the table sometime in the near future. Thank goodness.

L-methylfolate + SSRIs Decrease Symptoms of Depression

In a recent study, scientists gave L-methylfolate (or a placebo) in addition to a standard SSRI drug. Two randomized clinical trials were conducted with a total of 223 patients.

The participants were non-responders or partial responders to the SSRIs, meaning they didn’t respond well to the SSRI treatment.

The first trial was split into three groups:

  • The first group received 7.5 mg/day of L-methylfolate for 30 days and 15 mg for 30 days afterwards.
  • The second group received a placebo for 30 days followed by 7.5 mg for the remaining 30 days.
  • The third group received a placebo for 60 days.
Unfortunately, no significant differences between treatments were seen in the first trial.

The second trial was identical to the first, except that the L-methylfolate dosage was increased to 15 mg – two times the dose used in the first trial.

Fortunately, the results of the second trial were encouraging. Not only was the L-methylfolate well-tolerated, it was also effective in reducing symptoms.4

Twice as many people taking the 15 mg of L-methylfolate felt a response in 30 days compared to placebo, and they experienced an 84% greater reduction in depressive symptoms. Not bad at all, wouldn’t you say?

Folic Acid Supports Neurotransmitter Production

So why did these patients improve while taking 15 mg of L-methylfolate?

Well, it’s not 100% clear, but there could be a few different reasons. For one, they might have been deficient to begin with.

Research shows that people with folic acid deficiencies are more likely to be depressed.5 They also don’t respond as well to anti-depressant drugs.3 In contrast, higher intakes of folic acid are associated with a lower risk of depression.3

Next, folic acid plays a very important role in neurotransmitter production. It produces SAMe (S-adenosyl-methionine) and BH4 (tetrahydrobiopterin), which are used to generate serotonin, dopamine, norepinephrine, and epinephrine.3

These compounds are really important for a healthy mood.

Yes, The Form of Folic Acid Really Matters

Before you start taking folic acid to support your mood, make sure you take the right form. L-methylfolate is the most effective form and the one you should be seeking.

When you consume folic acid (synthetic) or folate (natural), it’s converted into L-methylfolate by an enzyme called MTHFR reductase.

This is the biologically active form and is the only form that will cross the blood-brain barrier for neurotransmitter production. It’s also highly absorbable, being seven times more absorbable than folic acid.6

Unfortunately, about 60 percent of the US population has a genetic mutation which compromises this conversion.3 This genetic mutation has actually been found to correlate with depression7 and other mental health disorders. Taking L-methylfolate may help to bypasses this problem.

The Bottom Line

So what does this information imply? Simply put, optimizing your folate intake is important, especially if you’re depressed and haven’t had success with traditional treatments.

Has a nutritional change ever made a big impact on your mood? Please tell us about it in the comments!


  1. Available at: Accessed April 22, 2013.
  2. Expert Opin Investig Drugs. 2009 Jun;18(6):767-88.
  3. Altern Med Rev. 2008 Sep;13(3):216-26.
  4. Am J Psychiatry. 2012 Dec 1;169(12):1267-74.
  5. Nutr Rev. 1997 May;55(5):145-9.
  6. Br J Pharmacol. 2004 Mar;141(5):825-30.
  7. J Nutr Health Aging. 2010 Dec;14(10):829-33.


Karen Maddening said...

i take bupropion and have no idea whether it works or not.

SmartEaters said...

A key factor you've not mentioned here is the MTHFR "mutation" or genetic polymorphisms (there are several) which are not uncommon and which can basically prevent those carrying the "defective" genes from properly breaking down folate in the diet no matter how much is ingested. These peoople can suffer depression, high homocysteine, atherosclerosis etc. just because they will always be lacking B9 no matter what they eat or how much normal folic acid they supplement. The reason that L-methylfolate works so well for some depression sufferers is that it effectively gets around this common genetic vulnerability as it is a "pre-digested" form of the vitamin so that the missing enzymes become irrelevant. So, in summary, L-methylfolate could help a percentage of depression sufferers who are either 1) genetically different as just discussed or 2) simply lacking folate in their diets. So it won't "fix" everyone but it's worth a try. Finally, for those so inclined, it is possible to get tested for MTHFR polymorphisms ...

Anonymous said...

Yes, methylfolate lifted my depression I'd had most of my life. I am MTHFR C667T +/+. So glad to have found this stuff.

Jim Logajan said...

The following claim, which is central to the whole article, provides the reader with precisely zero information while managing to appear quantitative:

"Twice as many people taking the 15 mg of L-methylfolate felt a response in 30 days compared to placebo"

How hard would it be to mention how many on the placebo felt a response in 30 days, and how many people in each group? For all I know there was 1 person out of an unknown number in the placebo group who felt a response, and that only 2 people in the L-methylfolate group felt a response. If there were around 74 people in each group then the results are not promising at all.

LifeExtension said...

SmartEaters - Actually, we did mention the mutation. We just didn't get into too many specifics. :-)

LifeExtension said...

Anonymous - Awesome! Thanks for sharing your experience!

LifeExtension said...

Jim Logajan - While we would love to mention plenty of details in our blogs, we have to keep them short and simple. Here's a link to the actual study in case you want to dig deeper:

Thanks for reading!

Jeff said...

Wow interesting and shocking stuff although I remember reading about this a few years ago. I guess it took time for these studies to be completed. Thanks for sharing LE and thanks for the info Jim.

LifeExtension said...

Jeff - It's our pleasure Jeff!

A. Patrick Jonas, MD said...

Every day, I see patients with this problem in my office as a Family Physician. Some respond to OTC L Methyl Folate (400-800 mcg) plus Methyl B 12 (1000-2500 mcg), others respond to SAMe 200-400 mg or prescription Deplin brand of LMF 15 mg, others don't respond at all, a couple even got manic on Deplin. This is a great area for further attention in multiple other conditions noted through and similar sites. Thanks for your post.

Life Extension said...

Patrick Jonas, MD- Thanks for sharing this information with us; we will look into it! :-)

Jolie Cameron said...

Its very Important to know topics like this. Thanks for the information.

Life Extension said...
This comment has been removed by the author.
Life Extension said...

Jolie Cameron - It's our pleasure!

Anonymous said...

i have the defective gene. how much optimized folate should i take daily to help with depression?

Life Extension said...

Anonymous- For optimal health, we typically suggest taking 1000 mcg daily of L-methylfolate. However, we would encourage you to discuss the appropriate dosage with your doctor! :)

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