34. Vitamin B12 Explained: Forms, Methylation, Homocysteine & Absorption

In this episode of The Histamine Well Podcast, Joanne is joined by scientist James Bradshaw for an in-depth discussion on Vitamin B12 and its critical role in human health.

Together, they unpack the complex biochemistry of Vitamin B12, exploring how it supports methylation pathways, homocysteine metabolism, and neurological function. This episode provides clarity on why Vitamin B12 deficiency is often overlooked, how genetic variations can impact B12 utilization, and why choosing the correct form of B12 supplementation is essential for optimal outcomes.

Joanne and James also examine the different forms of Vitamin B12—including methylcobalamin, hydroxocobalamin, adenosylcobalamin, and cyanocobalamin—discussing how each functions in the body and when one may be more appropriate than another.

 The conversation highlights common signs and symptoms of B12 deficiency, from fatigue and brain fog to neurological and mood-related concerns, and offers practical, evidence-informed strategies for assessing and supporting B12 status.

This episode is especially valuable for health practitioners, functional medicine clinicians, and individuals seeking a deeper understanding of how Vitamin B12, genetics, and methylation intersect to influence long-term health.

In This Episode, You’ll Learn:

• Why Vitamin B12 is essential for methylation, detoxification, and neurological health
• The different forms of Vitamin B12 and how they work in the body
• Common and often-missed symptoms of Vitamin B12 deficiency
• How B12 supports homocysteine regulation and cardiovascular health
• How to choose the right B12 supplementation based on individual needs
• The connection between genetics, methylation pathways, and B12 metabolism

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Transcript

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Hi, it's Joanne. Have you been told your vitamin B12 is normal but you still feel tired, foggy, flat, anxious, tingly, or like your brain just isn't firing properly? Then this episode is for you. In today's conversation, scientists James Bradshaw and I go deep into vitamin B12 and unpack a detail that flips the whole which Vitamin B12 supplement is best for me. Debate on its head. Methylcobalamin, adenosylcobalamin, hydroxycobalamin. Your body doesn't simply take that form and run with it. It actually strips those groups off, reduces it down to cobalamin, and then your cells rebuild the active form they need for the job. Which means the methyl in methylcobalamin isn't automatically donating methyl groups in your methylation cycle just because the supplement label says so. So if you want to understand what vitamin B12 is really doing in your body and why so much of the advice out there misses the mark. Stay tuned. You're gonna love this episode. Welcome to the Histamine Well Podcast. Designed for practitioners and patients alike. This is your trusted source for insights on histamine intolerance, methylation, gut health, women's hormones, and much more. I'm Joanne Kennedy. Your host, naturopath, author, and educator passionate about breaking down complex science into clear, accessible knowledge. Whether you are a health professional or navigating your personal wellness journey, the Histamine Well Podcast bridges the gap between cutting edge research and practical understanding to empower you with the tools to thrive. Hi everyone. Welcome back to the Histamine well. Today I'm joined again by James Bradshaw, scientist and the creator of Mood Sense. An at home Saliva swab test for methylation. I interviewed James last year all about over and under methylation. And that episode was such a favorite that I knew I had to get James back. And this time we are diving into one of the most important nutrients in the methylation story, which is vitamin B12. Vitamin B12 is one of those nutrients that gets talked about a lot, but often in a very surface level way. And yet biochemically, it sits right at the heart of methylation, homocysteine metabolism, neurological health, and even how folate functions in the body. In this conversation, we are going to explore what vitamin B12 actually is, the different forms it comes in, how it works at a cellular level, and how it influences homocysteine and methylation. How genetics can affect its function and even the role of the gut microbiome in B12 metabolism. So James, thank you so much for your time again today. Thanks for having me, Joanne. I'm glad to be back. Yeah, great. I'm selling so much of these mood sense tests to all my patients because we are getting amazing results. And we can really see what methylation is doing in real time if you're over or under methylating because it is really, really hard to tell without actually testing and using that test to get supplement recommendations. I had a girl who was diagnosed with ADHD and on Vyvanse. And she was severely over methylating. And when she took the niacinamide to reduce the methyl, she just came off that Vyvanse. So she didn't have ADHD. She was just an over methylator. this is just one of the incredible stories that I get to tell James. Often with the patients that I'm seeing in clinic. So it's great to have James back. And today we're gonna talk all about B12, which is a very misunderstood nutrient. And as I was saying, essential for methylation amongst other things. So, James, let's just dive straight in. Can you explain to our listeners what vitamin B12 actually is and what its main roles are in the body? So it's part of the B vitamin group. It's water soluble. It's really quite dynamic in terms of its overall chemical structure. It's real name is Cobalamin. We all call it vitamin B12, but it's called cobalamin'cause it has a cobalt, you know in the middle of it. And then it has all of these different chemical structures around it. What's unique about it is humans can't manufacture it. We have to get it from our diet. And you know, mostly it's microbiomes or microbes that are making it like in the gut of cows in the milk or animals will get it from eating insects that get it from that too. So basically it's one of those things that's manufactured mostly by bacteria and then comes up in the food chain. The main sources come from meats fish, milk, eggs and things of that sort. Humans cannot manufacture this vitamin. We have to get it through our diet. It's one of those key vitamins that without it, there are a lot of problems that will happen to us. Physiologically, neurologically, and especially in methylation. Its primary role is to reduce methylfolate and that's used in the methylation cycle And it's also used in the mitochondria for energy metabolism. So the energy metabolism part affects your cellular health and function fats and protein breakdown and things of that sort, which is why there's a lot of physiological problems that come and there are symptoms that we're gonna go over. But methylation is a key one where if you don't have enough vitamin B12, you can end up trapping methylation so that it can't process in your, then you're gonna have problems with Sam e manufacturing. And then of course you're gonna have the downstream problems with methylation itself. So the kind of the two main roles of vitamin B12 are in the methylation chemistry and in energy metabolism. And without those two, you get a whole host of problems. James, can you tell us some symptoms people are gonna get when there's B12 deficiency? Yeah. We see this in the elderly because a lot of times when they get older, they end up having malabsorption problems. You're gonna have some neuropathy, tingling, numbness, burning. Sometimes in the elderly cognitive decline, a brain fog. I mean, it doesn't always happen in the elderly. It can happen with others because of malabsorption or other things that cause vitamin B12 deficiency. It's gonna affect your mood because it affects methylation. You'll have problems like depression, anxiety, irritability. A lot of it's because though it's not a guarantee, it typically can cause under methylation in general, but there are exceptions, obviously. Because it affects the neurons, you can have memory impairment. And you can also have problems with the myelination of your neurons. There's a lot of cognitive issues that come about from vitamin B12 deficiency. But beyond that, you can also have systemic problems. You can have jaundice because it can cause a problem called megaloblastic anemia, where your red blood cells are affected by it. So it causes fatigue and weakness, poor wound healing. A lot of different things. It elevates homocysteine, so that's gonna have its host of problems as well. So you're gonna have problems with red blood cell production. So a lot of those things. And then you'll have also neurological problems such as neuropathy, brain fog, depression, memory, impairment, all of those types of things. It's kind of the short list. There's other things, but that's in general, when you start seeing those signs, they're gonna look at B12, they're gonna look at your diet. Look at a lot of different things to be able to kind of determine if that's what's the cause of it. That's how important vitamin B12 is. Yeah, it is extremely important. And James, you talk about it's useful for methylation and energy production. Cobalamin. Are there certain types of vitamin B12 that are useful for those processes? Yeah. So this one I could go off on a tangent, so stop me if I do. There are four main types of cobalamin in supplement form. Three of which occur naturally in foods and in our biological processes. The most common that synthesized is cyanocobalamin. That's actually cobalamin with a cyanide attached to it. Most people think, oh, cyanol. I'm like, it's got a cyanide on it. So the reason why they do that is because it has a high stability. They try to fortify foods with it because if you heat the foods up or other things. They found that it has the highest stability so that it doesn't break down.'cause a lot of the other forms of cobalamin, you'll lose like 50% of it just by cooking the meat or processing it. Or even if you store supplements of a different form with others, they can degrade them as well. And so even in the supplement industry, they're aware that other forms can be degraded if you put'em with like ascorbic acid or the things like that. So the other three versions, which are the natural forms, are Methylcobalamin, adenosylcobalamin, and Hydroxycobalamin. Now, adenosylcobalamin is kind of the main one you'll find in meat. So about 70% of the cobalamin in meat is a adenosylcobalamin. And then the rest of the 30% is methylcobalamin and hydroxycobalamin. Cyanocobalamin is not typically found in nature. They have found it generated in people. But usually is in people that are smokers that will have some cyanide in them and they'll find some residual. Cyanocobalamin, I could go off on that one. It's kind of the most common one that's used in like B12 shots when they're trying to rescue people. But my wife would get shots all the time because she was showing a lot of symptoms of that. Mainly because of her health problems. Once she switched to one of these other forms, all of a sudden her health improved. So the form really matters. The problems though, is there's a lot of misinformation about why the form matters, and I don't know how detailed we wanna get into that, but let's just say this for the shorthand. Whatever version you're getting of supplement of the natural forms, methylcobalamin, adenosylcobalamin, or Hydroxycobalamin, the body actually strips that away before it can use it. So when you have supplements that say methylcobalamin is the bioavailable form, that's true, but it's not true in the sense that it's going to increase your methylation because it's methylcobalamin. The body has to take away all of the parts. The methyl, the adenosyl, the hydroxyl, even the cyanol, the cyanide. And it strips it down to just cobalamin and then it makes it into methylcobalamin and adenosylcobalamin for your purposes. this is fascinating. Say I want to work on lowering my homocysteine. And you need methylcobalamin for that. Yep. I could take methyl or adenosyl Or hydroxy to give me the cobalamin that's required. Is that right? It's correct, except we haven't gotten into the genetics yet. One of the studies that they've shown is that the body kind of favors adenosylcobalamin in transporting it through the body to the cells because of a gene. There's a gene called Transcobalamin too. And it favors adenosylcobalamin to get it into the cells, but they found that once either version methylcobalamin or adenosylcobalamin it's in the cells, the body actually favors methylcobalamin to strip it down and then transport it. So adenosylcobalamin is like 67 times slower than methylcobalamin in its kind of processing where it has to remove that group and then reprocess it. So it's kind of one of those things where you're like, depending upon your genetics, one form of vitamin B12 might be better for you than others. Because there are even people with genetic problems that they actually can take methylcobalamin and adenosylcobalamin and the body can't process them very well. So they have to have hydroxycobalamin. So this is where genetics comes into play because there are some problems out there in how the body strips it down and then re constitutes it to be usable. Because they've done study after study after study that shows that the methyl group of the methylcobalamin does not go towards making methylcobalamin. And the adenosyl of the adenosylcobalamin doesn't go towards. That's an all internal process of your cells. That's independent of whatever form you're getting about Vitamin B12. But that doesn't mean that the form doesn't matter. If that makes sense. Thanks. Is so fascinating. You gonna have to do a gene SNP slash B12. I don't know, something for people a diagram I dunno. Have you done one of those? Actually the research papers that I have, have diagrams in them that show the genes and how it's being processed. That's really fascinating. So for someone listening though, if they're trying to support their methylation, they're trying to reduce their homocysteine, they're gonna get a supplement if done correctly through, you know, with the to lower homocysteine with some methylfolate and B6 trimethylglycine. Right. It will have methylcobalamin in it. For most people, any version will work. Methylcobalamin, adenosylcobalamin hydroxycobalamin. It's only a rare, rare few that you have to have a very specific version. I can say that from my research, cyanocobalamin is the worst. The body tries to get rid of it, but it can accumulate in tissues. They are finding that if you get a lot of cyanocobalamin, it can accumulate in fat tissue. Just like smokers that have cyanide buildup and whatnot. So you're literally putting cyanide in your body in small doses, but your body has to get rid of that cyanide. If you're taking a supplement every day, it adds up. Yeah. I mean we're, we're talking about, I mean, really, really small amounts, but yeah, they do worry about bioaccumulation over a lifetime when you're taking that.. Sorry. It's, especially if they've got methylation problems and they don't detox heavy metals properly. Right. It's an ion that interferes with ATP production. When it gets into the cell, it actually prevents your mitochondria from making ATP. That's why cyanide kills people is because it will literally stop your heart and other muscles from making ATP and your heart will stop. That's kind of the first thing that will go. It'll kill you in minutes. So cyanide is not your friend. So going to the health food shop and getting some B12'cause you're tired and they'll give you cyanocobalamin is not gonna work. Very interesting. Yeah. Okay. Plus your body doesn't absorb it very well. They found that it gets rid of it three times faster than other forms of it. Your body will absorb it, but then it'll excrete it because it's not the best form of it. They've done a lot of studies on comparative absorption of the different Vitamin B12, cyanocobalamin is the worst. So yeah, that's, I think that's very well known amongst naturopathic circles, but just not the general public. So I'm glad we've touched on that. Now, what about when people can't tolerate methyl. They can't take methylcobalamin, which is common, especially they've got high histamine. Is Hydroxycobalamin a good place to start? Yeah, especially because Hydroxycobalamin is one of those that even if you have some genetic issues, which some people do, they've done some research and found that it can bypass some of those genetic issues. It's the only one that can. So Hydroxycobalamin, can. For whatever reason, they're not exactly sure why they're still studying this, but it actually kind of skips over and the process where you have to have all these genes to, you know, pull off that portion to make cobalamin. And so in, in a way, hydroxycobalamin would be kind of the go-to if you're worried, if you've got some genetic issues in processing the other forms of cobalamin. So, yeah, if you're having problems with methylcobalamin, hydroxycobalamin typically is the way to go. I mean, you can try adenosylcobalamin, but I think most of them are pretty comparable in not only their price. I know Hydroxycobalamin, I think can sometimes be a little more expensive just because of how they manufacture it. So yeah, if you're struggling with methylcobalamin, hydroxycobalamin definitely could be the way to go. So let's just stick on methylation. Can you just explain to listeners how important vitamin B12 is for the methylation cycle and what it's actually doing In order to produce Sam E, which is the methyl donor in the body. This is ultimately what we're looking at with over and under methylation. Do you have too much, Sam E? Do you have too little Sam E? There are two ways of producing Sam E. One is the folate pathway combined with the methionine cycle. And the other way is kind of a sidestep with betaine. So we'll ignore betaine for a second. The main one, this is where methylfolate comes in. The folate pathway, ultimately you get folate from your diet. There's a couple ways which you can get it, and I'm sure a lot of your listeners know a lot about folate. If you get folic acid, which is usually the synthetic enriched, you know, vitamin form, your body has to go through about three steps to turn it into methylfolate. If you get natural folate from your diet, there's fewer steps it's ready to go. So the methyl folate is actually how the B12, the cobalamine gets methylated. So your body will take in vitamin B12. Turn it into just cobalamin. Nothing attached, just straight up cobalamin. And then the methylfolate will donate its methyl group to the cobalamin and that will turn it into methylcobalamin. So that's how your body makes methylcobalamin in it cells is through this process. So methylfolate becomes, tetra hydro folate instead of methyl tetra hydro folate, and that goes in. It could be used for other things. And then the methylcobalamin is used to regenerate homocysteine back into methionine. So this is why B12 is so important for homocysteine is because it is the methyl donor that ultimately converts homocysteine back into methionine. And then methionine basically gets an energy molecule attached to it and becomes Sam E. So homocysteine regeneration requires methylcobalamin or vitamin B12 that's methylated in order to regenerate it. Yeah, so it's interesting. Under methylators. I know there's genetics snips involved, but they're often got low B12 snips. So it's not all about N-T-H-F-R is it? Right? Like B12 is so fundamental and so many people are low in B12 because of lack of dietary intake. SIBO can cause malabsorption having a disruptive gut microbiome. And the large intestine can cause malabsorption. Low hydrochloric acid. Malabsorption. Proton pump inhibitors will block your uptake of B12. There's so many environmental things that cause B12 deficiency. And aging. So when we are looking at epigenetics and what in the environment is impacting the way our body works, it's like all these lifestyle things and aging and what you've done to your gut can significantly disrupt methylation.'Cause people just always think it's about MTHFR. They really still do. It's always go on about B12. This is why I got James on the show, because it's just like a fundamental linchpin in this process that falls down almost more than anything else. Yeah, so there's kind of three main routes. Four now, if you talk about getting it nasally and then absorbing it through the mucus, there is nasal kind of absorption of vitamin B12. But the main routes are oral sublingual, so under your tongue or intramuscular where they give you an injection. And each kind of has their advantages. But let's just talk about the oral route. When you take vitamin D or vitamin B12 orally, there's what we call the R factor. It is actually called haptocorrin, but everyone refers to it as R factor. That's what initially binds to the vitamin B12 in your food or even a supplement if you're taking it. So that it protects it when it goes into your stomach acid. And then it goes into the stomach acid. It breaks off the haptocorrin and then it attaches something in the gut called intrinsic factor. This binds to the vitamin B12 so that it can be absorbed in your gut. This is why people with inflammatory Bowel disease, celiac. All these problems that you can get, vitamin B12, all you want in your diet. If it's not being absorbed, the body not only has a limit of absorption, but these problems can ultimately cause malabsorption. So if you have weak stomach acid as you get older, that can affect your B12 If you have. A problem with your intrinsic factor. This is what they call pernicious anemia, where you have a problem producing this if or intrinsic factor that binds to cobalamin for absorption. There is another way that your body can passively absorb it, but it's like 1% of what you're getting that it can passively absorb. So a lot of the B12 has to be actively absorbed by your cells. And if you've got all these problems. That's really where a lot of malabsorption comes into. So people just think, oh, I just eat it and it gets absorbed. There are so many little steps that your body has to produce physiologically, not only with the stomach acid, but with the intrinsic factor that if you have these problems, especially with aging or other disease. You're gonna have a lot of malabsorption and that's assuming you're getting in your diet. This is where vegans and vegetarians don't get a lot in their diet and will need supplementation because most b12 is found in meats, milk, eggs and things like that. And high content. You'll get'em sometimes from fermented foods, but not substantially is what you might see. And then when your body absorbs it, it stores a lot of it in the liver. So if you're getting a good amount, it stores over half of it in your liver so that as your body, you know, loses some through this process, it can restore it. This is why a lot of times when people change their diet, they may not see symptoms for a long time because you have so much stored up, assuming you've been getting enough in your diet, that it'll start getting slowly depleted over time, and then all of a sudden you'll start having these symptoms from low vitamin B12 because your storage levels are almost depleted. That's Kind of the normal route is through orally. Other sublingual and intramuscular, they bypass these routes. And that's why a lot of times when people have low vitamin B12, they just go for shots to get it straight into the bloodstream or sublingual to kind of bypass the whole gastric process. Yeah. I often just get people to take the sublingual. It's easier. I think it's just giving them more of a steady dose. I agree. Especially the only reason why you want intramuscular is if you have like a comatose patient. Physically take it. It's just very simple to take a sublingual and kind of bypass a lot of those issues of the gastrointestinal process. And people don't wanna inject themselves every day. It's just not fun. Although, that's interesting. So it would be the most common nutrient deficiency I see in clinic. For sure, and the lab testing is way too broad. So in Australia, I think serum has to be like over 150. That's way too broad. Should be up over 500-600 and then active, which intracellular B12. I think some labs say it needs to be over like 45 or something like it. It is crazy low. It needs to be over 130. It's so critical. A lot of the symptoms like the fatigue and things like that we see. You know, brain fog, lack of concentration, fatigue, that can be kind of multifactorial. It's the tingling. Like I always ask my patients, do you feel tingling anywhere? And they're like constant tingling and it's like real sign of B12 deficiency. Especially when I can see lack of intake and gut issues. I just prescribe it. I get them to test, but I guess I always know they need it. Yeah, well that's one of the things they've found is there's, they don't really have an upper limit for vitamin B12 because, number one, the body just doesn't absorb most of what you intake anyway, and it's water soluble, so it'll just get rid of any excess that you have. And so it's not something to worry about that you're getting too much of. If you're taking it every day. I'm glad you said the Australians.'cause people go to the doctor and they test their B12 and it comes up at like eight, 900, a thousand. It's, they're supplementing and the doctor says, stop taking it. And I'm like, no, it's just picking up that you're taking a supplement. And it's just not all gonna be absorbed into the cell'cause then it would just be too much. Does the body sort of regulate how much it needs from a supplement? Yeah. And it, it really doesn't have any problem knowing how much to take in and what to just pass through. If it's too much, it'll just go right out of the kidneys. Especially if you're doing sublingual or intramuscular and it just gets into the bloodstream. It'll take what it needs and try to store what it can in the liver and then the rest just goes out through the kidneys. Not a problem. Yeah, no, I'm glad you clarified that'cause that's what I was taught at uni. So we don't get alarmist about those results. Before we go any further, I want to speak directly to the practitioners and students listening. If you're intrigued by histamine and methylation and eager to expand your knowledge in this fascinating area, we offer the Histamine and Methylation online group coaching course. The only program of its kind. It covers everything you need to know about histamine and methylation, providing both the theory and guidance you need to treat these issues effectively in clinical practice. We cover sibo, hormonal imbalances, oxalates, M-T-H-F-R, the four pathways of methylation, including the folate pathway, methionine pathway, tetra hydrobiopterin pathway, and the all important the transsulfuration pathway and much more. The program is delivered by detailed online webinars and handouts for you to keep. And for eight weeks you'll meet with me for live coaching calls in a private community space with other practitioners from all over the world dealing with histamine and methylation issues in their patients every day. Together we learn so much. To learn and apply, visit joanne kennedy naturopathy com. Let's just stick on methylation and just for people listening with high homocysteine levels.'Cause I think people do are rightly concerned about that. And I think you've touched on this, but can you explain to listeners how a vitamin B deficiency can be a major driver of their high homocysteine? So, you know when we were talking about the mechanism that methylfolate donates its methyl group to cobalamin to become methylcobalamin, and then methylcobalamin donates its methyl group to homocysteine to turn it back into methionine. So this is what's called the methionine cycle where basically homocysteine is the byproduct of the use Sam E. So as Sam E goes through the body and undergoes all the methylation processes that are necessary, the byproduct is homocysteine. Your body needs to recycle this, otherwise it starts getting elevated higher and higher, which can cause a wide variety of problems. Most of the community looks at high homocysteine and looks at cardiovascular problems, but it's also a symptom of the fact that your body is not recycling this. And therefore there could be issues like B12 deficiency. If you don't have enough vitamin B12, then homocysteine starts building up, and the body has an alternative way of recycling homocysteine, and that uses bettaine and choline, but that's restricted to the liver. It doesn't occur in the rest of the cells in your body, so it can only occur in the liver. And it's one of those things where you have two ways of regenerating Sam e and you're only using one and that's taxing the system. And then obviously you're not saying, oh, well I have another pathway. I mean, how many people drive on the road and hate that detour? And everybody goes through that detour and it just backs everything up. Amongst many things you don't wanna stop the main mechanism in your cells. That is literally the only way in your cells that homocysteine can be recycled to sam e on a local level. Obviously on a systemic level, you have your liver involved and it can do a lot, but it can still cause a lot of problems. So homocysteine builds up when you can't recycle homocysteine back to methionine with methylcobalamin. And that's kind of the main process on a cellular level. So when B twelve's low homocysteine builds up, and then you're gonna have a lot of problems that come about from that. So anyone who's got high homocysteine, that just won't budge and we can't get it down. These people need to look potentially doing some gene testing for B12. People do the supplementation that they're meant to and they just can't get it down. They're taking the wrong form of B12 for them. James let's have a chat about the relevant SNPs for B12. So there's, in the methionine recycling pathway, you've got two main genes that are responsible. One is called methionine synthase. It's called the MTR gene. This is the one that takes the methyl group from methylcobalamin and turns homocysteine back into methionine. So this is the main gene, MTR or methionine synthase that recycles homocysteine. It's the only gene that's responsible for this in the cell to do this. The other gene that's in the methionine cycle is called MTRR. This is called methionine synthase reductase. This is the one that basically regenerates cobalamine. So when methylcobalamin donates its methyl group and homocysteine is recycled back into methionine, then it has to go back. Get a methionine from methylfolate, and that's where the MTRR gene comes in. It basically grabs the methyl from the methylfolate. Reactivates cobalamin to methylcobalamin. And then the cycle continues. So those are kind of the two main genes in the methionine cycle. I've seen a lot of mutations in a lot of people. And so even if you're getting enough methyl cobalamin, even if you're getting all of these things in the cells, if you have some gene mutations in the MTRR or MTR gene, you could have problems with recycling your homocysteine or regenerating your, methylcobalamin. So James, just to stop there, what do people do about that problem? Obviously you can't change your genes, right? You can't alter that We found that even though these genes can have SNPs, they're just working at less efficiency. It's kind of like people with the M-T-H-F-R gene. Where they have a problem metabolizing folic acid into methyl folate. They can still do it, but it is reduced in its capacity. That means that you need a lot more of. You know what you are deficient in. So in this case, you might need a lot more vitamin B12 in your diet. Because they'll still work. If they didn't work, you'd already know the problems you'd have, but they're working at reduced capacity and so the only real way we know to fix this is to load up more of vitamin B12. That's why you were saying when people are low. Physiologically, they say, oh yeah, this is on average. Well, you may need substantially more to have things work properly because of these mutations. Yeah, no, interesting.'cause I've seen practitioners say, oh, you need intramuscular'cause you have, those SNPs. I was always like, no. You need the dosing up and you really need to watch your diet, I think. Right. These are people that are having already issues. Just like we've talked about folate before. If you've got metabolism issues for folate, you need to get the right source and you need to get enough of it. You know?'cause there are people that could have. Blood disorders that just need more folate. And B12, by the way. Blood disorder B12 is a huge one for red blood cell production. And that's why you get the anemia and the other issues of that sort. So you just, you need a lot more of that vitamin in your diet if you have these genetic issues. So far I haven't seen any work around, there's no magic.. Yeah, no, I'm glad you said that because I dunno any either. It's interesting to look at Gene SNPs, but it is often what we do clinically, which is not particularly tricky. It's working on absorption and intake. And getting optimal amounts. There's other genes. A lot of times people will look at Transcobalamin. This is the one that takes it from the bloodstream and brings it into the cells. And this is the one that kind of favors adenosylcobalamin in the blood, which is the major form in meat and fish and all of that. But as I mentioned before, it'll grab others as well. It'll grab methylcobalamin just fine. But there's other things that transport cobalamin to other places, other genes. So that's why I'm saying it's not that adenosylcobalamin is the best. It's just the TCN two gene. The transcobalamin favors adenosylcobalamin in terms of, absorbing it, but it will take hydroxycobalamin and methylcobalamin just fine too. So that, that is an issue too., I haven't really seen too many genes, problems in this, when I look at people, but. It can exist. You know, there are cases where people can have problems where it's just not able to get into the cells very well. And again, the only solution we know is to load up more on vitamin B12. And then the last gene, there is another gene that people talk about a lot. The, F ut two, the F two. This gene's interesting because it doesn't directly have a function with vitamin B12, but they find physiologically that it can affect intrinsic factor, which has to do with oral. Absorption of vitamin B12. So obviously if people have issues with that. That's where sublingual would actually be beneficial. So in, in that case, you can bypass that issue of a problem with intrinsic factor by doing sublingual or intramuscular, but sublingual is so easy. So that one you can bypass. By doing a sublingual vitamin B12, version. And then the last one is it's, it's one that really, people don't even talk about that much. It's got a long name so I won't go through it, but it's the one that strips the Methyl group and the Adenyl Group and the Hydroxyl Group and the Cyanide group to get it in the cells to make it ready for processing. And there are rare cases where people have issues with those genes. That's where Hydroxycobalamin comes into play. So if you have one of those rare genetic problems, this is where Hydroxycobalamin kind of bypasses that. So, unlike MTR and MTRR and and whatnot where you can't really bypass that, you just have to get more vitamin B12 in your diet. These are two processes where doing sublingual and doing hydroxycobalamin can bypass these two genetic problems. I always give sublingual hydroxycobalamin. Mainly because it's easy to get and it doesn't cause side effects, but there's many, this is a great conversation. I'm doing my patients a favor on many levels. With hydroxy saying that if someone's got high homocysteine, I'll always give them methyl cobalamin. Because usually because it's in the supplements that, with the other things to lower home assisting. Right. So that's interesting, Jane, so I can just see some kind of business for you with B12 and Janes and recommendations. I don't know. I think, well eventually we want to get there, but right now, you know, our main focus obviously is on the testing and the genetics and everything. But yeah, I mean even just. You educating people on this makes all the difference because the marketing out there for these supplements. You know, they say methylcobalamin, the bioavailable form, but they don't know that what we just talked about, that it doesn't add methylcobalamin to your cells. Your body will strip it down regardless of its form. So how about this? James, I'm so glad I met you, because there's just so much misinformation out there in education as well. Right. People talking about this stuff, because they're not PhD scientists and they're not looking at it like that. So it's just so interesting. So James, when it comes to over and under methylation, can a vitamin B12 deficiency actually indicate that or not? Not really. That's a good question because as I mentioned, there is another form of recycling. Homocysteine, and that's through an alternative pathway and a whole different set of genes that use beane to recycle homocysteine back into Sam E. But that only happens in the liver. That doesn't happen in the cells in your brain or your muscles or your body, so systemically. Your body can try to recycle homocysteine in the liver to lower homocysteine levels, but locally you could have elevated homocysteine levels and underm methylate. So it's one of those things where on a local level, you can underm methylate. But there's, you know, you have to look at all the other things. How is the rest of your body using methyl donors? Because obviously methylation is used all over the body, neurotransmitter production, energy, all of that. And so when you're looking at the entire system, that's a multifactorial problem. And so you can't always say that you're gonna underm methylate if you have vitamin B12 deficiencies. It will prevent the formation of Sam e, because that's the main thing. That's the one that all your cells use throughout your body, but then you have your liver doing an alternative process. So it's not clear cut and dry to say, oh, low B12, you're always gonna utter methylate because when you look at it, you have to look at the whole system rather than just what's happening on the individual cellular level. That's interesting James. So when you say it is not all about Sam E production, because even if you are making adequate Sam E or not enough Sam E, it still doesn't mean you're over under Methylating does it? Right? This is what I learned from James, when I started chatting to him about this stuff for my practitioner training course and like what we found is, well for women. Mostly the COMT enzyme will and COMT gene mutation seems to be such a powerful player. Like, like it just, it's just if you've got comped, it pushes you into over methylating pretty much regardless of these snips. Yeah, well'cause a lot of it comes down to how you use it, how fast you use it, and all of that. So that global amount of available Sam e isn't just about production, but also use. So utilization of course. Yeah. No, very interesting. So James, my next question, which I know a lot of listeners will want to get an answer for, is, what is the methyl trap and how does vitamin B12 deficiency create functional folate deficiency, even when folate intake is adequate? So going back to the folate pathways, we talked about before, the body, uses methylfolate to turn cobalamin into methylcobalamin. And when that happens, the methyl tetra hydro folate, which is, the methylated version of folate, it becomes tetra folate or the unmethylated version of that. That's. Really one of the main ways in the folate pathway to strip the methyl group from methylfolate. If you have low cobalamin and you're not absorbing that methyl, then methyl folate builds up, and when that builds up. You can't take folate into other areas of the body'cause folate is necessary for DNA synthesis. And if you don't strip the methyl group from the folate, it can't be involved in these other processes of making DNA. You have a lot of methylfolate, but it's trapped because low cobalamine. You can't get those methyl conversions and therefore it doesn't matter how much methylfolate you're taking, it's just gonna be stuck in that folate pathway and it won't be converted into folate and then be used elsewhere in other processes. A lot of times people just think methyl folates involved in, you know, methylation of Sam E, but there's other things that it's used for biologically, including DNA synthesis. So what happens with low vitamin B12, methylfolate can't be converted to folate and it gets trapped in that state. And then the body's looking at it like, well, what do I do with this? There's other ways it can kind of try to transform it, but the main way is to regenerate. cobalamin is a methyl cobalamin, just like we talked about. You take away the main highway, you go on these detours, things start getting backed up and you start getting all these problems. Listeners I just think, you know, if you do suspect you have B12 deficiency, just go over all those symptoms that James mentioned at the beginning and go to your doctor and ask them to do like an active b12 test, make sure it's well over 130. Or they'll say it, they basically say anything over 130 is fine. And that's true, but you don't want it at like 50. You don't want your active B12 down at like 50. And just taking, I think for most people, James's, some hydroxycobalamin, sublingual is gonna bypass any gut issues, some of the genetic issues, taking it daily. You don't need to do an injection, it's just taking it daily. Increase the intake of your animal products. Make sure you've got good gut health. I find just doing that in a lot of my patients, well, it fixes the neurological issues. It really helps with energy, with brain function, clarity, memory, cognition, cognitive function. It's definitely something that I see clinically lift people just getting the B12, like they feel like they're present again. Often people feel just like really kind of, like locked in themselves. Right? And then when the B12 R up there, like their whole brain function is working so much better and their cognition, and they've inevitably really supporting, like most of the time, if it's been that low, they're also getting their methylation working and they're using their methylfolate more efficiently. Does, if it's something important nutrient. Yeah, we didn't talk about it too much. But the other thing is the mitochondria, you need methyl B12 for energy, for breaking down fats and proteins. If you don't have that, that's the Deni. So cobalamin, and again, a lot of people will market a Deni. So Cobalamin as a supplement and say, oh, this is for energy. Yeah, but again, we talked about it. It gets stripped down and the body has to turn it into that. But that's why you get a lot of the neurological issues is because. If your mitochondria is not breaking down these fats,'cause that's one of the main things in your brain that your body uses is these fats to generate energy.'cause there are a lot better storage for energy and energy production. So, yeah, it's really, really important for metabolism as well. Yeah, James, we could get count on this stuff all day. It's, it's really fascinating. I love it. I'm so glad I was, listeners, I was gonna, it was on my list of podcasts that I needed to do, which is just get right into B12. And I spoke, when I spoke to James last year sometime, he said he was. All over it, which you completely are. It is just a nutrient that I wanna learn more about because I just think having all the different supplemental forms and a lot of misinformation out there, the how this chronically low in all our patients. And I'm so James, I'm so glad you talked about the mitochondrial function and like how it's just working with energy because it's like if I just give my patients B12. When I see them at their first consult, and I really think it's low, you can tell from symptoms and I send'em off for testing. If I just give them that, even they come back like significantly better often. Right? Yeah. Just'cause of all the reasons like a TP and like mitochondrial function and neurological function, methylation, using their methylfolate, and deficiency is so, so, so common. So it's great James. Well thank you so much. So guys, honestly, if you want to know what your methylation status is, the only way to actually know is to do the mood sense test. You can find the mood sense test with a discount code on my website, and I highly encourage you, just test your methylation, get an understanding of your. Over under you enter the information from your test onto the online portal and they will tell you what to take for over and under methylation. And then, you know, if you wanna see me to work on your absorption of your B12, your gut issues, supporting long-term methylation status, balancing your hormones, I'm obviously here to help, but I really encourage you to start to understand your methylation because it can really help with so many different health issues. So James, thank you so much for your time again today. Definitely we'll have you back on the show at some stage. Sounds great. Thank you again for having me on. I really enjoyed this. So thank you for joining me. I hope you found this episode beneficial. Be sure to subscribe to the histamine well so you don't miss an episode. Leave a review and you can also share this episode with someone who could benefit. If you have any questions you'd like answered. Or have a topic you'd like me to discuss, please go to my website, joanne kennedy naturopathy.com, where you can provide us with that information. Until next time, take care and be well.