S2E27: What is Really Going On With MTHFR Basic State?

Basic state is something that we’ve talked about before, but I want to dive a little bit deeper into why I feel it’s important when other fantastic practitioners, like Dr. Ben Lynch, aren’t really into it. Honestly, there is no right answer here.  So let’s look a little more closely.

The idea of over and under-methylators came originally from the research of Dr. Walsh from the Walsh Research Institute.The main thrust of his research was that mental and emotional disorders often stem from an imbalance or deficiency of nutrients in the brain. 

This research was not based on genetics and had nothing whatsoever to do with the MTHFR polymorphism, or any polymorphisms in the histamine pathway. It was based on Dr. Walsh’s clinical observations over years of working with vast numbers of patients. The terms “overmethylator” and “undermethylator” were his own and based on what he theorized was happening. The names, in my opinion, are a bit misleading because we don’t actually know what is happening with the genetics or if the DNA is really overmethylated or undermethylated. Hopefully, that research will happen eventually, but it certainly hasn’t happened yet.

The reason I like using basic states as a guidepost, is because it’s an easy way, especially in the beginning of your MTHFR journey, to guess how you might respond to certain supplements and drugs for mental health.  This can be hugely helpful because we all have a tendency to dive into the deep end with this, and believe me – taking a big dose of methylfolate if your body isn’t ready for it can scare you off of taking methylfolate for a very long time. 

Also, since the basic state is based on observable personality traits, allergies, and measurable signs and symptoms, we’re not looking at just one gene. We’re looking at how the totality of a person’s genes plays out in real life, because how they look on paper isn’t always how they act and how they act is what really matters at the end of the day.

Also, this is something that can be determined without any genetic testing, without any specialized help from practitioners and without the need for any fancy interventions at all. That makes it extremely valuable because for every one  person who thinks they have an MTHFR polymorphism who is working with a knowledgeable practitioner, there is another hundred who are doing this on their own.

For that, basic state is invaluable. Also, I love the fact that it’s based on what is called phenotype, or genetic expression, not genotype, or genes as they’re written. What that means, is that elements like personality traits or high or low histamine, represent the way all of your genes come together to express, which is by far more valuable information clinically than the actual gene polymorphisms themselves. 

There are so many genes involved in each pathway – when you look at actual gene expression, or phenotype, you’re seeing the way all the genes come together, which is more relevant than just the status of one gene or another. Also, all of your genes express or don’t express depending on a variety of factors including lifestyle, nutritional status, other health factors and even your mother’s health status while you were in utero. It’s far more complicated than just this or that gene, but looking at who you are as a person and how your personality expresses is actually a great way to sum up this information.

Knowing your basic state can give you some well informed starting places in terms of how you will respond to supplements, pharmaceutical drugs, and even the types of doses you might expect to be optimal. It isn’t 100% accurate, but it gives you a better idea of starting places than you would otherwise have. Still always start low and go slow, but knowing your basic state can speed up the process of discovery. 

The MTHFR Basic State Mirror Image

When you’re trying to determine your own basic state, it’s most helpful to think of them as flip-sides of the same coin with opposite traits on either side.  Your basic state will come down to how many traits you have from each side.

For instance, the traits of overachievement and perfectionism show a subtle but important difference. Both under and over-methylators express these traits, but undermethylators tend to be perfectionistic and overachieve in all areas, where overmethylators hyperfocus on the areas that are important to them and let the rest slide.

There is a very important difference in allergic response as well. High histamine type allergies and sensitivities are like classic hay-fever, where you open a window and the pollen instantly makes your eyes stream and starts the sneezing.  That is an undermethylation, high-histamine type reaction. Overmethylators, on the other hand, show more chronic allergies and sensitivities – the low-grade headache, neck tension, entire season with a blocked nose that doesn’t particularly change whether you’re indoors or out. That is a low-histamine sensitivity pattern. Also, overmethylators tend more toward chemical and food sensitivities, where undermethylators tend more toward histamine intolerance in foods.

UndermethylatorTraitOvermethylator
High, for everythingAchievement and DriveHigh for the thing that matters to them, low for other things
Typically follows rules and social norms wellRules and guidanceFollows rules that make sense to them, disregards others. Follows the beat of their own drum.
Typically pushes for achievement in everything they doAchievementPushes for achievement in the things that matter to them, but not interested in other things
High histamine and seasonal allergiesHistamineLow or normal histamine with chronic allergies/sensitivities
Typically lowerPain ToleranceTypically higher
Often intolerant to histamine in foods, but less often to foods themselves.Food reactionsTypically has sensitivities to specific foods and chemicals
High fluidity (saliva, tears, etc…)FluidityLow fluidity (saliva, tears, etc…)
The MTHFR Basic State Mirror Image

At the end of the day, trying to decipher the big picture by looking at each particular gene SNP can lead to a really messy situation in which you can end up taking supplements that look good on paper, but aren’t actually addressing the issues you have in real life.  This is far less likely to happen if you’re working with a good practitioner, but sadly I’ve seen some practitioners fall victim to this mentality as well. Even worse, you can end up taking one supplement for each gene SNP and getting completely overwhelmed by a cumbersome protocol that costs a lot of money and time, but doesn’t get you anywhere.

If you’re looking for a MTHFR basic state refresher, you can follow this link to learn more about the idea in general. Here’s a link to dive deeper into the undermethylator picture and here’s one for overmethylators.

Thank you so much for listening today, and if you haven’t done so already, check out the show notes at tohealthwiththat.com. There are resources, downloads, links to research, and best of all an email list where you can sign up to be sure you’re the first to hear about exciting new courses, free resources, and other great things.

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Supplements for Depression with MTHFR

MTHFR and depression are intimately linked. We’ve spoken about this before, and if you want to brush up, take a look at Season 1 Episode 8 where we explored the link between the MTHFR mutation and neurotransmitter formation via the BH4 pathway. The quick and dirty version is that when methylation isn’t working optimally, then the pathway that makes many of your major neurotransmitters, including serotonin, melatonin, dopamine, epinephrine, and norepinephrine gets stalled out too.

Season 1 Episode 33 was also all about MTHFR and depression, specifically the entirely fixable causes of depression that your doctor will typically overlook. This whole episode was about steps you can take at home to manage depression. Balancing your methylation is obviously a cornerstone, but there are so many other factors involved that are entirely in your hands.

Another great one to review is Season 1 Episode 34, where we talked about the component of depression that is quite simply a mental bad habit. The part that feels like falling into a rut mentally where your brain travels over the same tracks, the same complaints, the same problems without questioning them or without breaking those patterns. Also, Season 1 Episode 35 in which we talk about some great techniques for breaking those bad habits.

The part of depression we haven’t talked about yet is the supplement part and this is something that people ask me about all the time. At the end of the day, sometimes we really do need a pill to take the edge off while we’re making these other changes. Often, the supplement helps us to have the mental and emotional energy TO make other changes. So let’s talk about a few good options that are typically pretty safe for MTHFR folks and typically well-tolerated.

Some Amazing Depression Supplements We Won’t Be Talking About

There are some great supplements for depression that we won’t talk about today, mostly because we’ve talked about them before at great length. One of the best natural treatments for depression is, of course, balancing methylation using a good folate source or SAMe and a good B12 source. Since those are things we talk about pretty much every week, I’m going to assume you’ve got those covered. For most of my clients, balancing methylation – whether it’s through 5-LMTHF, folinic acid, food sources of natural folate, or SAM-e – is the cornerstone of their depression relief. That doesn’t mean it’s the only thing they need to do, but it’s certainly the foundation.

Another effective supplement for depression that we’ve talked about before is St. John’s Wort. We dove into that one at some length in Season 1 Episode 46 on the link between MTHFR and serotonin. Also, omega-3 fatty acids and fish oils are extremely well studied for depression and we’ve also talked about those at great length because they boost the effectiveness of B vitamins in MTHFR mutation (Season 1, Episode 42). Just remember that if you’re using fish oils for depression you may need a higher dose than the one listed on the bottle.

Saffron For Depression

Saffron is best known as a spice, adding brilliant yellow color and subtle flavor to Middle Eastern food and haute cuisine. Like most other highly-colored spices it’s absolutely packed with antioxidants, carotenoids, and biologically active compounds. In research and clinical practice, saffron shows major benefits for those with depression and it is thought that this could be through some serotonin-boosting mechanism, possibly similar to SSRI medications in which the saffron keeps serotonin in the synapse longer, basically making the same amount of serotonin do twice the work.

In fact, when compared to the actions of SSRI medications, saffron was found to be just as effective for major depressive disorder as these commonly prescribed pharmaceuticals.

Given that this is thought to directly affect serotonin levels, it is best to talk with your doctor before starting saffron if you are already taking an antidepressant medication because there may be an interaction between them.

Saffron is typically dosed around 30 mg per day in research studies.

NAC for Depression

NAC or N-acetyl cysteine is something that we have talked about before as a precursor to glutathione, which is one of your body’s key antioxidants. It is actually precisely because of this function that it is so useful for depression. People with depression are more likely to have higher levels of oxidative stress, inflammation, and inflammatory cytokines like C-reactive protein, tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6). By helping to moderate the inflammation, NAC actually eases symptoms of depression as well.

It is thought that NAC helps to regulate glutamine and dopamine levels in the brain and demonstrates a great ability to both cross the blood-brain barrier and also to increase levels of glutathione within the brain and central nervous system. NAC also shows promise for use with addiction and substance abuse issues.

NAC is actually an amino acid and so it is best taken on an empty stomach. If it is taken with food, then it competes with other amino acids for absorption. The doses typically used for depression are between 2 and 2.4 g/day. This can be divided into two or three doses depending on what is easiest for you to manage.

Rhodiola for Depression

Rhodiola is well known as a supplement for helping to get core energy back in situations of adrenal fatigue or exhaustion. This is because of its action as an adaptogen, and that adaptogenic ability is also thought to be the reason it helps with depression.

Studies have linked hypothalamic-pituitary-adrenal axis dysregulation (or HPA axis dysregulation for less of a mouth full), with depression. HPA axis dysregulation is exactly what is happening in clinical cases of adrenal fatigue or exhaustion. It describes a state of over-reactivity and subsequent burn-out of this vital neuro-endocrine system.

In a study that compared the effectiveness of Rhodiola to the common antidepressant Sertraline, the Rhodiola was shown to be effective, but not quite as effective as the antidepressant, but also far better tolerated with fewer side effects.

The typical dose of Rhodiola for depression is around 340 mg per day. There are other adaptogenic herbs as well, all of which may have similar benefits for depression. These include licorice root, ginseng, American ginseng, schizandra, and ashwagandha.

Thank you so much for listening, and if you’re interested in a 6-weeks to health with MTHFR course, make sure to sign up for the mailing list at tohealthwiththat.com and keep listening to the podcast for more info.

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MTHFR Questions – Specific products and Marmite.

This week, I’d like to get to some questions that listeners have been kind enough to leave on the website and within the community.

The first comes from Liana O and she says “Specific 5-L-methyltetrahydrofolate supplement recommendations and dosing, please?”


This is actually a really common question, and I’m probably not going to answer in a way that is satisfying because everyone is so different. Also, the products available to people vary so widely that the best I can give is guidelines.  In terms of people first starting on this journey, the absolute best, easiest, and most painless way to start is with a multivitamin that doesn’t have any folate or B12.


To my knowledge, there is only one such product on the market, which is made specifically for MTHFR  and by a fellow MTHFR mutant. It’s called Optimum Start by Seeking Health. This is a great product, and Seeking Health will ship internationally from their website, which is great, but as everyone who isn’t in the US knows, international shipping for something like this often makes it cost-prohibitive. I do have an affiliate account with Seeking Health, so if you’re ordering products I would so appreciate it if you’d do it via the link from tohealthwiththat.com to support the work I’m doing here.


Outside of that, there are a number of great multivitamins with low doses of methyl folate that can be really great for a starting place. One of my favorites is the Smarty Pants kids multi gummy.  It has a mere 37.5 mcg methyl folate per gummy. This won’t give you an adequate dose of everything else you need, but if you’ve had trouble with methylated folates before, it can still be a great way to start. Smarty Pants also has some great adult gummy vitamins that can be a good way to ramp up your intake slowly because typically the dose is split between 4 gummies, and also gummies are easy to cut in halves or quarters.


If you prefer capsules, look for high-quality multivitamins that have multiple capsules in the dosage and are made for adolescents or teenagers so the doses per capsule aren’t high. Some examples are junior nutrients from Pure Encapsulations, which has 100 mcg folate per capsule.  Thorne Research multi-encap is also a good choice at 130 mcg folate per capsule.  
In general, I prefer to buy from companies that follow good manufacturing practices and who sell primarily through practitioners. This includes companies like Thorne Research, Integrated Therapeutics, Pure Encapsulations, Xymogen, and NuMedica.  Divinci Labs also makes some nice products, as does Jarrow. 


At the end of the day, what matters most is local availability, even if it’s via amazon or a similar mail order service, and ingredients. Always look for doses on the low end of the spectrum, especially with methyl folate and B12. You can add in higher doses of those ingredients separately, which is the best strategy because it gives you more flexibility overall.


I know this seems like a non-answer to this question, but the most important to find something that works for you individually.

The second question is from Tim and is quite honestly, sending me on a bit of a hunt. He asks….

So, even though Marmite says it has Folic Acid, you’re saying it’s actually NOT Folic Acid, is that correct? You have me so scared of Folic Acid that I don’t want to be eating it. Thanks.

Now, you all know of my obsession with Marmite. It is a yeast extract quite similar to the one that was used in the initial research that found folate to be an important nutrient for pregnancy. Outside of being a huge fan, I have also always been under the impression that it was unfortified and that all the folate present was directly linked to the natural byproducts of the yeast.  I am at this moment, fearful that I might actually be mistaken about this.

These two pieces of information aren’t the same. But why? The answer is yet to be found.


I have a question pending with Unilever, the current manufacturers of marmite, but so far it remains unanswered. The label information is somewhat frustrating. The Food Standards Agency, which is the UK’s food regulation authority, also has a folic acid fortification program with wheat flour, but I can not find out whether or not the terms “folic acid” and “folate” are considered to be equivalent legally. If anybody from the UK can shed some light on that matter for me, I’d appreciate it.

I do know that the bottle in my pantry lists the ingredients as Yeast extract, Salt, Dehydrated Carrots, Spice Extracts, Dehydrated Onions. And that’s all. There is no mention of additional vitamins or fortification, which in Canada is a legal requirement. The label is definitely following Canadian guidelines otherwise, as it has all information in both official languages.

I called the information number on my bottle and left a message, which has yet to be answered.

Also, I “spoke” with the marmite website chatbot and I hate to say, the chatbot listed ingredients that I don’t see on my label. According to the marmite bot, it includes vitamins and one of those is folic acid. Sigh.

So, obviously, this still requires some investigation because if there is folic acid on there, why isn’t it on my label? Also – how much is actually in there? Is the entire 100 mcg dose listed as the amount per 8 g serving folic acid? It’s all a bit confusing.

I will certainly update you when I hear from Unilever and also from the Canadian helpline because the contradiction in information doesn’t make sense. It could be that there is a difference in the formulas depending on the country, but it seems like the label would be easier to change than the product.

To address the second point in the question, Tim mentions the fear of folic acid. This is something I want to talk about because while I”m not a fan of folic acid, the problems actually occur when it’s folic acid in high doses. Small amounts just slowly labor on in the process of being converted to something useful like 5-LMTHF, but they do eventually get there. So a small amount of folic acid isn’t going to be a problem if you’re just getting it from one source, like marmite, which still has good natural folates as well.

When it becomes a problem is when it’s the only source and you’re getting it everywhere. All the fortified grains, your multivitamin, some prescriptions, etc… Then is when we see folic acid building up and also folic acid gumming up the works of the methylation pathway. There is probably a safe threshold, but to my knowledge, that research really doesn’t exist yet. So at this point, minimizing intake is the safest bet.

Are There Other Yeast-Based Products Like Marmite?

Since Marmite is now in uncertain territory, I will give you some options. One of my favorites is nutritional yeast. It has a delicious cheesy-nutty-umami flavor and is easy to sprinkle on popcorn, add to sauces, sprinkle over veggies, or use as an additional flavor burst in things like salad dressings.

Like everything else with food, it’s a bit complicated. If your package doesn’t mention anything, then it is likely fortified, which means they’ve added extra B12, folic acid, and probably a few other B vitamins to the mix. This is kind of standard and so if they just say it’s a good source of B vitamins, then they’ve probably done this. Also, the fortification gives the flakes a bright yellow color – more like a true yellow.

Nutritional yeast is available unfortified as well, but you have to hunt for it. I can’t find unfortified at any of my local stores, but I can on amazon so I order a big bag once a year and that’s that. The unfortified tastes just as good but the color is a bit more gentle – more of a buttery yellow rather than a bright yellow.

If you have some in your pantry right now, check the color – I’ll put a picture below so you can compare.

Thanks so much for listening today and thanks Liana and Tim for the great questions. Make sure you’re signed up for the email list so you’re the first to know about upcoming courses.

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Checking In With Progress On The MTHFR Journey

Let’s check in with what is going on so far. If you’ve been following the process this season, you will have noticed that I haven’t really addressed what we’re doing in a while, so let’s touch base.

There are some reasonably long stretches in the MTHFR journey in which we aren’t really changing things, doses are just staying the same, and it might seem like not much is happening. The reality, in fact, is that lots of things are happening in your body but none of it needs additional input from you.

This phase of the journey is what I like to call “Burning Through The Backlog.” When you first start diet changes and methyl folate or SAMe or whatever workaround you’re using, you see the immediate activation of the methyl cycle and some immediate health changes. Usually, that feels like a better mood, less anxiety, etc… After that initial balancing phase, the progress slows down but it isn’t because your body has stopped doing things.

This part of the process involves unpacking your body’s to-do list. All of the things it couldn’t do in the past because methylation just wasn’t happening fast enough. It’s a time of more subtle change where neurotransmitters are slowly coming into balance, toxins are slowly being eliminated, inflammation is slowly decreasing and oxidative stress is balancing out. Even your hormones and energy levels are being influenced in this process

How To Make Sure You’re Burning Through The Backlog Efficiently – Check Your Basics

In this phase, it’s easy to forget some of the basics so the first thing I want you to do this week is to take a look at things you should be doing and tighten up where needed.

  • Folic Acid – Make sure folic acid is out of your diet and supplements and isn’t creeping back in without you noticing.
  • Balanced Diet With Natural Folates – Get lots of fruits and veggies, as much fiber as you can pack in, moderate protein, and plenty of good food sources of natural folate like lentils, black beans, spinach, asparagus, dark green leafies, avocados, marmite, and any kind of bean or pea you feel like eating.
  • Multivitamin – Keep up with the background of other B vitamins – this is usually in the form of a good basic multivitamin. All of the processes that are happening now, from neurotransmitter formation to detoxification, to energy production, to balancing your oxidative stress and reducing inflammation needs a good solid basis of all the B vitamins.
  • Sleep and Rest – I really enjoy the paradox presented by this particular issue. Most of my clients say they would love more sleep and rest, but it’s always the hardset possible thing to actually accomplish. Just keep trying to work actual sleep and actual rest into your schedule.
  • Moderate Exercise – because generally, MTHFR folks do best with regular exercise, but not extreme exercise. Ironically, there are lots of us who are professional athletes and serious competitive athletes, but for those people it’s important to make sure methylation is balanced and to compensate adequately for the extra damage being done to their bodies.
  • Detox Support – since detoxification is such a huge part of Burning Through The Backlog, it’s important to give your body the support it needs. This can be in the form of gentle detox teas, castor oil topically, sweating it out, extra dietary fiber, or some mish-mash of all of these things. We’ve done posts on detox support before as well.

Burning Through The Backlog Efficiently – Optimizing Your Dose Of Methylation Drivers

The supplement or supplements you’re taking that specifically support methylation should be dose-checked occasionally. Maybe quarterly in this whole process. This could include any one of the following supplements:

  • 5-LMTHF or another form of methylated folate
  • Folinic Acid
  • SAMe

These supplements are all pushing the methylation cycle forward and so may need an occasional check-in to see if you’re still on the right dose. Usually, this means trying to increase your dose to see how you feel.

Generally, in this process, you increase by the smallest increment you can and make sure you’re using your symptom tracker for a couple of weeks before and after so you can see if there are small changes that you might not notice otherwise. If you feel fine with the higher dose, that’s great. Keep using the higher dose unless you start to get symptoms that indicate that your dose is too high. If you get symptoms right away or within the first two weeks then go back to your original dose.

Symptoms That Your Dose Is Too High

Typically too high a dose of anything that drives methylation feels hyper-caffeinated. It’s anxious, restless, can’t settle down, fidgetty, has a racing heart, or feels like all-out panic. If you’re noticing any of that – even if it’s a small change, then your balance will be better with a slightly smaller dose.

What About Other Supplement Routines?

For some people, taking supplements that take an alternate route through the methylation pathway, rather than methylation drivers, is the best path forward. Especially if you’re starting out from a kind of messy health place. These are supplements like methionine or choline. Methionine just gives you more of the raw ingredients to make SAMe and choline cuts through the middle of the methylation cycle as a viable short-term work around. These are great band-aids, but probably not the thing you want to be relying on for the long-term. If you are looking for long-term solutions but really can’t manage any of the true methylation drivers – methylfolate, SAMe, or folinic acid – then choline is the better of these two options. You still need the other B vitamins, and as much natural dietary folate as you can manage.

Moving forward, it’s a good idea to check in with your body quarterly to see if your dose is sufficient or if you’re getting enough for your body’s needs right now. Your dose will always be somewhat dynamic. Eventually, you will actually catch up with all of the things on your body’s internal to-do list and need a far lower dose, so watch for those anxious/hyper symptoms and keep it on your radar that your best dose might need to decrease too.

Thank you so much for listening today and give some thought to joining us in Genetic Rockstars – the MTHFR community. This month we’re talking about some of the links between MTHFR and histamine, and it’s a great way to meet people who understand what you’re going through and who have great information to share.

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The Dangers of UMFA in Pregnancy

UMFA or unmetabolized folic acid is something that has been popping up on research radars more and more frequently in recent years. The combination of food fortifed with folic acid, multivitamin use, the popularity of B complex supplements for energy, and the standard practice of hyper-dosing women with at-risk pregnancies has led to UMFA becoming a common problem. Last week we discussed the remarkable results methyl folate produced in couples with infertility relative to the current standard of care, which is supplementing with folic acid. This week, I’d like to talk about the risks of too much unmetabolized folic acid or UMFA during pregnancy.

First, Let’s Talk Useable Folate

One very wisely designed study published in the American Journal of Clinical Nutrition, compared serum and red blood cell levels of total folate, 5-LMTHF, UMFA, and MeFox which is a methyl folate oxidation product – kind of the 5-LMTHF version of UMFA. The reason I call this study design “wise” is that it gives us a good window into what is actually happening here. Serum levels test the amounts in the fluid part of the blood, which is not yet inside the cells. This isn’t really a functional space for folate – it’s been absorbed digestively, but hasn’t reached useful cellular tissues yet. Red blood cell levels, however, measure the amount that is actually inside of the cell spaces and therefore doing something useful. This study didn’t differentiate between MTHFR or non-MTHFR, or at different forms of folate intake. It simply compares two different doses of folic acid.

One group received about 1.1 mg of folic acid in their prenatal vitamins. The other group received the prenatal vitamin amount plus an additional 4 mg to bring the total to 5.1 mg, or 5100 mcg of folic acid.

What they found in this study, was that the RBC folate level, which is the functional folate, didn’t differ significantly between the two groups. The high-dose folate group did have higher serum levels of total folate, UMFA, and even 5-LMTHF. Other parameters didn’t differ significantly.

The researchers came to the conclusion that there was some kind of tissue saturation happening, where more folate just can’t get into the cells, which makes sense. They also suggest that higher UMFA concentrations in the women receiving the high-dose folic acid indicates that these doses are “supraphysiologic.” That is a fancy way of saying the dose is just too high.

So What is All that UMFA Doing In Pregnancy?

Another study, also published in the American Journal of Clinical Nutrition, studied UMFA levels in cord blood relative to autism spectrum disorder. Cord blood is the blood that remains in the placenta and the attached umbilical cord after delivery.

This study found that babies in the highest quartile of UMFA percentages in the cord blood had the highest risks for autism spectrum disorder. This effect was highest in black babies and significantly correlated with race. This correlation did not apply to the concentrations of 5-MTH or to serum total folate.

Another study, published in the Journal of Allergy and Clinical Immunology In Practice, looked at the association between UMFA levels and food sensitivity and food allergy. This study tested total folate, 5-MTHF, and UMFA levels at birth and again in early childhood.

The researchers found that of 1394 children tested, 507 were found to have food sensitivities and 78 had food allergies. In those children who developed food allergies, the average total folate concentrations at birth were lower and the UMFA levels at birth were higher. Higher UMFA levels later on in childhood didn’t seem to have this same association.

I will quote from the conclusion of this study. “Higher concentrations of UMFA at birth were associated with the development of food allergies, which may be due to increased exposure to synthetic folic acid in utero.”

What To Make Of This?

These are just a few studies and so we really can’t, as much as we might like to, draw sweeping conclusions from them, but it certainly gives us some compelling evidence that too much of what is supposed to be a good thing, can rapidly become a bad thing.

Because we, with MTHFR polymorphisms, are more susceptible to problems associated with folic acid, I think it is important to have an informed and complete conversation with your health care practitioners about the risks of folic acid supplementation in pregnancy for us specifically, and the viable, albeit less well-researched option of supplementing with 5-LMTHF instead.

Links to the research studies I’ve talked about in this podcast are supplied in the complete show notes at tohealthwiththat.com, so if you’re planning a visit to your OB/GYN or midwife, go armed with research to show them.

Thank you so much for listening today and please make sure you’re signed up for our email list – the email list will be the first to know about new courses, programs, and freebies for MTHFR folks.

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The Harm That 5mg Folic Acid Can Do For MTHFR Fertility

This week I wanted to diverge on subjects a bit just because a very relevant question came up in the MTHFR community, This is such an important issue that I want to make sure it gets the attention it deserves.

One of our members in Genetic Rockstars is pregnant and her midwife is recommending 5000 mcg folic acid in spite of her MTHFR issue.  This is a common question because 5000 mcg folic acid is standard practice in many fertility centers and medical offices for pregnancies that are considered in any way at risk.

Like everything else involving MTHFR, research is limited but I do want to deep dive into a couple of relevant studies.

The most important piece of research to take to your midwife or fertility practitioner is a study published in the Journal of Assisted Reproduction and Genetics in 2018.

This study followed 33 couples in which one or both of the partners had an MTHR polymorphism who had fertility problems lasting at least 4 years.  This could include recurrent fetal loss, premature ovarian failure, or abnormal sperm parameters – so bear in mind this could be the mother or the father who has MTHFR issues. Two-thirds of these couples had previously failed assisted reproductive technology attempts.

Most of the women in this study had been previously treated, unsuccessfully, with 5000 mcg (or 5 mg) folic acid.

The couples in this study were given 600 mcg 5-LMTH, which is the active form of folate, for four months before attempting conception or starting another round of assisted fertility treatment. This four-month period was chosen to allow for a complete cycle of spermatogenesis, which is approximately 74 days.

The results of this one simple intervention were, in my opinion, absolutely astounding. Of the 33 couples:

  • 2 were still in treatment at the date of reporting.
  • 13 couples conceived spontaneously (this is after four years of unsuccessful reproductive attempts)
  • 14 achieved successful pregnancies using ART (assisted reproductive technology). ART typically refers to IVF or in-vitro fertilization. 
  • 3 couples did not achieve successful pregnancies.
  • 1 couple failed to report back.

I am going to read the conclusion of this research article verbatim because frankly, I couldn’t sum it up better.

“The conventional use of large doses of folic acid (5 mg/day) has become obsolete. Regular doses of folic acid (100–200 μg) can be tolerated in the general population but should be abandoned in the presence of MTHFR mutations, as the biochemical/genetic background of the patient precludes a correct supply of 5-MTHF, the active compound. A physiological dose of 5-MTHF (800 μg) bypasses the MTHFR block and is suggested to be an effective treatment for these couples. Moreover, it avoids potential adverse effects of the UMFA syndrome, which is suspected of causing immune dysfunction and other adverse pathological effects such as cancer (especially colorectal and prostate).”

Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. J Assist Reprod Genet. 2018;35(8):1431-1435. doi:10.1007/s10815-018-1225-2

The most startling result of this research, I feel, is the tremendous number of couples who conceived spontaneously after a simple few-month intervention with 5-LMTHF. Imagine the amount of heartache, expense, and medical intervention that could be avoided if 5-LMTHF became the standard of care?

The other issue considered here is something called Unmetabolized Folic Acid Syndrome, which has been demonstrated in  “wild type” people to cause pseudo-MTHFR. In pseudo-MTHFR, people who have fully functioning MTHFR enzymes have both high levels of unmetabolized folic acid and high levels of homocysteine in their blood. In people with an MTHFR deficiency, UMFA blocks the entry of folates into the folate cycle and further impairs the capacity of their already struggling MTHFR enzymes.

Unmetabolized Folic Acid has also been implicated in promoting colorectal and prostate cancer. And folic acid itself shows poor clinical success and in some cases, it tests worse than placebo in reducing homocysteine levels or downstream measures of cardiac health.

Next week I’d like to talk about some of the issues that have been linked to high levels of unmetabolized folic acid in pregnant mothers and the problems that travel downstream to those unborn children. If you haven’t done so already, please sign up to the email list on tohealthwiththat.com, or join the MTHFR community Genetic Rockstars at community.tohealthwiththat.com. I have big plans this year for courses and I want you to be the first to know.

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Supplements For Anxiety With MTHFR

We’ve talked about how MTHFR and Anxiety are linked a couple of times and had an interview with anxiety expert Jennifer Bronsnick, but all of that still doesn’t answer one of the biggest questions about anxiety that I get, which is, “What can I take to help me fix it?”

Good question. Obviously, everyone responds differently to different supplements, just like they do with medications, but here are a few of my favorites with some perspective about how they interact with MTHFR. I’m hoping it goes without saying, but balancing your methylation should always be the first step to dealing with anxiety. The rest of these are to clean up anything that is left.

GABA

GABA is, in my opinion, a highly underrated supplement. It is an inhibitory neurotransmitter, meaning it decreases the likelihood that the neuron will fire or send a signal. In the overactive brain of someone with anxiety, this is precisely what we want. It is also crucial to healthy brain functioning, with an estimated 60 – 75% of all neurons being GABAergic (or responsive to GABA.)

There has been a long-standing debate in the research world whether or not GABA that you take by mouth can possibly cross the blood-brain barrier. It is certainly well absorbed and blood levels rise sharply within thirty minutes of taking it, but it is much harder to demonstrate brain levels in a study. Research evidence and theorizing exist on both sides of the fence, but due to its potent clinical effects, I tend to think it either does cross the BBB or it takes action on something else which has a calming effect on the central nervous system and that is just as good.

GABA is probably most known as a sleep aid, helping to calm restless minds into healthy sleep. For anxiety, however, it reduces your feeling of actual anxiety and tension, but also helps to reduce cortisol levels, increase parasympathetic nervous system activity as measured through the vagus nerve (which means your nervous system is trending more toward relaxation than stimulation). The doses used in research tend to be between 30 – 100 mg. There is a great systematic review article about GABA and its effects on anxiety from Frontiers in Neuroscience here.

GABA is the type of supplement that I feel sneaks up on anxiety. What I mean by that is taking a dose regularly that is just below the dose that would make you sleepy (this might take some trial and error) isn’t necessarily going to change your life in that first week, but it does help to get your body into a rhythm of functioning without as much hypervigilance. I love this because it takes the edge off so that you can actually work on mindfulness or breaking mental bad habits in a more protected mental space – like the GABA makes it easier to see the things your mind is doing that it doesn’t need to be doing.

As an aside, GABA also shows remarkable clinical promise for Type I Diabetes, which is insulin-dependent. In much larger doses than those taken for anxiety, GABA helps to boost insulin response in fasting and non-fasting conditions and may help to both protect and restore pancreatic beta cells. While this has very little to do with anxiety in the way we tend to think of it, there is a link between anxiety and blood sugar.

MTHFR and GABA

There is only one relevant study pertaining to MTHFR and GABA levels. This study shows mice with MTHFR polymorphisms to have altered levels of many neurotransmitters, including GABA, in different brain segments relative to wild-type mice. This study showed that mice who were heterozygous for an MTHFR SNP showed altered levels of both GABA, which is inhibitory, and glutamate, which is excitatory, in the amygdala, cerebellum, hypocampus, and thalamus.

Passionflower (Passiflora Incarnata)

Outside of having one of my favorite names in all of herbal medicine, passionflower is remarkable as a calming and soothing agent for anxiety. It can be used for short-term anxiety, such as to help patients remain calm before dental or surgical procedures or long-term for such neuropsychiatric conditions as generalized anxiety disorder and post-traumatic stress disorder. In both cases, passionflower shows remarkable benefits.

A comparison study between liquid passionflower extract and the pharmaceutical drug oxazepam, which is a benzodiazepine, showed equivalent clinical effectiveness over a period of 28 days.

Passionflower has also been used to help people who are addicted to opiates to successfully withdraw. Studies showing passionflower as an addition to clonidine, which is the standard of care, demonstrate better handling of mental symptoms in the clonidine plus passionflower group than the clonidine alone.

Passionflower can be taken as a tea, a liquid extract, or as a capsule or tablet. As with all herbal medicines, quality matters and it’s important to find products that follow the highest standards of manufacture and testing.

While passionflower hasn’t been specifically studied for use in folks with MTHFR mutations, it works well clinically in a wide range of people, and I’ve seen great results in my own clients, the majority of whom have MTHFR polymorphisms. Also, it’s pretty easy to tolerate and side effects are not common.

Adaptogenic Herbs For Anxiety

Adaptogens are herbs that help the human body resist stressors of all kinds. They quite literally help us adapt to all manner of situations with grace and strength, both literal and metaphorical. The most well-known adaptogens are herbs like ginseng, ashwagandha, and licorice which might just as well come with a sub-heading that says “Strong Like Bull.”

While there is, sadly, no research specific to MTHFR and adaptogens, there is a literal boatload of research on adaptogens and anxiety. Ashwagandha, for instance, has been shown to reduce both the feeling of anxiety and also cortisol levels after 60 days in adults with a history of chronic stress.

In general, the effects of adaptogens on cortisol levels and conditions associated with excessive cortisol, including anxiety, fatigue, abdominal obesity, and metabolic syndrome, are extremely well known. These are wonderful therapies for the management of long-term stress and anxiety disorders, although they should be used with practitioner supervision and guidance.

Licorice, for instance, is one of my favorite herbs of all time, but it is known to elevate blood pressures and so is perfect for skinny, high-strung, anxious women like myself, but not a good option for someone who struggles with blood pressure or cardiac issues.

There are, of course, hundreds of other supplements for anxiety but these are three of my go-to staples. Don’t forget to sign up for the mailing list, or join our MTHFR community here.

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S2E20: MTHFR and Anxiety – An Interview with Jennifer Bronsnick

This week on the podcast we’re trying something new. An interview with an anxiety expert who has also gone through her own recovery process with anxiety. The interview was clipped for the podcast episode but you can watch the full thing, on zoom, here.

MTHFR and Anxiety – an Interview with Jennifer Bronsnick.

Jennifer Bronsnick’s suggestions for Anxiety

Jennifer mentions a few tools that have been helpful for her. Here they are!

  • Eliminating alcohol
  • Cutting down or eliminating refined carbs like white flour and sugar
  • HeartMath – for more info about this, click here.
  • Existential Kink – the book by Carolyn Elliott.
  • Getting quiet to actually hear what your body might be trying to say.

Let me know what you think of the interview format – I can do more of this, or not. Just depending on you.

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S2E19: MTHFR and Anxiety

MTHFR and anxiety are intimately linked, mostly, we presume, because your body needs folate to make serotonin, dopamine, epinephrine, and norepinephrine. Those are most of the major neurotransmitters that affect mood and mood disorders including anxiety and depression.

More specifically, a folate molecule is needed to convert BH2 to BH4, and BH4 is needed to convert the amino acid precursor tryptophan into serotonin and tyrosine into dopamine, norepinephrine, or epinephrine. We did a post about it here.

Because of this link, working on optimizing your methylation can have a huge impact on anxiety and depression, but it isn’t the only thing you can do. Of course there are pharmaceuticals for anxiety and I’m not really going to cover those because those will probably be your doctor’s first go-to solution. And that’s fine, but there are other things as well. We’ve already talked about anxiety as a mental bad habit, and also about breaking mental bad habits. So today, let’s talk about steps you can take in your own real life to reduce anxiety.

Eat Regular Meals

This kind of sounds like a soft-ball. Like it couldn’t possibly make a difference to anybody’s anxiety level because it’s just too simple. In reality, keeping your blood sugars balanced and stable can cause a huge drop in anxiety levels, and here is why.

When your blood sugars drop, either from a skipped meal or after a sugar rush and the inevitable sugar crash that follows, your body has a low-sugar stress reaction. Sugar is absolutely vital to the functioning of your brain and so your blood has a tightly regulated amount. If that amount drops, your body literally goes into panic mode, activates your HPA, which is your hypothalamic-pituitary-adrenal axis, and pumps out stress hormones to bring your sugar levels back up.

Skipping meals is incredibly stressful for your body – and that translates to actual stress hormones that affect your level of anxiety. Keeping your blood sugars balanced through the day is far more important than you realize, and if anxiety is an issue for you, then it’s important to back some of the sugar out of your diet and make sure you eat regularly.

I know plenty of people who run on adrenalin and skip meals regularly because they’re too busy, there’s no time when the kids are running around, etc… but making time for this simple self-care can have a huge impact on how stressed you feel and also on the long-term effects of stress like sleep quality, weight gain, belly weight, and fatigue. Interestingly, blood sugar fluctuations and their corresponding changes in insulin levels are also highly linked to brain fog.

Clean Out Your Medicine Cabinet

Oddly a number of medications are known to increase anxiety. Some of those are because they have a negative effect on folate status, like birth control pills or methotrexate. Some are because they cause a caffeine-like reaction (or actually contain caffeine). These include cough and congestion formulas, many pain pills, and cold and flu medications. Also, medications for weight loss are well known for causing anxiety. Also if your dose of thyroid medication is either too low or too high it can lead to anxiety.

Decrease Your Caffeine

First, a disclaimer. I am a *huge* fan of coffee and will never, ever, ask you to stop drinking it. Having said that, different people have different levels of sensitivity to caffeine and also, women at different points in their cycle have different sensitivities to caffeine. It can help to experiment with your caffeine intake to see what works best for you, but keep a symptom tracker for a few months and try different caffeine levels – you might be surprised. In truth, any human with more caffeine than their body can easily process, is going to experience more anxiety, more edginess, and more irritability. That is just biology, so it can be a good idea to check in with your body every now and then and see if the amount you’re getting is ok for you.

Many medications contribute to anxiety, especially those like methotrexate or birth control pills that decrease folate levels.

Exercise, Yoga, and Meditation

These are all well-known moderators of anxiety, so I won’t belabor the point, but there are a few tips.

  • According to a study published in Psychiatry Research, higher intensity exercise like jogging or fast walking shows better results for reducing anxiety than gentle stretching.
  • Yoga shows better effects for anxiety than stretching or resistance training in Parkinson’s disease, but that effect may translate out to the general population as well.
  • Mindfulness meditation (as opposed to other forms) has been well documented to reduce anxiety symptoms.

There are, also, a number of supplements that are helpful for anxiety as well, but we’ll cover that in a separate post.

Thank you so much for listening today and please sign up for the mailing list at tohealthwiththat.com – we’ve got some great things coming this year and I want you to be the first to know.

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S2E18: What is the MTHFR Lifestyle?

I mention the MTHFR Lifestyle a lot, but don’t always clarify what I’m talking about, and at this phase of the journey, it matters a lot. If you’re following along with the process in this podcast series, then you have done a number of remarkable things. You’ve:

  • Taken folic acid out of your diet and supplements
  • Added a good foundation of other B vitamins
  • Started 5-LMTHF, folinic acid, or SAMe – whichever of those options is the most easily tolerated for you.

Chances are you’re feeling better – clearer, more energetic, happier, less anxious, and generally like you’re on the right track. And you are. You are doing amazing and I am so proud of you for coming this far.

When I talk about the MTHFR Lifestyle, it’s really to remind people that our genes are for life. We will always have them, and when we happen to have MTHFR it can stand as a great reminder that we will thrive the best when we actually make health a priority.

Many people ignore their health until the wheels fall off the cart. That usually looks like a heart attack or a big diagnosis, or hitting some kind of health and functioning wall. Some of us may have done the same. The thing is, with MTHFR we will always do the best when we are making space in our lives to take care of our bodies. We will always do the best when we’re living the MTHFR Lifestyle.

What Is the MTHFR Lifestyle?

Put simply, it’s a life that puts physical health, mental health, and even spiritual or soul health on your radar every day. This isn’t something that we have the dubious luxury of forgetting – when we have something like MTHFR, it matters to make health a priority. To always be mindful of how we are treating ourselves and how we are caring for ourselves. It’s easy to rail against it and think that it’s unfair we have to pay so much attention to this when other people seem to be able to do whatever they want, but it’s also a blessing in disguise.

Living the MTHFR lifestyle gives us permission to make our own self-care a priority every day. That is actually kind of huge, when you think about it. It’s a good reason to take the best possible care of yourself.

What is the MTHFR Lifestyle in concrete terms?

This lifestyle involves making health a priority without getting too extreme. It focuses on things like:

  • Discovering and avoiding your food sensitivities.
  • Clearing as many toxins and chemicals out of your diet, home, and water as you can.
  • Keeping healthy fruits, veggies, beans, and pulses in your diet.
  • Making good sleep a priority.
  • Mindfulness meditation or some other mind-taming activity.
  • Moderate exercise (not too much and not too little).
  • Moderate protein (not too much because it can raise homocysteine).
  • Good hydration.
  • Gentle detox support like hot baths, saunas, dry skin brushing and castor oil.
  • Taking time for rest, relaxation, and joy.

When you look at it like this, it sounds sort of idyllic. Good sleep, relaxation, joy, some exercise, great food. This is the MTHFR lifestyle we’re striving for.

I know, being a realist, that it’s hard to maintain this kind of lifestyle in a busy, overstressed, modern world. I also know, that taking small steps towards it can have a huge impact on your wellbeing and quality of life. When you think about it, who do you know who doesn’t need a bit more self-care?

I feel like it’s especially important now, in this time of global pandemic and the related stress because even if you don’t consciously feel like it’s a stressful time, there is an underlying chunk of mental burden related to covid that we don’t normally carry. For everyone this is new, and for everyone it adds another weight. All we can do is take better care of ourselves so we can support that weight more gracefully.

Now, please be clear that I’m not the type of health cheerleader to ever tell you your life/diet/self-care or routine all need to be perfect. Sometimes the thing you need most for your wellbeing is a churro. Or a Christmas cookie, or a gin and tonic. A healthy lifestyle has lots of wiggle room for treats. Also, if your foundation is solid, then small treats bring benefits rather than harm. I am never going to be the one to preach to 100% clean. If you can get to 90% then you’re doing amazing.

Also, be gentle with yourself. I’ve been doing this for years, have a doctoral level education in how to take care of myself, and I still go through ups and downs. It’s human nature. Sometimes my self-care is rocking – I’m doing everything right and I”m on fire and it’s amazing. Sometimes, it isn’t. I go through periods where I’m just not as motivated to do it all, or I don’t have the bandwidth, or the rest of my life has eaten my self-care. That’s ok too. This is all a process of continuing to make the choice, every day, to make caring for yourself a priority. There isn’t any judgment, there isn’t any winning or losing, it’s just a process that allows you to take steps toward a richer life.

Thank you so much for listening today, and I really hope this inspires you to give yourself just a little more care. Also, I”d love it if you’d take the time to sign up for the mailing list -there are so many great things coming up this year and I want you to be the first to know.

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