After a false start over a year ago, I've decided to try start taking methylation supplements again. I've read a lot of the Fredd v. Rich protocol debates and learned a lot, mostly that we are all different. Neither approach seemed exactly right for me, and I am thinking of taking a combination of mb12 and hb12 along with methylfolate. Instinctively, a higher dose b12 approach makes sense. My experience broadly is that I am chronically deficient in many nutrients, and it goes beyond GI absorption. For example, I was taking magnesium injections almost daily at one point in time, and still had low normal serum levels and improved but still low RBC levels. I wonder if for reasons of low ATP or another reason we are all just bad at active transport. It would not surprise me if for the same reason that fairly high levels of magnesium keep me only just magnesium replete, I might also need high levels of b12, in particular for uptake by my nervous system. (I imagine any transport across the blood brain barrier is "active.') I've also never had the hypersensitivity to medication many PwMEs have and am doing just fine on 5000 mcg b12, 1200 mcg m folate (divided doses) to start. That said I have had many experiences in the past that suggest I may not be a dead ringer for a high dose mb12 approach: 1) No clinical improvement on moderate dose methyl b12 When I first became ill, I had a low serum b-12 level of around 250. I took sublingual methylb12 supplements (probably 5000 mcg/day) to bring my levels up (I don't recall what dose but probably whatever was on the bottle). By about 18 months later, my serum levels were retested and they were somewhere in the 1200-1800 range. My MMA was way down (below normal and, at least a year ago, I had high normal methionine) as was my homocysteine. I thought "problem solved!" and stopped taking them because I did not want to go too high (this was before I knew anything about B-12). Even with normal blood levels, I did not have any noticeable clinical improvement that I could say for sure was the B-12. 2) Good response to injectable cyanocobalamin A few months later I was doing quite badly (not directly related to stopping the B12 - I crashed when traveling to the other coast). My mother was visiting and had injections for cyanocobalamin (apparently, and I did not find this out until even a year after that, she had a period of time in her 40s when she had trouble even walking up a flight of stairs and diagnosed herself with early stage pernicious anemia...I've recently found that I have anti-parietal cell antibodies) . She has been taking this form of B12 ever since. Anyway, she had me try one of her injections and I had I felt AMAZING. I went from being virtually bedridden to being able to do strenuous garden work for several hours of the time. Not normal, but a huge increase in my quality of life. Unfortunately, either the effects only lasted for a few weeks or I ran out – I can't quite remember. (This is before I knew anything about methylfolate or cofactors). I got a prescription for methyl b12 injections and started taking them (I don't recall the dose) every three days. I never noticed any improvement. In fact, I had regressed. 3) Short lived response to methylfolate A few weeks laster, I started taking methylfolate and was back in the garden again. However, this time the effect only lasted a few days. (Again, I had no sense of cofactors) 4) Null (possible poor) response to injectable methylcobalamin Several months later I was in bed 24-7. There were a number of reasons for this, but my POTS was out of control. Someone suggested I was perhaps overmethylating and suggested I take hydroxocobalamin to mop up the extra methyl groups. I did this (and did several trials over weeks) and within minutes of dissolving, it would bring down my heart rate to almost normal. Once I was sure of the relationship, I stopped taking the methyl b12 injections except for very rarely. I continued taking 800-1200 mcg methylfolate throughout this time. 5) Glutathione is OK I have never had any noticeable positive benefit from taking NAC but liposomal glutathione (while probably too expensive to justify) takes the edge of just about anything. When I take it just before going to bed, I have a deeper, more restful sleep. I have never noticed any issues with high sulfur food, etc. I have a good foundation as far as the minerals go now, got my potassium packets handy, my digestion in general is much better than it once was, and my AdB12 and LCF arrive in a day or two, so I feel I am in a good place to start again. My instinct, though, is to do neither a Rich nor a Fredd and to take a mix of mb12, hb12, and ab12. And to eventually try doing CNS-loading doses (I am not sure of mb12 or hb12). I am also not convinced liposomal glutathione will harm me, either. It hasn't helped a ton but it engenders this subtle feeling of well-being and calm every time I take it. Anyway, I know that is quite a long story. I suppose the short of it is that my instinct is I am more of a Rich-style patient, but that I do have very low CSF cobalamin and am eager to try high doses (without overmethylating). Genetics: MTHFR C677T +/- COMT V158M +/- COMT H62H +/- VDR Taq +/+ MAO A R297R +/+ MTRR R415T +/- CBS C699T +/- Has anyone had a similar experience or tried high dose combinations? If so, any suggestions on how to start? Is it even possible to do hb12 + mb12 loading doses for the CNS?