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Methylation—What Is It and Why Should You Care?


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Revolution Health Radio podcast, Chris Kresser

Methylation is a vital metabolic process that happens in every cell and every organ of our body.  Life would simply not exist without it.  It takes place more than a billion times per second in the body. That should give you some idea of how important methylation is.  Anything that’s happening a billion times per second is probably pretty crucial to our survival and well-being.  It happens when one molecule passes a methyl group, which is a carbon atom linked to three hydrogens, to another molecule, so it’s a pretty basic biochemical process.  These reactions that occur when one molecule passes a methyl group to another make things like creatine, carnitine, CoQ10, phosphatidylcholine, melatonin, and tons of other really important substances in the body.

In this episode, we cover:

0:57  What Chris had for breakfast
6:36  What is methylation?
14:12  The developmental origins of health and disease hypothesis
20:52  What affects how the body methylates
31:58  Where to get testing and treatment

Steve Wright:  Hey, everyone.  Welcome to another episode of the Revolution Health Radio Show.  This show is brought to you by  I’m your host, Steve Wright from SCD Lifestyle, and with me is integrative medical practitioner and New York Times bestseller, healthy skeptic Chris Kresser.  Chris, how’s your morning?

Chris Kresser:  It’s great.  How are you doing?

Steve Wright:  Pretty great.  I’ve already had, like, seven vials of blood drawn off me today, so it’s been a good start.

Chris Kresser:  Oh, wow.  Getting some testing done.  Nice.

Steve Wright:  Yeah, it’s my annual checkup I do.

Chris Kresser:  Good.  Hope it goes well.

What Chris Ate for Breakfast

Steve Wright:  Thank you.  So what did you have for breakfast this morning?

Chris Kresser:  Yeah, Steve, we haven’t done that for a while.  I think the natives are probably getting restless!

Steve Wright:  They are.  They want to know.

Chris Kresser:  It’s good timing because I didn’t have my typical breakfast.  We actually tried something new this morning.  We had flourless plantain waffles.

Steve Wright:  Ooo, that sounds delicious.

Chris Kresser:  Yeah, we learned about this recipe from a friend, Jessica, who learned about it from The Paleo Mom, which I think is Sarah Ballantyne, right?

Steve Wright:  Yes, it is.

Chris Kresser:  I love plantains.  Anyone who has listened to the show for a while knows I eat them pretty regularly.  I often have them in the morning.  I will usually just slice them and fry them in a little bit of expeller-pressed coconut oil because that’s easy and quick, but there are so many great uses for green plantains.  They’re such a great starch carbohydrate source for people on a paleo type of diet, and I just had the idea this morning to write a post about green plantains and all the different ways you can use them that was inspired by my breakfast.  So anyway, you can make batter for either pancakes or waffles super easily by just taking green plantains, putting them in the blender with eggs and coconut oil, some baking powder, soda, a little bit of maybe nutmeg or vanilla extract if you want, blend it up, pour it in the waffle iron or on the griddle, and that’s it.  You’ve got great flourless pancakes.  We’re not even talking about nut flour or coconut flour here.  It’s just pure plantain as the base, and that’s 100% paleo.  It’s not a flour-based product at all, so I think it’s probably even a little bit better than the nut flour and coconut flour products, which are pretty easy to overeat because of how they’re broken down that way and processed in flour, and it’s even less processed, and they were delicious.  I thought they were great, so I’m excited about that, and I’ll get that post up soon with some recipes for how to use plantains in a number of different ways.

Steve Wright:  Yeah, that sounds delicious.  Now, did you use a waffle maker?

Chris Kresser:  We did have an old waffle iron lying around.  We occasionally, really occasionally would make, like, almond-coconut flour mix type of waffles, but we had to dig that thing out.  It was really quick to make them, and they were really good.  Sylvie loved them.  She was thrilled to be eating waffles, and that’s the only kind of waffles she gets, so she loved it!  We cut up some strawberries and put a little bit of coconut whipped cream on there.  It was great.

Steve Wright:  I knew there had to be some fat in there somewhere.

Chris Kresser:  Oh, yeah, and butter, of course.  But there’s coconut oil in the waffles, too, so there’s fat built into the mix.  Delicious.  Highly recommend it.

Steve Wright:  Awesome.  Well, before we get to this week’s question, I just want to let everybody know if you haven’t been over to, Chris has been spending a lot of time and energy and resources over there to redo the site and make it very easy to navigate and find all the work that he’s been doing.  And you’ll notice on the front page there that he has allowed everybody to get access to his 9 Steps to Perfect Health eBook.  This eBook was taken off the market for a while, and he has re-released it.  It’s a 63-page eBook, and obviously it has the 9 steps that Chris has been taking about for perfect health for a long time.  We’ve done a number of podcasts on these steps, but if you want the greater detail, including probably some references and hyperlinks and things like that, I’d really encourage you to go over to, put your name and email in there, and go ahead and get that eBook and start reading it today.

Chris Kresser:  All right, so we have another great question.  Thank you, everybody, for sending in your questions.  They’re coming in fast and furiously now, which is great.  Lots of really good questions, and it’s so great to have a show that’s listener driven because that way I know that we’re giving you the information that you want.  We’ve gotten a lot of good feedback on the new format.  People seem to really enjoy the shorter, single-topic episodes.  They like hearing from other people who are listening to the show, hearing their questions played back.  It seems to be working well, so keep it up.  Keep sending up your questions.  So let’s have a listen.  This one is from Leslie.

Question from Leslie:  Hi, my name is Leslie.  I’m homozygous for MTHFR defect on the C677T gene, and so is my son.  I have autoimmune issues, and my son is autistic, and my husband we know is heterozygous.  And I just wanted to know your opinion on treating these mutations, what you typically recommend for your patients, those that have the double gene defect and those with the single.  Thank you.

Chris Kresser:  OK, great question, and there’s so much discussion about MTHFR and methylation out there these days.  I’m sure this is going to apply to a lot of people or interest a lot of people.  Let’s kind of take a step back from Leslie’s question and cover some basics about methylation, what it is, why you should care about it, and then we’ll dive into the specifics because it’s a topic that can get pretty complex pretty quickly.

Steve Wright:  Yeah, I’m excited to cover the basics again because I swear they don’t stick in my head.

Chris Kresser:  Yeah.

Steve Wright:  Can you, just for my pleasure, Chris, and hopefully probably a few listeners, make sure to cover heterozygous and homozygous one more time because I always forget that, too?

Chris Kresser:  Sure, no problem.

What Is Methylation?

Methylation is a vital metabolic process that happens in every cell and every organ of our body.  Life would simply not exist without it.  It takes place more than a billion times per second in the body.

Steve Wright:  Wow.

Chris Kresser:  That should give you some idea of how important methylation is.  Anything that’s happening a billion times per second is probably pretty crucial to our survival and well-being.  It happens when one molecule passes a methyl group, which is a carbon atom linked to three hydrogens, to another molecule, so it’s a pretty basic biochemical process.  These reactions that occur when one molecule passes a methyl group to another make things like creatine, carnitine, CoQ10, phosphatidylcholine, melatonin, and tons of other really important substances in the body.  Methylation controls sulfur metabolism, which balances the need for methyl groups, glutathione to control oxidative stress, and other sulfur metabolites like cysteine, taurine, and sulfate.  Methylation influences the production of ATP, which is the fundamental energy unit of the cell.  If you remember back to your high school biology course, you probably remember ATP.  If the cell can’t produce ATP, then there’s going to be inadequate energy in the body, nothing will work well, and you get a breakdown or an impairment of your mitochondrial function.

So this is something that can affect pretty much every tissue and organ system in the body, as you can see, because it’s working on the most fundamental processes within the body.  Methylation, in particular, though, seems to affect certain systems more than others.  One of the main systems is the brain and the production of neurotransmitters.  With methylation defects, you see autism spectrum disorders, ADHD, all kinds of cognitive and behavioral issues, depression, anxiety, etc.  Those are really typical manifestations.

It affects detoxification.  As I mentioned, methylation is required to produce glutathione, which is one of the major molecules in a detoxification cycle, but if you don’t methylate properly, you won’t be able to detoxify properly, so what this can lead to is a higher susceptibility to heavy metal toxicity and toxicity from any source like pesticides, other environmental toxins and pollutants, mold toxicity, toxicity from lipopolysaccharide or any other bacterial or pathogen-based toxin – so just in a general, an increased susceptibility to toxic overload because the body is not able to detoxify properly.

Methylation also influences histamine breakdown in the gut.  A lot of people recently have become more aware of histamine intolerance and mast cell activation syndrome.  We’ve talked about those on the show, I’ve written about that a little bit, but what a lot of people don’t know is that one of the potential underlying causes of histamine intolerance is poor methylation.

So methylation can affect just about anything, but it seems, like I said, preferentially to affect the brain, cognitive issues, the gut, and the detoxification system perhaps a little bit more than most other things.  Those are the problems we tend to see clinically more than anything else with people with methylation issues.

A little more about the basics of methylation that’s important to understand is one of the most crucial functions of methylation is that it regulates gene expression, and by that I mean methylation controls the turning on and turning off, which is otherwise known as activating and silencing, genes, gene expression.  A methyl group binds to a gene, and then it changes the way that a gene expresses itself.  This is known as DNA methylation, and it’s one of the mechanisms that cells use to control gene expression.

Steve Wright:  Now, is this epigenetics?

Chris Kresser:  This is epigenetics.  When you go back to the age of Darwin and then the discovery of DNA, scientists basically thought that biological inheritance was something permanent.  It was set in stone.  You inherit the genes your parents gave you, and then that’s what you pass on to your children, and there’s no change.  It’s hardcoded, the DNA.  It doesn’t change.  But over the last couple of decades, we’ve learned that genetic inheritance is a lot more complicated than that.  We know now that environmental factors like diet and stress and sleep and toxins lead to molecular changes that are not encoded in DNA, so they’re not actually changing the hardware of the system, if you want to use a computer analogy.  But those changes are still passed down to children and even grandchildren, so even though they’re not affecting the hardware, they are affecting the software, and the software, in a sense, is passed down to the children in a way that can affect their hardware or can affect the health of future generations.

So you have this really complex interaction between the genes themselves and then all kinds of environmental factors that regulate and activate or suppress the expression of those genes, and that whole sum total of influences, things that we’re exposed to, that our parents were exposed to even before they conceived or at the time of conception, which is amazing to think about, and then what we were exposed to in utero, and then what we’re exposed to through our whole life is now known as the exposome.  It’s the sum total of all of these epigenetic influences that can affect our gene expression.  That’s a really new term.  A lot of this stuff is really new in terms of the understanding of science.  As you said, Steve, this is known as epigenetics, and I want to give you some examples of how this works because I’m sure a lot of people are kind of scratching their heads right now; it can be a little bit abstract.

A couple examples from the animal kingdom, and there are many, but one would be depending on the time of year that they’re born, baby voles are either born with a thick coat of hair or a thin coat.  If they’re born at a time of year where the weather is warmer, there will be an epigenetic change that changes the expression of the genes that code for hair production, and they’ll be literally born with a different coat depending on what time of year they’re born.  In fact, more accurately, the gene for the thick coat is always there for these voles, but it’s just either turned on or off depending on the level of light that the mother senses in her environment, so once again that’s a way that the environment interacts with gene expression.

There’s a freshwater flea called the Daphnia that produces offspring with a larger helmet and spines, which are protective mechanisms for the flea, if it’s born into an environment that’s crowded with predators.  I’m not sure exactly how that works, but I imagine there is some sort of stress signals that the mother experiences which then affect gene expression and leads to the infant flea being born with more protective mechanisms.

The Developmental Origins of Health and Disease Hypothesis

This works in humans, too.  Studies have shown – there’s a new one that just came out very recently – that a mother’s and even a father’s diet at the time of conception, so not even just her diet during pregnancy, but the father’s diet prior to conception and at the time of conception and the mother’s diet prior to and at the time of conception affect not only their children’s health, but their grandchildren’s health.  This article was actually called You are What Your Grandmother Ate, which is really a profound concept to take in.  I mean, it really kind of puts everything in a whole new perspective.  Our responsibility for our bodies and taking care of ourselves and eating a good diet is not just about our own health or even our children’s health if we have children, but our grandchildren’s health.  That’s probably pretty heavy for some people to contemplate, but we’re learning more and more about this, and it’s true even for fathers, which is really new.  We didn’t really understand the role that the father’s diet played in the health of the offspring.  It seems like that would be mostly, if not completely, related to the mother’s diet, but we now know that the father’s diet can cause epigenetic changes that affect sperm quality, and then the changes in sperm will affect the health of the offspring and even the offspring’s offspring.

Steve Wright:  I’m just really excited that my grandma basically subsists on coffee and dark chocolate.  I’m pretty excited right now.

Chris Kresser:  Yeah, an antioxidant-rich diet, right?

Steve Wright:  Exactly!

Chris Kresser:  We have another study that came out recently.  We’ve known for some time that kids who are born to mothers who have had C-section have a higher risk for developing obesity and metabolic disease and other conditions, and one of the main reasons for that is because of the effects of C-section on the gut microbiome, but scientists have actually identified another reason, which is that C-section births cause changes in gene expression that then contribute to these potentially lifelong changes in health.  Now, that doesn’t mean if you’ve had a C-section your child is doomed.  The good news about epigenetics is that a lot of these factors which we considered to be unchangeable before are, in fact, modifiable by changing the environmental influences.  The bad news is that environmental factors like C-section and poor diet and everything can alter gene expression in a negative way, but the good news is that a good healthy diet and then fixing the gut microbiome and all the things that we talk about can have positive changes on gene expression in the future.

Steve Wright:  Yeah, it takes that whole ‘I got dealt a bad hand’ and now you realize you get to go fish as much as you want.

Chris Kresser:  That’s right!

Steve Wright:  You can throw the cards back in and go pull some others.

Chris Kresser:  Yeah.  I mean, certainly there are factors that are more modifiable than others, so it’s not like we have complete control over this.  There are genetic factors that we can’t change that influence our health, but I think we’re learning more and more that we have a lot more control and influence than we thought we did.

The last example in humans of how methylation can affect gene expression and how that translates into lifelong health is something called the Developmental Origins of Health and Disease hypothesis.  This is a theory that came out of research by a scientist named Barker, I think, in the ’80s in the UK, and he noticed that rates of heart disease were increasing in the UK, and everybody thought, oh, this is a disease of affluence; the rates must be increasing because people are eating more rich and fatty food, etc.  But what he noticed is the highest rates of heart disease were actually in the lowest-income communities where they definitely were not affluent.  He was puzzled by this, and he did some research to figure it out and found that the people with the highest risk of early heart attack before the age of 65 later in life were people who were born at the lowest birth weight, which indicates poorest nutritional status of the mothers.  So what he pieced together was that if the nutritional status during pregnancy is poor, that triggers epigenetic mechanisms in the developing baby to hoard calories when it’s born because essentially the baby senses that it’s being born into an environment of scarcity because it’s not getting the nutrients that it needs to thrive.  In the body’s wisdom, at a time when that was actually true, when there weren’t many nutrients, it would have been a survival advantage for that baby to be born with a system that would aggressively store whatever nutrition was available.  Then these babies are born and they have a much higher risk of obesity and metabolic disease and, thus, cardiovascular disease later in life.

Really fascinating stuff, and methylation is one of the main mechanisms that controls this turning on and off of genes.  So that’s the background.

Steve Wright:  Just to wrap this area up, the pre-training for the answer here, in case anybody was as curious as I was, a vole is kind of like a mouse.  It kind of looks like a little mouse.  I was really confused for a long time here.

Chris Kresser:  Right, I should have said that.  A little rodent-like creature, yeah.

Steve Wright:  Yes.

Chris Kresser:  Thanks, Steve.  This is why you’re here, one of many reasons, actually, so my runaway brain doesn’t get out of control.

All right, so let’s get back to Leslie’s question, and I still am tracking your question, Steve, about heterozygous and homozygous.  We’re going to talk about it in this next section here.  Leslie notes that she’s homozygous for MTHFR and has family members that are heterozygous, and there’s autism and autoimmune disease, which as I described earlier, those are fairly typical manifestations of methylation defects because of the effects of methylation on brain and immune system, detoxification, etc.  She wonders how you should treat those mutations and what you should do.

What Affects How the Body Methylates

Well, again, we need to kind of take a step back here and look at why methylation goes wrong in the first place and how you figure out what the cause of your methylation problems is or what the causes are and then what to do about it.  There are many things that affect how the body methylates, but they can really be broken down into two categories.  One is genetics and the other is environmental factors.  The environmental factors would be gut health, diet, exposure to toxins, stress, all of the typical environmental factors that we talk about on this show that affect our health.  But then there’s genetics.  There are several enzymes in the methylation cycle, and if you want to geek out a little bit, you can go to Google and type in ‘methylation cycle,’ and you’ll see lots of crazy charts with lines going everywhere and connecting.  It’s a pretty complex cycle.

Steve Wright:  Makes my brain hurt.

Chris Kresser:  Yeah!  You can find some simplified versions that are a little bit easier to understand, but it’s an extremely complex metabolic cycle, and it involves the action of several enzymes that are coordinated.  Mutations in certain genes that code for those enzymes can lead to decreased activity of those enzymes and, thus, decreased activity of methylation in general.  The most important enzymes in that cycle are MTHFR – that’s probably the one that’s best known; it stands for methylenetetrahydrofolate reductase – and then CBS, COMT, VDR, MTR, and MTRR are other genes that are involved in the methylation cycle.

Now, we inherit these genes from both parents.  You get genes from one parent and genes from the other parent, right?  If you have two copies of a mutated gene, you’re considered to be homozygous.  That means both of the copies of the MTHFR gene that you have that you inherited from parents are mutated.  If you’re heterozygous for a mutation, that means you have a single normal, non-mutated copy of the gene and then you have another copy that’s mutated.

Generally with genetic conditions, homozygous mutations are more serious because you have, of course, two mutated copies of the gene and whatever that gene does, whatever enzymes that that gene codes for are not going to be produced as effectively when there are homozygous mutations.  Depending on the gene and the mutation, a homozygous mutation can be quite serious in some cases, like with familial hypercholesterolemia, a genetic mutation that leads to very high levels of cholesterol.  If someone is homozygous, which means they have two copies of the mutated gene, they will often die in their 20s if not before that because they are completely unable to produce LDL receptors for their cells, which means they’re unable to clear LDL out of their circulation at all, and that leads to a very high LDL particle number, which leads to atherosclerosis, which leads to heart attack and death.  People who are heterozygous for that mutation tend to have very high total cholesterol levels, like over 300, 350, 400, even into the 500s.

That’s a very serious homozygous mutation that can be fatal, and even the heterozygous mutation can be quite serious, but with methylation, even if you have the homozygous mutation, you have a decreased activity of that enzyme of about 60%, so you have only 40% of the normal enzyme activity.  In many people, that will produce symptoms, but not in everybody, so that’s an interesting thing to understand about these methylation effects.  And then with the heterozygous mutations, depending on what genes are affected and what the specific nature of the mutation is, you’ll get varying levels of decreased enzyme activity.  In some cases, a heterozygous mutation isn’t really associated with much of a decrease in enzyme activity at all.  In other cases, it’s associated with more of a decrease.

Then, of course, those environmental factors are not isolated from the genetic factors, right?  You have someone with a genetic mutation for MTHFR and maybe some other mutations in some of the other genes, like CBS and COMT, and that person has been exposed to mercury, they’ve had SIBO and leaky gut and many other gut infections, they are extremely stressed out, they’re sleep deprived, they’re not exercising, they’re eating a poor diet, and then you compare someone with the exact same genetic picture to somebody else who has a healthy gut biome and a great diet and is exercising and managing stress and sleeping well.  Logic and clinical experience both would dictate that those people will have probably very different actual methylation capacity because of the influence of environmental factors on genetics.

Steve Wright:  Do we also have to take into account here, Chris, that just because you’re homo or hetero on one of these different genes, it might not be actually be switched on or off, the methylation of it?

Chris Kresser:  If you’re homozygous or heterozygous, it’s a good question, but it indicates that that mutation of the gene is there and there’s very likely to be reduced activity.  It’s a little bit different than the epigenetics of whether the gene is switched on or off, but it’s actual mutation in the gene itself.

Steve Wright:  OK.

Chris Kresser:  This is a change in the hardcoding.  It’s not an epigenetic change.

So if you have these genetic mutations, what it means is you’re more likely to have methylation problems, and that typically would manifest with low levels of folate, of adenosylcobalamin or methylcobalamin, which are the active forms of B12; S-adenosylmethionine, or SAM; or other metabolites in the methylation cycle.  It also typically leads to low levels of reduced glutathione, which is the beneficial form; possibly high levels of oxidized glutathione, which is potentially harmful; high levels of S-adenosylhomocysteine.  You get a buildup of homocysteine in the blood, which is an inflammatory molecule.  There are all these potential markers for poor methylation, and then this in turn leads to increased susceptibility to toxins, impaired detox capacity in part because of the glutathione, increased susceptibility to infections because of the immune dysregulation that causes histamine intolerance, depression, anxiety, chronic fatigue, infertility, and miscarriage.  Methylation defects are a very common cause of infertility and miscarriage and a whole array of other problems.

But as I mentioned before, the really key thing to understand is there isn’t a one-to-one relationship between mutations in the methylation cycle and actual methylation problems and symptoms.  Methylation mutations are not like mutations in genes that cause things like sickle cell anemia or cystic fibrosis.  If you have a mutation in that gene, it’s virtually guaranteed that you’re going to develop those conditions, and that’s not how it works with methylation.  There’s a lot more of a range in terms of how people are affected.  The best way to think about it is as a predisposing factor that could potentially lead you to having problems with methylation depending on all the environmental factors that we mentioned and probably some factors that we don’t even fully understand yet, including the interaction of other genetic mutations that you might have.

This is where this stuff starts to just get really, really complex, yeah, and it’s one of the reasons why I’m excited about genetic testing and the potential for all of these tests to help us clinically to treat patients as clinicians and also to get treated as patients, but I think we need to be cautious about extrapolating too much from these things.  I think we’re really kind of in the infancy of understanding how these mutations affect health in general and how other mutations in the methylation cycle will affect the basic mutations in MTHFR, which is the most common enzyme that people often check.  There’s a lot of work out there, like the work of Dr. Amy Yasko, that speculates on the influence of all of these other mutations in genes like COMT and CBS and VDR.  And when you start getting into that, as anyone who’s listening to this show if they’ve looked into that at all, you see that it’s a real hornet’s nest.  It’s like, OK, if you have this mutation, this kind of cancels out the effect of this other mutation, but then you have to look at this other mutation gene to see what effect that will have, and people who go down that road often end up taking about 52 different supplements based on all this mutations, and the evidence base for how those mutations affect one another is very thin.  We have evidence definitely on MTHFR and how those mutations affect human health, but beyond that, there’s very little information in the peer-reviewed scientific literature about CBS mutations or COMT or any of that sort of stuff.  That doesn’t mean that some of the clinicians out there who are on the frontier aren’t right, and it doesn’t mean that they’re not doing valuable work, but it does mean that if we’re going to stick with the scientific method, we want to see these things studied and reproduced, especially when they lead to patients spending a lot of money and making big decisions about their health.  That’s just a kind of sidebar.

Steve Wright:  Yeah.  This is where we’re entering into the art of medicine.

Chris Kresser:  Absolutely.

Steve Wright:  And there are people that can really benefit from those doctors, and I know of several.

Chris Kresser:  Yeah.

Steve Wright:  But I think it’s a great point that let’s differentiate these and make sure people know what they’re in for.

Chris Kresser:  Yeah.  Lack of proof is not proof against, as I’ve often said, and we need more research here.  It’s just something to know that some of this stuff falls into the realm of clinical experience, which is totally valuable in many cases, but we need more research.

Where to Get Testing and Treatment

Let’s just talk briefly about testing and treatment.  The genetic testing, one of the best ways to get tested is  A lot of people know that the FDA shut them down from doing health interpretation of their data, but the good news is you can still get the raw data.  It’s 99 bucks, I think.

Steve Wright:  Yeah.

Chris Kresser:  You go to, you order it, and when you get the results back, you can go to a few different sites to get it interpreted, get the methylation genetics interpreted.  One of them is  You go there, you click on Methylation Analysis, and it hooks up to your 23andMe data and it spits back a report.  A much more comprehensive report is available at, and this can give you information that will probably just totally confuse you unless you have any training in this area, but it’s something that you can then take to your functional medicine practitioner for interpretation.

Steve Wright:  And you’re liable to learn really fascinating things like what I learned, which is that I have a genetic defect for being prone to sneezing fits.  I always thought that it was just that my inflammation was really high, but I’m just prone to sneeze.

Chris Kresser:  Yeah, and you can learn if you’re homozygous for MTHFR.  That’s useful information to have because it’s likely you’ll have a tendency toward folate deficiency and low glutathione and other things that we talked about before.  It’s really good to know that.

But as I mentioned, genetics do not always predict functional methylation capacity, which means how you are actually methylating.  I really believe that we need to be testing both of those things as clinicians because one doesn’t, as I said, predict the other necessarily.  There are different ways to test functional methylation capacity.  Doctor’s Data has a methylation panel blood test.  Health Diagnostics and Research Institute has a Methylation Pathways Panel that’s good and I tend to use in my practice.  Genova has a Complete Hormones profile that, among other things, looks at the ability to convert proliferative estrogen metabolites into less proliferative metabolites, and those conversions are methylation dependent.  So if you see poor conversion happening there, that’s a methylation issue.  The urine organics acids profile from Genova has some methylation markers, active folate and B12 deficiency.  And then a urine amino acids profile can be helpful to look at taurine levels and levels of other metabolites in the methylation cycle.  Those tests can be helpful.  You can talk to your physician or functional medicine clinician about that.

If you have decreased methylation on a functional panel, then you would probably want to initiate a methylation protocol.  Those can really run the gamut.  Lots of people approach them differently.  One of the most popular and commonly used ones was developed by a great researcher and health advocate named Rich Van Konynenburg who sadly passed away last year, I think.  But if you search for ‘Rich Van Konynenburg methylation protocol,’ you’ll find it.  I do recommend working with someone on this because there’s a risk of over-methylation if you become too aggressive with the methylation supplements.  That can cause its own problems.  When you start methylating, you’re going to be up-regulating your detox capacity, so that can cause a lot of die-off type of symptoms as your body starts to clear toxins that have been stored for a while or latent infections, things like that.  It is something you can do on your own in the sense that a lot of the supplements that are used, like B12 and folate, are pretty safe, but it’s better if you can find some supervision because it can be kind of difficult to work through sometimes.

This was a little bit longer of an episode than normal.  It’s a pretty complex topic and hard to cover in a 20- or 25-minute format, and I know we’re only scratching the surface, but I hope this was helpful, Leslie and everyone else that’s listening, and we’ll come back to you next week.

Steve Wright:  Yeah, thanks, Chris.  Obviously this is a new area of research and new area of clinical experience, and so definitely the takeaway, I think, here for Leslie is to get the extra next-level testing for all of her entire family to figure out where those genetic defects are actually causing issues or if they are causing issues because we don’t know that data yet, and then from there, a protocol could be created based on that test results.

Chris Kresser:  Yeah.  I mean, it’s likely they are in her case because she mentioned autism spectrum and autoimmune disease in the family and those are typically correlated with methylation, but they’re also multifactorial, many different causes, many different possibilities.  But it’s definitely good for you to get that functional methylation testing, Leslie, for you and your family.  Steve, thanks for being here, and we’ll see everybody next week.

Steve Wright:  Yeah, thanks, Chris.  And the light bulb just went off in my head from sixth grade science or maybe seventh grade that a homogeneous solution is one that is completely dispersed and a heterogeneous one has the solids, and so if we think back to our genetic question of homozygous and heterozygous, then you can learn whether they’re both copies or one of the other copies, so thank you.

Chris Kresser:  Yeah, if you talk about a homogeneous culture, you’re talking about one that’s very similar; everything’s kind of the same.  Heterogeneous is more diverse and varied, so that’s another way to think about it.

Steve Wright:  Perfect.  Well, thanks, Chris.

Chris Kresser:  All right.  Take care, everybody.

  1. Do you think that midline defects like having a tongue tie are caused by poor maternal methlyation? Quite a lot of children I know (including my son) were born with tongue ties. I was taking folic acid at preconception, and was wondering if that may have been a factor.

  2. This is a topic I’ve just started researching, and I’d be so interested to know what protocol you tend to use with your patients who are have symptoms of MTHFR problems.

    I appreciate that you make such a clear connection between these symptoms and our environment. It’s not JUST our genes, and it’s not JUST our food, and it’s not JUST our guts…but it’s all of them, and everything else!

  3. Hi. I am prepared to purchase a Case Review with Chris. However, I have a question before I do. I had a full hysterectomy in 2007. (I am 48.) So, obviously, I know that many of my problems are related to hormones and that I will mosy likely require some type of hormone replacements. My question is: Is Chris able to “prescribe/recommend/sell” any type of hormone replacement? Or will he just tell me what I need, and then I would have to be seen additionally by a doctor to actually receive hormone replacements?

    • Lithium has something to do with the ability of B12 to get into our cells.

      The best source of info on this that I know of is Dr. Amy Yasko. She’s written a little about it, but I think the concentrated info is in a talk she gave. Check the listing of free web-casts or downloadable talks. You can always email the office and ask which one it is.

      ‘Sorry not to be more specific. It’s on my list of things to study but I haven’t gotten there yet.

  4. Really appreciate the very interesting discussion. thanks for the links. Anyone recommend a book on this topic? hopefully with references/studies??
    Thanks, PLM

  5. THANK YOU!!! One of the best explanation videos! I will be passing this on. Unfortunately out of 14 MTHFR I am double on 9 of them and single on the rest except 677 all the others you mentioned they are mutated as well along with BHMT all double and MOA. I have had great results with medigenics supplements especially vessel care. Literally felt like my brain turned on. I tried to do paleo for years and continued to get more exhausted then I found our I have a mutation 4,3 in APOE. WOULD LOVE YOUR INPUT ON THE APOE MUTATION. Since April I added back servings of complex carbs and eating every three hours and things are much better. Do you have any wisdom on the APOE?

  6. This is a very good write-up on methylation and I say that as someone who is very tired of reading sketchy or inaccurate information on this topic. It would be great if you could also touch on the consequences of oxidative stress and co-factor deficiencies. Here’s an example of what I mean. In some disorders, methylation happens under conditions of oxidative stress and inflammation. For example, B12 is a vital co-factor for methionine synthase, an important enzyme in the methylation cycle, and oxidative stress can cause B12 to be oxidized. So even if you have adequate nutritional intake and normal plasma B12 levels, you can have a functional deficiency of B12 which impacts methylation. I don’t hear enough about the impact of factors like oxidative stress on methylation since the conversations all seem to center on static polymorphisms like MTHFR C677T. It would be great if you could touch on this along the way.

  7. I am homozygous for the 677 gene and have MS. I take methylated b12 and folate, eat very clean, no gluten, very low sugar and low dairy and make my own non-toxic cleaning fluids. I take no MS drugs but do take LDN (low dose naltrexone). I have done exceptionally well with my MS 6 years counting (much to the amazement of my neurologist who wants me on the MS drugs) but before my diagnosis I was very sick.

    It is a struggle to maintain my gut health though-I guess I should go back and research histamine intolerance again. When my gut gets screwed up my general health goes south (achy joints, headaches, low energy). I would like to get to the point where I have it all figured out.

    • Some gut bacteria are potent histamine producers – eg. streptococcus, morganella morganii.

      Suggest getting some gut testing to see if you have an overgrowth of any histamine producing bacteria.

      I’m also homozygous for C677T and also have these bacteria lurking.

      You can also try natural anti-histamines such as stinging nettle, quercetin, Vitamin C, black seed oil (Nigella Sativa) and quercetin containing foods.

      Best wishes, I know how difficult all of this can be!

    • Hi Sara,

      I was reading the comments on Chris Kresser’s blog about methylation and I read yours. I wanted to put you in contact with
      Terry Wahls MD on Facebook. I’ve listened to her on a couple of summits and she’s great. Go look and see, she’s a doctor with MS, who went from a wheel chair to bicycling. She did it through, DIET. Good luck 🙂

    • Dr. Yasko finds that people with SHMT SNPs have a hard time maintaining a healthy gut, especially in relationship to balanced flora (and therefore leaky gut). She doesn’t say a whole lot about SHMT mutations nor how they relate to gut issues–I suspect it is simply clinical correlation on her part–but I have found taking her SHMT+ RNA quite helpful. (It is expensive, but nothing else has worked for me, and I’ve been in functional medicine for years.) My best guess as to why it works is: SHMT relates to methionine levels. Cabbage juice, which is high in a particular form of methionine, is one of the best ways to heal gut ulcers. So I’m thinking that rebalancing SHMT function gives the digestive system mucosa better access to methionine such that it can repair itself better. It has certainly made it easier for me to eat foods which used to give me canker sores or otherwise bothered my mouth. Jury is still out (haven’t been on it long enough yet) about whether it will finally allow my gut flora to stay balanced.

      You can read what she has to say about it (just a few paragraphs) in her book “Autism: Pathways to Recovery”. It’s available to download for free on some of the pages of her website, as well as can be read on Scribd (with an account, but the first 30 days are free).

      • My family has SHMT mutations. When we compared our 23andme results with extensive labwork and docs we’d ccollected describing the various SNPs, we realized that the severe deficiency of glycine we all have is related to this mutation.

        Apparently, glycine is a key amino acid for healing the gut lining (along with glutamine).

        I’d be interested to know if anyone else has any thoughts on how to get the SHMT working optimally, and any experience with high dose glycine supplementation.

        • I’m not aware of having glycine issues, personally (and I have had amino acid testing done). I don’t like to take it, as it puts me in a stupor – super sleepy and can’t think (glycine is an inhibitory neurotransmitter).

          Glutamine (not glycine) is the amino acid which can be helpful for gut healing; and, unless there is some very new information available of which I am unaware, glycine does not convert to GABA, glutamate, glutamine or glutamic acid (which all interconvert with each other).

          Someone must have misspoken recently, because all of a sudden there are all these Yasko chat group people saying that glycine can convert to glutamine. Not that I’ve ever heard of (if you have the reference for this, please let me know. I’d like to see what’s up).

          • Glycine and glutamine are definitely different amino acids -I’m not aware of anyone confusing the two.

            They both are inhibitory neurotransmitters and they both are necessary for healthy gut function. We have not had any issues with sleepiness related to glycine. But our amino testing has recommended supplementing with 2-4g of glycine. It is helpful in bile production and building connective tissue. Proline is another good one for gut health. Good food sources for both are gelatin and bone broth.

            • Can you say any more about how glycine relates to connective tissue integrity? I understand the connection to bile production, but the other is new info to me.

  8. hello chris,
    since you’re in the bay area, are there any practitioners you can recommend for folks who want to work under the supervision of someone trained to handle this issue?
    thank you in advance!

  9. I am so frustrated with these articles. You say you know people who can help treat someone like me who is homozygous for C677T. Please let me know who in the Austin, TX area? So far all you have done is stress me out more than I was before I found out about MTHFR. Who has training in this area please! Your words: “A much more comprehensive report is available at, and this can give you information that will probably just totally confuse you unless you have any training in this area, but it’s something that you can then take to your functional medicine practitioner for interpretation.”

    • You can run your results through the MTHFRsupport utility for about $20. It gives you a report. You can Google Roberts Heartfixer Methylation for a good overview by Doctor Roberts of the various mutations.

      Focus on your red ones and genes where you have multiple yellow mutations. See what you can figure out on your own.

      Then, download Amy Yaskos Pathways to Autism and look through her descriptions. They’re more in depth, and realize she’s applying this to children with autism, not you, so take it with a grain of salt.

      Then, get some good nutritional testing done, including vitamins, minerals, aminos, and heavy metals, and reread the material with your results in hand, and you’ll get a better understanding.

      To be honest, there are very few doctors with much experience in this, and those that are are very busy people, as you might imagine. To find one, go to the Institute for Functional Medicine website and look for a provider there. And sift through them to find one on your health plan, not cash only. And one that can spell MTHFR and nutrigenomics. This is cutting edge stuff and many doctors aren’t there yet.

      And treatment will require high quality supplements, which will likely cost $2-300 per month. And, as you begin to work your issues, you’ll find the list will change over time as you prioritize which problem to work in what order.

      Being an educated consumer is the only way to tackle this for now, even with a top quality doctor who knows their stuff. It’s worth the effort and has dramatically improved our quality of life.

    • Gina I think the MTHFR Support website lists practitioners in different states with experience treating the methylation cycle.

    • You can also run your 23andMe results through Genetic Genie or Know Your Genetics (supported by Dr. Yasko). I believe they are both free. ‘Not sure how much info you get with either of them, but I’d guess that at least Dr. Yasko’s provides some. In any case, either will take your 23andMe raw data and convert it to a chart that names the methylation SNPs according to the nomenclature used in these discussions (the 23andMe raw data uses a different cataloging/naming system).

      By the way, for those debating about getting gene testing done: 23andMe is cheaper ($99) but is less accurate (accuracy rate of 70-80%, if I remember correctly) due to differences in testing methodologies, and the use of saliva rather than blood. The blood spot test which looks at only the 30 SNPs (e.g., Yasko’s or through Drs. Data) has an accuracy rate somewhere in the low 90s–but costs in the high $300s to $500 depending on who runs it (it’s worth asking your ND how much they would charge for it, if they have a Drs. Data account.)

  10. Thanks for this. I know I have at least one MTHFR-related mutation but I can’t remember if I’m homozygous or heterozygous. I think the results told me my methylation capacity was only reduced by about 33%. I had already taken steps to ensure that when I supplement vitamins, I only supplement the methyl folate and methyl (or adeno) B12, just in case, and I think I will continue that practice. Every little bit counts, I think.

  11. Yes, I have compound hetero MTHFR and food high histamine makes my ears ring/yell. We need help with this 🙁 also, my doc found that much out and I don’t know if I need 23andme or not. Thank you! I just made banana egg pancakes with no screaming ears thanks to you 🙂

  12. While “one of the potential underlying causes of histamine intolerance is poor methylation” may be true, the other side of the coin is: excessive folate or folic acid supplementation fosters higher histamine as well as increased cell proliferation. So genetics need to be known vs. guessed/assumed/bypassed, appropriate supplement amounts need to be determined and not be excessive (as they often are as rx’d by some NDs or the public just making assumptions), and personal/familial history of allergies, asthma, hives, angioedema, and cancer need to be taken into account in relation to folate supps (and this is almost never done).

    • It takes some real effort to go so excessive with any nutrient that you are hurting yourself with it. The little bit that any researcher has bothered analyzing pre-industrial diets, we find that they habitually had intakes of micronutrients much higher than what we consider sufficient now. And nutrient values in foods vary widely; the USDA’s database is all averages! So it’s not realistic to tell someone, “Only get 100% daily value between diet and supplementation and go no higher.” 150%-200% is the more likely scenario if you’re eating enough and eating varied enough, and sometimes it goes even higher. I know that taking a nutrient in isolation changes the equation somewhat, but some foods have one or two nutrients in much greater supply than the other nutrients they contain, which has pretty much the same effect.

      That said, I wish SOME nutritional supplement company would come up with a multi that just contained 100% daily value for each nutrient. That would be a true supplement and safety net, and there would be much less risk of overdose. Not that there’s a great risk to start with, if you follow label instructions.

      • Actually it’s not difficult to overdose yourself with supplements, especially folate and methyl B12, and all minerals are toxic in exces.

        And I’m *not* necessarily taking the conventional minimum daily requirements as my starting point and calling anything over that excessive. My starting points are usually higher than that. It’s a wide spectrum that needs perspective to sort out. Individual vary in their needs and tolerances.

        For example, 400 mcg folic acid or folate *is* the minimum daily requirement and is what’s commonly found in most vitamin-mineral supplements and B-50 complex. I do take 400 mcg as a starting point, and would add on from there in 400 mcg increments, fine-tuned further +/- in 100-200 mcg increments, if indicated by genetics and functional testing, but I’m not on board with the huge amounts of folate rx’d by many health professionals, an extreme example being the 7.5 – 15 mg Deplin med, due to histamine issues and excessive cell proliferation. Obviously we have a large spectrum here, and we need to find the right amount for the individual, not too low, not too high, but just right, and something that will be sustainable without side effects and not just a short-tem “feel good”. Increasing folic acid / folate can feel very good short-term, a perceptible boost to lung and brain function and emotional outlook, but may not be sustainable at that level.

        Another example: B12 in any form. No concensus on minimum daily requirement, but somewhere between 1-6 mcg. Most vitamin-mineral supps have more than this, and a B-50 complex has 50-100 mcg B12. 50 mcg B12 is my starting point, then go up from there as needed and tolerated long-term by the individual. If you see 1 mg B12 on a supplement label, don’t be confused, that’s 1000 mcg B12. Further, sublinguals are 2-10x more powerful than regular oral, due to bypassing “1st pass thru the liver”; all sublinguals are fast-in and fast-out of the system, so may not make for optimal stability.

        Many people think that just because a vitamin or other substance may be water soluble that you just excrete any excess beyond what you need, with no side effects. That’s not always true, and especially regarding folic acid / folate and B12 supplements. The substance can DO quite a lot before you excrete the excess. Folic acid / folate can have histaminergic and cell proliferation issues, and B12 can have nervous system sensitization issues. So it’s important to fine-tune amounts of these supps as needed, especially in more sensitive persons, and not be glib or heavy-handed in dosing as an everyday practice. Just because a substance/dosage is rx’d by a professional doesn’t mean it’s a safe or optimal dosage for you personally. Doctors who open with medium-to-high dosage amounts of substances are going to blow their sensitive patients out of the water. First, do no harm.

        • “Folic acid / folate can have histaminergic and cell proliferation issues…”

          Please provide research or clinical studies to back up this claim.

          Folic acid is completely different from active folates, like folinic or methylfolate, but even a cursory PubMed search turns up the exact opposite of your claim.

          Like this study:

          “Inhibition of Histamine-Metabolizing Enzymes and Elevation of Histamine Levels in Tissues by Lipid-Soluble Anticancer Folate Antagonists”

          Folate (in the form of folinic or methylfolate) is part of methylation, which as Chris describes above, helps lower histamine.

          Unless of course you can show otherwise?

          • Kelly, google “folate cell proliferation” and “folate histamine” and look through at least the first page of returns on each. There may be some controversy on this, but my bet, and from at least 10 years of experience and observations, and based on Pheiffer’s work that I cite in other comments here, is that both folic acid and folate (yes, these are different, no one here is saying otherwise) are histaminergic and foster cell proliferation. To some extent these actions are normal and desirable, but after that point they can become excessive and undesirable. So much depends on constitutional tendencies as to where the tipping point is.

            • Hi Carol,

              I’m not arguing about cell proliferation. We need new cells to replace old ones every day, especially if one is chronically ill or malnourished or has malabsorption/digestive issues.

              There is a huge, huge difference between ‘folic acid’ and active (or “reduced”) forms of folate. The synthetic ‘folic acid’, which is what Pfieffer based all of his research on, is also known as pteroyl-L-glutamic acid, or pteroyl-L-glutamate. Glutamate or glutamic acid could explain the reactions he talked about 40+ years ago.

              The other forms of folate have no glutamic acid molecule attached, so are completely different from ‘folic acid’.

              I went ahead and googled ‘folate histamine’. The first result was from the Phoenix Rising forums, with Rich Van Konynenburg’s explanation regarding Pfeiffer’s work:

              “High histamine occurs in people who are getting folic acid as their main source of folate, but are not able to convert it readily to the active, chemically reduced forms of folate…due to having inherited a slow version of the DHFR (dihydrofolate reductase) enzyme, which normally carries out this reaction.

              Folate normally impacts the degradation of histamine levels in two ways. One is that the normal breakdown of histidine, from which histamine is made, requires tetrahydrofolate, a reduced form of folate. The other way folate impacts histamine levels is that the intracellular breakdown of histamine is carried out by a methyltransferase reaction, and this depends on having adequate methylation capacity, which in turn depends on having enough methylfolate, another reduced form of folate.

              So the problem in histadelia is not caused by too much B12 or folate, but not enough of the proper forms. Folic acid should be avoided particularly by people who have elevated histamine. ”

              The 2nd site was Dr. Ben Lynch’s, who has spent the last six years researching genetic polymorphisms like mthfr and many others.

              His advice, based on this new research:

              “If histamine is high, then you need things like methylfolate and methylcobalamin.

              If histamine is low, then you need things like niacin and to limit methylfolate and methylcobalamin for a bit.

              High histamine = low methylator = greater need for methylation support such as methylfolate and methylcobalamin.”

              The only sites that connect ‘folic acid’ to histamine problems are the ones that reference the ancient Pfieffer hypothesis.

              It just could be that the problem lies with folic acid, and not the other forms of folate?

              • There is definitely a problem with too much folic acid for high histamine persons. But there can also be a problem with too much folate — I don’t think it’s as severe per mcg, but it’s there. Some folate is normal and desirable, but my concern is that too much folate for the person especially in supplement form can foster too much cell proliferation, which is not a good thing especially the older we get, and likely to foster some higher histamine as well despite what we’re led to believe on paper. Have your own experience.

                MTHFR genetics + urinary FIGLU testing in relation to folate, and urinary MMA (methylmalonic acid) help to suggest an appropriate amount of folate for the person. Histamine can be tested, and allergic tendency, asthma, eczema, hives, heat sensitivity, low blood pressure, over-vasodilation etc (high histamine symptoms can be important checks before and after folate supplementation. As to folate and methylB12 supps, personal experience over time will usually further tell a person whether they’re taking too much. Amounts need to be just right for the person, short term and long term. Many MDs and NDs overdose med and supplement amounts IMO, and the patient’s experience can work as a double-check against excesses.

                Pheffer’s term “undermethylated” has always been curious, as he recommends lower folic acid and lower B12 for these persons and I believe rightly so in most cases (genetics and personal history might make for exceptions). I would practically bet money that you’ll find more C677T SNP wildtype people at the higher histamine end of the spectrum.

                On a personal note, I’ve been a higher histamine person all my life, am wildtype on C677T, exactly normal on FIGLU and slightly high on MMA, do well with 400-600 mcg of either folic acid or folate, and 50-100 mcg any kind of B12 with more being a problem of too much nerve sensitization. The above testing and experience have served me well. Persons with different genetics and functional testing results would need different kinds and levels of supplementation, and they should also pay attention to their own experience over time.

                I’ve found Pheiffer’s biotypes involving high vs. low histamine to be very useful over the years, as a spectrum of extremes (using physical symptoms only). Since the high histamine persons also have more risk for cancer generally, on Pheiffer’s model and in more recent research (google: histamine cancer), I’m concerned about OVER-supplementing folate especially in older persons with high histamine tendencies. It’s commonly said that cancer involves general undermethylation but specific gene over-methylation. I’m concerned about excessive amounts of folate possibly driving specific gene overmethylation. On Pheiffer’s model again, his “over-methylated”, low histamine type has more risk for colon cancer specifically, and though this type needs more folate and B12 than other persons, it’s still possible for them to get too much folate so my concern is that it might drive excessive cell proliferation in the colon, with an increase in polyps being a precursor.

                It comes down to being aware of various viewpoints on a subject, but attending honestly to your own experience over time, which may fly in the face of what some authorities say should happen.

                • Hi Carol,

                  I guess we’re just going to have to agree to disagree on this topic.

                  Just a couple of points though before I go:

                  “Genetics and personal history may make exceptions”.

                  YES, that’s one of the main points that Pfeiffer never addressed — genetics. Plus, he always used man-made folic acid, never methylfolate or folinic, the latter of which is used in cancer therapy to IMPROVE outcomes.

                  There are other vitamins involved in methylation as well, like riboflavin, just as one example. It has also been shown to make a difference when it comes to cancer prevention.

                  I would personally avoid ‘folic acid’ like the plague, as it was never meant for human consumption, but instead opt for folinic or methylfolate, or folate from food.

                  But having said that, even folic acid, in high doses (5 milligrams), was shown to prevent recurrence of colonic adenomas, whereas 1 milligram doses were linked with a higher rate of colorectal adenomas.



                  Lastly, for anyone interested, here’s a better overview than I can provide, from Dr. Mark Hyman:


                  Take care everyone,


      • I disagree. Taking an isolated supplement is completely different from getting it from your food. Nutrients in nature are always complexes, which function very differently than a pill full of their various components (or worse, a pill full of only one of it’s components, which the government says is all that has to be in there to call it that vitamin).

        For example, the government uses ascorbic acid to “prove” vitamin C is in actually in your product when you claim it is. In the legal system, ascorbic acid is the definition of vitamin C, so manufacturers can say anything containing pure ascorbic acid has vitamin C in it. In nature, ascorbic acid is only about 15% of the vitamin C complex. The rest includes tyrosinase (a copper-containing protein which functions as an enzyme), various species of flavonoids, and maybe other constituents. The two do not behave the same way in your body.

        So saying that our ancestors ate much higher amounts of vitamins than we do is deceptive. The vitamins they got in their food are a different substance than what most people are swallowing in their supplements. They can’t be compared or used as a guideline.

        That said, there are time when a supplemental vitamin can be very helpful. It just isn’t the same thing as its natural counterpart.

  13. SO grateful to you for covering this. It’s the main thing I am tryin to figure out right now. Many thanks for the helpful info.

  14. Chris, could you share some information about histamine intolerance and mthfr connection? Have you seen that addressing methylation would help with histamine problems clinically?

  15. Yes, I had the testing done and put the raw data into the genetic genie website. I was amazed that the issues I was predicted to have were an exact match to the results I received from my organic acids test I had run at the same time. The OAT also gives suggested supplements to help you. Hmmm, I probably need to get back on those…

    • Same with me – my organic acids testing matched pretty closely to my Amy Yasko test results and pyroluria. I wouldn’t completely go with the suggestions from the organic acids results though as a lab doesn’t know your health history or current status. Best to see a practitioner.

  16. Excellent work, Chris! I will second your caution to some of the lesser researched mutations. I discovered I had a homozygous CBS mutation, and it really freaked me out to read all of the stories and recommendations people were throwing around to deal with it. I couldn’t deal with the crazy protocols people were suggesting for CBS (giving up meat and eating like a rabbit for instance). But, I was relieved to learn that the science isn’t settled.

    Yasko’s work was certainly revolutionary, but she also focussed on children. Now her work is being extrapolated to adults. For adults with CBS mutations, I encourage you to read this counter-opinion, which makes it seem far more benign in most adults:

    CBS Upregulation, Myth or Reality?

    I also heard that Yasko’s interpretation of CBS may have been in error. As one commenter explained:

    “She misinterpreted a research paper where they intentionally and artificially created a SAM-e independent upregulated CBS enzyme by introducing a stop codon that chopped off the entire 3′ tail of the enzyme (some several hundred residues). That “artificial” enzyme is 10 x upregulated relative to normal WHEN there is no SAM-e present. In the presence of SAM-e the wild type and the artificial were essentially similar activity.

    Yasko et al made a gross error when they assumed any SNP in the regulatory “tail” would cause the same level of effect. It does not work like that, not even close! In fact the C677T homozygous mutation leads to a 10-15% increase in trans-sulfuration flux post methionine loading. While 10-15% may have biological impact, it does not equate at all to the bogus 10x upregulation that falsely terrorizes people on these boards. Just bad science pure and simple.

    The 10x claim always bothered the heck out of me because if true there is NOTHING you can do to correct a defect that severe, and in fact … it does not exist. So paradox resolved ….”

    I Hope that helps anyone who gets freaked out by their CBS mutation!

    • Having done the 23andme on 5 family members, mapping our methylation mutations, and comparing them with 5 years of nutritional lab results and our collective symptoms, I can say that I’ve found much of Amy Yasko’s and Dr. Roberts’ (heart-fixer) info to be quite helpful.

      It is not just having one mutation, but a combo of them that can really impact our health. And, coming from a family where we have them all over the complex diagram, they certainly do – we have cancer, mental illness, Parkinson’s, Aspergers, and high blood pressure/stroke running through our family tree. We are always short on glutathione and pick up toxins easily and have a hard time getting rid of them.

      And I wouldn’t discount the CBS mutations, we have 2 CBS mutations, both hetero and homozygous… magnifying the number of supplements we need – it is like a black hole…. I take 52 capsules of supplements every day, including 60,000% of the daily value of methylcobalamin (B12) but I am MUCH healthier now than before I went down this path.

      And, though we are aware of the sulfur issues, we’ve been ok so far with plenty of protein and cruciferous vegetables, though we limit extra sulfur elsewhere.

      All in all, this is a topic well worth discussing. It IS complex, takes patience, and the latest knowledge out there, but has the potential to positively impact many people. My biggest frustration is finding knowledgeable doctors that aren’t overbooked and tracking down the plethora of supplements we continually need.

      Thanks for bringing this up!


    • Thanks for the links and further thoughts on CBS. Very interesting.

      One thing, though: Dr. Yasko’s work is NOT only with children. She started out working with adults with crazy impossible neuroinflammatory diseases (e.g., Lou Gherig’s, ALS, Parkinsons, etc.) and was one of very few practitioners to actually be able to help some of those people. Anyone with neuro issues (including depression, anxiety, learning disorders, Lyme, etc.) may find her system to be incredibly helpful–adult or child.

      Also: Dr. Yasko’s system is just that: a SYSTEM. If you simply look at her thoughts on your particular SNP of interest, it will be out of context, easily misunderstood (e.g., she doesn’t say eat only rabbit food if you’re CBS+, she simply says limit protein), overwhelming, and maybe won’t work, since you haven’t put the foundational pieces in place first. Those include both essential non-genetic interventions (diet, mineral balance, GABA/glutamate balance) and knowing in which order to address your SNPs, since many of them impact each other. It is important to view her work as an integrated series of interventions, not as isolated data bits.

    • I think one thing that may account for some of the difference between what some of the articles say and what Dr. Yasko says is the (extremely common) discrepancy between research findings and clinical findings. While Dr. Yasko absolutely does comb the research, a lot of what she says is based on her clinical experience, having looked at lab reports for tens of thousands of people. And having helped a lot of those people get a lot better.

      It’s kind of like off-label prescribing. The test may not be designed to show X means Y, but when you see 10,000 tests where X has been a good predictor of Y, you start to believe they go together, and that X can be a reasonably good predictor.

      I have to say: I’m late 40s, female, with neurologic Lyme and methylation SNPs all over the place. I’ve been slowly making my way through her protocol for the last couple years (just about to start working on CBS issues, so no data there yet), and so far, she’s batting 1000–pretty much everything she’s said has born out for me, both experientially, and with lab testing.

      More importantly, I feel SOOOO much better than I did. I’ve always managed the Lyme with a functional medicine/ functional nutrition approach, and I’m way better than most people with Lyme–many people don’t even know I have it. But that seemed to only be able to get me from -8 to about 0. It was hard to get into the positive range with how I felt and consistent body functions. Her protocol seems to be getting me past most of those hurdles that I otherwise could never over come–I’m finally able to live somewhere up in the positive numbers most of the time. Hooray hooray!

  17. Chris,

    What tends to be your conclusion when a patient has high homocysteine and a confirmed MTHFR mutation but nevertheless has high serum B12 and normal folate even without supplementation?

    This was true for me, and supplementation with Methyl-Guard resulted in lowered homocysteine (good!) but sky-high serum B12 and folate levels (bad?).

    • David: folks I asked about sky-high folate in my tests told me that means the folate is not getting into the cells — it was suggested I start a low dose of lithium to support the process. Haven’t done it yet, but thot u might find this interesting…

  18. Really good stuff. I would recommend to anyone who’s interested in the methylation issue and its connection to psychological/emotional effects, to listen to Kiefer’s recent BodyIO podcast with Dr. William Walsh. He talked not just about under-methylation, but also *over*-methylation, and it was fascinating. Both are connected to very different “personality types” or traits.

    • Dr. Walsh saved my life and completely changed the way I work with my clients (I’m a nutritional therapist).

      What’s disconcerting about the genetic tests is that they have no way of telling you how much methyl is present. And giving an undermethylated person methyl folate is a recipe for disaster because we don’t respond well to them at all. This also includes folate-rich foods and supplements containing folic acid.

      And this explains why undermethylators are more prone to cancer and producing autistic children.

      I found this out the hard way when I was raw vegan several years ago. Paleo diets rich in folates can also create problems despite the zinc from animal products.

      Overmethylators however respond beautifully to folates.

      Thank you Chris for this wonderful post!

      • Sami, you mention Dr. Walsh, working with Carl Pheiffer’s use of the terms under- and over-methylators, very confusing terms since it’s the under-methylators in his system that need to be more cautious about getting too much folate since they are usually higher histamine already, and may have more predisposition to cancer, whereas his over-methylators need more folate and B12. So the terminology around methylation can be very confusing. I’m very inclined to agree with the physical aspects (not emotional) of Pheiffer’s biotypes.

        Functional testing complements genetic testing — it’s a matter knowing how to use these modalities appropriately in concert. I expect you may use this in your own practice. Some organic acids tests (e.g. Metametrix Comprehensive Organix) has a line item for FIGLU that shows whether the person needs more folate, and MMA that shows whether the person needs more B12 than they’re currently getting.

        To use myself as an example, wildtype on C677T, 400mcg folic acid in my B-50 complex is fine for me, no need for specialty folate supps, FIGLU was exactly normal. I did buy some Solgar folate 400 mcg as Metafolin to experiment with though; adding this to my B-50 complex felt very “good” at first but within a few days or so I had signs of high histamine. I cut back the folate to 200 mcg, which was OK but still “pushing it” for ongoing use. So I abandoned the extra folate. (I experiment with a lot of things just to get a better feel for them firsthand.)

        However the other end of the dosing spectrum is that Drs. may give too-high amounts of specialty folate supps, an extreme example being Deplin folate med by Rx at 7.5 – 15 mg. I do question whether a person who is homozygous variant on BOTH key MTHFR SNPs would need that much, or whether something like 1600-2000 mcg might be sufficient, but we’re still quite far away from 7.5 mg. Pheiffer’s “over-methylated” biotype who needs more folate and B12 is also more predisposed to colo-rectal cancer specifically, and my concern is that too-high folate supps could contribute to the growth of that type of cancer. In general, I find many MDs and NDs et al are too heavy handed with meds and supplements, and are not adequately taking into account different types of constitution and sensitivity.

      • And this is where I get so confused! Dr. Walsh and Dr Ben Lynch seem to recommend two very opposite things. Dr. Lynch, and others, recommend methyl cobalamin and methyl folate for those who have mutations and are under methylated, with a tendency toward high histamine. But Dr. Walsh recommends avoidance of folates for this.

        From my own personal experience, many of my current nagging health issues stem from taking methyl supplements to reduce my high homocysteine. I’m heterogenous for A1298c and C677t, as well as others (but not SUOX). After taking these supplements, I’ve developed nonstop tinnitus, swollen eyelids, sometimes inner trembling, and occasional burning of the hand and foot, among other things. I remember exactly when the tinnitus started. I’ve been off the methyl supps and B vitamins for over a year, with the very occasional B complex and B12 when I feel the need. I’ve tried every other recommendation under the sun to improve this. None of these issues have dissipated, and it’s disheartening.

        • Ginger, the terms “under-methylated” and “over-methylated” are used oppositely in the Pheiffer tradition vs. Yasko tradition. I’ve never been able to find out why Pheiffer used the term “under-methylated” for people that didn’t need much folate or B12, compared to “over-methylated” for people who need a lot more folate and B12. (I speculate there may have been an ambiguous use of the term “methylated” in Pheiffer’s system, that could be sorted out only by understanding the term in context.) Nevertheless I came to the Pheiffer tradition and observation of it’s physical biotypes many years before exposure to Yasko and genetics 2007-2009.

          I’m in Pheiffer’s “under-methylated” biotype, and have correspondingly wildtype C677T, with a standard 400 mcg folic acid or folate as adequate for me. I would expect to see this as one common correlation, though when you start trying to mix models or systems, models rarely map neatly one on top of the other, else they would be the same model if they did. Further, Pheiffer’s biotypes are more of an either-or, but folate needs fall on a spectrum.

          Folate and B12 are companion nutrients in regard to methylation, often considered together.

          B12 in its various forms, delivery methods, and dosing seems to have the most individual variation in people’s experience of just about any supplement. B12 sensitizes the nerves, so the nerve pains described can be excruciating and untenable but are common at too-high doses for the individual (people are rarely told about this and find out only by comparing notes with others online), even if an organic acids test for line item MMA (methylmalonic acid) elevated shows a need for more B12, that extra B12 may not be tolerable. Personally, I had to retreat to the amount of B12 my B-50 complex, as extra B12 even at small amounts was problematic for me, again tracking with Pheiffer’s “under-methylated” biotype.

          The Yasko, Lynch, et. al. direction in methylation is different from Pheiffer’s . The 2 vectors look more like skewed lines, owing not only to opposite uses of some methylation terminology, then ambiguity of meaning around some uses of terminology, also their driving concerns, characteristics of their patient base, and treatment approaches. There may be some small amount of overlap.

      • I have to disagree with you Sami.

        Dr Walsh’s view of methylation is much more simplistic than Amy Yasko’s and doesn’t tend to take in to account COMT, CBS etc. Even my own doctor who follows Walsh doesn’t agree with his views on folate.

        Also, an undermethylator generally needs more methyl groups, so would technically do better with methylB12 and methylfolate, however they need to do this very carefully by looking at different SNPs in their cycle. For example, if they are homozygous for COMT, then they may have a tendency towards overmethylation and need to avoid or minimise methyl donors. If however they are homozygous for MTHFR C677T then they are more likely to be an undermethylator. Having said all that, I have both of these mutations so my picture is more complicated and I need to be careful to address COMT before introducing too much methylfolate. This is where Walsh’s approach is limited, because he doesn’t address the other SNPs, just uses a one size fits all approach if you are boxed in to the “over-” or “undermethylator” approach.

        I also think one’s reaction to methylfolate is often dose dependent. The amounts in Deplin for example are very very high and some practitioners will start someone off on this straight away, whereas if they were to start on a much lower dose of 5MTHF, then they’d probably be just fine.

        Also, Chris mentioned the functional testing that can (and should) be done along with the genetic testing to see how the SNPs have affected the person in reality. I had organic acids testing which was very enlightening.

        Your comment really needs to distinguish more clearly between 5MTHF and folic acid as it’s not clear.

        • Allison – I did distinguish, thus the link. Dr. Walsh’s approach is not simplistic, nor is it one-size-fits all by any means. I encourage you to read his book to get a better understanding.

          And we also do functional testing because as pointed out here, we have to look at where an individual is at biochemically first, then create a treatment protocol based on that. There are always myriad variables.

          Any form of folate, folic or folinic acid will function the same over time, regardless of whether it comes from food or supplements.

          Folic acid works in different ways in different parts of the cells. The part we need to be concerned about is the nucleus because it’s inside the cell that we see methyl loss, and folic acid strips more methyl than it provides.

          Methyl folate is not a better form, it’s simply a different form.

          My personal physician, Dr. Albert Mensah addresses it here:

          My life was transformed with proper supplementation and dietary choices.

          For me this means all those years of suffering from depression, anxiety, compulsive overeating, and GI issues (and that’s the short list) are completely gone.

          Today I am happy and thriving and this is a blessing.