(added 5/2015; updated 7/2016)


  • Begin, if needed, with a basic version of the MTHFR enzyme story.
  • If you need the chemistry diagram that shows where the problem enzymatic step is, one is copied here from Wikipedia (which is otherwise too technical).
  • Folate supplementation alone doesn’t help treat depression; it might help prevent them.
  • Fancy folate (“methylfolate”, more expensive) was better than placebo in one fairly small trial, which followed an earlier larger trial in which it was not better than a placebo. Both studies were sponsored by PamLab, makers of the expensive stuff. Such studies should be regarded with suspicion.
  • Why use fancy folate? because it gets around a cellular chemistry step that 15% of the people can’t do  very well, and about 30% of people do less well than the rest.
  • My conclusions: I’m still suspicious that this is a fad, even though it’s got a good chemistry explanation to back it up. But good explanations are not the same as randomized trials showing a treatment actually works.  There are two of those trials:  the large one said no, the smaller one with the bigger dose said yes, and both were sponsored by the manufacturer. So I’m going to wait. Fish oil has much, much better evidence for antidepressant effects and a similar-quality chemical explanation.
  • Meanwhile (Update 1/2016), it appears that if you’re taking lamotrigine, you shouldn’t take folic acid supplementation.

A basic version of the MTHFR enzyme story

It just takes one chemical step to turn folate from your diet into methylfolate (methylation, get it?) Nearly all the cells in your body need to be able to do this, because methylfolate is involved in DNA synthesis, as well as making other useful things like serotonin and norepinephrine (“neurotransmitters”).

The cellular enzyme that converts folate to methlfolate is MTHFR. You can make up your own pronunciation (careful). That’s short for methyltetrahydrofolate reductase. Okay, call it MTHFR, right?

Problem: some people have a version of the enzyme that doesn’t work so well. The gene that codes the MTHFR protein has several versions. Some versions are better than others for making methylfolate — but don’t oversimplify and assume that these variations are “bad”. In regions with plenty of dietary folate, it looks like the less-efficent MTHFR protein might be an advantage somehow: around the world, there are huge variations in the frequency of the gene for the less-efficient protein . Gueant-Rodriguez, Leclerc

The MTHFR gene has two different regions that affect the effectiveness of the enzyme. You don’t need to know these names but you may see them around the internet: C677T is the most studied variation. There’s also A1298T.  (Yes, you can get your genes tested but I’m not sure that’s a great idea just yet. It may not hurt you, if you’re careful with your research and conclusions, but it will cost you over $100 and I’m not sure it will lead you to a treatment you might not have just tried anyway. That’s a longer story.)

Remember that you get one version of the gene from one parent, and one from the other parent.  If you get the C677C version from one parent, the efficient one, and the C677T version from the other parent, the not-very-efficient one, you are a “heterozygote” for that particular gene.  The more efficient enzyme makes up pretty well for the less efficient one, so you might not be very affected by all this.

But if you get the C677T version of the gene from both parents, you are “homozygous” for the less efficient enzyme and you will not make methylfolate as well as everyone else. Does this matter? Well if you listen to people who want to sell you methylfolate, you will certainly think so.  They’ll tell you all about  a condition with a name that might be one of the longest names you’ve every encountered (translation follows): “hyperhomocysteinemia” .

Translation (this will take a minute): cysteine is an amino acid, a standard part of protein, you eat it every day. Your body converts some of it to homocysteine, a closely related compound. Too much homocysteine in your blood (“hyper… homocysteine…emia”) has been connected to a bunch of illnesses. But it is not yet clear that lowering high levels of homocysteine by taking methylfolate lowers the risk of these problems. That’s a leap. It might be true. But that’s not certain yet, at least for the problem we’re looking at here, namely depression.

Hyperhomocysteinemia is just one problem that has been associated with the less-efficent versions of the MTHFR enzyme.  Another is depression. More on that below.  First, I have to stick in a chemistry map for medical students for use when this topic comes up. If you stare at it long enough it make some sense to you too. For the large version go to Wikipedia’s page:

Does folate help antidepressants work better?

First let’s look at folate alone, then the fancy methylfolate in the next section below.  Folate:  A PUB MED (National Library of Medicine) search on folate depression randomized trials comes up with a large review.  The authors conclude ( italics mine; followed by my translation): “The number of available trials remains small and heterogeneity between studies high. The results of these meta-analyses suggest that treatment with folic acid supplements and vitamin B12 does not decrease the severity of depressive symptoms over a short period of time, but may be helpful in the long-term management of special populations.


  1. There have only been  a few trials in which folic acid supplementation was compared to placebo in the treatment of depression. Some found a benefit, some did not (“heterogeneity”).
  2. Such supplementation was not better than placebo, overall.
  3. But for prevention, especially in “special populations” (which I presume means pregnant women or people with low folate), it may have value.

But wait a minute. That’s “folic acid”, a pill version of folate.  There’s also “folate”, also known as Vitamin B9, found in many vegetables, but not studied as a mood treatment.  Third, there’s a different pill supplement called methyl-folate.  See the Basic Story above if you’re not familiar with the difference in folate supplements and why that difference may matter.

How about methyl-folate?

One company has made a lot of money selling methylfolate after convincing people, especially psychiatrists, that it makes antidepressants work when they’re not working (or work better). Is that true?

Back to PUB MED, this time searching methylfolate depression randomized trial.

Two studies were reported together. Papakostas  Methylfolate was not better than placebo when the dose was 7.5 mg, later raised to 15 mg. So in the second go-around, they used 15 mg from the start in a smaller group, and that time, methylfolate beat placebo. Both studies were supported by PamLab, makers of Deplin. I’m still waiting for a study by someone not associated with PamLab (because studies sponsored by manufacturers turn out “positive”, supporting the drug, more often than studies not sponsored.Cochrane)

Meanwhile, a new paper by the same PamLab-supported group is a “post hoc analysis”. This means you go back to see if any of your data are significant. But you’re not following your original hypothesis (in this case, that methylfolate is better than placebo as a booster for antidepressant treatment of depression). You’re looking for anything that was significant. This is acceptable as a means of generating new hypotheses but is not generally accepted as reliable evidence.  (It’s like the difference between predicting that you’ll find buried treasure under a particular tree, versus digging all over a couple of acres and finding a doubloon. It could mean there’s treasure somewhere all right, and it might tell you where to look next time, but it doesn’t mean the chest you originally sought is really there).

My conclusions

I’m still suspicious that this is a fad, even though it’s got a good chemistry explanation to back it up. But good explanations are not the same as randomized trials showing it actually works.  I found two of those:  the large one said no, the smaller one with the bigger dose said yes, and both were sponsored by the manufacturer. So I’m going to wait. Fish oil has much, much better evidence for antidepressant effects and a similar-quality chemical explanation.

Cost is the other issue: to get to the Deplin-study dose (15 mg, because 7.5 didn’t work) you’d spend an incredible amount of money buying L-methylfolate over the internet (watch the mg dosages carefully).

Update 1/2016: don’t take folate with lamotrigine?

A new study was just published showing that lamotrigine is indeed an effective treatment for bipolar depression.  That was not news.  But what is news is this:  patients who were taking folic acid supplementation did not improve on lamotrigine. Patients not taking folic acid supplementation who were give lamotrigine had a very substantial improvement. Bottom line, then: if you’re taking lamotrigine, probably better not take a folate pill, at least for now, until this possible problem is better understood. Maybe don’t even use bread that’s been made with enriched flour (as it routinely is in the U.S.), but that’s just a (very possibly unnecessary) precaution while we learn more.

For the details, see a summary of that study.