Saturday, August 27, 2011

Folate! The Beginning.

Did I ever mention that I'm not a big fan of the folate cycle?  Not because it's not important, but because it is intensive, poorly understood, and hard to remember.  Probably a bad reason to dislike it, as far as those things go…

Let's just start with a diagram, and an explanation for those of us who were taught some basic organic chemistry.  Folate does not equal folic acid.  I know.  It's weird.  For all the other acids, -ate equals -ic acid (such as phytate and phytic acid), but for whatever reason, folate = dihydrofolate, and folic acid equals synthetic folate that is used to fortify foods in the US and in multivitamins.  Let me supply you with a handy diagram:

Please click on the diagram to make it bigger!
The blue formulations are those that can be had by prescription or supplement.  The yellow are the natural forms.  Folic acid is put into grains and multivitamins.  Folinic acid is used in chemotherapy.  5-MTHF (methyltertrahydrofolate, or the active enantiomer l-methylfolate) is a "medical food" pharmaceutical grade folate one can get by prescription.

Now why would a psychiatrist care about this pathway?  Well, folks with depression have increased risk of having crappy dihydrofolate reductase activity (meaning they have a hard time turning synthetic folic acid into dihydrofolate - this enzyme is also inhibited by the medication lamotrigine).  In addition, folks with depression are more likely to have issues with the MTHFR enzyme (I know - it stands for methylenetetrahydrofolate reductase but that's not what I call it in my head either).  So if you prescribe medications meant to maximize the efficiency of neurotransmitter* transmission in order to treat depression or anxiety, or if you just want nature to maximize the efficiency of neurotransmitter transmission (which everyone would agree is preferable, if possible), you want plentiful tetrahydrobiopterin in the brain.

You can see from the diagram that cheap, plentiful folic acid may not aways become the final active product in the brain.  You can also see that expensive, prescription 5-MTHF (deplin) might be useful for some people, though you may be annoyed if you know that deplin has never been tested head to head against folic acid.

5-MTHF and folinic acid have had some decent studies increasing response rates to antidepressant therapies, and decreasing cognitive symptoms of depression.  The results for folic acid supplementation itself have been mixed.  And, given some genetic polymorphisms (such as C677T, affecting the MTHFR gene), a peripheral folate level (which I have drawn routinely) will not necessarily tell us about folate levels in the brain.

But why not just pour tons of folic acid into the system - well folic acid has some risks.  For one, it has been shown to mask some of the first symptoms of B12 deficiency (which I have seen - none of my patients with low B12 have had the classic hemotologic signs that doctors have long relied upon to help diagnose B12 deficiency - possibly because folic acid supplementation is now abundant in the food system).  In addition, folate is a growth factor, and one has to be careful about pouring growth factors into the system, lest one risk cancer - the risk of colorectal cancer being the most studied and the most likely (1) caused by widespread folic acid supplementation. (The results of the epidemiological studies are mixed however, with this large US study showing no correlation).

Now, if you take a ton of folic acid (more than 800 mcg daily - 800 mcg being the normal dose in prenatal vitamins), it has been shown that the excess folic acid won't be metabolized, and that excess folic acid in the serum actually reduces the amount of l-methylfolate that reaches the brain, with a potential increase in depression.   Supplementation with l-methylfolate will not mask B12 deficiency and is less likely to be a risk for colon cancer (since the upstream agent, folinic acid, is used to kill cancer).  But… the cost.  A thirty day supply of deplin can cost as much as $80 at the pharmacy, and the cheapest I have found it is $70 for a 3 month supply direct from the manufacturer.  As a "medical food" it is not covered by insurance.  And yes, in my clinical experience, I have some patients who have not responded to folic acid supplementation who have done very well on deplin.

Folate, real, natural happy dihydrofolate from food is most plentiful in leafy green vegetables, fruits, and (ahem) legumes.  Cereals and grains are fortified with synthetic folic acid.

Hopefully this article will clarify some things… or maybe we will consume  few more leafy green veggies and fruit along the way...

*serotonin, dopamine, and norepinephrine are neurotransmitters

Fava, M and Mischoulon, D. Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues.  J Clin Psychiatry 2009;70[suppl 5]:12-17

Frankenburg, FR, Folate supplementation: is it safe and effective? (letter) J Clin Psychiatry.  2008;69(9):1352-1353

35 comments:

  1. Nice blog....I may use it to eventually talk about SCD of the posterior cord.

    ReplyDelete
  2. Thx Emily, interesting!

    Emma wrote some nice posts on folate too:

    http://autoimmunethyroid.wordpress.com/2009/11/28/those-test-results/

    http://autoimmunethyroid.wordpress.com/2007/08/29/the-folate-trials/

    ReplyDelete
  3. thanks! and in the diagram it is tetrahydrofolate but I can't fix it right now...

    ReplyDelete
    Replies
    1. Emily,
      This is interesting to me. I have anxiety and mild case of ocd (more obsessive) and doc suggested that i get on folic acid in addition to two ssri's i am currently taking and have been for years. I have only been on 1 mg for a few days and my mood has gotten more sad, and i am feeling worse. Could it be a possibility that folic acid is causing this problem? I dont know if its the folic acid or my imagination.

      Delete
  4. http://www.iherb.com/Solgar-Folate-Metafolin-Folic-Acid-800-mcg-100-Tablets/13961
    Solgar, Folate Metafolin Folic Acid, 800 mcg, 100 Tablets
    $12.40

    Since deplin is 7.5 mg/dose, one would have to take 9 to 10 doses of the Solar to equal 1 dose of deplin.

    ReplyDelete
    Replies
    1. The most recent studies show that 7.5 does not get the desired effect. 15 mg is required.

      Delete
  5. Emily, my patients get their Deplin 15mg from Brand Direct Health for $48 for #30 if they buy 90 at a time. Is the $70 for #90 for the 7.5mg dose (half of 15mg tab)? Many of my patients do better on the 15 mg qam. Also, my rep suggested supplementary folic acid be limited to 400mcg to avoid blockade of the BBB recptors. Also, for your chart: Deplin is not racemic 5-MTHF, but just the l-, no?

    ReplyDelete
  6. Psych - my patient was just able to get 45 15mg tablets (for 90 day supply of 7.5mg) for $79 from Brand Direct Health last week. And I also thought deplin was plain old l-methylfolate - but Fava and Mischoulon seemed so very sure, and they are hot tickets. Unfortunately they use methylfolate, l-methylfolate, 5-MTHF, and MTHF interchangeably in the paper - and here is what they say about deplin: "The most active form of folate, 5-MTHF, has recently been approved in the United States as a prescription medical food for depressed patients with folate deficiency. Doses are usually 7.5 to 15mg daily.

    ReplyDelete
  7. Um, so does one significantly up spinach and kale consumption to counteract the effect of 300mg of lamotrigine? Or call the pdoc and ask for a blood draw and possibly a prescription for the deplin?

    ReplyDelete
  8. In psychiatry we measure folate directly, but I've also seen papers (Klee GG. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate. Clin Chem. 2000;46:1277-1283.) that suggest we measure homocysteine also. I find lamotrigine works well for a year or two and then putters out for mood benefit - if the diet is crappy, I will supplement (though most of my patients will not pay for deplin) - I've convinced some to get methylfolate elsewhere. Problem with measuring homocysteine too is that it may be elevated for several reasons, not just folate deficiency.

    ReplyDelete
  9. the deplin site, says l-methylfolate: http://www.deplin.com/DeplinFacts,VsFolicAcid

    ReplyDelete
  10. Very interesting. How do I go about finding a Psych in Illinois who will presribe vitamins? Don't really think my body needs more drugs... I over-react to anti-depressants.

    ReplyDelete
  11. As a food rich in folate, what of liver? Surely we mustn't forget liver.

    ReplyDelete
  12. Emily, which lab tests do you recommend to your patients? Thanks.

    ReplyDelete
  13. I wonder if the masking affects of folic acid is what allows some vegans to get by on B12 deficit for a while?

    ReplyDelete
  14. Good point, strake. A quick look at nutritiondata.com suggests that liver has 50% more folate than spinach, by weight. And it's rich in B12 too!

    ReplyDelete
  15. Wow. I didn't know folate and folic acid are not the same. As always, whole foods are the way to go.

    I wrote in my blog about beans, the most consumed food here in Brazil (actually, rice and beans). With a recipe of brazilian beans included, I looove it :-)

    http://tinkeringwithnutrition.blogspot.com/2011/08/lovely-beans-wonderful-beans-recipe.html

    ReplyDelete
  16. Emily, you may interested in reading this blog post at the SCM Blog. After reading the post, I was wishing I could find a multi that did not contain Folic Acid.

    http://www.sciencebasedmedicine.org/index.php/the-benefits-and-risks-of-folic-acid-supplementation/

    Here is an excerp:

    Could a vitamin with proven benefits in one group cause harm to another? That’s the growing concern with folic acid, the vitamin that dramatically reduces the risk of neural tube birth defects such a spina bifida. Studies designed to explore the possible benefits of folic acid for heart disease, stroke and cancer are giving out some worrying signs: At best, folic acid is ineffective, and at worst it may be increasing the risks of some cancers. So what does this say about routine supplementation for the typical healthy individual, and its overall risk and benefit?

    ReplyDelete
  17. I read two articles about the importance of micronutrients:

    http://www.lef.org/magazine/mag2011/aug2011_Interview-with-Dr-Bruce-Ames_01.htm

    http://www.sciencedaily.com/releases/2011/05/110531115323.htm

    From the second:
    Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. "As this report shows, taking a multivitamin that contains selenium is a good way to prevent deficiencies that, over time, can cause harm in ways that we are just beginning to understand."

    After reading this post I am not sure about multivitamins, also most do not have good quality mineral salts or all the variants of a vitamin e.g. only alpha tocopherol.

    Anyway, I frequently take a multi, especially for the Bs. Not sure if I am doing right.

    ReplyDelete
  18. Facinating post. From 23andme I found I am heterogeneous for C677T, giving me a 65%~ of normal ability to make the MTHFR enzyme. As someone who has nearly always suffered from (mild but persistent) depression (even on a paleo diet), I am wondering if this could be a key piece of the puzzle. I'm having my homocysteine levels tested soon and will also consider supplementing.

    ReplyDelete
  19. This comment has been removed by the author.

    ReplyDelete
  20. This comment has been removed by the author.

    ReplyDelete
  21. Dr. Deans wrote: "So if you prescribe medications meant to maximize the efficiency of neurotransmitter* transmission...."

    Now that "chemical imbalance" is an embarrassment, is this the current rationalization for psychiatric drugs? Maximizing efficiency of transmission? Is there any evidence for this? Thought not.

    I read the 5-MTHF findings of M. Fava etc. differently: That people with low B-12 or folate status are being diagnosed with psychiatric disorders and treated with drugs that do not address the nutritional problem. The nutritional deficiency worsens while inappropriate therapy is pursued (overall health risks also increase because of the medication).

    These people naturally perk up when an appropriate nutritional supplement is added.

    M. Fava etc. should be writing an apologia to the millions misdiagnosed and treated psychiatrically for physiological conditions. Instead, he's published infomercials for Deplin as an "add-on" to vastly profitable psychiatric drugs.

    M. Fava was hired by Deplin's manufacturer (see Completed Trials http://www.pamlabrd.com/clinical-trials ) to produce papers touting this brand-name 5-MTHF.

    There is nothing special about the 5-MTHF in Deplin. 5-MTHF supplements have long been available at lower cost from other manufacturers to treat those with the MTHFR genetic variation affecting folate metabolism. (I am one of those people, and I was misdiagnosed and treated with Paxil, which effectively has destroyed my life.)

    By calling Deplin a "medical food" available by prescription, it can be reimbursed by health insurance and Medicare. This is enormously profitable to Pamlab, Deplin's manufacturer. Brand-name 5-MTHF Deplin is a health insurance scam.

    I am very disappointed in you, Dr. Deans.

    ReplyDelete
    Replies
    1. I'm in complete agreement. Pamlab has much to gain with Deplin as a "medicianl food". Education regarding this supplement is crucial.

      Delete
    2. I have BXBS and it's a good policy, but it is not covered by my insurance...sad. It has improved my depression significantly. I suffered from depression for 15 years with no real relief until starting the Deplin 8 mounths ago...what a life saver. It would have been great if I had had a Dr. who knew about it sooner.

      Delete
    3. Hi Emily. Do u know if the MTHFR enzyme is really involved in the BH4 cycle??

      Delete
  22. I never understood Deplin. My son needed tons of 5-mthfr and we used a well regarded, monitored supplement company. They produced a product not laced with fillers and additives. $30/mo for his very high dose.

    ReplyDelete
    Replies
    1. cath I need the name of that company that has the supplement without the fillers , and do you know if it is for MTHFR people who can not break down the folic acid on their own and if the product is already broken down like Deplin is , I am alergic to some of the ingredients they use as fillers and need a quick alternative ty

      Delete
  23. Cath,
    I, too, need the name of the supplement company you mentioned.
    TY

    ReplyDelete
  24. Hi! Great blog and article. I have a question though: why does folic acid makes me depressed? I have diagnosed major depression + anxiety (although mixed biploar was suspected in the past)and doing somewhat better on effexor+neurontin. I've read of the usefullness of folate in depression but each time I try taking it I get severely depressed. This is the case regardless of dose and brand, and even multivitamins with folic acid have this effect. It was the same when I tried folic acid before being put on meds, so interactions aren't the problem either. Any thoughts?

    ReplyDelete
    Replies
    1. Two possible reasons:

      a) folic acid can (besides masking the blood signs of B12 deficiency) also worsen B12 deficiency symptoms
      b) as mentioned in this article, folic acid may actually reduce the efficacy of methylfolate.

      So you should likely be taking a methylfolate supplement together with an active form of B12 (methylcobalamin).

      Delete
  25. This comment has been removed by the author.

    ReplyDelete
  26. I have to comment about the insurance aspect of taking deplin. I took deplin in 2011 and 2012 and insurace DID cover it. Additionally, there is a generic version of the prescription as well. Deplin is $80, l-methylfolate calcium is $10. My insurance covered both forms.

    ReplyDelete
  27. Brand or website source for something comparable to Deplin 15? Taking 19 800 mcg little pills seems cumbersome plus you seem to need to spread them out throughout the day. Thanks.

    ReplyDelete
  28. These guys claim this is very similar to Deplin 15 and it is less than a dollar a pill. Anyone else know anything about the company or their claims? http://www.methyl-life.com/methylfolate-15.html#

    ReplyDelete