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Methylfolate is one of a handful of supplements with better quality data showing it could be useful as a possible adjunct treatment for major depressive disorder in addition to standard treatment. This special form of folic acid (or vitamin B9) can be carried through the blood brain barrier and used for all sorts of goodies we need, such as neurotransmitters, DNA, and cellular detoxification.

Synthetic folic acid from supplements or its form in the food we eat has to be metabolized, but taking methylfolate will bypass any inefficiency that comes from genetics or medications that inhibit folate metabolism, so that you can ensure your brain gets the type of folate it needs. Up to 70% of folks with depressive illness have this genetic inefficiency of folate metabolism, at least in a European population (1). The brain could potentially work better with methylfolate supplements, and medicines (such as antidepressants) that need folate in the brain to work could potentially be more effective.

At least that’s the idea that researchers have looked into and supplement makers have bet quite a bit of money on…when it comes to randomized controlled trials on methylfolate and depression, we now have a collection. These studies are for adjunctive treatment, meaning added to antidepressants, often in populations resistant to depression. Acute side effects in the controlled and observed trials seem to be minimal, which is always good news (anecdotally some people report irritability**). When you sort out what data there is, a couple findings have popped up more than once:

  • Methylfolate can be helpful, but not generally doses below 15 mg
  • Methylfolate seems to be especially helpful in obese patients.

Both of these findings are a bit surprising. First off, 15 mg is a massive dose of folate. It’s over 35 times the recommended daily allowance. I asked a prominent psychiatry researcher why the makers of methylfolate supplements settled on 15 mg even before a lot of the data came in supporting the higher dose, and he told me that earlier studies of folate in humans of up to 50 mg a day seemed to be safe at least in the short term, and higher doses such 7.5 mg and 15 mg would maximize the amount that goes through the blood brain barrier. Folates are water-soluable vitamins, so it is generally thought that in the worst case, if you have too much methylfolate, you will end up with expensively supplemented urine.

But let’s not be too glib. There are three major safety concerns about high dose folate supplementation. First, as folate helps cells to divide, there’s some worry that massive doses of folate can increase risk of colon cancer, which is controversial. However, colon cancer patients treated with anti-folate chemotherapy use advanced folate metabolites such as folinic acid to keep folks from experiencing the serious effects of folate deficiency caused by the chemo. Since methylfolate is further along the metabolic pathway than folinic acid, the risks of methylfolate may be lower. 

Second, folic acid competes with methylfolate at folate receptors, so a high amount of folic acid floating around in the blood stream may *reduce* the amount of methylfolate in the brain (imagine a crowd people in yellow jackets (methylfolate) trying to get into an elevator, but you flood the hallway with people in blue jackets (folic acid) trying to get on the same elevator…you effectively reduce the ability of the yellow-jacketed folks to get a ride on the elevator). By supplementing with the “advanced” form, methylfolate rather than plain old folic acid, you bypass this problem. 

Third, both folate and B12 deficiency cause the same type of megaloblastic anemia, and folic acid supplementation can effectively “mask” this anemia by shrinking the blood cells back to normal and lead to untreated B12 deficiency. In modern times, B12 levels can be measured directly (and should be if you have a diagnosed depression) and there are other symptoms of B12 deficiency besides megaloblastic anemia, so I don’t consider this much of an issue, but if you are concerned about taking high dose methylfolate, ask your doctor to measure your B12.  

Now that we have the major safety questions out of the way, let’s go back to methylfolate used as an adjunct for treatment of depression. Methylfolate at prescription dosage comes in 7.5 mg and 15 mg forms from places like Brand Direct Health and Methylpro, and it is pricey. The 7.5 mg form failed to separate from placebo in adjunctive depression treatment, but 15 mg has worked. It’s also been shown to decrease unhealthy metabolic markers and improve depression in folks who are for reasons of genetics less efficient in making methylfolate from folic acid.

Also, 15 mg of methylfolate seems to help folks with resistant depression who are also obese. Follow up studies show reductions in inflammatory metabolic markers, which suggests the methylfolate is doing what folates are supposed to do, help cell machinery clean up after the messy cellular engines do their thing making energy for the cells.

Finally, a very important issue is raised by the success of methylfolate for adjunctive treatment of depression and the tests for inefficient MTHFR alleles. Genetic testing (usually including MTHFR c677t and sometimes MTHFR a1298c, along with what sorts of liver enzymes you have to metabolize psychiatric meds and measures of what type of serotonin reuptake transporter promoters you have) is now available and marketed to psychiatrists to ostensibly help them design personalized medication treatment plans for patients. This genetic testing is now paid for by medicare and the VA, but I’ve seen skeptics and fellow psychiatrists call all genetic testing “quackery” at the worst or “not yet ready for prime time” to show gentle displeasure at the marketing and enthusiasm that has come with these tests. Personally, I have found the tests useful in certain situations (usually resistant depression or repeated weird side effects) with careful acknowledgement of the caveats and unknowns.

MTHFR c667t is just one gene in a long circle of interdependent genes that are translated into the enzymes that are part of the folate cycle, which we saw in the last post. It may be the most important and the most studied gene, but a lot of other stuff has to be working efficiently** for us to make methylfolate. Second, some of the interactions of psychiatric medications and the genetic findings (particularly of the serotonin reuptake transporter promotor region gene) seem to be applicable only to certain ethnic groups, and more studies need to be done to see if it can be generalized to everyone. Thirdly, just because you metabolize a medication poorly doesn’t mean it won’t work, you just have to be careful about the dosing, and the reverse is also true. Giving folks lists of medicines they metabolize normally or poorly may cause some people to cross some meds off the list that may well be inexpensive and effective.

With those caveats (ie the genetic testing is *not* a rosetta stone but rather a somewhat limited tool), I’ve found it to be extremely helpful in the following instances: people with rarer and unusually poor metabolism of medications and homozygous MTHFR c677t (meaning the person has very inefficient processing of folic acid into methylfolate). We’ll have to wait for more data and understanding of the genetic interactions before these tests become solidly mainstream…genetics tells us some things, and at this point we don’t know how all the combinations of all the alleles interact in the vastly complicated folate cycle, leading folks like Walsh to lean more towards measuring metabolites than using genetics to see how metabolism is actually working.**


*For the purposes of this article, “folic acid” is the common supplement in multivitamins and added to grains in many countries. “Folinic acid” and “methylfolate” are also specific forms of folate that are metabolites of folic acid. “Folate” refers in general to folic acid and its various metabolites.

**I know some of you have read Walsh and/or Yasko who take a much bigger view of folate, the folate cycle, and genetics, particularly since Walsh warns against high dose methylfolate for certain conditions. That’s an upcoming blog post, and I do want to say upfront that Walsh and Yasko are not mainstream, and the complexity of the system, the genetics, and the number of supplements they recommend have not been systematically studied in straight-up head to head supplement vs. placebo as methylfolate has. I do get a lot of questions about Walsh/Yasko so I will give you my opinions in the next blog post.

Thank you Dr. Mischoulon who was so kind in answering my question about folate research dosing history and safety.

Normally I link far more papers in the text, but I thought I would switch gears today and link papers by group for clinicians who want to chase down folate for themselves if interested. The abstracts also show the progression of thought about methylfolate. Many but not all of these papers were used as references for this article.

Early methylfolate papers of interest (typically used in folks with folate deficiency):

General discussion of folate and depression as of 2008-9 (including addressing history of folates and their use in depression as well as safety issues…free full text once you sign up at JCP site)

Later trials of methylfolate as adjunctive treatment for depression:

retrospective analysis: (free full text)

big trial showing 15 mg more effective than 7.5 mg from the Green Journal:

New trials following inflammatory markers and showing more efficacy in obese patients: (both free full text available from JCP site)

Longer 1 year follow up with 15 mg methylfolate (also free at JCP)

Lancet Psychiatry editorial on pharmacogenetic testing 

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Copyright Emily Deans MD

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