This material is taken directly from Dr. Amy’s upcoming free online book about what to do with test results:
There are two key reasons to support with low doses of both folate and folic acid, in addition to the use of specific types of folate, such as 5 methyl THF, that help to bypass mutations like MTHFR C677T. First, since 1959 it has been known that “folic acid deficiency results in inability to degrade formiminoglutamic acid (FIGLU) to glutamic acid, so that FIGLU accumulates in excessive amounts and is excreted in the urine”.(Luhby, Am J Clin Nutr). FILGU levels are measured on the MAP test, and high levels suggest a need to use low dose folate and/or folic acid support.
The second reason to use low dose folic acid and/or folate is the pathway that involves MTHFS. A low dose form of plain folate or folic acid is supplemented in part to address possible MTHFS mutations, especially since they are not generally identified on most nutrigenomic tests. MTHFS is another enzyme in the methylation pathway. It functions at 11:00 in the folate cycle, between 5 formyl THF (folinic acid) on the way to produce tetrahydrofolate at 12:00. MTHFS functions to address SHMT and the formation of the purines guanine and adenine for DNA and RNA.
If there is a mutation that impacts the ability of MTHFS to function, it can increase folinic acid to high levels and limit the synthesis of purines, as well as decrease the THF level. In this program, my policy is to use only low dose folinic acid, to add nucleotides to support DNA and RNA production, and to use low dose folic acid along with probiotics as a secondary way to make THF. In this way, I bypass the impact of any possible MTHFS mutation, even if I do not have nutrigenomic data regarding this gene.
This again highlights why I want to think about all aspects of the pathway when adding support. I choose to add only low dose folinic acid to help keep SHMT in balance without allowing the levels of folinic to climb, which might happen if you are adding high dose folinic and have a MTHFS mutation. I add nucleotides to supply purines and pyrimidines in case the pathway for their formation is not fully functional. I add low dose folic acid to have a secondary route for making THF that consumes excess glutamate in doing this.
The rationale behind also adding low dose 5 methyl THF is that the way to bypass an MTHFR C677T mutation is with 5 methyl THF. If you look at the biochemical diagrams you can see this. No amount of folinic acid, folate, or folic acid is going to bypass a MTHFR C677T mutation. So, the whole conversation about folic acid or folate is actually misplaced, as the real issue is 5 methyl THF.
There is some sort of misconception out there that folate will bypass MTHFR. To be clear, 5 methyl THF is the only way to bypass MTHFR C677T. I have it in low dose form in both All in One as well as MethylMate B. If you are C677T ++, using high dose 5 methyl THF can trigger more detox than you can handle, especially if you are an adult. This is why All in One uses only low dose 5 methyl THF, and my stand alone source of 5 methyl THF, MethylMate B, is a liquid, so you have exquisite control over increasing or decreasing its dose.
MOST of the folate that is used for this program is 5 methyl THF, with some low dosefolinic acid. Folinic is useful for those who are SHMT + or have iron levels that may increase SHMT activity. Some low dose folic acid and/or folate is helpful for other aspects of the pathway, and that is why some very, very low dose folic acid is included in the formulation.
To summarize, I do feel that some low dose folinic acid is needed to help to control SHMT, which is why All in One also has some low dose folinic. I do not like high dose folinic acid as those with MTHFS mutations can have a problem with it. Finally, for adequate processing of FIGLU, I want some low dose folate and/or folic acid in the system. Because the various forms of folate compete with each other for transport into your cells, the ratio in the All in One is mostly 5 methylTHF, with a lesser amount of folinic acid, and finally the least amount of folic acid.
Now I am going to be very specific with regard to why I use low dose folic acid rather than folate. Folate is basically a chain of glutamates. The difference between folic acid and folate is the stability and the length of their glutamate chains. So, if you are MTHFR C677T++ and you take high dose folate, you potentially have a chain of unused glutamate molecules left in your system. You cannot process it efficiently to 5 methyl THF because of your SNPs. You run the risk of folate breaking down to release glutamate into your system. STEP 1 of this program is focused on glutamate/GABA balance. I have made significant progress for some individuals merely by getting their glutamate and GABA into balance. Thus, I am not choosing to add high doses of a form of folate that could break down into glutamate, especially in the population I work with.
One of the main differences between folic acid and folate is that folic acid has a shorter glutamate chain than folate. Folic acid is also more stable, so it is less likely to break down into glutamate. I am using only a tiny bit of folic acid, to allow FIGLU to convert to glutamic acid. I am not using high dose folic acid, as that is not going to bypass MTHFR in any event. I understand there are other programs out there that use higher doses of plain folate. Perhaps those programs are less concerned with the glutamate issue.
I have specific reasons for the choices I make in terms of supplements and the forms that I use. Natural folate has more glutamate residues and can break down more easily to release those glutamate molecules into your system, so I prefer to use a VERY low dose of folic acid. There are only approximately 15 micrograms of folic acid in All in One and about 25 micrograms in Ultimate B. This program uses some very, very low dose folic acid for the reactions that need it, but the focus is more heavily on the use of 5 methyl THF and low dose folinic acid.
The use of LOW dose folic acid is a choice, to limit the risk of increased glutamate in your system. The RDA for folate/folic acid is 300 micrograms for a child that is 1 year old, up to 1,000 micrograms daily for an individual 19 years of age or older. Thus the 15 to 40 micrograms used for this program is not an issue, especially since the body does need some folate/folic acid aside from the need for 5 methyl THF and folinic. To put this in an easily understandable perspective, a bowl of cheerios has 400 micrograms of folic acid, as compared to the 15 to 40 micrograms used in this program.
In addition to making rational choices in terms of folic acid versus folate, and only using low dose folinic out of consideration for possible MTHFS mutations, I am already taking into account the need to balance the production of purines, thymidine levels, controlling SHMT, and producing methionine from homocysteine with the supplementation I have in place for the methylation cycle.
To reiterate the approach: (1) get the BHMT pathway moving with PS/PE/PC plus DHA, SAMe if tolerated, All in One, Ultimate B, and low dose methylation RNA; (2) add some low dose lithium support with BeCalm, and run a HMT to be sure you have checked lithium to see if you need low dose lithium orotate. If aggression is an issue, pay close attention to potassium and rubidium on your HMT. If your lithium is very low, run a HMT every 3 to 4 months to keep an eye on levels; (3) once lithium is in balance, you can add extra B12; (4) add methylmate A and B to be sure you have the methylation cycle fully supported; (5) if you have SHMT + status or high iron on HMT and UEE, use SHMT support along with step 1 and 2 above; (6) be sure you have probiotics in place, focusing on Lactobacillus and Bifidobacter; (7) run a HMT to check lithium every few months once you have extra B12 in place.
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Nancy Mullan MD
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Dr. Nancy Mullan is best known for her natural treatment of chronic illness, including Autism Spectrum Disorders, Lyme and MTHFR+.
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