There are many people trying the methylation protocol, but with much variation in reactions to the components of it. Freddd seems able to tolerate huge amounts of methylfolate in the dozens of milligrams per day range whereas others cannot even handle 0.1mg. I am sensitive to methylfolate but am able to tolerate 0.2mg recommended by richvank. I was planning on increasing it but after 3 months I am beginning to question again whether I even need any at all and wondering if it is causing long term problems. Several years ago I had a bad experience with 200mg SAMe which may suggest a block somewhere in the methylation cycle and/or an overdriven cycle causing issues elsewhere and/or I already have too many methyl donors. Some people swear by potassium to handle effects of methylfolate, but I suspect I have the opposite reaction with potassium. There is talk of cofactors blocking healing etc but frankly I can't handle them at the doses suggested.
This year I did the 23andMe SNP testing, and I have been since been trying to understand the methylation cycle via Google and PubMed and Wikipedia and SNPedia, but according to this website (
http://www.heartfixer.com/AMRI-Outcomes-Non-CV-Autism-Methyl Cycle.htm), I have a moderate MTR upregulation (+/-) and severe MTRR downregulation (+/+): "
This combination produces a double whammy on methyl-B12. You cant make it well because MTRR is not functioning well, and any B12 that you do make gets sucked up by the overactive MTR. Here the need to supplement with B12 is greatest."
However, richvank has stated:
Note that I have specified hydroxocobalamin rather than methylcobalamin as the main supplemental form of vitamin B12. Ive done this to accommodate patients who may have downregulating polymorphisms in their COMT (catechol-O-methyltransferase) enzyme, which many CFS patients seem to have. If they do not have these polymorphisms, methylcobalamin would be more effective, but in this simplified treatment, the patients polymorphisms will not be known. I am also including a small amount of SAMe, which is also a compromise, since the amount needed will again depend on COMT polymorphisms, which will not be known for this simplified treatment. The amount of B12 specified is also a compromise, since those with certain polymorphisms will benefit from a higher dosage than will those without them. (
http://aboutmecfs.org.violet.arvixe.com/Trt/TrtGSHMethISimple.aspx)
Out of the 4 COMT SNP mentioned by Dr Yasko, I am (+/+) for 2 (rs4633 H62H + rs4680 V158M), the rs769224 P199P is (-/-) and data for rs4818 L136L is missing. Do people with these SNPs really need methylfolate? My supposed COMT downregulations indicate need for hydroxy-B12 over methyl-B12 but my supposed MTR upregulation and MTRR downregulation would indicate increased need for B12, methyl-B12 in particular. I am considering focus on B12, dropping methylfolate and just continuing the hydroxy-B12 and methyl-B12 (and maybe adenosyl-B12 later on). I still don't know for sure if folinic acid is good or bad for me, it doesn't seem to cause obvious problems. Below is my SNP data, only including the ones which had data available and were not (-/-) according to Dr Yasko:
(CBS) rs1801181 [A360A +T/-C]: AA=TT | (+/+)
(COMT) rs4633 [H62H +T/-C]: TT | (+/+)
(COMT) rs4680 [V158M +A/-G]: AA | (+/+)
(MAO A) rs6323 [R297R +T/-G ]: T | (+)
(MTHFR) rs1801131 [E429A A1298C +C/-A]: GT=CA | (+/-)
(MTHFR 03) rs2066470 [P39P +T/-C]: AG=TC | (+/-)
(MTR) rs1805087 [A919G A2756G +G/-A]: AG | (-/+)
(MTRR) rs1801394 [A919G (A66G) +G/-A]: GG | (+/+)
(VDR) rs1544410 [Bsm/Taq +A/-G]: TT=AA | (+/+)
(ACAT1-02) rs3741049 [N/A +T/-C]: AG=TC | (+/-)
(SHMT) rs1979277 [C1420T +A/-G]: AG | (+/-)
As richvank has said before, these only suggest tendencies. I tried finding information on CBS rs1801181 A360A but it seems conflicted. I have tested slightly high in homocysteine in the past but another test was normal. MAO-A (+) probably worsens COMT (+/+) status? 2 x MTHFR (+/-) may suggest reduced ability to make methylfolate, but would COMT downregulation negate this? I'm still unclear on the degree of effect that VDR Bsm/Taq (+/+) would have on the above. I still haven't looked into ACAT1 and SHMT yet. The science for all this is complex and not properly established. I haven't reached the stage where I want to spend $500 doing the tests, at least not yet.