Histamine Well Podcast: Exploring Histamine, Methylation & Holistic Health

Insights Into Over & Under Methylation with Scientist James Bradshaw

• Joanne Kennedy • Episode 8

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In this episode of the Histamine Well, Joanne is joined by scientist James Bradshaw to discuss the complexities of methylation and its critical role in genetics, mood, and overall health. 

James shares his extensive background in biochemistry and cellular biology and introduces Mood Sense, the first saliva test for assessing methylation-related mood disruptions. 

They explore the essentials of methylation, its impact on neurotransmitter production, and the difference between over and under methylation. 

The episode also delves into genetic mutations, environmental factors affecting methylation, and practical approaches to managing methylation in clinical practice. 

Listeners gain insights into the role of methylation in various chronic health conditions and how personalized testing can lead to better health outcomes.

Connect with Joanne:

Joanne Kennedy:

Hi everyone. Welcome back to the show. Today I'm really excited to be joined by scientist James Bradshaw, who specializes in methylation and genetics. James holds a Bachelor of Science in Biochemistry and cell Biology from the University of California and a PhD in Physiology and developmental biology from Bringham University in Utah. He served as an instructor and director in the biotechnology program at Utah Valley University for nearly 20 years with over 25 years of experience studying genetics, bioinformatics, and cellular biochemistry, james has dedicated the last eight years to researching methylation and genetics to address health, mood, and behavioral issues within his family. Over the past year, he has developed the first saliva test for methylation based mood disruption called Mood Sense. Currently he is the head scientist at Somaticode, the company that owns Mood Sense. 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. So James, thank you so much for your time today.

James Bradshaw:

Thanks for having me on, Joanne. That's great. Glad to be here.

Joanne Kennedy:

Yeah. Great guys. I'm using this mood sense test all the time in my patients and getting really amazing results and I'm learning so much from James in particular around under methylation and over methylation. So I'm really excited to have James on the show and we are just gonna have a really good chat about what methylation is and how we can support methylation in clinical practice. So I'm putting my, James has got his scientist head on and I've got my naturopath head on. So together we are gonna try and make sense of this complex biochemistry. So James, I'm just gonna first start. What is methylation and why is it so important?

James Bradshaw:

So methylation is one of the most important things that nobody's heard about. Because when you are growing up even in the basic science classes, everyone talks about general biology. Probably most people have heard about a molecule called ATP, which is the energy molecule of your body. And everyone knows, you know, you need energy to make things happen. But what we don't always explain is how does the body know how to use that energy? And that's what methylation is. Methylation is the body tells the cells, tells your brain to make neurons to make the neurotransmitters. It tells the body how to metabolize the food you eat, how to regenerate your cells, how to get rid of poisons and toxins, how to deal with, you know, infections. That's methylation most of the time. If you ask a scientist about methylation, they'll only cover one part of it. And that is DNA regulation. Which is a big part of it. It methylation tells your cells when to turn things on and off, when to turn on making insulin and you know, to respond to sugar in your diet and when to turn on these things at different times in your life. So methylation is essentially the governing system that tells your bodyto use ATP here to make neurotransmitters. Use ATP here to regenerate a cut that you had. To, to do all the different things and. It's involved in everything, yet nobody knows hardly anything about it. In general.

Joanne Kennedy:

No, I know. It's kind of like,'cause I geek out on this stuff. I think that people do, but they, they, they really don't. Yeah. Yeah. It's fascinating. So it's like it is on like an on off. I always knew it was an on off switch, but it actually governs your entire biochemistry and how your body works.

James Bradshaw:

Absolutely. And, and so it's a really simple molecule. Um, and we're, we'll probably talk about this as we go along. The main molecule that your body makes is called S-Adenosyl-L-Methionine or Sam e. This is the molecule that is literally just an amino acid combined with ATP. But in that combination, that amino acid with that energy goes around and the body knows that when that is there, oh, I'm gonna turn this on, I'm gonna turn that off. So things are already ready and to go. But with this molecule, when it gets to the various locations, they, they generally know how to use it. But as with things, we're over simplifying the concept. It can be something that, especially when you throw, uh, a wrench into the machinery, can really disrupt things. And, um, it may be hard to get back on track, especially with all of the things that it affects.

Joanne Kennedy:

Yeah. So James, interestingly, like I know a, not a lot of people aren't sort of know about methylation, but I can tell you, and you know this, in clinical practice, people have methylation issues all of the time due to a complex mix of genetics and environment. So can you speak to our listeners about, I think, some of the main genetic mutations and environmental impacts that can disrupt methylation?

James Bradshaw:

Absolutely. So the normal, like let's say you have the perfect human being where everything is working as it should. The body is designed to, as it uses up the, these SAMe molecules, these meth, we call them methyl donors, um, they're the ones that are actually doing the methylation. When your body uses it, it creates a byproduct that then. Kind of shuts down the use and makes it so you don't overuse it. And then when you have too much of it, it has this feedback loop to bring it back. So we call this homeostasis. The body is really good at maintaining homeostasis when everything is working properly, and that's how it should be. You know, sometimes we need to increase our blood pressure because we're running and we need more oxygen and we need more things to our body. And, and so it does that. And then when we calm down, things change and that that's homeostasis. The problem is none of us are perfect. None of us eat perfectly. We're exposed to so many environmental and mental stressors that this homeostasis keeps getting thrown outta balance. And for some people, they actually have a genetic predisposition to not make enough of this methyl donor or, or not use it enough. And so they have excess amounts of this, um, kind of a buzzword today is M-T-H-F-R. You can go look that up, and most people have heard about it. The reason why this gene is given so much attention is because in the process of making, uh, SAM e the body has to use a vitamin called, um, vitamin B9 or folate. Now everyone's heard of folic acid. Folic acid is actually a synthetic version of, um, of a, the natural vitamin B9 that you would find in leafy greens, food, vegetables and such. And folic acid can be metabolized by people, but it has three steps. It actually has to be metabolized three different times. Now, the last step is a gene called M-T-H-F-R. And it's like the only one in this step. So it's almost a choke point that a lot of people focus on because if that gene's not working properly, then the process of creating these methyl donors can be, um, slowed down. Now does that cause a problem? It depends because there are so many other genes involved in making methyl donors using the methyl donors, recycling the methyl donors. We know just in the biochemical pathway alone, there are over 11 genes involved. So M-T-H-F-R is one of at least 11 genes that could be causing problems. and then you have to deal with all the other genes that aren't directly involved in making SAMe but use methyl donors. A lot of people have heard of the gene COMT. C-O-M-T. This is used in, a lot of different functions. One of them is neuro neurotransmitter recycling, but it's also used in recycling of other compounds that uses methyl donors. Sometimes if you look that up, people will say, oh, I've got a Fast COMT or slow, and they base their methylation just off of that gene. And so you, you kind of have these groups online where everyone focuses on M-T-H-F-R. Everyone focuses on COMT and it's, it's really more complex than that. So, yeah. Right. Yeah. Right.

Joanne Kennedy:

So it's, yeah, it's, I'm glad you brought that up, because people are very fixated on these genes, and I know I say I do M-T-H-F-R. But I'd say I do it because I'm trying to set people on the, on the right path. So they'll come to me taking methylfolate and feeling terrible. Mm. And so, yeah, I, I've, I learned that really early in the picture, James, that it's just mte is definitely not the be all and end all of ever of, of this whole cycle.

James Bradshaw:

Right. Absolutely. And you know, one of the things that we found too was, you know, even with all of the genetic mutations, there are so many other biological factors that have nothing to do with genetics that can affect methylation. Um, bacteria and the gut, the gut biome, and the foods that you're eating and the stressors that you're under, and whether you're fighting off infection, um, you know, all of these things play a role in that. Even your hormone levels, um, play a big role. One of the things that we learned early on was no matter what your genetic mutation is for the comp gene, um, estrogen and testosterone actually affect the rate at which that gene functions. So just your levels of hormones. Regardless of any genetic problems can also influence that. And so it, it was one of those things that as we were going down this path, because I started really diving into this over the last eight years because I have an autistic daughter that was having a lot of health problems and no one could really give us any answers. And I broke down her genetics and we looked at these things. And really just, I, I, I almost consider this my second PhD'cause I did that much effort and research on it, and we were able to find a lot of answers and do a lot of things. But in the development of the, the tests that you mentioned at the beginning, this was something we found to basically take all the guesswork out of what all of these different factors are. Because you can mentally think about them and say, okay, but where am I really? Am I over methylating? Am I under.'cause one of the things we found from a lot of the studies is you can have depression and anxiety on both ends. You can have issues on both end. It's not just depression is under and anxiety was over and whatnot. And so really we found that it was necessary to have a better diagnostic than just, you know, I mean, guessing can help. If you understand how it works, you can make a guess and push it one way and if it doesn't work, then you push it back the other way. But there's a lot of suffering involved in that process. Yeah.

Joanne Kennedy:

Educated guessing was kind of what we were doing because until we've, um, until I've seen my patients do this mood sense test every day, you would presume these women, they're women, right? They have MTHFR, maybe COMT. They are eastern dominant, they're high histamine. Very anxious. Uh, you know, you would presume that they were under methylating. Right, right. They're all over methylating. Yeah. And why I've always been, I've never given people methyl, like I just don't, because I just see people having massive adverse reactions to them. Yeah. Because we could never see in real time what their methylation was doing. James and I were talking about before the show. I've had a lot of patients do some methylation panel testings in blood or Dutch hormones testing in blood, and it comes back that they're sort of balanced or low methylation. But then when we test it in real time, they might be sort of normal, slightly under, and then when their hormones change, they're, they're severely over. So this is why it's so important to do it each, each day to actually understand. Yeah. Yeah. James. Great. I also just wanna, I'm so glad you said that about comp. So what I learned about comp. Makes sense to me is comped is impacted by the environment. So if you have a lot of estrogen, that that enzyme's just gonna be overloaded with estrogen, isn't it? Yeah, it does. You could be minus, minus fast comp, but it's, it's just, you're full of estrogen, so it slows it down. Yeah. Yeah, exactly. That's just how I, that's how I've always, that's what I learned and that's what I've always thought about comp, so there's no point in, it's just, it's just not good practice to supplement due to a gene. Right. And I know that this is happening all the time. Supplement companies, testing companies are, are giving you a report and giving you advice on what to take based on one on genes. Yeah. And it's never, ever helpful. It's often quite harmful.

James Bradshaw:

Well, it's interesting you brought up the, the histamine relationship because that was the kind of the gold standard years back is that if you had high histamine, it was always assumed that you had low methyl, because I. Your body should be able to take care of the excess histamine if, um, uh, regarding your methylation status. And, and so it was assumed that if you had high histamine, then you just had too, too low of methyls that you couldn't take care of it. And that if your methyl were high, you should have lower histamine. But there are genes, um, both in the gut and in the body that are responsible for getting rid of histamine. People can have genetic mutations on those, or they could have other gut microbiome problems that even if you have high methyl groups, you'll still have high histamine. And so, oh, it's, yeah.

Joanne Kennedy:

Yeah. That's what I see all the time. I see that all the time. I'd never even look at that histamine blood test. It's because, you know, the DAO enzyme takes the brunt of histamine in the gut and people have histamine issues often from SIBO and dysbiosis and oxalates and mold disrupting the microbiome. Right? So it's just a bit, you know, the DAO enzyme is so important when it comes to histamine that you just can't be looking at methylation and high low histamine. It's just symptoms of histamine are just so obvious and we can, I work with symptoms more than anything. So James, I really now want to ask you, um, so I'm actually gonna go straight into over methylating because I think this is just something that a lot of people aren't aware of how common it is. Mm-hmm. Especially with women. So can you explain to our listeners what exactly is over methylation and what, what are the symptoms, signs and symptoms? Which often are similar to under, I know that, but what are some of the signs and symptoms and the, maybe the classic key signs and symptoms of over? Yeah. And what is happening? Why are people over methylating?

James Bradshaw:

Okay. So, um, some of the classic signs there, even though there's similarities between over and under methylation, there are certain psychological, um, I, I'm not sure sure how you would classify them, but they're, they're states of mind that are very different for over methylation versus under. And one of the ways that my wife has helped me simplify them, because being a woman, she's basically spent a lot of her life over methylating. She is hitting perimenopause right now and she's finding herself becoming under methylating a lot of the time because of the hormone changes, which is fascinating. But she always found that when she was over methylating. Much of what she did, much of her anxiety was more internal, where there was self blame, there was rumination, uh, over things that you did in the past, things you just couldn't let go, hurts that you couldn't let go. She always wondered how I can let things just roll off my shoulders. Well, I grew up under methylating all the time. I didn't care about other people's feelings in general, as a lot of guys don't. And, and that is actually a psychological state of under methylation is, you know, you have this high competitiveness and perfectionism, but you generally are blaming outward and not looking internal and say, oh, it must be my fault. You're usually blaming others. Whereas over methylation, they tend to blame themselves. They, they, um, overthink and overanalyze. Now it's not that that, that's a bad thing because I think there is a need to. Think about the future, plan for the future, analyze what you're doing. But obviously when that's taken to an extreme, it becomes debilitating and almost paralyzing. Um, when we've looked at the level at which people over methylate, we've actually categorized them into a point where they get to a certain point. It almost becomes clinical where, where they just can't really make decisions because it's so overwhelming. Now, one reason why this is occurring is because. The methyl donors play a big role in neurotransmitter production, and so if there is too many methyl donors, the body will tend to overproduce neurotransmitters, and that overproduction is that overstimulation can lead to a lot of the psychology. That you see with over methylation, um, that, that inability to regulate, um, those, those neurotransmitter levels and it just becomes overwhelming. Um, there could be more to it than that, but that is the current hypothesis that we're going off of from the research that we have. Um, but there's been a lot of psychology done. There's a couple of institutes here in the US and I'm sure there's other places around the world. Um, but they focus a lot on the psychology of over and under methylation. And that's kind of where we got our start. And so they've looked at over 30,000 people over several decades and taken the full profiles. They've done the methyl test to see whether they're over and under. Um, most of their focus was on mental health, but a lot of the data that came about from this fundamentally gave us an understanding of. Over methylation and what it does to you psychologically? Um, I've experienced it myself, and I can tell you that it's almost impossible to fall asleep when, when you're just sitting in bed and your mind is so overwhelmed by everything, you're just running it over. When I was growing up, I never had a problem with sleep. I stopped moving and I'd instantly be out. But now in my older age, um, as I've not only methyl balance for the last, you know, seven or eight years, and I tend to over methylate a little bit more now because of that, I'm now experiencing a lot of this not to the extreme that a lot of women typically do, but enough that I can get an idea of how, how problematic it can be.

Joanne Kennedy:

Why is it the women can be more over methylating? It's obviously got to do with hormones.

James Bradshaw:

Um, it's a combination of, of hormones. But I've seen women that under methylate a lot and it that they tend to have genetic problems in the methylation pathway that make them under. So it's not as common, but I do see it. And uh, interestingly enough, we've had enough experience with people that we had someone, um, do their DNA and I, I knew them personally. I'm like, I bet she's an under methylator and got the DNA back and she was predisposed to be a big under methylator and then she'd take the test and they came out as under methylating. So estrogen plays a large role. It's obviously not the only factor. That's one of the reasons why women tend to over methylate in general more than men because of estrogen. But there's also the factor of ethnicity. Because I've done, I've looked at different groups and some groups tend to have women that over methylate more than other groups. And so again, it's a lot of the shared genetics. And where that predisposes you to and then how estrogen and other things. And then there's lifestyle and diet as well. Those play a large role as well.

Joanne Kennedy:

Interesting. James, do you know what, what ethnic groups are more prone to over?

James Bradshaw:

Caucasian, obviously. Um, yeah. We've had some data come in from Pure American Indians. They have like no methylation problems. Zero. And, and

Joanne Kennedy:

oh no, the Zen, of course, that makes sense. They were so zen.

James Bradshaw:

And so I found that interesting. You know, I actually did some genetic studies on, uh, she never told me anything about her background. This, this woman who was American Indian. And I did some DNA on her daughter, and I'm like. Was her father, Caucasian. She's like, how did you know? I'm like,'cause I could see the bad genes in methylation that he gave your daughter versus the ones that you have in yours. And I thought it was just so fascinating because it was such a stark contrast. We do see those of, uh, Mexican descent have some methylation issues as well, but not nearly as much as Caucasian. And then it's a little less with those that are black. And so we, we obviously don't have it from everybody, but when I've gotten different clusters, I've been able to see that. Especially American Indian, it's, uh, native Americans just have no methylation issues and so they tend to over methylate an amazing amount because there's nothing really stopping their methylation. Then they have estrogen and all these other things that.

Joanne Kennedy:

Oh, they do. Oh, okay. Sorry. So they're, they're over methylating?

James Bradshaw:

Yeah. But, um, but at the same time, I can see why with the men who don't have that, they tend not to under methylate as well. But here was the thing that I noticed as well in those groups is there comes a point where if you over methylate too much, and this is one of the, some of the highest numbers I've ever seen in our data, it almost becomes to the point where you become numb, where you don't even respond anymore because to, to the stimuli because it's so high that the body has just decided to be numb to it. And I've seen both extremes. I've seen that on the under methylating side and the over methylating side. And so there comes a point where it gets past what we would literally consider clinical relevance, where it's so high that they've just learned how to be numb to the emotions and then you just kind of see a whole different kind of psychology behind that.

Joanne Kennedy:

Is that kind of like learnt behavior over time?

James Bradshaw:

Yeah, I think so. I think so because everything that we've seen is that they were constantly this high. Like it was almost to the extreme of what we would see in, in our test. In terms of what it was able to measure. And um, I imagine,'cause I had coping mechanisms growing up with under methylating. I had ways that I had to deal with those, that psychology so that I peered fine on the outside, but internally there was a rage going on.

Joanne Kennedy:

Yeah, it's fascinating. Yeah, I think people, we all adapt. It's, we just need to, so interesting. So James, I just need to stick on this over methylation still. Are there any physical signs of over methylation?

James Bradshaw:

I'm trying to remember from the, the list we've seen that over or under there are issues with fighting off infection. Because inflammation isn't just an over under methylation thing. And the way that the body regulates inflammation has to do with obviously methylation. And so our response to stress and these other factors when, when you're on either extreme, both over or under, there could be some immune compromisation in the process. And so we haven't really done too many. I haven't looked too much into that physical aspect. Most of what we focused on is the psychology, but there are studies that show when there's an imbalance in methylation. That there's a higher prominence of cancer. And other issues because you're, again, one aspect of methylation is DNA regulation. And if you're not regulating the DNA, genes are being turned on that shouldn't. They're being turned off that should or that should be active. You know, a lot of times people will look at cancer and they'll think, oh, it's just a genetic mutation. It's something gone wrong. That is definitely not the case. there are health issues that come about with cellular regeneration and cancer being one of them that when methylation is off illness and sickness of a variety of type can be prominent. As far as any particular physical things we haven't seen. At least from my observation, we haven't seen an increase in say, you know, like rashes. Like if you had like autoimmune thing of that sort, but it could fall within that category. So we haven't really seen. Whether or not that's an issue, but I imagine it's related.

Joanne Kennedy:

Yeah. Interesting. So listeners, I'm getting a lot of my patients to do the mood sense methylation test. Usually these are sort of women that have been struggling with mood, or depression, anxiety, irritability, m massive PMS, mood swings. And they also have chronic physical ailments, right? Just chronic fatigue, chronic pain, chronic gut issues, et cetera. And I can't tell if they're over or under methylating from their symptoms. Really? And so just as a warning to anyone giving methyl b supplements out like candy. It's actually can be very problematic because what I've found in all of these women, it's all of them. James, this, I don't know, I've done like a hundred tests now, all of them. They're very over methylated. And when we reduce their methyl, and it is game changing for their mood. I spoke to my beautiful patient, she's in la she's listening. She'll know who I'm talk, I'm talking about Australian girl living in Los Angeles. She started doing that test and I spoke to her yesterday and yes, she did have a bit of a migraine when she got after a period, but it's lessening. I said, how's your mood? She's like, I haven't even thought about it. She's like, I'm just stable. For the first time in years, she has no anxiety, no overthinking, no depression, no agitation, no anger. Just so calm and. I'm just so excited about that because she's actually doing, um, nervous system work at the same time. It's the, um, the Gupta program and Irene Lyon's work. Um, I, anyone that's listening to this show, I talk about that over all the time. So it's somatic retraining and it's limbic system retraining. And I'm just very encouraged by how stable her mood is that I really expect her to see more improvement with the limbic training and the somatic work that she's doing on, that she's doing. And that when the limbic system and the nervous systems out of whack, you own chronic fight and flight, you're just not in rest and digest. So it's so hard to get on top of these chronic gut issues when your nervous system is just jacked up. And that's what it seems like. That's what these over methylators are. It's like their nervous system's just jacked up all the time. Mm-hmm. And so they, James, they must been in fight and flight. They're just in fight and flight, aren't they?

James Bradshaw:

Yeah. Yeah, I would imagine so. I mean, that. That's when the, the brain is supposed to increase and decrease neurotransmitters based upon situational awareness. But some of us that are, imbalance live with that all the time. And that's where you have the chronic anxiety, the chronic, because it's, it's puts you in a mental state because of the neurotransmitter excitability of, I should be in panic mode right now. Something's dangerous. I've gotta do something about it. But then once it becomes balanced, I remember the first time that I balanced my methylation. I had this feeling of euphoria that said, is this how normal people feel?'cause I, I hadn't, I hadn't felt that my entire life. It was so new to me because I had spent all my life in this imbalanced state. Now obviously I was under, but there's a lot of similarities between over and under in terms of the, the panic state that you're in because that fight or flight. And our body's meant to make those adjustments when there's a real danger, but then we're supposed to go back to normal. And so, you know, I I, I love hearing these stories of these women and, uh, that are, it's mostly women because it's very difficult to get men to care about their feelings enough to do something about it, or, or admit that there's something wrong with themselves.

Joanne Kennedy:

That's totally true.

James Bradshaw:

And that's a, that's a aspect of under methylation, it's very difficult for men to say, oh, there's something wrong with me. I should probably do something about it.

Joanne Kennedy:

Um, well, that's, that's, yeah, that's, it's really, really true. Before we go any further, I want to speak directly to the practitioners and students listening. If you are intrigued by histamine intolerance and eager to expand your knowledge, particularly around methylation and how to apply this understanding in clinical practice, 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. To learn more and apply, visit joanne kennedy naturopathy.com. So James, let's just talk about under methylation. what are the personality traits of an under methylator. Yeah. And I guess, can we, can you just chat, chat about some of the genetics, the popular Janes that could potentially be contributing to that?

James Bradshaw:

Yeah, absolutely. Um, so obviously there's the basic methylation issues. I, I guess we can start with the genetics first. Um, M-T-H-F-R COMT genes, testosterone works in the opposite way as estrogen. Estrogen slows COMT down, testosterone speeds it up. So, so that was something we, we learned in our development is that, again, this is one of the reasons why men tend to under methylate is because of the testosterone levels. But there's other factors as well, obviously. So, when you have disruptions in the methylation pathway and then you have all these other factors involved your body may not make enough Sam e and therefore you could under methylate to varying degrees. We have a scale that we use with the mood sense. It goes from negative eight to positive eight with zero being what we have found to be homeostasis or what your body is, is needing to be at, to, to have the, the normal methyl levels. I grew up at a negative four. So I spent most of my life as a major under methylator, and not only from my own experience, but from the research that was done by these institutes. perfectionism, competitiveness, aggression. Everybody else is at fault. I'm not to blame, you know, I'm not saying narcissism, but, but there is a level of you don't look inward as if the things, the problems in your life are your own issues. You're always looking at, well, it's somebody else's fault. And that's one of the reasons why I was able to let things roll off my back.'cause I never really took a lot of blame for the things that I did. Now that I'm older and more balanced, I can look back and be like, yeah, I was definitely to blame for that. Um, which makes me a better husband, by the way. Not my wife.

Joanne Kennedy:

No, no, it does. It's so true. It just, you just sound like you just, you're describing most men. Yes. No, I'm joking.

James Bradshaw:

Um, no, I, but, but that's, I just like on women, I have rarely found men to genetically be predisposed to over methylate. I have found some, and I've seen it in their disposition. They definitely have that inward. I'm to blame overthinking, over analyzing. They have the same symptoms of over methylating and, and when we do the test and look at the genetics, we, it comes out exactly as, as we observe. So, you know, but there's a lot, there's a, there's another psychology behind the under methylating because just like with over where you're producing too much neurotransmitter with under you're starving, you're not producing enough dopamine, serotonin there. There's other things that go into obviously neurotransmitter regulation besides methylation, but methylation does play a large role in the overall production of neurotransmitters. Um, you know, you do have to factor in genes like COMT and others that play a role in the neurotransmitter recycling as well. Um, but. Looking for that stimuli. This is why I think a lot of under methylators, kind of our adrenaline junkies are seeking that those dopamine hits, because having lower levels of SAM E, they're looking for that stimulus and we haven't necessarily seen whether or not A DHD and other things are. There's obviously some aspect to that that plays into this, where they're looking for that stimuli because we've seen, um, that A DHD medication is a stimulus, it does stimulate certain neural transmitters, so there is some aspect to that. There are other factors involved. But that's one of the things that I've seen beyond the normal personality of competitiveness. OCD. OCD is another thing that can play into under methylating. Again, these are generalizations. There's obviously a lot of other factors that go into it, but, um, uh, yeah, I definitely was a thrill seeker when I was younger and, uh, and as I got older. Interestingly enough, one of the things that we found that improves and increases methylation is exercise. Rigorous exercise, not just running on the treadmill for 10 minutes. I'm talking, I ran track and cross country in high school that did so much for my mental stability during that time in my teenage years. Because just as far as the science goes, exercising actually slows down neurotransmitter recycling and increases the availability of methyl groups. So, um, so it's, it's kind of a roundabout way, but it can actually increase your methylation having rigorous exercise. Now, case in point, I have a sister who is over methylating a lot. And when she runs her body feels good, but mentally she feels horrible because it raises her methylation and she's already an over methylator. And so she feels good because of the exercise and all of the things that it does, but she feels mentally horrible afterwards.

Joanne Kennedy:

So that's fascinating. I have a lot of patients have adverse reactions to exercise. Yeah. Yeah. James, what about someone that does a lot of running. Sort of like long distance running. Mm-hmm. And has chronic insomnia, like chronic insomnia? Potentially under

James Bradshaw:

That is a good question. I'm not sure.

Joanne Kennedy:

Okay. I've got him to do the test. I've got him to do the test. Okay. I would like, because when you, like, so if you're running, like if you're an endurance athlete running all the time, it's doing something. It will be impacting your methylation for sure.

James Bradshaw:

Right? Absolutely. Yeah. I guess it, it fundamentally will come down to all of the factors, his genetics, his environment, what he eats, all of those things. So I'm fascinated to see how that, how it affects insomnia and, and his situation because, um, you know, again, we have these generalizations for everything. But you're always seeing exceptions. You're always seeing individual.

Joanne Kennedy:

Just don't think you can. No, you just can't. From what I've seen with the testing, yeah, you just can't, you just can't generalize. You have to test and see. Yeah. Uh, so James, what are the common things that can cause low under methylation?

James Bradshaw:

So interestingly enough, one of the first things that we discovered as we were, um, doing the genetics research for my daughter,'cause we were wondering why she, she, she would, under methylate, we would learn later on she was under methylating, but we weren't sure why. And one of the things that we found was every time she would eat some food with a high amount of folic acid.'cause she has the mutations for the M-T-H-F-R, she, she is that we've clearly defined and that's what got us started in all of this. And so when she would have, um, here in the US we enrich our flour. So we put folic acid and all sorts of things in it, uh, synthetic vitamins. Um, and every time she would get something with folic acid and she would go into this rage. She would just be so aggressive and violent. And we were, we didn't know at the time, but now we understand that because of the mutation in the M-T-H-F-R gene, her, the folic acid was gumming up the system. It was being metabolized so slowly that her methylation was slowed down. She was under, methylating. And then, you know, her body would eventually catch up like the next day, but she would eat some more folic acid. So it was just this constant cycle of we knew the food was affecting her, but we did not know exactly what was doing it. Now here's the, the thing that we learned. You don't have to have an M-T-H-F-R mutation to be affected by folic acid. Because you, it, it still, there's been studies where they've shown, especially here in the US there's so much folic acid in our food that people have this uncirculating folic acid in their blood and it's actually interfering and acting as if they've got a genetic mutation in the MTHFR gene in terms of meshing up their methylation pathway.

Joanne Kennedy:

That, so that was, I love that you said that that was where we began It's environment. Yeah. What in the environment is impacting the way your genes express? Yeah, that's so fascinating.'cause there's so many other genes in that folate pathway that DHFR and all those other folate receptors and all of it. Absolutely. It's not just one, it's not just one gene in the folate pathway.

James Bradshaw:

And we, we found too that aluminum. Because you have aluminum deodorants, you have it in medications, you have it in a lot of things. Aluminum was a big disruptor of the methylation pathway. And sometimes they don't even have to say it. Like here in the US they, they churn ice cream on these metal surfaces and it gets aluminum in the ice cream, but they don't label it in the ice cream. And so there are actually certain brands that have a higher content of aluminum that's in your food. And a lot of times people will think, oh, I'm not getting an aluminum on my diet. It's in the cosmetics, it's in certain foods. aluminum is a large disruptor of the methylation pathway. I'm trying to think..

Joanne Kennedy:

What, what about all those? What about those B12 SNPs? MTR and MTRR and b12. Yeah, B twelves just such a thing. People are so deficient in B12 due to Yeah, stress and low and proton pump inhibitors and SIBO and things like that. But then you've got those genes that recycle B12.

James Bradshaw:

Yeah. MTRR recycles the B12 and MTR is then what takes it to make Sam e Um, and there Yeah. We've seen, um, interestingly enough, we've seen that people with certain mutations in the MTR gene, even though they don't have a problem making methyl donors, it causes them to fluctuate from over to under. We've actually seen it in some people. They're genetically predisposed to be at homeostasis for their methyl donors, but they'll over methylate one day and then they'll under methylate the next day, and then they'll over and they'll flip back and forth. And they'll literally have the classic signs of bipolar. Um, from that. And it's not that they have a issue with, um, methylation, but rather the body will rapidly make SAM e and then it'll exhaust itself, and then they'll go down to under and then it'll, so, so it actually causes them to fluctuate wildly in their methylation. Um, yeah. MTRR with the vitamin B12, that's something I've done a lot of research on. Here again, in the US, when they enrich foods, they don't add methylcobalamin or Aden cobalamin, they add cyanocobalamin and those cyanocobalamin is readily absorbed. It competes and is not usable. Like the body struggles to use the cyanocobalamin, but it'll outcompete methylcobalamin and Adenasol cobalamin, your body actually has to strip it down to even use it. And so it becomes a disruptor when you're using that synthetic. My wife had B12 issues most of her life, and she kept getting B12 shots, but they were giving her cyanocobalamin. Once she started getting methylcobalamin, she started doing a lot better because of, because of the MTRR gene issues that she had. So, oh, um,

Joanne Kennedy:

fascinating. But B12 is such a important part of the whole process. Yeah. So James, what about BHMT?

James Bradshaw:

Oh, um, so BHMT is the betaine, gene. When your body, here's one of the things we've interestingly found, there's two ways to make Sam e. One is the classic way of taking folate, vitamin B12, couple other, you know, important elements like zinc and making Sam e but there's an alternative pathway. Now this pathway is only turned on in the liver. It's not turned on in the rest of your cells. But the liver has this gene turned on and it can turn choline into betaine and then betaine into Sam e. And so betaine real name is Trimethylglycine. So it has three methyl groups on a glycine and the body can strip one of it off to make SAM e. And then it takes the dimethyl glycine and kind of puts it in the other part of methylation pathway and then it can use that second methyl group to do so. So betaine, through the BHMT gene. Can actually, we've used it sometimes when, when our kids back in the day had to eat some food with folic acid in it, we've actually given them betaine and it's temporarily corrected that problem because it's a secondary pathway to make Sam e And so it kind of alleviates some of the problems that folic acid causes, uh, with that. Now some people can have issues with that gene as well. Um, yeah. That's fascinating. We have seen, we have seen a small percentage of people with a mutation to where if they take betaine, it doesn't actually help them make Sam e so,

Joanne Kennedy:

wow. Fascinating. So it's interesting, I learned that when people are deficient in methylfolate, they're gonna be heavily reliant on that short route pathway. Yeah. Taking homocysteine to methionine through BHMT. Mm-hmm. That's interesting. And then you're just churning through your choline and you need that for, you need that for, um. Phosphocholine, don't you?

James Bradshaw:

Right. And will cannibalize itself to get some of that.

Joanne Kennedy:

Yeah. Yeah. So you can end up just deficient in choline and folate. Yeah. Yeah. So it's so folic acid is such a problem. So James, it's interesting'cause when I've seen my patients do the tests and they're over methylating, it's trimethylglycine that you recommend they take under, sorry. When I see my patients under methylating. It's trimethylglycine that they're prescribed instead of Sam e. Yeah. Can you explain why that is?

James Bradshaw:

Yeah, so Sam e um, at least here in the US I'm not sure, uh, where else, but Sam e is usually only prescribed in two doses, 200 milligrams and 400 milligrams. Um, and I know in other countries it's actually prescribed as a pharmaceutical here in the us it, it, um, you could just get it over the counter. I'm not sure how it is in, in Australia. Um,

Joanne Kennedy:

yeah, we can, we can just, but I can, I can prescribe it. Yeah, you can just buy it at Health Food store.

James Bradshaw:

So, um, Sam e when you take that, it's a huge kick. if you take, you know, 200 milligrams, it's gonna raise your methylation quite a bit. And the same thing for 400 milligrams. Not everybody needs that big of a kick. Especially if they're only slightly under methylating. You know, so betaine is one of those that it, you can do smaller doses or smaller increments of pushing methylation up. So, for example, a hundred milligrams of Sam e pushes up your methylation with the equivalent of 500 milligrams of betaine. And so you, you know, if you can't get less than 200 milligrams of SAMe yet you're only pushing your methylation up a little bit. That's why we generally, uh, per have people do betaine plus it's cheaper. It's pennies compared to. Yeah, because Sam e you have to keep it in these oxygen packets because it oxidizes from the air Yeah. So easily. And so it's a lot more expensive. You gotta package it right. betaine is a cheaper, it comes from the processing of sugar beets, and it, for most people works well and you can do smaller increments of methyl pushing your methylation up than the big kick that is SAM e.

Joanne Kennedy:

Fascinating. Yeah. Yeah, I was interested. Um, yeah. SAM e's expensive and has to be extorted in the refrigerator and come in an ice pack and it's, yeah, it's a bit of a nightmare. That's, and it's really expensive. Yeah. Yeah. Yeah. So, James, can you explain to listeners, um, why people should be taking niacinamide and vitamin C if they're over methylating?

James Bradshaw:

Well, um, def one of the things with vitamin C first as a warning is it's not for everybody because there no, it's not. There are people with oxalate issues. There are people that have a number of issues that I it could just make things worse. Um,

Joanne Kennedy:

and yeah, oxalates totally don't, if you've got high oxalates, don't take vitamin C.

James Bradshaw:

Yeah, no. And, but what vitamin C is, is a co-factor for the HNMT gene that methylates histamine. And so it basically supports the body in, in getting rid of histamine and using up the methyl groups. And we found that to that, that's one of the fastest working mechanisms. But as we mentioned, the warnings of, it's not for everybody. But we found it to have the fastest relief for lowering methylation because as that co-factor, it forces the body to essentially process. Now obviously if people have issues with histamine metabolism, it, it might not work as well. Niacinamide, which is a version of vitamin B three. This is something that your mitochondria will use and it actually has to methylate it to, to process it. Um, the reason why we recommend niacinamide is'cause niacin would work, but there's a lot of adverse reactions to niacin. Causes, you know, flushing and things of that sort. And it's not, the body has to first convert niacin into niacinamide, but that's not what uses up the methyl group. It's converting niacinamide and methylating that to use it up and get rid of it. It takes a while though. So niacinamide, the studies show that it could take up to four hours to really start lowering the methylation because it has to get into your cells, it has to work its way into the biology and, and. As we mentioned, you know. 50% of the Sam E is processed in the liver. The other 50% is in the rest of the body. And so it takes a while for the niacinamide to essentially be methylated and to lower your methylation. So we have found that when people take niacinamide, they won't mentally feel better right away. And, but it's usually, well, more well tolerated and especially has a higher impact on lowering methylation. So, for example, to lower methylation by a little bit, you need a thousand milligrams of vitamin C. To lower it by the same amount, you only need 400 milligrams of niacinamide. Interesting. Okay. So you need a much lower dose of niacinamide to have the same effect. So this is sometimes why we say if you take vitamin C right now to lower it a little bit and niacinamide at the same time, you'll get some lowering the methylation, and then you'll get the rest of the methylation, um, lowering through the niacinamide, but you'll feel mentally better right away. But again, that's if you can tolerate vitamin C. So a lot of times we suggest kind of a combination of the two, and we've looked for other ways of lowering methylation. The only other ways that we found that dramatically lower methylation aren't always the preferred method, although some people might enjoy it. Alcohol, fermented foods, a couple of things that might be enjoyable to lower methylation.

Joanne Kennedy:

Um, yeah, probably not a good, definitely not a good idea if you're high histamine.

James Bradshaw:

No, no. And that's what I'm saying too. You these things can complicate those other issues. And so, that's where a lot of food comes in. Chocolate is one of those foods that we know lower methylation. And so if, if chocolate is well tolerated, my wife always has her closet chocolate dark, it has to be like 85%. Um, which I can't say Wow, that's, but well.

Joanne Kennedy:

Because the sugar wouldn't be good food. Yeah. Okay. Interesting.

James Bradshaw:

No, no. But the chocolate itself, a lot of the things in the chocolate we found, has an effect. So food besides the vitamins can lower methylation. But again, it's one of those things where there are things that people can tolerate because of histamine

Joanne Kennedy:

Yeah. others that they can't. Yeah. It's just the big, um, the big problem is the oxalate people'cause dark chocolate's, high oxalate, and Right. Vitamin C is high oxalate. Right. But James, I've been the niacinamide. Do you recommend people take, um, say if they're, I think some people are very over methylating or mm-hmm. Prescribed what, like 1500 milligrams of niacinamide? Yeah. Should they take that all at once or in increments throughout the day?

James Bradshaw:

So, um, from what the research that I've done, niacinamide and niacin as a result, are very well tolerated at higher doses. I know, I know There's been a study and it's like almost one study that these people were on like four grams a day for weeks, and they saw obviously some side effects from that. Anything in that amount of excess is, is not gonna be good. Yeah. The only problem that we've, we've seen so far is that if you lower your methylation too fast, people tend to get headaches. we've actually seen people complain about headaches in, in two rapid of methylation change. So that is something to consider. Even though if you were to take a high dose of niacinamide and it takes a long time to kick in, like three or four hours, if it lowers your methylation according to our scale by more than three points, it can cause a severe headache. I don't know if you've seen that in some of your patients.

Joanne Kennedy:

Uh, James, I haven't actually checked with them. Yeah. It only, I only became aware of this the other day when one of my patients said, should I take it in increments or all at once? And I wanted to ask you. Yeah. So, yeah. Okay. So if, if you're a headachey person, probably just in increments, but probably in increments. Yeah. Yeah. I'm not, I'm gonna double check with my patients, but I can tell you my patients have had remarkable improvements in their mood. I'm talking like girls with PMDD who were rushed to hospital with anxiety. And then the an then the depression that's come from that, it, it fixed it. It's gone. Like their mood's stable. It's amazing. That's amazing. So, yeah. And then, yeah, a, a girl yesterday just reported back really, really stable. I just need to check with them if they're taking the full dose or what kind of dose they're, they're actually taking. I did have one lady get a headache, but she was a migraine girl. Ah, and this is the interesting thing, a bucket of histamine and, um, high homocysteine is a whole other conversation. High homocysteine and, um, totally over methylating. So James, here we go. What about homocysteine? High and low? Because I've got patients that are high and patients that are low. And you would presume if you're low, definitely If you're low homocysteine, you wouldn't be methylating, right? Well, but that's not necessarily the case.

James Bradshaw:

Yeah, that's the excellent point. So again, as things should function. The body, um, regulates what we call the SAM E to SAH ratio. So what is, what is SAH. SAH stands for s adenosyl homocysteine. And so as the body uses up Sam e, it. When it uses up the methyl group, it becomes SAH or basically SA homocysteine. And then that gets converted into homocysteine. Now what happens after that? Well, there's one way which the homocysteine can go, which is to be go down the transulfuration pathway, which makes cysteine, and then it goes into making NAC and then glutathione. And this is part of the detox pathway. So the body can convert the homocysteine down that pathway using vitamin B six and some other, um, minerals. And that's necessary to be able to produce the chemicals that the cells need to get rid of heavy metals and, and free radicals and all of those types of things. Homocysteine can be turned back into sam e two ways, as we mentioned. One is BHMT, where it will take it and, and, um, through the use of betaine remethylated it and turn it into SAM e.Or it can go through the other pathway, which uses vitamin B9, uses folate, vitamin B12, and then through MTRR and then MTR goes and makes semi, so homocysteine can be recycled basically three different ways. Mm-hmm. Well, there are things that can prevent homocysteine from being recycled that cause homocysteine to build up and, and really get elevated. And so in those ways it gets confusing because just like back in the day before we measured these things directly, people usually assumed if you had high homocysteine that you were an under methylator. Because your body should be able to metabolize histamine and get rid of it and make it low. So they, they kind of compared these two. But as we know, people can be an over methylator and have high histamine. The same thing for homocysteine. In general, high homocysteine means that your body is low in methyl because the way chemistry works is the more you use of some, uh, the more you use of a substrate, the more product you produce. The caveat to that though is as Sam e gets lower, the body will respond by trying to make more Sam e, but the excess homocysteine will fight it on that. But it also needs to survive. So there are situations where someone could have high homocysteine, but still over methylate because of the issues with homocysteine recycling. So interesting. So, you know, those are, those are not the norm. But that's, but that is something that has to be considered when, when measuring that, because

Joanne Kennedy:

I'm seeing it, James, I mean, these, I mean, they don't have very high homocysteine, but yeah, I think it was like 12 severely over methylating. And then one girl with like, homocysteine, like 3.2 and then she's severely over methylating. I just, it's like such an interesting eyeopener. Yeah. Yeah. So, but you know, for sure though, a lot of our patients with low homocysteine have big oxalate problems'cause of the sulfur depletion. Yeah. that they might not necessarily be under methylating that could be over due to, I think the body potentially is just trying to overcompensate and, right.

James Bradshaw:

Yeah. Yeah. Anyway, I mean, it's complex and that's, that's one of the things why it's complex. We have, we have these general things that help us, and then there's always things that throw us for a loop. Now, as a scientist, I love that because that's the opportunity to find new knowledge. When something doesn't fit our pattern, then we look into it. I mean, that's what got me started on this in the first place is

Joanne Kennedy:

yes, I'm sure this will keep you busy forever. Yeah. It'll keep you busy forever. Because I, what, from what I've learned with this testing is, uh, I'm no longer relying on homocysteine tests. Mm-hmm. To understand someone's methylation. I'm absolutely relying on it for an oxalate problem because it's, yeah. Very causative. I, I find that low homocysteine iss very often, but it's very low, like three, four. Yeah. But I would always presume. That they didn't have enough homocysteine to recycle back through to create SAM e. Yeah, but it's, but yeah, so, but it's not necessarily the case. My one girl, she had, um, massive adverse reaction to marijuana. And, um, she was, she got locked into a, like a frozen state and is now in severe panic. Oh wow. I don't usually take on cases like this, but her homocysteine was 3.2. I'm like, this just what is going on? And she, um, I just, I had to give, go her to do the test. The mood sense test, and she was severely over methylating. Yeah. I don't know how this all happened. Yeah. But this is why the test is so great, because it can just show us. And she's, uh, she was in a con she was a, she had the classic picture of an over methylator. Yeah. Yeah. Like paranoid.

James Bradshaw:

Oh, wow. Yeah. Yeah, it's interesting. I've, I've definitely, you know, there are, um, biochemistry, uh, things, things like a folate trap as we call them, and other things where it gets stuck in, in this cycle and it can't break free of it. And, um, so we see that chemically a lot going on with our cells. If something goes in, it can literally lock it into this cycle that you need some external intervention. Um, the, the best way I can describe it is when a woman goes through labor, she, the, oxytocin increases until labor is complete. But it's a positive feedback loop, so it will just keep building on itself until some external mechanism comes in and shuts it down. Most things in our body are not like that. Most things have a negative feedback loop where we produce something and it has some mechanism to come turn off the thing that's producing that. So there are a couple of mechanisms that can create these positive feedback loops. And there's definitely some things, especially when you're dealing with plants and other compounds that can really mess with the system. So that's really interesting that she Yeah. Is kind of stuck in that.

Joanne Kennedy:

Yeah, no, I've seen it. I've, I sometimes have patients come to me who have had. Uh, adverse reactions to drugs. Yeah. And, um, I've never sort of, I was like, oh, goodness, I don't know. But definitely we'll be doing the methylation test just to give us a baseline of what's actually happened. Yeah. Yeah. These pla plant compounds scare a bit scary. Yeah. Well, James, this is so, so fascinating. So I think I've got all my questions. So listeners, I know this is all complex, but I think the take home message is that we can now test methylation at home. It's a simple saliva swab test. It's available for sale via my website. I've actually got 10% off, um, for listeners of this podcast. So you can, you can find it on my website, joanne kennedy naturopathy.com. Just got a methylation test. You'll see it all there. So I encourage anyone, if you have considered that you've got methylation issues before, this test will show you in real time your methylation status is and what you can do about it, which is brilliant. James. That's great. Thank you. It's helping me clinic, it's just helping me clinically so much. And I was saying before patients that have, um, all these chronic health issues and when my, I, I said like this, I have become very hyper aware of nervous system dysfunction, trauma in the body and from long-term inner illness, childhood trauma, car accidents, surgery, chronic stress. All of these things are causing chronic, nervous system dysfunction. And it affects your parasympathetic nervous system, so it impacts your digestion. It impacts your hormone regulation and it throws the menstrual cycle out. And so people are coming to us with these chronic gut issues and multiple food intolerances that are outside a simple SIBO case. And then we've got the mold patients that it mold disrupts the nervous system. And so these patients, we send them off to do these, the limbic training and the somatic work, some of them don't really improve with that too much, James. So these are the people that I've found are severely over methylating. And so they try so hard and they've always, they, they do the exercises, but it wipes them out. Mm-hmm. Like these are simple exercises. And they're exhausted for the rest of the day, or they can only do a couple of a week because it's just so traumatic to their nervous system. And so these are, they're over methylating. So we're getting their methylation way more balanced, and they're so much calmer. And therefore they can start to move through this nervous system work. And they knock on effect is their gut health will really improve. And as gut health improves, well, everything improves. So this is how I'm using it clinically now. So guys, I met, I met James and his wife about three months ago, and they said, Hey Joe, we've got this methylation test. And I'm like, what is this test? And I kind of drilled them a bit on what it was and then have just sort of started using it. I just used it in my girls with PMDD girls that had been with me a long time that trusted me. They got great results. And now I'm just sort of getting more patients to do it. Collecting data and just seeing how I can work with it clinically just to, just to like, as a, um, an extra addition to my clinical practice. And I can tell you it's been really game changing and really exciting. I'm really happy you, James, happy about that. Yeah. So I'm sure I'm gonna have you on for more questions at some stage. I will definitely have more questions for you.

James Bradshaw:

Absolutely. Yeah. Thank you so much. It's been, it's been quite enjoyable to be able to find answers for ourselves, but then things that apply to other people. And that's really been the joy in, in doing this.'cause as a scientist, I spend my whole life just gaining knowledge, but to have something that can have a real life effect, real, real effect in people's health management has been really exciting. And, uh, we're really excited for what's next and, and the future. So,

Joanne Kennedy:

no, it's good. We love it. James, thanks so much. Thanks so much for your time.

James Bradshaw:

Thank you. Thanks for having me on.

Joanne Kennedy:

Welcome. 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.