Low and Methylfolate

The role of methylfolate in the treatment of patients with depression has one time again been highlighted past an article published in the American Periodical of Psychiatry in 2016.

Later successfully treating treatment resistant depression in a patient scarce in cerebrospinal fluid (CSF) tetrahydrobiopterin (necessary for biosynthesis of several neurotransmitters) with sapropterin (a synthetic form of tetrahydrobiopterin'southward active isomer), investigators searched for this and other potential metabolic abnormalities in 33 patients with treatment resistant depression.

The study found that a very high proportion of teenagers and young adults with well documented treatment resistant depression had some kind of CSF metabolite abnormality (an abnormality in some metabolite suggesting a disorder in the production of neurotransmitters) and by far the virtually common abnormality was normal serum folate and a depression 5-methyltetrahydrofolate (5-MTHF) level, suggesting a functional deficit in the active grade of folate that is involved in the production of the monoamine neurotransmitters that seem to be closely tied to low.

The researchers then treated these patients in an open label fashion and found some evidence that reversing this apparent deficiency improved depression:

Of the 12 patients with CFD, all were treated with folinic acid (ane–2 mg/kg per mean solar day) for at to the lowest degree half dozen weeks (range vi–79 weeks), while standing their pre-evaluation treatment regimen. Ten of the 12 patients showed reductions in symptom inventory scores at follow-up.

Diagnostic Testing

For people without the MTHFR gene mutation associated with reduced activity of the enzyme (see beneath) this algorithm is a reasonable approach to testing for possible folate and/or vitamin B12 deficiency.

Diagnostic Testing for B12 or folate deficiency

Folate, Folic Acrid, Methyfolate and Folinic Acrid

folate folic acid methylfolate tetrahydrofolate folinic acid

Relationship betwixt folate and 5 Methyl Tetrahydrofolic acrid (levomefolate)

Supplements and Medical Foods

Folate supplements come up in ii forms. Regular over the counter supplements and medical foods. Medical foods are reviewed and approved by the FDA which may have some advantages.

It is worth because what a medical food is, and is not, according to Upwards To Date (a well regarded review of medicine):

A medical food is formulated to be administered enterally under the supervision of a physician and is intended for the specific dietary management of a disease or status for which distinctive nutritional requirements are established by medical evaluation. Medical foods are non drugs and, therefore, are non bailiwick to any FDA regulatory requirements that specifically employ to drugs (eg, requirement for written/oral prescription prior to dispensing, premarket review or approval, proof of safety and efficacy).

Available Forms of Folate

Folic Acid

This is the form of folate that is establish in most over the counter vitamins. It is the monoglutamate form and it is non found in nature. Folate in nature is institute as diverse polyglutatmate molecules. Available show suggests that natural polyglutamates are converted to the monoglutamate course before absorption (run into the NIH Folate document beneath).

Folinic Acid

Folinic acrid is a supplement that enhances folate activity in the body. It is the grade contained in leucovorin, which is used when a patient with cancer is treated with methotrexate. It is a vitamer, like methylfolate, which is to say a molecule that substitutes for a recognized vitamin. It skips some of the steps in germination of methylfolate and thus may be somewhat more active than folic acrid, all the same information technology does not skip the MTHFR rate limiting step.

Methylfolate

Methylfolate is known by various names: Methylfolate, v-MHTF, and MTHF. And it comes in ii isomers, the "50" or "6S" isomer is the active class, and information technology is also known as Levomefolate,Fifty-5-MTHF, L-methylfolate and L-five-methyltetrahydrofolate and(viDue south)-v-methyltetrahydrofolate, and(half-dozenSouthward)-five-MTHF.

Forms of Levomefolate

Merck holds a patent on a specific type of calcium table salt of the "L" isomer (which is markets every bit Metafolin®) and licenses other companies to make that compound and distribute it in the United states of america.

Gnosis' Extrafolate-S®, it is like in likeness to Merck's Metafolin® in that it is a calcium-salt based molecule that the (6S) isomer of v-MTHF is bound to. The pregnant difference between the ingredients Extrafolate-S® and Metafolin® is the salt molecule'southward grade type. Basically the Extrafolate-S®methylfolate is an baggy salt grade and the Metafolin® methylfolate is a crystalline salt form (Type I). A crystalline salt molecule is more stable which means that Merck's chemical compound is non as likely to lose authorisation over time.

Gnosis makes another class of levomefolate, Quatrefolic®, which is the glucosamine salt of levomefolate. The disadvantage of this form is that you take to accept roughly double the dose of Quatrefolic by mg compared with the calcium salt forms because glucosamine is heavier than calcium. The reward is that the glucosamine table salt is absorbed faster. Patients report that this course may exist associated with subjective benefits more often than the calcium common salt due to faster absorption.

Finally, there are a number of over the counter forms of methylfolate which are fabricated up of a combination of the 6S and 6R isomers.

Encounter the diagram beneath for the relationship among these forms.

methylfolate comparison

Annotation that the biologically active course of methylfolate is l-methylfolate and there is at least a theoretical possible that mixtures of the two isomers of methylfolate (which is what you will observe in many online supplements, whether or not they advertise themselves every bit containing l-methylfolate – since mixtures practise incorporate l-methylfolate) might be less effective.

Other forms of folate supplements include folate itself (which is what is added to fortified wheat in this land), folinic acrid and tetrahydrofolate. There is reason to recollect that in people with C677T mutations folate may not be effective. Folinic acid is a "vitamer" – meaning a chemical compound that appears to take similar activity to the vitamin itself. It is non articulate to me that it is useful in patients with C677T mutations, since it still must exist converted to methylfolate via MTHFR. Nonetheless, note that the study described in the beginning of the commodity used folinic acid every bit the supplement.

  • Jarrow Formula Methyl Folate is an over the counter conception that has been tested past an independent research laboratory and approved. It contains Quatrefolic®, the glucosamine common salt of levomefolate (run across above).
  • Douglas Laboratories Methyl Folate is an over the counter conception also tested and approved. It contains the Merck calcium salt, Metafolin®.

Currently available medical foods are –

  • Deplin tablets 7.5 or 15: l-methylfolate 7.five mg or fifteen mg
  • L-Methylfolate Formula seven.5 or xv: l-methylfolate 7.five or 15 mg
  • Fifty-Methylfolate Forte: l-methylfolate vii.5 mg or fifteen mg
  • Generic  tablets l-methylfolate xv mg
  • Deplin capsules vii.5 or xv: 50-methylfolate 7.5 mg or fifteen mg
  • Elfolate capsules: 7.5 mg, 15 mg
  • Generic capsules: 7.5 mg or five mg
  • Enlyte: contains a mix of folate, folinic acid and l-methylfolate

Who Might Benefit?

Unfortunately the prescribed form of l – methylfolate (Deplin) can be expensive and for that reason it would be helpful to know who is likely to respond and who will not.

MTHFR and Genetic Testing

We do know that some people with depression have a gene that may predispose to folate deficiency even when they are getting an adequate dietary supply of folate because they take difficulty converting folate to the active form of the vitamin which is methylfolate.

The MTHFR gene affects the enzyme involved in breaking down the amino acid, homocysteine and converting folate and folic acid into its agile form, L-methylfolate.

Roughly 1 third of Americans acquit ane re-create of a common MTHFR gene mutation (C677T). People who acquit ii C677T mutations, which is about xi% of Americans, have a 16% higher chance of developing coronary eye illness compared to people without these mutations and have elevated levels of homocysteine in their blood (homocysteinemia) or urine (homocystinuria) (NIH Genetic and Rare Disease Data Center). MTHFR cistron mutations are likewise associated with an increased risk of other weather condition, including low, but a crusade-and-effect human relationship has non been established (Liew, Eur J Med Genet 2015; Gilbody, Am J Epidemiol 2007).

  • In theory, it makes sense to believe that for people with this gene mutation supplementation with the agile grade of folate (l-methylfolate) may be helpful. There are several methylfolate supplements that are available equally "medical foods" for the treatment of depression associated with methylfolate deficiency

People with C677T mutations  in the MTHFR cistron may exist more probable to have a deficiency in vitamin B-12 (Zittan, Am J Physiol Heart Circ Physiol 2007) as well as in encephalon methylfolate levels. Supplementation with both methylfolate and vitamin B-12 may be helpful.

For more on genetic testing please follow this link.

Overweight and Inflammation

A small written report that was presented in affiche form a year and a half ago at the United states Psychiatric Congress suggested that those people most likely to respond not only had handling resistant depression but besides were overweight (obese) and had bear witness of an ongoing depression-level inflammatory process (an elevated C-reactive protein).

The written report seems pretty well-designed and the upshot was very significant. On the right you can see a graph that shows that the response rate to methyl folate was significantly higher in those whose BMI (Body Mass Alphabetize) was loftier.

The study constitute that an elevated C-reactive protein also predicted greater likelihood of response to methylfolate.

All the same one concern that I have is that this report has not been published and usually a well-designed study with an interesting effect would observe its fashion into a periodical in less than a twelvemonth and a one-half.

Risks

Loftier dose folate supplementation carries certain risks. Prolonged intake of excessive full look acid can cause kidney damage and can likewise make it harder to diagnose vitamin B12 deficiency because full look acid supplementation can mask the symptoms of B12 deficiency. L-methylfolate may non have this adverse consequence. Also loftier folate levels in the claret in older people who also have low B12 levels may exist associated with increased cognitive impairment, whereas high folate and high B12 levels seem to protect against cognitive impairment. Fifty-fifty when B12 levels are normal, high folate levels tin can significantly increase the risk of peripheral neuropathy in older people who accept a common genetic variant in the TCN2 gene. High dose supplementation mostly is equivalent to doses above 600 µg of folate (or about 700 µg of Metafolin).

References

"Clinical Effect of Fifty-methylfolate in Patients Stratified by Baseline Obesity and Inflammation in a Randomized Clinical Trial of Patients with Major Depression." Charles Raison, Doc; Richard C. Shelton, Doc; Stephen K. Stahl, MD, PhD; et al. Presented at the US Psychiatric and Mental Health Congress. September 30, 2013.

Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal BehaviorLisa A. Pan, Petra Martin, Thomas Zimmer, Anna Maria Segreti, Sivan Kassiff, Brian West. McKain, Cynthia A. Baca, Manivel Rengasamy, Keith Hyland, Nicolette Walano, Robert Steinfeld, Marion Hughes, Steven K. Dobrowolski, Michele Pasquino, Rasim Diler, James Perel, David N. Finegold, David G. Peters, Robert K. Naviaux, David A. Brent, and Jerry Vockley. American Journal of Psychiatry2016

UptoDate. Clinical manifestations and diagnosis of vitamin B12 and folate deficiency.

Consumer Labs. Product Review B Vitamin Supplements.