1- Coming soon in the next couple of days: Free Pre-conception and Fertility course in the classroom !! 2- Just posted in the supplements section : common question about what is happening when you react to methyl B12 : Methyltrapping , Overmethylation and B12 stalling 3- Live Q&A schedule will be published soon and returns on Thursday evening (BST )

Posting this here because the Instagram version only has room for the headlines, and the part that matters clinically is the part that gets cut. If methyl B12 has ever made you feel worse, you have probably been given one of two pieces of advice: stop taking it, or push through. Neither is a plan. Before you do either, work out which of these three things is happening, because they need opposite responses. 1. Overmethylation Methylation is fuel on a fire. Sometimes the fire is already too hot. COMT clears your catecholamines using methyl groups. The Val158Met variant swings COMT enzyme activity by three to fourfold (Chen et al, Am J Hum Genet 2004, PMID 15457404; Tier A). Stack high-dose methylcobalamin on top of methylfolate in someone whose catecholamine turnover is already brisk and you get the picture people describe to me every week: wired, flushed, anxious, awake at 2am. This is a dose problem. The B12 is not the enemy; the quantity of methyl groups arriving at once is. Reduce the methyl donors, use niacinamide as a buffer, and reintroduce slowly. 2. Methyl trapping Folate is a key that keeps sticking in the lock. 5-MTHF can only be converted back to usable tetrahydrofolate by methionine synthase (MTR), and MTR needs active B12 to run. Without it, folate accumulates in a form the cell cannot use, homocysteine stays elevated, and adding more folate makes it worse rather than better. Scott and Weir described this in the Lancet in 1981 (PMID 6115113; Tier B). It is not new science, and it is still routinely missed. The fix here is the opposite of the first one. B12 first, then folate. 3. B12 stalling This is the one almost nobody talks about, and in my clinic it is the most common of the three among patients with mould exposure, chronic infection, heavy metal burden, or long-standing gut dysfunction. In those states, nitric oxide production runs high. NO reacts with cobalamin directly. Danishpajooh and colleagues showed spectroscopically that NO reacts with all three valency states of cobalamin and inhibits methionine synthase in living mammalian cells, disrupting carbon flow through the folate pathway (J Biol Chem 2001, PMID 11371572; Tier C, cell culture).

Most people arrive at methylation from the wrong end. They have a genetic result, usually MTHFR, and look for a supplement to match it. Bloods are the more useful starting point, because they tell you what is happening now rather than what has been possible since birth. Below are the six patterns I see most often in clinic and the first thing I reach for in each. Some look similar on paper but lead somewhere quite different. 1- High homocysteine, low red cell folate Suggests: not enough raw material. Where I start: 5-MTHF or folinic acid, plus B12. 2- High homocysteine, low active B12 or raised MMA Suggests: a missing cofactor. Where I start: methylcobalamin or hydroxocobalamin. 3- High homocysteine, folate and B12 already corrected Suggests: a blockage further down the pathway. Where I start: B6 as P5P, serine, glycine, betaine. 4- Low SAM, low methionine, low protein intake Suggests: not enough starting material. Where I start: dietary protein and methionine adequacy. 5- Low SAM to SAH ratio, normal homocysteine (specialist testing, not on a standard panel) Suggests: a manufacturing or clearance problem. Where I start: check kidney function, then consider SAMe. 6- Low choline intake Suggests: methylation traffic being diverted elsewhere. Where I start: choline or phosphatidylcholine. Why the last two matter more than people expect The SAM-to-SAH ratio is the one nobody measures. SAM is the molecule that carries methyl groups around your body; SAH is what is left after one has been delivered. SAH is a potent blocker of almost every methylation reaction there is, so a person can have plenty of SAM and still methylate poorly if the SAH is not clearing. Kidney function is the usual reason it does not. Choline is the quiet one. Building phosphatidylcholine consumes three SAM molecules for every molecule made, and it accounts for a large share of all the methylation traffic in the liver. A low-choline diet pulls methyl groups away from everything else and pushes homocysteine up in a way the B vitamin picture alone will not explain.