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RHR: Methylation: Are We Supplementing Too Much?—with Dr. Kara Fitzgerald


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Methylation has been a popular topic in the alternative health world for quite some time. The ease of access to genetic testing and the ability to look at things like the MTHFR gene have led many people to be concerned about their methylation status, or their body’s ability to detoxify. However—as with many things in functional medicine—genes don’t tell the full story. Today I talk with methylation expert Dr. Kara Fitzgerald about the impact of diet and lifestyle on methylation and why supplementation can sometimes be harmful.

Revolution Health Radio podcast, Chris Kresser

In this episode we discuss:

  • Why methylation is so important
  • Why SNPs don’t tell the whole story
  • How to support your body’s natural methylation process
  • The concept of methylation adaptogens
  • When is supplementing with methyl donors appropriate?

Show notes:

Chris Kresser: Hey, everybody. It’s Chris Kresser. Welcome to another episode of Revolution Health Radio. This week, I have an interview for you with Dr. Kara Fitzgerald. She received her Doctor of Naturopathic Medicine degree from the National College of Natural Medicine in Portland, Oregon. She completed the first Council on Naturopathic Medicine-accredited post-doctorate position in Nutritional Biochemistry and Laboratory Science at Metametrix Clinical Laboratory, which is now Genova Diagnostics, under the direction of Richard Lord. Her residency was completed at Progressive Medical Center, a large integrated medical practice in Atlanta, Georgia.

Dr. Fitzgerald is the lead author and editor of Case Studies in Integrative and Functional Medicine and is a contributing author to Laboratory Evaluations for Integrative and Functional Medicine and the Institute for Functional Medicine’s textbook for functional medicine. Her latest ebook is The Methylation Diet and Lifestyle, which we are going to be talking about in this interview. She has published numerous articles in peer-reviewed journals.

Dr. Fitzgerald is on the faculty at IFM, is an IFM-certified practitioner, and lectures globally on functional medicine. She was formerly on the faculty at the University of Bridgeport in the School of Human Nutrition and is a clinical researcher for the Institute for Therapeutic Discovery.

Dr. Fitzgerald maintains an active blog and podcast series on topics related to functional medicine on her website www.drkarafitzgerald.com, and her clinical practice is in Sandy Hook, Connecticut.

I reached out to Dr. Fitzgerald because I read her excellent ebook on methylation, and she and I share a concern about how methylation is being approached in clinical practice, specifically the genetic tests that are being used to prescribe long-term, high-dose methylation protocols and some of the research suggesting that overmethylation may have some significant adverse effects and long-term risks. The genetic tests are really an imperfect way of determining what kind of methylation support is needed. There’s a lot to talk about. Methylation is a complex topic and I’ve already covered it a few times on the show previously, but this is a new and I think pretty important perspective to bring to the table.

Let’s dive in and talk to Dr. Fitzgerald.

Can too much methylation supplementation be harmful?

Chris Kresser: Kara, thanks so much for being here. It’s a pleasure to speak with you.

Dr. Kara Fitzgerald: Absolutely. And I am delighted to be with you today too on this important topic.

Chris: Before we jump into that topic, I’d love to hear just a little bit more about your background and how you got interested in methylation in particular.

Dr. Fitzgerald: Yeah, absolutely. So, by training I’m a naturopathic physician, and then I had the privilege to do a post-doctorate in Laboratory Science at the lab Metametrix, which was in Atlanta, Georgia. Now, it’s a part of Genova, but it was an extremely progressive lab. We were looking at the early “omics”—looking at organic acids, looking at amino acids, fatty acids, etc.

We were looking at you know how genes are behaving to one extent or another. We were looking at toxins. Actually, we offered a clinical test in the microbiome and so forth. We did some really really cool stuff, and then eventually, we had access to single nucleotide polymorphisms. We would dance through biochemistry sort of inferring imbalances and what might be happening at the level of the gene. I was also concurrently in clinical practice as well at the time and continued to be so, lecturing and working behind the scenes writing and educating other professionals. I’m staying as current as possible in the literature, and the epigenetic world just exploded. Being very interested in omics, I turned my attention there and began to look more and more closely at what was happening. One of the best understood areas of epigenetics is methylation, the methylation marks on DNA and other genetic material and what they’re doing and how their role in disease and health. It changed my practice as that data, as that research, unfolded, and it’s continuing to. We’re just in the middle of it now.

There are new studies being published just all of the time and our understanding there is expanding exponentially. As I looked at epigenetics, it really compelled me to pause. I came from this idea of like this orthomolecular influence, the right amount of a nutrient and the right dosing and you can affect biochemistry. You can influence the kinetics of a particular enzyme. I mean, that’s where I came from and I was really excited about that and liked to look at that in the lab, lots of various B vitamins and nutrients and so forth to really push reaction kinetics.

But with the advent of epigenetics, it just caused me to pause. I mean, what are we doing to the epigenome? And this was particularly true with high-dose B vitamins where a lot of us kind of jumped on in the age of single nucleotide polymorphism, and so when those became readily accessible and when we started to look at them more and more in our patients, even our patients treating themselves based on what they think they need to do, there was this wholesale movement towards really high-dose, aggressive supplementation. Layer in epigenetics and looking at hyper- and hypomethylation and a very strong association with really pretty much every disease out there, and I shifted internally.

Why Methylation Is so Important

Chris: We’ll have plenty of time to talk about that. I’m looking forward to it because I think it’s an important topic and is misunderstood, the topic, both professionally and amongst patients. But before we do that, I’d like to do just a little brief review of methylation and why it’s important. We don’t need to go into a lot of detail. I’m going to refer my listeners to previous podcasts I’ve done on this topic for more detailed background. But methylation is a concept that I think is a little tricky for people to understand. We often get a lot of questions about it as practitioners, and it can be difficult for people to get their head around. Given that we’re going to be diving into the deep end of the pool and talking about some of the problems with approaches to methylation, we should probably at least start with some basics for people who aren’t familiar with it.

Dr. Fitzgerald: Yeah, and absolutely just stop me. Cut me off at any point in time, Chris, and have me—

Chris: We can geek out, but we will leave a lot of people behind, so I’ll definitely do that.

Dr. Fitzgerald: Yeah, yeah, yeah. Ok, good, good. Well, it’s such a fundamental process. It’s almost nuts, it’s like mind-bogglingly fundamental. It’s happening in every cell in the body really pretty much all of the time. Either we’re making the universal methyl donor, which is adenosylmethionine, we’re making it, or we’re using it in some capacity, and we’re doing it everywhere. We’re using it not only to make DNA but actually doesn’t go in and alter how DNA is expressed. We’re certainly using it in the central nervous system, immune cells, and neurotransmitter production, as well as metabolism.

We use methylation to detoxify. We use it in the mitochondria and various phospholipids for cell membranes and so on and so forth and on and on. It’s incredibly fundamental. It’s happening everywhere all of the time and it has its tentacles in—really, what physiologic process doesn’t it influence?—and I think that reason, it’s difficult to kind of put your arms around it because of that level of threat.

Chris: Yeah, it’s so ubiquitous, it’s almost easier to talk about what methylation doesn’t effect, although that isn’t very much.

Dr. Fitzgerald: Right, right, right. That is a good question. I would say it’s probably not much. Go ahead.

Chris: And the other issue with it, I think it’s important to grasp how important methylation is to all various body systems and processes because that of course informs the discussion that we’re going to have about potential adverse effects of long-term, high-dose methylation supplement protocols especially when they’re not supervised because there’s so many different ways that that can alter the function of the body. We’re not just talking about one limited area. We’re talking about everything from detoxification to neurotransmitter production to metabolism to turning on and turning off genes that affect pretty much everything to hormone clearance. There are so many areas that can be affected, so we need to be careful.

Dr. Fitzgerald: You know, that’s exactly right, and because it’s so far-reaching, as we began to dive into the research and then really just put this program into place in our clinic, when you look in the data around how you can safely impact methylation, so you’re not always—and we’re going to go on this in more detail—but you don’t always have to lean on the obvious methyl donors—B12, folate, etc. Inflammation can negatively impact methylation whether you’re exercising or not, what’s going on in your gut, your microbiome, your mitochondria, what medications you’re using, the foods you’re eating, etc., etc. All of these things that we don’t think about as potentially influencing methylation do influence methylation and it’s here that I think we’ve got our strongest leverage points. It’s way upstream and look at diet and lifestyle.

Chris: I think that’s the good news about this show and if you’re pressed for time and you just wanted the takeaway, I’ll give it to you right now, which is that it comes back to the same thing: diet and lifestyle—particularly this ancestral perspective where we realign our diet, lifestyle, and behavior with our genetics and our biology. Continually, the reason that is such a powerful lens for me is that when things start to get really complex and they seem overwhelming, you pull back and you look through that lens and it often brings us back to the same interventions that we talk about all the time, you know, getting good sleep, managing your stress, eating the right foods, anti-inflammatory nutrient-dense diet, making sure that you are getting the right kind of physical activity, not too much, not too little. That’s the really good news. This can seem really complex and overwhelming and to some extent, when you dive into the details, it is. But from a practical perspective, what we all need to be doing about it is still pretty … maybe not easy, but simple.

Dr. Fitzgerald: Yeah. Well, I know it’s equally exciting for me too Chris. The more omics we have available … we’ve mapped the genome, we’re looking at the exposome and the epigenome, and the transcriptome, and the microbiome, etc., etc. … the more omics data that we’re swimming in, the more upstream we go and the more we remember: take a breath and get your sleep.

Why SNPs Don’t Tell the Whole Story

Chris: Yeah, exactly. Let’s look this up because this is a trend that has been bothering me for some time, and it’s one of the reasons I reached out to you to do this interview and I found your book and read it and enjoyed it. I thought, okay, this is someone who feels the same way about this and has done the research and understands the risk here because this is the phenomenon that we’ve seen. I think it’s starting to back off a little bit, but for a while, everyone was talking about genetic testing for methylation using 23andMe.

I had patients coming in to me with shopping bags full of supplements that were recommended to them sometimes by a practitioner, but other times by an algorithm that’s used from a website that interprets these genetic results looking at single nucleotide polymorphisms, or SNPs, and genes related to methylation, which we’ll talk about second. Then, the website actually makes supplement recommendations based only on these polymorphisms—not looking at any functional markers of methylation or the patient’s diet, lifestyle, or anything else—just making supplement recommendations exclusively on the basis of these polymorphisms and not telling the patient to ever stop taking those supplements. I had people coming in who’ve been on high-dose methyl donors and a whole bunch of other supplements, some of which really kind of conflict with each other, for years at a time. Let’s talk about what’s wrong with that approach.

Dr. Fitzgerald: I know. Gosh, I know. We’ve all seen that. I think anybody who’s working in this functional medicine space is seeing that and such anxiety, I think, too, with these single nucleotide polymorphisms. I had a patient exasperated. I think I mentioned her in the preface of my book saying, “I can’t detox. I can’t detox.”

Chris: Just let me add one more thing, I know you’ve seen this too. Some patient comes in and says I’m heterozygous for MTHFR A1298C, so my methylation is all screwed up.

Dr. Fitzgerald: Yeah, that’s right. That’s right, absolutely.

Chris:  Along with 30 percent of the rest of the population.

Dr. Fitzgerald: Right. At least. That’s right.

Chris: Let’s kind of pick this apart starting with let’s talk a little bit about the genetic testing: what it can and can’t tell us, how it should be used, what’s the appropriate use for that testing. Then we’ll move onto why jumping in and staying with a high-dose methylation supplement protocol may not be the best option even if we do determine that there is a problem with methylation.

Dr. Fitzgerald: I think there’s a place for SNP testing. I think it’s pretty cool. But they are, by definition, extremely common. I mean, we all have four million of them and I think it’s kind of interesting. I think when we use it as a sort of suggestion and when we go way upstream with how we address it, if we address mostly through food, etc., I think it can be a useful tool or if we allow it to guide us in healthier lifestyle changes, I think it can be useful. But the fact of the matter is, they’re incredibly ubiquitous; any single SNP isn’t associated with extremely strong data around it being a major deal breaker. They’re just risk factors. They don’t … they’re not shoe-ins for a disease. They are suggestive risk factors like MTHFR or the APOe’s have a little bit of stronger data around them and are worth paying attention to or working with the clinician to kind of pick through and see whether they’re making an impact and how you might support it. But for I think for the most part in this where we are now in the current state of investigation, we don’t have a lot of answers.

I think Chris, honestly, what’s going to emerge as systems medicine becomes more available to clinicians, as these big massive databases are more available to us, we will start to see SNP patterns emerge, a collection of certain SNPs being associated with increased risk. There’s actually a pretty cool 2011 paper out looking specifically at breast cancer risk and manganese superoxide dismutase cytochrome 1B1, glutathione as transferase, and a lesser extent COMT. In different patterns of this, these collections of single nucleotide polymorphisms, there was an associated increase, and in some cases pretty significant. I think we can use that to guide us in a much more effective way than just clinging to, you know, handfuls of SNPs and drawing conclusions about our health from that.

Chris: Right. And then, we can combine functional markers where we can look to actual predicted downstream effects metabolically of those SNPs and we can see if they’re actually occurring, which is what we do in our practice. If someone has SNPs that might predispose them to impaired methylation, but they have no functional markers of impaired methylation, then we’re going to approach that person differently than someone who has SNPs that suggest a risk but do have impaired functional markers that support that, and even someone who doesn’t necessarily have genetic markers of risk, but does have many functional markers so that methylation is not happening properly. It can be any of those permutations.

Dr. Fitzgerald: That’s exactly right. You always want to—to the best of our ability as clinicians, we want to dance around the various biomarkers that might give us some insight into what’s happening at the genetic level. Absolutely, that’s right.

Why High-Dose Supplementation Can Backfire

Chris: Let’s say we do that and we have a patient maybe homozygous for MTHFR C6770, which as you said, is one of the SNPs that has more research behind it than others, perhaps especially for people who have two copies, which is more rare than people who just have one copy, which is very prevalent, and then let’s say we look at their homocysteine and it’s elevated, we look at oxidized glutathione and it’s high, we see some other markers and we say, “Okay, this person has a methylation problem.” So far, the kind of approach that has been advocated most commonly (and that I’ve used myself at times) is to go in with high-dose B12, methylfolate, folinic acid, trimethylglycine, and all these other compounds, typically B vitamins but also some others that are a part of the methylation cycle. In your research, what is, what did you discover that gave you pause with doing this kind of approach for a long period of time?

Dr. Fitzgerald: As I said in the beginning, the research on the epigenome is just galloping ahead. There’s a lot of animal research. More and more human studies are coming out, there are cell studies, and so forth. But we know without question that hypermethylation of the promoter regions of DNA is associated with shutting down gene promotion or expression. When the promoter region is hypermethylated, then that particular gene can’t express, and that’s been shown to occur in many different disease states, but most powerfully and consistently is cancer. Really, virtually every type of cancer is associated with this promoter region, hypermethylation, and there are plenty of data at this point. The human stuff is still emerging, but it’s there to show that folic acid, I mean we’ve got a lot. We’ve been … we’ve been fortifying grains for a long time now, so we have more folic acid data than others, but it absolutely increases this potential for hypermethylation. So, higher dose foliate, folic acid exposure, leads to this hypermethylation state and it shuts down. It’s literally shutting down this gene expression in these genes, our tumor suppressor genes, for one, so our ability to fight cancer is inhibited, and we see this, like, the famous BRCA1 and 2 can be inhibited by hypermethylation. You don’t have to have the mutation. It can be shut down and participate in cancer oncogenesis that way.

Chris: With those when you were looking at folic acid, was there any differentiation between the effects of metabolized folic acid because of our inability to process that effectively versus high-dose methylfolate?

Dr. Fitzgerald: No, no. They’re not out there, but what’s clear in the research is that SAM-e, so production of CME, that’s the cofactor for DNA and methyl transferase enzymes, so anything that’s pushing methylation in any capacity. If you’re using those natural or bioidentical methyl donors, you’re going to be increasing CME production, you’re going to be pushing methylation reactions forward. We know that hyperhomocysteinemia, when you normalize hyperhomocysteinemia that hypomethylation of the epigenome also improves. I actually want to step back for a second, and again, just step in if I’m getting too complex. So, there’s promoter region hypermethylation that’s associated with many disease processes, most well studied cancer, so these promoter regions are shut down, tumor suppressor genes are also shut down. But in the rest of the genome, there can be methylation or hypomethylation, insufficient methylation, and interestingly enough, that insufficient methylation can be associated with oncogenesis as well, so these oncogenes can be allowed to be turned on because they’re not methylated. It’s an imbalanced methylation picture. Hypomethylation is associated with certain problems without question, and so we want to support healthy methylation, but we also don’t want to push it aggressively because there is suggestion that we can … it will lead to hypermethylation.

Chris: And I think we see this. I mean, this shouldn’t be surprising because we see this in other areas as well, where we know even looking at things more simply, that most nutrients have a U-shaped curve in terms of sufficiency. If you have no iron is a good example. If you have too little iron, you get anemia. If you have too much iron, you get iron overload, the effect of hemochromatosis, and that’s actually the rule for most nutrients. There are exceptions like B12 and vitamin C which seem to be tolerated at very high doses without obvious ill effects, except for potentially some of the ones we’re discussing now with B12 in methylation, but they’re not toxic in the way that other nutrients are. But typically, when you’re talking about nutrients that we need, we’re talking about a balance. We’re not talking about “more is always better,” and it shouldn’t be that surprising for us to see this in the world of methylation.

Dr. Fitzgerald: I was just going back to your other point—have we seen natural methyl donors influence DNA methylation? And so, there was a study that showed epigenetic methylation improved as homocysteine was treated and dropped. There are human studies absolutely looking at that and noting that shift.

Chris: Right. I think it’s a really good paradigm shift to start moving away from this mentality of oversimplified idea of, if you have a SNP, that means your methylation is not working, then you add these things, these methyl donors, and it fixes the problem. We need to move more towards this paradigm that you’re suggesting of balancing methylation.

Dr. Fitzgerald: Yes.

Chris: In some areas, methylation may need to increase, and in other areas it may need to decrease. We don’t have the knowledge yet to be able to approach it with that precision. But the body does.

Dr. Fitzgerald: That’s right.

How to Support Your Body’s Natural Methylation Process

Chris: We need to support the body and do what it needs to do. If we think of strategies for doing that in your book, you talk about two basic categories, things that can improve methylation but also removing factors that inhibit methylation. I think that second thing in particular, that second strategy has been the one that’s been neglected the most. Let’s talk about what are some of the things that inhibit proper methylation where we can intervene so that the body starts doing what it knows how to do naturally.

Dr. Fitzgerald: That’s a great question. I know this is where the rubber meets the road. So, we know that certainly if we’re not eating a good, rich, whole-foods diet that we’re not going to be ingesting adequate methyl donors, adequate protein. We want to make sure we have choline, choline is a major player, the full complement of vitamins and minerals.

Chris: I just want to jump in. You outlined very clearly in your book, this is really for people who want this level of detail, it’s awesome. She’s got tables with all of the nutrients that are supportive of methylation and exactly what foods you can find them in, which I really appreciated because that’s time consuming to do that kind of research, and you’ve done it for everybody to make it easy. You can just look at it and say, “Okay, I’m not getting these nutrients because I’m not eating this category of foods.” And when you look at that list, you see that you a need diverse, nutrient-dense diet, which of course, what we’re always recommending anyways.

Dr. Fitzgerald: But there are some, you know, some so-called methylation superfoods, and we’ve got our whole list where you can really lean on those, especially if there’s reason to. If you see these biomarkers or if you’re concerned about a certain SNP pattern, then you can lean on some of them, like beets, spinach, mushrooms, and eggs, again.

Chris: Organ meats are always on on the list, and then there’s shellfish.

Dr. Fitzgerald: Yup, that’s right and it’s good. I have to give a shout-out to my nutritionist, my co-author Romilly Hodges, because she just worked endlessly at putting together those recipes and getting all of that data that you’ve just mentioned. It’s an amazing labor of love and it’s really done well in our clinic. Our patients have responded to it fabulously.

Chris: Great. Okay, so nutrient-dense diet, we’ve got that one.

Dr. Fitzgerald: Yup. And we’re thinking about our microbiome, so all gut function in general, as you’ve talked about to your folks ad nauseam, but you know our microbiome is going to make or break methylation locally. It’s going to influence it globally and it’s also going to help make methylation donors like folate. And some of the microbiome’s major players can actually consume folate a lot, so do we have a nice balance? And it looks like most of the Bifidos are more likely to be folate producers, and there’s pretty interesting research out there looking at lowering homocysteine just using Bifido adolescentis, I think it was.

Chris: Interesting. That’s interesting.

Dr. Fitzgerald: I know. It’s so cool, just the Bifido. And this was actually in dialysis patients, so it was a select group of patients, but there is plenty of research out there showing that Bifido can make a lot of folate, whereas Lactobacillus tends to be consumers. We can think we can take care of our microbiomes not just to allow those nutrients to be produced, but just to nourish general epigenetic methylation as well.

Chris: And you mentioned before, chronic stress inhibits motivation, environmental toxins—

Dr. Fitzgerald: And chronic stress actually, as a poor diet does, chronic toxins, etc., lead to what we call aberrant methylation, or that hypermethylation occurring where we don’t want it and that hypomethylation occurring where we don’t want it, so that aberrant imbalanced methylation is going to be pushed hard with a high-stress lifestyle with insufficient sleep, with toxin exposure … Really, all toxins, you can see the metallic toxins, but lots of research on the organic toxins, the POPs and so forth. Sugar, just a poor-quality diet, can alter methylation in a powerful and lasting way, allowing for upregulation of inflammatory proteins, and then those inflammatory proteins will in turn alter or cause imbalanced methylation. It’s a web; it’s very interconnected.

Chris: Absolutely. And I think the more I think about methylation, I start seeing it more in the context as a mediator or a mechanism that sits between environmental inputs and then the expression of pathology and disease, and that’s how I understand the microbiome. Justin Sonnenburg has talked about the microbiome that way. Rather than seeing it as kind of a separate disease influence, the best way to look at it is as a mediator of all of the various environmental inputs and how they could lead to disease in the body. To use an example, poor diet leads to disruption of the microbiome, which then leads to inflammation, which is the root of all chronic disease. Physical inactivity causes adverse changes to the microbiome, which then leads to blah-blah-blah-blah. Stress causes changes to the microbiome, which leads to blah-blah-blah. And then, we have the same thing with methylation as sitting there in the middle as well. All the environmental inputs that we’re talking about, the way that they actually cause disease is via methylation, the microbiome, and some of these other primary mediators. And not only that, as you were just pointing out, these mediators affect each other. Stress affects the microbiome adversely, which then probably adversely affects methylation, which then adversely affects the microbiome, and it’s this vicious cycle or web. Again, it’s complex, but the simplicity is beautiful because it just comes back to doing the things that we know we need to be doing.

Dr. Fitzgerald: That’s right. And there’s a lot that we are already doing right, which is exciting. However, I do think this book is cool because we spent a lot of time doing a drill-down into, you know, how we can directly and aggressively address it, and we’ve seen that bear out with the biomarkers in our patients. One of the coolest, coolest areas of research for us that’s been just, gosh, it’s just endlessly exciting, is looking at these methylation adaptogens. Can I talk about this now?

The Concept of Methylation Adaptogens

Chris: Yeah, please. So, we’re talking about this aberrant methylation, this imbalance—the hypo and hyper, and what do we do about it? We know we have to have these methyl donors. We have to support global healthy methylation. So, we do all of that in all the ways we’ve already talked about, but how do we inhibit this hypermethylation process, or how do we allow for this balance? So, this is where this whole class of compounds that we’re calling methylation adaptogens—actually, that term was coined by my friend Dr. Michael Stone in Ashland, Oregon—these are compounds that seemed to have a balancing effect, and they are, again, players that were consuming all of the time if we’re eating a good whole-foods diet, they are all of our plant polyphenols.

One of the major ones that has clear adaptogenic properties is curcumin. It can actually promote healthy epigenetic methylation, as well as inhibit the process of hypermethylation at those regions, at those suppressor gene sites. Curcumin, sulforaphane, luteolin, lutein, lycopene is a big one, rosmarinic acid. All of our go-to polyphenol compounds seem to have this beautiful capacity to balance out methylation. And I think as research continues to come down the pipe, we’re going to see that these compounds that have long traditional use history act at the epigenome as one of their primary sites of influence. I mean, we know curcumin, you can look in data and find a zillion different mechanisms for it. I think a big one is the fact that it can augment epigenetic methylation expression.

Chris: I love this concept of adaptogens for methylation because it’s so much more in alignment with our understanding, what we’ve been talking about through the whole show, this concept of balance rather than hitting the gas really, you know, full pedal-to-the-metal sort of thing or slamming on the brakes, which seems kind of crude as a means of intervening in a system that’s this complex. I think, not to get too far off on this tangent, but this to me is emblematic of the kind of paradigm of allopathic medicine which is based in a kind of war. It often uses metaphors of war and attack, and this kind of idea that everything is separate and the whole is just the sum of the parts, and we have a sort of ultimate power and control and understanding, which I think is a complete fallacy.

Like anything else that’s worth doing and learning, the more we know, the more we realize we don’t know. And for me as a practitioner, that makes me want to embrace a paradigm that is more about kind of like tending the garden and facilitating, supporting, recognizing the wisdom and complexity of the ecosystem of the body and realizing that there’s still a lot we don’t know, and so the best thing that we can do is to support the body in doing what only it really knows how to do at this point. And I’ve used this analogy with discussion about TH1 and TH2 autoimmunity, like, this idea that we know how, we can just go in and support TH1 or TH2 and all these various disease states, which was pretty popular early on, which we now know is really, it’s not that simple. And the best thing to do is to support the T-regulatory cell function, so that the body can take care of itself and decide what it needs to suppress and promote. I think that that’s relevant here with methylation.

Dr. Fitzgerald: Absolutely. Just put the nutrients and allow the body to make the decision points. It’s just very cool. D3, retinoic acid, even DHA, all of these guys seem to have this epigenetic balancing capacity.

Is There a Time When Supplementing with Methyl Donors Is Appropriate?

Chris: So, let me ask you this. This is an interesting question that we’re exploring. I’m curious to hear how you guys are approaching it. Most patients I’ve seen, the diet and lifestyle interventions addressing all using a functional medicine approach basically, you’re removing factors that inhibit methylation, some of that is diet and lifestyle change, but some of it may also be, if there is a cause of inflammation like a gut pathogen, you have to address that, right? So, it’s the same kind of functional medicine approach. Many people will experience an improvement of their functional methylation markers like homocysteine. What about the patients who do those steps and for whom we go through the functional approach and address their various issues as well as we can, but their homocysteine is still, you know, 17, and they still have other markers of impaired methylation or imbalanced methylation? Is that where you’re using the adaptogens? Have there been patients for whom you have needed to use methyl donors for a shorter period of time? What’s your current approach there?

Dr. Fitzgerald: I do have some patients, I think we all do, who absolutely don’t tolerate methyl donors of any kind, either they have heightened anxiety, super-super-sensitive. For those folks, if they’re willing to jump in and really adapt to this, we can absolutely improve their biomarkers and lower homocysteine. They have to really hang in there with it—and their methylation index, you can look at SAM and SAH. You can see that improve with this program. No question about it. I might give them a little bit of choline as well, if they can handle choline, or just have them go heavier on eggs or a little creatine. We spend a lot of S-adenosyl methionine making creatine, a ton of it to just maintain muscle mass and energy. If you could do a little bit of creatine, that can be well tolerated, and that helps us well in hypersensitive people.

I don’t have a problem at this point using methyl donors and sometimes high-dose methyl donors, but I have an end point now. I absolutely have a clear end point, and we introduce the methylation diet and lifestyle principles to our patients immediately, and then transition them onto that more and more. So, we’ll move through the heavy therapeutic phase, which can include methyl donors, but they’re transitioning into the methylation diet and lifestyle principles, and we’re stopping the methyl donors. If somebody is an active disease process or they have been diagnosed with cancer, I might be a little bit more careful and really have very clear reason for using high-dose B vitamins and have a clear stopping point. I think in oncology we need to be way more conservative here than we’ve been.

Chris: Yeah, I agree, and that’s pretty much how we’re doing it. It’s interesting to hear you say. It’s kind of how we do it with everything. I mean, with the gut, we start off by doing testing and we find stuff that needs to be fixed, and we fix it often with supplements or sometimes medications. But then from there, we always want to move the patient to a prevention program where they’re eating plenty of fermentable fiber and fermented food, a gut-healthy diet, so they don’t end up in the same place again. And it sounds like with methylation, that’s kind of the same thing. In some cases, patients are going to need a heavier hand—it might not be the best word, but a more intensive intervention upfront to get them back into that range of tolerance. It’s like the engineering concept, once they’re in that tolerance range, it’s easier to maintain them in that range than it is to get them back there in the first place.

Dr. Fitzgerald: Yup. That’s absolutely right. Although I’ve been really kind of pleasantly surprised seeing just the MDL program work on its own and seeing those biomarkers that you would normally interpret as absolutely requiring high-dose methyl donors, not needing to do that. It’s pretty satisfying to see that happen. It’s really pretty cool.

Chris: Yes. I’ve seen that as well. Well, I wanted to just put in another plug for your book. It’s an excellent resource for people. There’s so much information about all of the various interventions from a diet and lifestyle perspective that can support methylation balance, including all of the tables with the various nutrients in foods and a much deeper discussion of everything we’ve covered, including the research on the danger of overmethylation or imbalanced methylation.

I really recommend it. It’s a great resource to have on hand whether you’re a patient just trying to work this stuff out yourself and make sure you’re protecting yourself, or whether you’re a clinician and you’re interested in a more balanced approach to methylation. I really recommend this. Kara was generous enough to provide a discount code for our listeners, which is kresser15. Where can they find your book? Where is the best place to get it?

Dr. Fitzgerald: It’s on our website. It’s a downloadable ebook. Just go to drkarafitzgerald.com and you’ll see a link right on the home page to the methylation ebook

Chris: Great. What’s next for you? What are you working on? What’s on the horizon?

Dr. Fitzgerald: Well, I’m about to jet off to Austin. I’m a faculty for the Institute for Functional Medicine. I’ll be doing the Immune Module, which is a lot of fun. Well, actually, Chris, you know what we’re working on doing that’s super-cool, I love doing my IFM stuff. But we … what we want is to research this. So we’re working on a proposal. We just really want to put it to the test and have as big of a cohort as we possibly can manage and then publish on it. Write it up, demonstrate what we’re seeing, use some biomarkers. I’d love, love, love to actually have epigenetic data. It’s not available clinically yet. It’s only accessible in the research setting, but I want to do that and just show that this upstream—well, hopefully show—that this upstream approach really can make a significant difference. That’s one of the most exciting things on my horizon.

Chris: Cool. That is really exciting. I can’t wait to see that data.

Dr. Fitzgerald: Well, I’ll keep you posted for sure.

Chris: Good. Well, thank you so much for joining us. I really enjoyed this discussion. I think it’s going to help a lot of people, both patients and clinicians alike.

Dr. Fitzgerald: Thanks for having me, Chris.

Chris: All right. Take care. Bye.


Join the conversation

  1. So I was recently diagnosed with Hashimotos Thyroiditis and Candida overgrowth as well as AS and heterozygous MTHFR. I was put on some supplements and after listening to this I am honestly more confused. My homositine levels were low (7) when checked about 4 weeks after diet change then added NAC 900mg, molyb 500mcg, and homocytex plus- which has riboflavin 25mg, b6 15mg, folate 800mcg Dfe, b12 1000mcg, and TMG 700 mg (obviously methylated)…. You talk about too much methylation in high doses but what is considered high dose? Are these doses too high???

    • Dear Bridget, you may be a candidate for dietary and lifestyle support rather than supplemental. It’s fine to try supplemental first to see if you see clinical improvements, but it sounds like MTHFR may not be playing as significant a role in your case since your homocysteine levels were already lower. Using other interventions to support methylation may be helpful, such as exercise, stress management, diet, and microbiome support. A full Functional Medicine assessment to understand your full picture and design a program for you is essential. Warmly, DrKF

  2. I am homozygous C677T. My Functional Med Dr. gave me Methyl Protect by Xymogen. Each capsule (one per day) has:

    Riboflavin (as riboflavin 5′-phosphate sodium) 25 mg 1471%

    Vitamin B6 (as pyridoxal 5′-phosphate) 10 mg 500%

    Folate (1000 mcg as calcium folinate and 1000 mcg as Quatrefolic® (6S)-5-methyltetrahydrofolic acid, glucosamine salt) 2000 mcg 500%

    Vitamin B12 (as methylcobalamin 1000 mcg 16,667%

    Betaine Anhydrous (trimethylglycine) 500 mg

    I’ve been taking it for almost one month. Am I ok with this? My Dr. said I may need to take a supplement like this for life. Do I need to retest at some point to confirm this?

    Thanks! I wish you were in Florida…

  3. So I got: high dose supplementation can backfire because of hypermethylation that leads to cancer. We all want to avoid cancer, right? Balanced methylation is diet and lifestyle. Yet seems each person has individual differences in body health…I have two copies MTHFR C677T and A129BC Heterozygous, IgE 880 after allergist prescribed immunology shots for dust mites and black mold for 8 months unable to build up to maintenance dose, and then xolair shots that did nothing to improve skin rash. I am no longer employed as a house cleaner. I have five multiple chemical sensitivities: Cobalt Dichloride (Vitamin B12 supplements/shots), p-Phenylenediamine, Disperse Blue 106, Fragrance Mix, Balsam of Peru. I have asthma occasionally from volcano vog. Because of B12 deficiency and Hashimotos I lacked energy to exercise with heavy fatigue thruout day. Motivated to get to a better place, I got rid of any fortified folic acid added to gluten free pastas, soups, breads, etc. Added more probiotics such as kefir, kumbucha, sauerkraut, bovine whey supplements. I also added hard boiled eggs, B12 organic and no hormone cheese to my “vegan” strict vegetarian diet of whole foods. I began methyl B-12 5000mcg andthen cut pills in half, alarmed about high dosing, yet wanted the narapothy foot cramps and itching burning palms and loosing balance to go away), added B-right vitamins, biotin 5,000 mcg, selenium 200mg, iodine drops, mega-magnesium drops 400mg, zinc picolinate 30mg, buffered bio C 1,000mg, and Curamin extra strength one tablet a day…(about $150 in supplements already at 20% health food store monthly discount). I am holding off on SAMe (main methyl donor) and 5+MTHF until I can afford to pay out of pocket to see local ND. I am pending appt with endocrinologist another island away. I know I already have done myself in with folic acid unknowingly at the time and the immunology shots putting more in body than can detox, allergist never heard of MFTHR as it’s not her “doctor speciality” didn’t care to learn either from this patient, sending letter to my general practitioner to refer me to dermatologist, endocrinologist, oncologist or rheumatologist who could help with “immune system” issues. General doctor finally referred me to endocrinologist and told me to see a NP. If I was actually working again and not on a fixed income, then I could readily afford an NP and your ebook! Still hanging in there another year

    • Some days ago I’ve just been discussing about it on FB.
      Someone was claiming that we need a hubris of supplementation and I pointed out my perspective which is 100% like this great article.
      Reductionism is everywhere and people seem unable to learn from errors. We have billions of variables working at the same time in a manner that even the most sofisticated software on the most powerful pc is far from scratching the complexity of biology. Despite this evidence everyday we see reductionism work at full pace, even among paleoists and alternative medicine community. Instead of drugs they push supplements with the same root problem. It’s not so easy guys.
      Supplements are definetly not harmless as someone led people to believe.
      Nature is extremely simple if taken as it is but it becomes the most complicated thing to conceive if we analyze every tiny piece of the web and try to interconnect everything.

  4. Hi, I would be interested in how Kara’s approach to methylation matches up with the Walsh Institute’s approach.

    • I very much appreciate Dr. Walsh’s work in this important area. There’s overlap, but other than Dr. Michael Stone, I haven’t really seen anyone else stepping back to take a big picture approach and incorporating specific dietary and lifestyle factors, microbiome connections, mitochondrial support and more. The potential risks of excess methylation beyond Walsh’s depression subtype, while abundant in the scientific literature, haven’t been widely disseminated yet: Imbalanced epigenetic methylation and disease association is an area we really need to be considering carefully. – DrKF

    • Hi Ruth, in general anything over the recommended daily intake of 400 mcg/d for adults could be said to be ‘high dose’. Therapeutic dosing is usually in the range of 800-2500 mcg/d, although we might go higher in specific cases such as Cerebral Folate Deficiency or severe depression. However, when we’re doing such high dose interventions we’re tracking with labs and clinical outcomes, and limiting the duration to as short as possible. We strongly recommend supporting total body methylation balance as we outline in the book as it will reduce reliance on supplements.
      My best,

  5. I know Dr Fitzgerald has mountains of Healing importance and
    Value. The time was so short and I wish Chris Kresser would let her use all the time!!!!

  6. Wow! Thanks so much for this information! It actually makes me feel better now that I decided against genetic testing because insurance companies in Canada use the information to remove coverage for certain diseases if you are “at risk”. I always felt like I was missing out because I didn’t know what I was predisposed to. I agree that the basic tenets of functional medicine and nutrient-dense diet will help reduce your chances of having your genes express problems. Great podcast 🙂

  7. After reading the conversation above, my question is would taking Bifido help the methylation process by the way that it works in the gut? Thank you, Gail

  8. WOW! Why is the book so expensive? ( even with the kindly offered discount) I guess it’s possible to get it in Kindle format. I like to keep all my books together. It’s really too expensive for most of us.

    • Hi Julia,
      I understand your concern – the book is primarily a resource for health professionals, hence the higher price point that reflects the rigorous scientific research that went into its development. Those who are familiar with the field of methylation/MTHFR will also be able to apply the information, even if they are not healthcare professionals–the dietary and lifestyle measures are especially applicable.
      We are going to be working on making information accessible at different price points – if you’re interested, make sure you’re on our newsletter distribution lists to receive the info.
      All my best,

  9. In your conversation above, when you referred to Bigido, are you saying that this would be a very positive form of probiotic to take in order to help mentholate?
    Thank you Gail Hunt

  10. Hi–
    I too had no time to listen but skimmed the copy and did not see my troublesome SNP– the CBS 699T– which is of more importance to me than my MTHFR A1298C, MTRR, BHMT, MAO A and NOS.
    Yes absolutely jumping into over supplementing w/ the wrong B-12 and folate can backfire– hard $$$ lesson learned for me.
    I have to say though for anyone who has been dealing w/ chronic illness for some time– Methylation is a key but not the whole thing. I think it underlies other issues– but these issues have to be dealt with first to heal– a Catch 22. Chris your interviews w/ Dr Ritchie Shoemaker on Mold/Biotoxin illness were stellar. To dig out of the hole– to keep from having to rely on a boatload of supplements– you MUST take care of air quality first. Its like Emergency Medicine– look at breathing first. If you are one of the 25% of the genetically sensitive Haplotypes– and don’t know you are currently or in the past have been exposed to biotoxins– you can’t supplement your way out of this. I have been dealing w/ Environmental Sensitivities– so am one of the 10% subset of the Mold/Biotoxin sensitive– a more rare canary. (12-3-52B and 7-3-53.)
    If you are chronically illl– make your living space a clean room. Check with a Mycometrics test first your environment– make sure it is OK. I am the most mold sensitive person I know and detect Stachybotris– but not all the molds and my space was keeping me sick as it was 2 x higher than the safe level. What I have learned on your site Chris has been very valuable– and also Survivingmold.com, Biotoxin Journey, and BetterHealthGuy. Addressing MARCoNS has been key for me as I have Sleep Apnea– which an 80K surgery was not able to fix. Not being able to breathe fully is a whole other topic and set of cascading issues.
    In summary– I think the genetic Methylation issues that many come into this world with underlie their genetic mold/biotoxin issues– but the major Mold/Biotoxin issues must be dealt with first– (move or remediate) then work with Methylation and Biotoxin together along with the other modalities described on the above sites. If I have known this 4 years ago I would have saved about 40K– as I have tried to detox out Heavy Metals using only Methylation with no luck. it is just that I start the Biotoxin Protocol with the binders that things are moving out.
    Thanks for all your great work Chris!

  11. hello thankyou for talk
    if you have low intrinsic factor score 1 in range 0-5
    can this be improved by diet or lifestyle ?

    • Hi Marcus –
      Assuming you have pernicious anemia and/or associated conditions– yes, diet/lifestyle/functional medicine is indeed beneficial! You might require (if you’re not already doing them) B12 and other nutrient injections.

  12. Thank you Chris for all of this information. It is quite overwhelming even though I have been delving into this for sometime. Over a year ago I hurt my back and was put on OxyContin and at the same time found out that I am heterozygous for the MTHFR. I went through a horrible withdrawal time from OxyContin after only being on it for 10 days, and when I was better I started the methyl folate full force because I was never told otherwise. I also did a holistic Lyme disease protocol. As a result my adrenals took a nosedive to say the least. just as a bit of background I was diagnosed with Lyme disease and Bartonella In the year 2004 and had been misdiagnosed for probably a couple decades at least, but was very asymptomatic and very healthy during most of that time. I had weaned off most of my benzodiazepines and Lexapro, which were the “Band-Aids” that I have been put on during the seven years that I was ill with Lyme disease and misdiagnosed as being “Just your hormones”. My functional medicine doctor has pretty much given up on me and I am using a coaching service that is on the West Coast to do with adrenal fatigue and how to heal it. I also see A holistic practitioner who is quite good and at this point attempting to get me off of the drugs, and help supplement my body while doing a mild methylation of about 1200 µg. You mentioned the Boffido(sp) bacteria which I do take on occasion. Would it be a good idea to take that consistently? And I would greatly appreciate any other suggestions. I have not started the holistic practitioners protocol yet, as I have had a difficult time with anxiety and stress, and would like to even out a bit first. He only prescribed it this past week. Your suggestions are most welcome! Many, many thanks. Gail

  13. I was recently diagnosed with Celiac Disease and am supplementing with OTC B-12 and D per my medical doc, as these are “low”. I’m currently working on The Paleo Cure and, while a bit intimidating for this layman, I think adding the Methylation Diet and Lifestyle to my arsenal will be a perfect complement. Hopefully soon I can review my need for supplements with this methylation idea in mind.

    Any other advice, cautions, or links to info on this topic (especially for those with Celiac) would be great! But in any event, I’ll keep on trucking with diet and lifestyle makeovers and see how it goes.

    Thanks Chris and Dr. Fitzgerald for all that you do!

    • Thanks for your generous words, Chris! Keep at it, make sure your doc is checking other nutrient deficiencies (you’re at risk for suboptimal nutrient levels) as well and working to stabilize the Celiac disease process.

  14. About two years ago, it was determined that I have the MTHFR gene and began supplementing methylfolate immediately based upon a recommendation from a practitioner that my body was not getting enough folate. After a camping trip, I broke out in a poison ivy type rash on my arm and hands after exposure to some firewood. The problem was that the rash came and went in the same exact place month after month for over a year! After trying a myriad of different things (topical treatment, diet elimination, etc.) I stumbled on some blog posts from Chris on this topic. Thank goodness! After connecting the dots and stopping this supplement, it cleared up immediately and hasn’t come back. Obviously this supplement was really disrupting my own methylation process to get rid of the poison ivy from my system. So strange.

    • Will, a dietary and lifestyle approach to methylation support would be ideal in your situation. Ideally, tracking methylation markers such as homocysteine, and folate/B12 status.
      Wishing you the best –

      • Fr. Fitzgerald,

        Do you know why so many practitioners recommend such massive doses of methylfolate? I understand using megadoses in pharmacologic amounts that are considerably higher than the amounts that are produced endogenously to achieve a treatment effect for depression (similar to taking megadoses of niacin for hypercholesterolemia) but, if one wants to replace the amounts of methylfolate that they are not endogenously producing due to an MTHFR polymorphism, why are such large doses being recommended? I have been unable to determine how much methylfolate is produced in the body daily, but I’m assuming that it is less than 400 µg since 400 µg of folic acid (which, as you know, is the earliest precursor in the chain) is enough to maintain serum folate levels in most people. Taking methylfolate in amounts that are supraphysiologic seems to cause a lot of problems unlike mega-dosing of other B vitamins so it seems that it should be treated similar to HRT we are you use doses that approximate endogenous production. Be curious to hear your opinion on this? Thank you so much for your time!

  15. Hey Chris, I like to recommend glycine to poor methylators – I find that taking precursors to glutathione, particularly glycine*, are sometimes better than taking glutathione itself. I know some Lyme patients will do the glutathione pushes, but the results are always quite temporary. Precursors can be used in the body for many different things, and are more suggestive than they are allopathic. Do you think glycine is an appropriate antidote to over-methylation?

    • Glycine is a great consideration for many reasons, not the least of which it’s participation upstream of MTHFR and its presence in the glutathione tripeptide. I think we underestimate the demand for glycine. Good call. KF

  16. When it comes to supplementing vitamins, say B-Complex, would choosing a “food state” brand be a good idea? My husband has atrophic gastritis and needs B12 injections. He also uses some methylcobalamin sublingual drops. He also takes a B-Complex supplement to hopefully balance things, but not always the same brand.

    • Hi Vivien,
      I think the B12 injections and sublingual drops are both smart/needed. Ideally he’s working with a Functional Medicine clinician to specifically resolve/improve the atrophic gastritis itself in addition to addressing the associated nutrient deficiencies.
      – DrKF

  17. To my mind this interview cries out for an executive summary. I skimmed through it – I’m sorry to say that’s all I’ve got time to do today – I grabbed a couple of decent takeaways, thank you – I’m just wondering if the supplement TMG is mentioned anywhere here and what the consensus is about it, if there is in fact a consensus.