S2E9: MTHFR Questions

I love it when listeners leave me questions so here is this month’s roundup!

I don’t have a doctor that advises me about MTHFR. A mental health provider suspected the mutation because of years of resistant depression. She did a swab to test genetics for specific medication absorption which included MTHFR testing.we found that I have compound heterozygous mutations. I’ve been on high dose methyl folate and B12 for a few years and wonder if I should be getting regular tests for levels etc. where should I go? I have researched the topic myself online but it’s very confusing and there seems to be no general consensus. Can you help me? Thank you,

– Jamie L

This is a great question, Jamie because so many MTHFR folks are out there doing it on their own. Unfortunately, online and between practitioners, there is absolutely no consensus on the best way to do this, so really it comes down to finding the right way for you.

I notice you mention methylfolate and B12 and that is great, but make sure you’re taking the other B vitamins as well because they are all necessary for this to work – especially riboflavin. Also, if you’ve been taking high doses of methylfolate without other Bs, then cut your dose down before you start them because the dose might be too high once you get the other pieces of the puzzle in there.

In terms of testing, the things we want to look at specifically for MTHFR are folate, B12, and homocysteine. Testing every couple of years is fine. Testing folate is complicated because unmetabolized folic acid can be mixed into your total so the test isn’t so valuable except to show us trends (like it’s getting higher or it’s getting lower). B12 testing is straightforward as is homocysteine testing and if you aren’t familiar with homocysteine, check out Season 1, Episode 40: Homocysteine by The Numbers.

Outside of testing, the biggest determinant of whether or not you’re on track is your symptoms. How are you actually doing? If you’re not where you want to be, then maybe it’s time to work with a practitioner who has knowledge about MTHFR and can help you on your path.

Hi! I have an 8 year old boy. He was diagnosed ADHD at the age of 6. We started him on methylphenidates at age 7. We have tried nearly all of them and none of them agreed with him. We had gene testing done earlier this year and MTHFR came back as “Low to Intermediate activity”. Majority of the ADHD medications came back with lower odds of response. What do I do with this information? We have family history of bipolar and anxiety disorders. The adhd medications really brought out a lot of anxiety in my child. He is very competitive. He is obsessive. My son has a terrible issue with skin rashes that started when he was 4. We had skin patch testing done. He’s allergic to hydrocortisone, formaldehyde, fragrance. Once we took gluten out of his diet as well his rashes were more under control. Every time I listen to your podcasts I think some of my son’s issues point back to his MTHFR. Do I take this to his pediatrician? Do I work with his psychiatrist? Do I see a functional medical doctor? What do we do next?

– Mindy J.

ADHD on top of MTHFR is very common and it’s a difficult situation because the medications that help so many other kiddos just don’t work here. I DO think that addressing the MTHFR is the next best step. I would talk with both his psychiatrist and his pediatrician and see if either of them is comfortable fielding this issue in a way other than prescribing massive doses of folic acid, because that won’t be helpful.

If they aren’t familiar enough with MTHFR, then find a practitioner who is. It’s always best to work with someone local, but if you can’t find someone then I do still work with people one-on-one. Check the Amy + Health Coaching link at the top of the page on tohealthwiththat.com

This is why MTHFR folks need other Bs. It isn’t just about folate.

Hi! I am compound heterozygous so I of course have the C/T and A/C copies. I am hoping to start trying to get pregnant soon and I want to know what vitamins I should be taking that will work with the copies that I have. I am on 5mg of l-methylfolafe right now but no B vitamins. I tried a b complex and it made me very mean and hateful so I have been scared to try anything else. I want to have the best chance at a healthy pregnancy, thank you!

– Breonna H.

Congratulations on future baby-making, Breonna. That is such an exciting time. I’m so glad you brought this up because it’s really common for people to start 5-LMTHF before other B vitamins or B12 and then have weird reactions to other Bs when they start.

It is absolutely crucial that you do start other B vitamins. I think the reason why the B complex made you mean and hateful before was that with the other B vitamins there, suddenly your dose of 5-LMTHF was way too high so it was actually that causing the mood and attitude changes and not the Bs.

Basically what is happening in this situation is that your MTHFR enzyme is still really limited because it needs other B vitamins to work – riboflavin is a direct cofactor and without riboflavin, it just won’t go. So your dietary intake of riboflavin was maxing out the amount of 5-LMTHF that you can use.

So you do need to add a B complex back in there, but before you do, drop your 5-LMTHF down to 1mg for a couple of weeks and then add the B-complex. Also, check the B12 in the B complex because some people have a weird reaction to methyl-B12 too. Here’s a post on all the different forms of B12.

When you do give this a try, let me know how it all goes!

How do my folate levels drop after starting Metanx and multivitamin with active folate?

– Human

This is another great question, and I’m actually guessing a bit because I don’t know where your folate levels were before you started. I can say that what I see often in clients is that they come in with super high folate on lab tests, but functional folate deficiencies. Once we eliminate the folic acid and get them started on active folate then blood levels are technically getting lower because we’re clearing out the unmetabolized folic acid that hangs around in there cluttering up the works. Or at least that’s what we hope to do. Even as folate levels look like they’re dropping, the person is symptomatically improving.

I see that happen a lot, but if that doesn’t sound like what is going on for you, reach out again and give me a bit more detail so I can answer more thoroughly. Just remember that serum folate measures everything in the serum – usually that includes natural folate, 5-LMTHF that has been made by your body, whatever folate you’re taking, PLUS any unmetabolized folic acid that is still kicking around. It isn’t a great test on in terms of value on its own, but what we can do is exactly what you’re doing, which is compare numbers over time. But typically we want this to drop a bit as the unmetabolized folic acid (or UMFA) is leaving your system.

I *love* listener questions and I’d love to answer yours. If you happen to have a question, let me know. There is a video-ask for questions on the home page of tohealthwiththat.com. I’ll try to do an answer podcast every month or two just depending on how many questions come in. I also love meeting you guys in Genetic Rockstars, it’s an MTHFR community away from the craziness of social media with lots of inside information, polls, tips, and generally other MTHFR folks who are talking about their experiences. Please join us at community.tohealthwiththat.com.

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Gene Expression, Fish Oil, and MTHFR.

Fish oil, which we talked about last week as well, continues to be a big deal for people with the MTHFR mutation. Today, I want to discuss a couple of studies about gene expression, fish oil, and MTHFR, but first I want to make sure everybody understands the basics of gene expression.

When your body makes something out of your genes, it doesn’t just read the DNA and make a protein. There is more to it than that. The process, however, can be broken down into two big chunks – bear in mind that there is far more to it than this as well, but this will help you to understand the research we’re going to talk about..

  1. Transcription -Transcription is the process in which the DNA is opened like a zipper and mRNA is made from one side of the zip, and the resulting mRNA molecule is processed by the body.
  2. Translation – Translation occurs when the mRNA molecule we made above, is used to direct protein synthesis. This is how the MTHFR gene makes the MTHFR enzyme, which is the protein this gene codes for.

mRNA is genetic material just like DNA, but the difference is that while DNA might be the ultimate blueprint, it is also giant, double-stranded, and not easy to work with. RNA of all types, including messenger RNA, is single-stranded and generally transcribed from the master DNA. It is created in small segments and is the signal needed for your body to actually build proteins.

What this means is that mRNA is a good marker, in research, specifically this research about fish oil and MTHFR, for the action of the MTHFR gene and one of the only ways we can measure when the gene is acting.

Gene expression in the homocysteine cycle with Fish Oil and MTHFR

Last week we mentioned that levels of fish oil and homocysteine were linked – the higher the fish oil intake for the person studied, the lower homocysteine levels became. Let’s expand on that.

This study, published in Nutrition Journal, looks at the gene expression, meaning the mRNA levels for different enzymes along the homocysteine pathway. This includes MTHFR, but also other enzymes including MAT, CSE, SAHH, CBS, and MTR. See the diagram to place each enzyme within the pathways for recycling and converting homocysteine.

Human liver cells were treated with either decosahexaenoic acid, DHA, eicosapentaenoic acid, EPA, or alpha-linolenic acid, ALA for 48 hours. A control group with no treatment was also kept for 48 hours and then studied. After that time, mRNA levels were measured from each enzyme in question. It was found that:

  • MTHFR was upregulated by both DHA and ALA.
  • MAT was down regulated by all three treatment groups, but most in the DHA group.
  • CSE expression was increased in the DHA and EPA groups.
  • No significant changes were shown in SAHH, CBS, or MTR.
Omega-3 fatty acids like EPA, DHA, and ALA have an effect on the action of certain gene SNPS and the enzymes they code for.

This study is remarkable because it shows that the action of MTHFR can be influenced with something as simple as fish oil. The next study is even more remarkable.

Pregnancy, Fish Oil, and MTHFR

Methylation is one of the primary drivers of a person’s epigenetic state, and some of the most important methylation happens during gestation, so research involving this period is especially important. This particular study, published in Biomedical Research International, was conducted on rats.

Because previous research has shown that nutritional changes in the mother affect both poly-unsaturated fatty acid metabolism and global methylation in the placenta. This study theorized that the changes are due to some regulation of the maternal enzymes in the methylation cycle by dietary nutrients.

This study divided pregnant rats into six groups.

  • Normal folic acid and B12 (this is the control group)
  • Normal folic acid, B12 deficient
  • Normal folic acid, B12 deficient with omega-3 fatty acids
  • High folic acid, normal B12
  • High folic acid, B12 deficient
  • High folic acid, B12 deficient with omega-3 fatty acids

Placental mRNA levels were tested for MTHFR, MTR, MAT2a, CBS, PEMT, and GAPDH. Placental glutathione and phospholipid analysis were also performed.

In an effort to not bore your pants off, I’ll get to the relevant details about MTHFR.

As expected the mRNA expression of MTHFR was decreased in both B12 deficient groups relative to the normal B12 groups. Interestingly, omega-3 fatty acids were able to return the mRNA to a normal level in the normal folic acid, B12 deficient group but not the high folic acid, B12 deficient group.

This tracks with what we know about folic acid’s double-edged effect on the MTHFR enzyme. A small to normal amount is good (and far better than no folate intake) but too much inhibits the MTHFR enzyme

Placental glutathione levels followed much the same pattern. In the normal folic acid, B12 deficient group the glutathione levels were lower than normal (although not statistically significant). With excess folic acid however, glutathione levels with higher in those rats with normal B12 and significantly lower in the rats with B12 deficiency. Omega-3 fatty acids were able to correct the glutathione level in the normal folic acid, B12 deficient group but not in the excess folic acid group.

My theory about this is that glutathione manufacture is more difficult in the presence of imbalanced folate or B12, but that it increases in the most imbalanced group, which is excess folic acid and deficient B12, in an effort by the body to protect itself with glutathione buffers against increased oxidative stress.

Phospholipid levels tested higher in both B12 deficient groups compared to the control group. In both of those groups omega-3 supplementation reduced them.

This study is so remarkable because we’re looking at the time period when epigenetic is at it’s most potent and when the protective effects of omega-3 fatty acids could potentially alter the course of these pregnancies. While placental levels are being measured, these changes may have an impact for the developing fetus as well. This means that even in the presence of a somewhat unbalanced diet leading to unbalanced methylation, omega-3 fatty acids offer a regulating effect and may mitigate some of the worst of the consequences of the unbalanced diet.

Thus, the metabolisms of folic acid, vitamin B12, and DHA are interdependent on each other possibly through the one-carbon methyl cycle.

Khot V, Kale A, Joshi A, Chavan-Gautam P, Joshi S. Expression of genes encoding enzymes involved in the one carbon cycle in rat placenta is determined by maternal micronutrients (folic acid, vitamin B12) and omega-3 fatty acids. Biomed Res Int. 2014;2014:613078. doi:10.1155/2014/613078

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MTHFR and Homocysteine By The Numbers

These past few weeks we’ve gone over some general information about MTHFR and homocysteine, the link between methionine and homocysteine, and the new information about MTHFR, homocysteine, and Covid-19. What we haven’t talked about is Homocysteine testing and parameters – what is normal, what isn’t, and what is considered normal but maybe shouldn’t be.

Testing Homocysteine

Homocysteine tests are simple blood tests that can be ordered by your doctor. It must be performed fasting for accurate results. Any protein you eat before your test can skew the numbers because methionine in your food may cause a temporary rise in homocysteine. The best way to ensure a blood test is fasting is to schedule your blood test early in the day before you have eaten anything. 8 – 12 hours of fasting (like you would get overnight) is best for the most accurate results.

“Normal” Levels

The current medical standard in the U.S. is a normal range from 5 – 15 umol/L (that is micro mols/Litre). Anything above 15 micro mols/L is considered high, or hyperhomocysteinemia. There is a growing body of evidence that the normal level should be adjusted:

  • A study published in the New England Journal of Medicine shows that carotid artery thickening and stenosis risk begins to increase for men by 9.2 umol/L (although the risk for women seems to remain stable until 11.4 umol/L). Both of these are significantly lower than the 15 umol/L that is considered normal.
    • Risk increases at 9.2 umol/L
  • A meta-analysis published in the Journal of the American Medical Association shows that a 3 umol/L decrease in homocysteine leads to an 11% lower risk of ischemic heart disease and a 19% lower risk of stroke.
  • A strong linear relationship exists between homocysteine levels and death in patients with coronary disease. The lowest risk group has homocysteine below 9 umol/L and the risk increases from there both within what is considered the normal level and outside of it.
    • Homocysteine <9 umol/L = 3.4% risk of death
    • Homocysteine 9 umol/L – 14.9 umol/L = 8.6% risk of death
    • Homocysteine >15 umol/L = 24.7% risk of death.
    • Risk increases at 9 umol/L
  • The study we discussed last week dealing with homocysteine levels as a predictive marker for worse outcomes with Covid-19 also showed an increased risk for pathological lung changes on CT at 8 umpl/L
    • Risk increases at 10.58 umol/L

If The “Normal” Levels aren’t Ideal, What Is?

All of the risks for negative health outcomes seems to be lowest around the 6 – 8 umol/L mark, so we’re going to call that “Optimal.” This is an estimation based on the research that we talked about above. Joe Pizzorno (a legend in the natural wellness community), estimates the ideal range to be 5.0 to 7.0. Ben Lynch, the epigenetic expert, estimates ideal to be between 6 to 9 umol/L.

If Homocysteine Is So Bad, Why Aren’t We Aiming for Zero?

Too much homocysteine is bad for sure, and with MTHFR and homocysteine that is the direction we usually trend, but remember that homocysteine is absolutely essential. If your homocysteine is too low (hypohomocysteinemia), then there are also health consequences. Without homocysteine you can’t make glutathione, which is one of your main defenses against oxidative stress. Without glutathione, things would go sideways pretty quickly.

Homocysteine is also the precursor for something called alpha-ketobutyrate, which is a vital ingredient in the process that makes cellular energy. Very few studies are done about low homocysteine levels (I mean VERY few. I can count them on two hands). By far the most interesting one shows a link between low homocysteine and peripheral neuropathy. It states that fully 41% of people with low homocysteine have peripheral neuropathy, which is hugely significant.

In my opinion, this implies that the lack of glutathione and consequent difficulty with free radicals is leading to higher levels of inflammation and nerve damage. Ben Lynch put forward a similar theory on his website here, and Joe Pizzorno, here.

I wouldn’t be surprised to see a link between low homocysteine and chronic fatigue, as well, although the research has never been done.

The bottom line is that we need homocysteine, but too much of it becomes a big problem. Aim for 6 – 8ish micro mols/L. Next week we’ll talk about ways to lower your homocysteine levels if they’re too high.

Has your homocysteine ever tested too low? I”d love to hear your comments here, or in Genetic Rockstars, our amazing MTHFR community.

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Pssst. There Are Different Types of Folate. And One of Them is TOXIC.

This can be such a confusing distinction, made far worse by the fact that supplement companies and nutritional information labels often use “folate” and “folic acid” interchangeably. Thanks, regulatory agencies.

Did you have any idea there were different types of folate?


Folate is the general name for a group of natural related substances, all in the category called “vitamin B9.” They are essential to the human diet because we can’t make them for ourselves (hence “vitamins”) and are best found in foods. Great sources include dark leafy greens, lentils, chickpeas, yeast extracts like marmite, and legumes. Folates are not shelf-stable and can’t be used to fortify other foods because they degrade quickly so the only sources are natural sources. This form is not stable enough to be made into supplements or prescriptions. Folate must go through the MTHFR enzyme to be converted into 5-LMTHF and so this might be slow or impaired in MTHFR mutants.

Folic Acid

Folic acid is the crystalline, shelf-stable, entirely man-made form of folate. It functions in the same way that folate does, but has to go through an initial enzyme in the liver, called dihydrofolate reductase, in order to be useful. This enzyme is slow and because of this, high doses of folic acid often build up as unmetabolized folic acid in the blood. Folic acid has been shown to be toxic at high doses – you can read a whole post about it here. When foods are fortified, they are fortified with folic acid. This includes foods like bread, pasta, cereal, and baking flour. Folic acid doesn’t absorb well for people with inadequate stomach acid. This is everyone who takes antacids, heartburn medications, or prescriptions for reflux. Folic acid also masks symptoms of a B-12 deficiency and so can prevent you from getting the treatment you need if your B-12 is low. This is the most common form in supplements and there are prescription folic acid formulas as well.

Folinic Acid

Folinic acid is the only shelf-stable form of natural folate. It is naturally occurring in some bacteria, although the forms sold as supplements are man-made. Also, there is a prescription form of folinic acid called leucovorin which is used to counteract methotrexate and fluorouracil toxicity as well as folate deficiency and methanol poisoning. Folinic acid is easier to tolerate, for some MTHFR mutants, than 5-LMTHF and does convert to the more active forms (like THF and 5-LMTHF) although it still needs the MTHFR enzyme to do it. This form leads most easily into:

  • DNA base pair production (purine synthesis)
  • DNA repair
  • BH4 pathway and neurotransmitter formation
  • ATP synthesis (cellular energy production)


This is the most biologically active form of folate – it doesn’t have to undergo any conversions in the body to be used. It is found in both supplements and prescriptions like Deplin (labeled for depression, but off-label for weight loss and MTHFR issues) and Cerefolin NAC (for Alzheimer’s dementia or in pregnancy), and Metanx (for diabetic neuropathy). Oddly, none of these are actually intended for MTHFR polymorphisms. Go figure. 5-LMTHF is well-absorbed even when your stomach pH isn’t what it should be (like if you’re taking antacids or prescriptions for reflux or heartburn). 5-LMTHF also doesn’t mask symptoms of B-12 deficiency as readily as folic acid does, and so you are able to get appropriate treatment. Also, 5-LMTHF is the only form that is able to cross the blood-brain-barrier to increase levels of folate in the cerebrospinal fluid. Crossing the blood-brain-barrier is extremely important during pregnancy (and fetal development) and in those with severe MTHFR mutations. 5-LMTHF can convert to folinic acid but does so extremely slowly and in a difficult manner, so it’s best to take both. This form is best for:

  • Bypassing the MTHFR enzyme for MTHFR mutants
  • Supporting methylation of DNA, proteins, lipids, and toxins.
Not all types of folate are created equal, and certainly not folic acid! This is why it matters to get the right type for you..

Naturally occurring 5-MTHF has important advantages over synthetic folic acid – it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking hematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase, and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation.

Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488. doi:10.3109/00498254.2013.845705

Key Points to Notice about the Different Types of Folate

  • Folic Acid is the only form that has to use the “Slow DHF” enzyme, and the only one that often lingers in the blood as unmetabolized folic acid (which is toxic).
  • Naturally occurring folate from unfortified foods can convert to folinic acid or 5-LMTHF, but the conversion to 5-LMTHF in MTHFR folks is slow or impaired.
  • Folinic acid can convert to 5-LMTHF, but it still needs to go through the MTHFR enzyme and so it might be slow or impaired in MTHFR folks
  • 5-LMTHF is the most active form, but it doesn’t convert back to folinic acid very easily.

The Best Folate For MTHFR Mutants

Those of us with the MTHFR mutations do have to be mindful of our types of folate. Natural food sources of folate are great for us and for many people it can be enough to eat a diet high in natural folate. This means lots of dark green leafy vegetables, pulses like lentils and chickpeas, beans, and yeast extracts like marmite. We’ll talk more about food sources of natural folate next week. Some MTHFR folks will find they need a supplement as well, which should be folinic acid or 5-LMTHF or ideally, a combination of both because they can interchange, but they lead to different pathways. Folinic acid leads most easily into purine synthesis and the BH4 pathway which helps to make your neurotransmitters.

Next week we’ll do a deep dive into food sources of folate because for everyone with the MTHFR mutation, trying food sources and ramping those up should be step one (step two, actually. For all the steps, check out our Start Here for MTHFR guide.)

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MTHFR and Serotonin – an Unhappy Marriage.

Let’s talk BH4, biopterin, and the whole sh*t show. Remember the interlocking metabolic loops in which the methylation pathway intersects and cogs into other pathways, essentially so that it affects everything your body does? Yeah. We’re getting back into that mess.

the MTHFR lifestyle matters because of the way these cycles all interconnect.

You’ll notice that the green MTHFR process sits smack between the folate cycle and the BH4 cycle. The other inconvenient thing you might notice is that the products of the BH4 cycle are, inconveniently, serotonin, and dopamine. These are your internal happy pills – when your body takes you to a happy place it is because of these molecules. Neurotransmitters = happy pills. MTHFR and neurotransmitters = problem. Also, serotonin and melatonin (your sleep hormone) are linked, so there are other consequences to this whole thing being out of whack.

I’ve Never Even Heard of BH4!

Right? BH4, also called tetrahydrobiopterin, isn’t something that people talk about because normally it happens in the background. BH4 doesn’t do too much that is exciting other than contributing to other reactions, so nobody talks about it. The problem is, the other reactions it contributes to just happen to be the ones that make your neurotransmitters (also, our nitric oxide, which will be important when we’re talking about blood flow and heart disease).

Nobody likes it when this goes wrong.

Without MTHFR You Can’t Make Your Internal Happy Pills

Without a fully functioning methylation pathway (and it’s end-products like 5-LMTHF and SAMe) your body has a decreased ability to make Serotonin, Melatonin, Dopamine, Norepinephrine, and Epinephrine. In short, with an MTHFR issue, your body struggles to make enough neurotransmitters. Also, via this same BH4 nonsense, Nitric Oxide but we’ll have to cover that in a separate post.

Low Serotonin Feels Like 😞😢🍽

Low serotonin feels not so good. Sad, low mood, low enjoyment, hungry – probably craving carbs. Just not feeling the zing in life, even if your life is full of zing. You might be feeling irritable for no reason, you might be feeling tired -even tired to the point of chronic fatigue syndrome. It could feel like hopelessness, and at the extreme end, you see thoughts of suicide. Depending on how low your serotonin is you could have mild symptoms or you could be clinically depressed. Serotonin also has a number of functions outside of mood including regulation of digestion. If your serotonin is really low, you might want to read this.

Low Serotonin Leads to Low Melatonin. 😳

Low Melatonin feels pretty bad too. This is the can’t-fall-asleep, gaining weight for no reason, brain fog and dog-tired problem.

Low Dopamine Feels Like 😑😕

Low dopamine feels like being bored. Bored, bored, bored. Loss of satisfaction, joylessness, apathy, and low energy. Also low drive, low attention, lack of motivation, and enthusiasm. Extremely low dopamine can lead to something called anhedonia (the opposite of hedonism) which is absolute lack of pleasure in anything. Also, low dopamine levels are highly associated with addictions, because if you can’t get joy anywhere else, you might get a high from a drug.

Low Dopamine Can Lead to Low Norepinephrine and Epinephrine

These can lead to low energy, lack of concentration, attention deficit and also anxiety or altered fight-or-flight response.

This is Miserable. How Do I Fix It?

Your doctor will probably suggest antidepressants, which work miracles for some people, but tend not to work as well in those of us with MTHFR mutations. So there is that. For MTHFR mutants, it all comes down to balancing out the methylation cycle so that there is enough 5-LMTHF, SAMe, BH4 (or tetrahydrobiopterin), and generally enough methyl-groups to go around. If you’re ready to get started doing that, check out our Start Here for MTHFR document!

There are a few BH4 supplements available, but they haven’t gained a lot of traction for neurotransmitters and are used mostly for cardiovascular disease (to boost nitric oxide, which is a big deal) and also for a condition called phenylketonuria, which is unrelated to this discussion.

There Is Good News!

SAMe supplements can be extremely helpful to begin to enhance neurotransmitter formation without actually fixing methylation directly, and can be a great stop-gap while you’re working to get your methylation sorted out, because that can take some time and patience.

A Note About Melatonin

Melatonin is your body’s sleep hormone, but it also crosses the blood-brain barrier to act as an irreversible antioxidant in the brain and helps to regulate your weight. For many years there has been a myth that taking melatonin as a supplement will decrease your body’s own production, as is the case for many hormones. In good news, there is zero researched evidence that this is true – there is no evidence that taking melatonin decreases your body’s own production. Also, if you’re not sleeping well and haven’t been for some time, then chances are your natural melatonin is all being used to protect your brain and none is left over for sleep. Supplemental melatonin can help you get to sleep and increase your sleep quality. Usually, a low dose is enough, but if you’ve been sleep deprived for years you might need to up things a little. A typical starting dose is 3 mg. Doses of 20 mg and greater have been used with some success for many solid-tumor cancers, and some people are sensitive enough to it to need only 1 mg or less.

Mmmmm. Delicious, happy sleep.. Thanks, melatonin!

When you take melatonin, if you fall asleep well but wake in the night feeling wide awake, then the dose might be too high for you. If you don’t fall asleep easily, then the dose is probably too low. So at least this is one BH4 problem that we can solve.

Next week we’re starting the dive into fixing your methylation because it seems like you should be able to just take some folic acid and be sorted, right? Yeah. except that for MTHFR folks, there is some pretty compelling research showing that folic acid is actually the next best thing to toxic.

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MTHFR and Estrogen. Why Are These Linked?

There is no obvious link between MTHFR and estrogen – they seem to be in unrelated fields in the body, affecting different spheres. Sadly, that isn’t true. While it is true that the MTHFR gene is not involved in estrogen metabolism, it is also true that the products of the MTHFR gene are. So in the end does MTHFR end up in bed with Estrogen? Yes. Yes, it does.


Why Does MTHFR Affect Estrogen? It’s Another Detox Issue.

The word “detox,” when you have an MTHFR issue, starts to trigger a nervous eye-twitch pretty quickly. You just know there is some catch or some little loophole that you’re going to fall into and spend months crawling out of. Estrogen detox is no exception. But first, estrogen is a useful substance – it’s called the “Marilyn Monroe Hormone” and that sounds amazing (more on that in a minute). So, why do we even need to detoxify it?

Why Do We Need to Detoxify Estrogen In The First Place?

Estrogen is a highly useful hormone for both men and women, although women have it in larger quantities. Estrogen helps boost sex drive, thicken bones, protect your heart from cardiovascular disease, and decrease anxiety. It is responsible for the majority of female sex characteristics like breast growth and without it there would be no fertility. So why get rid of it?

Hormones are SHORT TERM Messengers

Hormones are meant to send their signal and then go away. They fluctuate day-by-day during the female menstrual cycle and in order for a hormone level to change, you need to be able to get rid of it. Plain and Simple.

How Do You Get Rid of Estrogen?

Remember we talked about Phase I and Phase II detox reactions? Estrogen goes through both of those. To be clear, there isn’t just one thing in the body called “estrogen.” Just like folate, there are many forms of estrogen, some better and some worse. These forms interconvert in various ways and affect tissues differently. Below, is a diagram of how estrogen changes as your body gets it ready to go out with the trash.

Red “x”s are not our friends

Ok, So I See A Few Hitches Here.

Hitches galore! I added some red “x”s where there are possible problems for MTHFR folks and that’s a lot of “x”s. The methylation cycle is plopped smack in the middle of estrogen metabolism because we methylate some metabolites into their less harmful forms in order to excrete them. If you can’t methylate at that partcular moment, then your body has to convert estrogens to quinones, the worst possible pathway. Glutathione, which can be a bit shakey in MTHFR folks, is necessary to help neutralize these quinones, otherwise, they have potentially carcinogenic effects.

Not All Estrogen Is Created Equal.

Different types of estrogen have different relative impacts on body tissues (different strengths, so to speak).. Here’s the breakdown:

Estradiol (E2) is 1.5 to 5 times more active in tissues than Estrone (E1). These two forms of estrogen can interconvert. Estriol is only biologically active in pregnant women, so doesn’t factor in so much. In terms of Estrogen metabolites, 2-hydroxyestrone (2OH-E1) helps modulate the activity of more biologically active estrogens and has been shown to decrease the risk of breast cancer. 4- and 16-hydroxyestrogens have been shown to be more biologically active and also more carcinogenic (meaning they promote cancer).

What Does This Mean For Me?

The bottom line in all of this is that without good methylation in Phase II detox, estrogens are oxidized and converted to quinones, which have potential carcinogenic effects. These effects can be mitigated by glutathione, but with MTHFR issues you have the potential to be short on that, too.

MTHFR Mutants Are Prone To Estrogen Dominance

Estrogen dominance means that your estrogen levels are, relatively speaking, higher than the levels of other hormones. It doesn’t mean that they are “too high” on a lab test, it means that the ratio between estrogen and progesterone (in women) or estrogen and testosterone (in men) is out of balance.

Signs and Symptoms of Estrogen Dominance

In Women:

  • Fibrocystic breasts or uterine fibroids
  • PCOS, endometriosis,
  • Heavy bleeding, clotting and cramping with periods
  • Irregular periods and infertility
  • fatigue, depression, anxiety

In Men:

  • Gynecomastia (a.k.a. man boobs)
  • Loss of muscle mass and more typically female fat distribution
  • Sexual dysfunction
  • fatigue, depression, anxiety

What Can You Do About Estrogen Dominance?

  • Eat your veggies! – Cruciferous veggies including broccoli, cauliflower, kale, Brussels’s sprouts, and cabbage help shift your metabolic pathways away from the cancer-promoting 16-hydroxy metabolites. This also helps to reduce symptoms of estrogen dominance by shifting from high-activity forms to lower activity forms.
  • Eat your fiber – You are an inherently thrifty creature and even after your body eliminates something into your gut, you often go back and sort through the trash to pick it up again, because it might be useful. If you have a good amount of fiber in your system, then lots of toxins (like hormone-waste) bind to that fiber so that you can’t retrieve it.
  • Eat your lignans – lignans, which are found especially in flax seeds but to a lesser degree in sesame seeds, are estrogen modulators. They help to balance excess estrogens and are the foundation for the gentle form of hormone balancing in women called seed cycling.
  • Supplement with NAC – N-acetylcysteine is a readily available supplement that acts along with selenium as a precursor to glutathione production. This works even for MTHFR folks and it boosts the levels of glutathione so that if you are creating damaging quinones, you have the capacity to minimize the damage. If your multivitamin doesn’t have selenium in it, you can get enough by eating three Brazil nuts daily.
  • Eliminate Estrogen Mimetics – you don’t just have to worry about the effects of estrogen that your body makes, you also have to worry about environmental toxins that *look* like estrogen to your body, because if they look enough like estrogen, they can bind to estrogen receptors. These include phthalates and parabens from things like lotion, perfume, synthetic air fresheners, and body wash (the name will be long, but ‘phthalate” or “paraben” will be in there somewhere), BPA and related chemicals from plastics (don’t ever, ever microwave your food in plastic.) Plasticizers in soft plastic construction products like caulk.

What About MTHFR and Other Hormones?

Great question! No known link between MTHFR and testosterone levels has been demonstrated, but high estrogen can lead to low effective testosterone through the back door of sex hormone binding globulin. SHBH rises when estrogen levels become too high in order to bind to and therefore inactivate some of the excess estrogen. Unfortunately, SHBH prefers testosterone, so it binds to that more frequently (thereby inactivating that as well.) So high estrogen levels often lead to lower levels of free testosterone, which is the active form.

Also, stress hormones and MTHFR have not been studied, but there may be a link. A paper published in 2017 from the NURSES study, showed that MTHFR polymorphisms affect perceived occupational stress levels. This study didn’t actually test levels of cortisol, which is the major stress hormone, but it did show that people who were homozygous (two bad copies) for C677T mutations perceived higher stress levels than their heterozygous (one bad copy) or wild-type peers. The heterozygous group did perceive a higher stress level than the normal group, but the difference wasn’t great enough to be considered statistically significant.

Back to the Marilyn Monroe Hormone?

Estrogen – specifically estradiol (E2), the most potent estrogen, has been called the “Marilyn Monroe” hormone because the results of a high estradiol level are so visibly apparent in the famous actress. She had symmetrical facial features, an hourglass figure with large breasts and a low waist-to-hip ratio, and a tendency to have sex with partners outside of her relationship. Also, high levels of estradiol make it more likely that a person is considered attractive, both by themselves and by other people. Unfortunately in women it also means they are more likely to be disliked by other women.

Marilyn knows all about the glamorous MTHFR lifestyle. Actually, if I had to place a bet, she was an MTHFR mutant too!

Next week we’ll talk about MTHFR and neurotransmitter formation, because that is the basis for so many other topics (like how MTHFR intertwines with anxiety and depression). After that, we get into the good stuff, like why your multivitamin might actually be doing more harm than good. If you want to jump right to what to do about all of this, check out our Start Here for MTHFR guide.

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