I was diagnosed months ago as compound heterozygous for two mutations of the MTHFR gene -- C677T and A1298C. I've been taking a prescription called Deplin, which is the converted form of folic acid, L-methylfolate. I break the tablets in half and take 7.5mg a day. In addition, I've been taking 2.5mg of sublingual methylcobalamin and 12.5-25mg of P-5-P every day. I found that even 1mg of methylcobalamin was messing me up. It would make me feel tired and sluggish and groggy and depressed. It seems like I was overmethylating and my body was getting overwhelmed by that. I seemed to be able to handle 500mcg okay although it still was a tiny bit iffy. Interestingly, over the past couple weeks, since I started taking 500mg of niacinamide in the morning and 500mg again in the late afternoon, I've been able to take 2.5mg of methylcobalamin with no noticeably adverse effects. I remember reading on mthfr.net that niacin can act as a methyl 'sponge' that soaks up excess methyl groups. Dr. Ben from mthfr.net seems to very rarely if ever recommend Deplin, since he seems to be a fan of using the lowest dose that gets results. I'd agree with that. I get a prescription though and my psychiatrist wanted me to take 15mg because that's what worked in studies on depression, and I wasn't able to get him to prescribe me the 7.5mg tablets which I could've broken up into 3.25mg tablets. So I've been stuck with 7.5mg, although I do have to admit that it does seem to work. When I've stopped taking it for a week or two I definitely notice my suicidal depression coming back full force. Anyway, here's an interesting bit on overmethylation, undermethylation, and niacin: http://mthfr.net/overmethylation-and-un ... 012/06/27/ ... The only issue is the doctor did not realize how effective methylation is at supporting neurotransmitters and thyroid hormone production. So what happened is the gentleman decided to skip his methylfolate and methylcobalamin dose, take a lot of niacin (which is a methyl ‘sponge’) and he immediately tanked his methyl groups which caused symptoms of undermethylation. Then, upon restarting the methylfolate and methylcobalamin, and maintaining his current dosage of medications, he felt great for a few hours. Then anxiety hit due to excessive neurotransmitter production and likely thyroid hormone production. So – in order to quiet those symptoms, I told him about how niacin works and how to take it and his anxiety decreased almost immediately. "Nicotinic acid (Niacin USP) requires SAMe to be metabolized. SAMe is a major methyl donor. Thus, when one consumes niacin, SAMe gets used up and methyl donors drop. Thereby excessive methylation goes away. Nicotinic acid is a cofactor for the COMT enzyme. This enzyme helps breakdown norepinephrine and epinephrine – and estrogen. These are all commonly elevated in those with anxiety. Since the COMT enzyme sped up, the breakdown of these occurred faster. Does anyone else here have any mutations of the MTHFR gene? Given how important methylation is, it seems like it would be a good topic to cover in light of Ray Peat's research, although I've read next to nothing from Peat or any of his followers about the MTHFR gene mutations.