I get a lot of questions about the methylation cycle and taking methylated folate. In articles and podcasts, I go into great detail about undermethylation. This causes a lot of confusion amongst patients because most providers don’t understand how methylated folate works. Folate is a wonderful vitamin for many people. But for undermethylators, folate can cause problems. Why is that? To understand the issue, we have to first understand more about methylation, DNA, and why genetic tests may not be the right approach.
Undermethylators is one of the primary subtypes described by the Walsh Protocol. To understand why folate is a problem for them though, we should discuss undermethylation.
To begin, let’s discuss what methylation is. Methylation is the process where DNA gets “tagged” by a small hydrocarbon group. Methyl is one carbon and three hydrogens. Carbon can bond to four different atoms so a methyl group has one spot that allows it to attach somewhere else. The body uses methyl in many different reactions and one of them is to turn off DNA.
How does it do this?
We don’t know the exact mechanism. It appears that the methyl group stops the DNA from turning on at particular locations. Methylation seems to be responsible for turning genes off. Acetylation (a different hydrocarbon) and folate are responsible for turning genes on. In some cases, the reverse is true but for now, let’s simply the thought process.
One gene methyl turns off is the serotonin reuptake gene. Folate or folic acid appears to turn this gene on. If you have too much serotonin reuptake happening, serontonin levels will be low. If you have too little, serotonin will be too high. (Yes, you can have too much serotonin in your body and some people do.)
Undermethylators are particularly vulnerable to folates. The folates turn on the serotonin reuptake gene that is already not downregulated due to the lack of methyl. For some people, they find that a sudden intake of folic acid causes a precipitous drop in mood or exacerbation of symptoms.
NOTE: If you are a pregnant woman, take your folate even if you’re an undermethylator.
What about Methylated Folate?
What about methylated folate? Isn’t that suppose to help undermethylators? Many providers prescribe it. A good number of patients have seen other providers that believe this. And why not? It was what we were taught in medical school. I was. But Dr. Walsh has shown something different. All folates including methyl folate probably cause a net reduction in methyl in the body. Couple that fact with how folic acid turns on the serotonin reuptake gene so that serotonin levels drop and you have a recipe for problems.
That all said, many undermethylators do show temporary improvement as a result of taking methylfolate. After two to three months, the person devolves again. The methyl donation from the methylfolate gets overshadowed by the effects of folate on the body. So the person gets worse.
This is when patients call me. Fortunately, it’s not too late to feel better under this circumstance. A proper treatment plan can benefit someone at any time. Undermethylators respond slowly; some people may not get a benefit for almost a year after treatment starts.
If you think you may be an undermethylator or overmethylator, call today to schedule an appointment. Let me review your medications and supplements to ensure you are taking what is right for your healing process.
Hi there,
I’m almost positive that I’m an overmethylator as I have many of the features listed in the overmethylation category. I live in Winnipeg, Manitoba Canada and there aren’t any MTHFR doctors anywhere nearby. If I started on methylfolate how many grams should I take? Is there any way for me to do a test from here? What is the treatment for undermethylators?
Thank you!
Jessica
There are treatments and tests to determine if someone is an over or undermethylator. If you call or email the office, we can help find a way to get you tested.
Hi Dr Gil!
Quick question because I’m totally confused! I have MTHFR one copy of each c677 and a1298.
I am +- for COMT and +- CBS. DOES THIS MEAN I SHOULD OR SHOULDNT TAKE METHYL FOLATE. I have been taking a Thorne b complex with methyl folate and methyl b12…. Is that a bad idea? Please help!
Thanks so much
Samantha
In theory, if you have a problem with folate synthesis, you should take methyl-folate. But the genetic tests aren’t necessarily showing that people have problems with folate. In fact, many of my patients who show an MTHFR “defect” are actually UNDERMETHYLATED (and should avoid folate if they have anxiety or depression.)
One more question… I thought that serotonin reputake means that it INCREASES the amount of serotonin in the body? Ie; isn’t that what SSRI’s do?
Thanks again
Samantha
Serotonin reuptake DECREASES the amount of serotonin in the synaptic junction (where it’s active in the nerve.) An SSRI inhibits that action.
Hi, Dr. Winkelman, I’m an overmethylator. Very miserable right now. Using niacin to mop up my methyl groups. I have to much Same. I am going to stay away from my b-complex for awhile, just eat foods high in folate instead. Do you think this approach will help me?
Hi Lori,
It’s really hard to say. Some overmethylators benefit from a lot of folate. On the other hand, I’ve had patients who thought they were overmethylators but they weren’t. The SAMe issues they experienced were due to other reasons.
so is Pyroluria disorder causing Cu/ Zn imbalance or is a Metallathione disregulation causing Cu / Zn imbalance? Or can it be both?
Isn’t it possible that oxidative stress or other micronutrients are the cause of Pyroluria or Metallathine disregulation and neither are disorders but just symptoms of nutrient defiencies?
Finally, however the Cu/Zn imbalance is treated, can it be done without Cu dumping symptoms?
Pyroluria is unrelated to copper and zinc imbalance. It’s a sign of oxidative stress but we don’t know what causes it. Likely there are multiple causes. You can have normal blood levels of zinc and still have signs of zinc deficiency which is what pyrrole disorder.
Copper dumping symptoms are very common. We try to regulate with other supplements
My 21yr old son was just diagnosed with BiPolar 1 and hoshimotis last year (TSG was a 6) . He takes a low dose of levothyroxine, .o25 and all thyroid and antibodies are now good. His blood tests show: high homocysteine, low Methylitic acid b12, (undermethylator??) Gluten and Wheat both very high IaG of 18, low creatine, high glucose. Zinc and copper on low end. Folate wasn’t tested. He is looking at all around supplement and dietary changes. The doctor wants him on Abilify. Praying for natural relief of symptoms. Suggestions?
I emailed you a response. But there are definitely natural options available. Feel free to call the office. 503-894-7437. Or check out schedule now.
Re the high glucose. He needs to check fasting to rule out diabetes. Spikes in blood sugar increase histamine.
So in other words, the MTHFR mutation test really doesn’t tell you much? Instead you should be tested to see if you are a over or undermethylator by testing your histamine levels?
Hi Todd,
Sorry for the delay on the response. Yes that is correct though the histamine test is not always accurate. Many medications for example effect whole blood histamine.
I have been told by a William Walsh trained GP that pyroluria causes zinc/copper imbalance. Would you mind clarifying your statement above that it does not?
Many Thanks
Pam
I think this is the same comment. But Pyroluria technically doesn’t cause zinc/copper imbalance. What it does is make you functionally low in zinc. There may be normal levels of zinc in the blood but the patient will still present as if low. That is because the kryptopyrroles bind to zinc (and B6 and other nutrients) and render them biounavailable. (IOW, not useable by the body.) I distinguish pyroluria from low zinc though because other nutrients are affected by the kryptopyrroles, such as Omega-6s, biotin, and B6.
Good afternoon Dr Winkelman,
I am curious about an email answer you gave above “Pyroluria is unrelated to copper and zinc imbalance. It’s a sign of oxidative stress but we don’t know what causes it. Likely there are multiple causes. You can have normal blood levels of zinc and still have signs of zinc deficiency which is what pyrrole disorder.”
I have been told by a “William Walsh trained ” GP that Pyroluria can cause Copper /zinc imbalance so I am trying to understand your comment above.
When you say it’s a sign ,do you mean Pyroluria is a sign or do you mean copper and zinc imbalance is a sign …. of oxidative stress.
Also I wonder what “normal” zinc blood levels means to you. Does it mean normal levels with in the medical model or with in what is seen as normal levels for one with pyroluria?
Many thanks for your time.
Regards
Pam
Hi Pam,
Thanks for the question. Pyroluria is unrelated to copper/zinc imbalance in part by definition. Pyroluria measures pyrrole levels in the urine. Copper and zinc imbalances refers to blood. You can have normal zinc/copper balance in the blood and still have pyroluria. That means that you may be effectively low zinc but they are independent factors.
What I mean by the oxidative stress is there are a lot of people who say pyroluria is caused by this or that. But the reality is we do not know much about pyroluria except that it occurs when there is oxidative stress. That said, the reverse is not necessarily true. You can have oxidative stress and no pyroluria.
As for normal blood zinc, I too am Walsh Trained. His numbers are 90-135 mg/dL. Typically I like to see those numbers closer to 100 on the low end. And this is PLASMA zinc levels. Serum levels measure a little higher.
Thank you for your answers Dr Winkelman
Regards
Pam
I am an undermethylator. Just got back blood works and my folate is low, not normal.
Is this normal for an undermethylator? No folate supplements?
Folate may be low for an undermethylator. Folate is generally avoided if you have anxiety or depression.
I’m diagnosed as an undermethylator with whole blood histamine of 74. SAMe for 4 months and methionine treatment for 9 months did nothing for me, if not made worse. Taking high doses of zinc, molybdenum, b6 for copper overload for years didnt help neither. Going gf helped tremendously. Reacted badly to folic acid (synthetic) when I tried it, before I knew my methylation status. Due to lack of results and worsening really, I had to abandon the methionine protocol and trying methylfolate for 3 weeks now and for the first time in years I can literally feel depression (but not anxiety) melting away, supercharged with energy. I just wonder, is this only temporary, and I’m going to crash eventually? On the other hand, methionine and SAMe failed and I was really taking it religiously and for a long time. If methylfolate is going to make me worse in few months time, then I will really run out of options in terms of supplements.
Is this possible that I’m undermethylator but still somehow need folate, or the histamine test doesn’t reflect my methylation status and I might be an overmethylator or neither?
Whole Blood Histamine is a good cursory test but it’s not always accurate. And other things (such as heavy metals) can afect both sides of the methylation cycle.
Also, bad reaction to folic acid and good response to methylfolate makes me wonder about MTHFR. Walsh says it’s not that crucial, and only methylation status will tell you the truth and point to correct treatment, and that all folates are bad for all undermethylators because they will lower serotonin activity. But what if it’s not all about serotonin in some cases? After all, he clearly states his protocol has 60-70% success rate. I am just looking for answers, I love dr Walsh work and his concepts absolutely agree with me but since I wasn’t improving on his protocol, there must be something else to it.
There could be something else. You could call the office to make an appointment.
Hello, I tested as an undermethylator by a Walsh trained GP. My Zn/Cu levels were good (I’m on the carnivore diet so get plenty of zinc), so I was “prescribed” Biotin, SAMe, and Vit C. The Vit C caused kidney stones so I had to stop taking it, the SAMe made me manic for about 2 weeks and then I just ended up in a low grade depression (no sex drive or joix de vivre, just existing) so I stopped it as well. I’m not sure why the Biotin was prescribed but I did notice my eyebrows filled in, and lastly, a few months after this I had more blood work done and my Folate was in the toilet and my B12 was well above the average. Any thought you could shed on what is underlying all of this?
Hi Andrew,
I’d need to do a full intake to figure this out.
I apologize, I need clarification. So if I do not methylate, shoudl I be taking methylated folate or not?
If you do not methylate well that does not mean you need folate. We would need to do an intake and find out more to determine if you need folate or not.
Hello dr Gil!
You mentioned undermethylated pregnant women should still take their folate. This is exactly my case but high dose of folate prescribed by my obgyn is giving me severe problems – high levels of stress and tension, constantly high heart rate and even difficulty breathing. I had been battling depression for many years, taking ssris, but last 2-3 years I’ve been managing it naturally. I feel like last one month of taking folate has undone all these years of work and I’m back to my worst stage of depression and anxiety. I don’t believe its healthy for me or the baby. Should i really continue taking it? What about supplementing with SAMe? Is it safe in pregnancy? What are my options? Thanks a lot in advance!
Laila
Please call the office. The quick answer is not to add SAM-e as we don’t know about the safety in pregnancy. Also you might be able to reduce the folate or try a different form.
I am homozygous c677t, and a comt t met met.I have a lot of over methylation symptoms. I Would I most likely be considered an overmethylator with those mutations.
You may be an overmethylator. And it may be related to the mutations but medically speaking we can’t make that jump.
Hi there,
I don’t understand this. My son is undermethylated (OCD, tics, social anxiety, ADHD). He has the MTHFR C677T gene homozygous. So if they cannot produce enough folate and this is the problem, then wouldn’t taking folate help it? And if they don’t supplement with folate, then wouldn’t their problems not be resolved or managed ever? Having too little folate can cause all kinds of other health problems. So what is the solution then? No folate?
MTHFR isn’t about folate production but recycling. The SNP tests aren’t useful because a) they are sensitive enough in most cases and b) they assume every cell is the same which they aren’t. The other factor is that having the mutation only means the gene is less efficient. But that doesn’t mean it’s not working. We generally should get enough folate from our diet. If your son takes folate and tolerates it (less tics, anxiety, etc.) by all means you can continue it. But if he gets worse then it is best to reevaluate its usage.
You need Folic Acid to be able to recycle homocysteine (which is toxic to neurons) to something useful (Methionine). Methionine is needed to make SAM-e which donates methyl groups to aid with many important processes including manufacturing neurotransmitters.
A homozygous C677T mutation decreases MTHFR enzyme activity to 25% so you can’t metabolize Folic Acid correctly. In other words, you can’t convert it to the type that can be absorbed. So taking more Folic Acid won’t help if you can’t absorb it, and it might accumulate and cause damage.
On the other hand, you can have a normal serum Folic acid test and still have low cerebral Folic Acid. That’s why you need to see someone like Dr Winkelman who is trained to interpret individual results.
Good evening Dr Winkelman
I started having symptoms of tingling in hands, feet and nose a few months back. I had high normal levels of B12 serum, high folate and high Vit D (really shouldn’t have, in the UK!) Raises mcv and mch. I treated myself with B12 injections and methylfolate which improved my MCV and Heamoglobin, but not my tingling so I’ve increased the folate to 5mg a day, still no improvement.
I’ll now thinking I’m an undermethylator and that I’ve been making things worse?
I would really appreciate your support.
Thanks
This is hard to say. Some people have tingling for many different reasons. B1 could be deficient but it could be something unrelated to B vitamins (such as diabetic neuropathy).
Hi Dr. I have made an amazing discovery, for years I suffered with histamine intolerance (high histamine), I have MTHFR. I also thought I was an overmethylator. For years, I took methylfolate B12. I was miserable. I had lots of bad symptoms including depression, not being able to be happy. Etc… I stopped my methylfolate and B12, and my B complex. Wow!!!!! I am feeling 100% better. I am an undermethylater. I am now, using, Sam-e, methionine, calcium/magnesium B-6, I was deficient in methyl donors. This will help lower my histamine levels significantly. Thank you for your wonderful article on why people think they need methylfolate and the harm it can truly cause. I do have a quick question, I have a B complex that has B1, Riboflavin, B6, Niacin (as inositol hexanicotinate and niacin USP), Biotin, pantothenic Acid. Will this harm undermethylators? I am doing so well right now, I don’t want to rock the boat. Appreciate you lots, thank you for your amazing help!! Lori
You’re welcome. Generally, the B complex doesn’t harm undermethylators. What’s interesting is that some undermethylators can tolerate folates while others can’t. We need folate but most of us get enough through our diet.
Hi Dr Gil, I do poorly on methylfolate. I have MTHFR and HIstamine issues. I increased my methyl donors, to deactivate histamine. Didn’t work for me. I had blood work done months ago, showed high folate. I stopped methylfolate. How long does it take for my folate levels to come down after stopping methylfolate? Thank you
Hi there. That varies greatly from person to person. But gernally it will come down.
Where can I find a good B complex without any kind of folate?
B-Minus from Seeking Health is a good version with B12 or Folate. If you create a Fullscript account through this website you can order htrough them.
Hello, doctor. After reading a lot in depth, I’ve realized I must be undermethylated and have pyroluria. I have serious histamine intolerance and IBS. What tests are reliable for this sort of thing? I did read that one should avoid folate if one is often quite depressed and undermethylated? That surprised me because I had read, in the past, that people should take folate if they’re undermethylated. Anyway, I emailed you. It seems like regular GI doctors don’t seem to be able to help my health. I appreciate what you’ve got on your website and will read Dr. Walsh’s book.
You’re welcome. Folate is one of those things that is often over-prescribed these days. Not that it isn’t important.
Hello Dr. Gil,
Thank you for your time. I much appreciate this article, and your website has answered many of my questions.
One I haven’t found an answer to: Does NAC (N-Acetylcysteine) create acetylation groups in your body (that turn on genes)? And if so, does NAC also turn on the serotonin reuptake gene, as with folate? Thank you for your insight.
Great question Eden! I don’t know if we know the answer to this. In my experience, NAC doesn’t do enough by itself to move the symptoms of overmethylation. It is a fast acting antioxidant which could help some people. But we see that it seems to work as an NMDA antagonist which basically means that it might help undermethylators if there is addiction or schizophrenia but not undermethylators who are depressed or anxious. This is why this is so complicated to answer.
Can Paxxet mask undermethylation due to lowering histamine?
Thanks!
Not sure what you mean by “mask”. It lowers histamine so the Whole Blood Histamine test may not be accurate. The plasma methylation test will give a more accurate reading. But often you can go off of symptoms and the presentation instead of testing.
Hi. My daughter is having quite a few uncomfortable and bad side effects since starting methyl folate. Mainly insomnia, anxiety, nausea and a few others. Will these symptoms stop from quitting the medication? Thank you in advance
It’s hard to say for sure, but definitely possible. Nausea, though, is not something I think of as a side effect of methyl folate.
Dear Dr.
In my case with Histamine Intolerance (insomnia) I have seen a huge improvement with vitamin b2, but still a way to recover completely.
I do bad with methyl-b12, choline, glutamine, all them triggering a brutal insomnia.
I see myself like an undermethylator profile, but react badly with methyl-donors some few days after taking them (even at very low dosages).
Why? if it is supposed to be in the under-side ?
Creatine, SAM-e, Methionine, ? what would be safer to try?
Homocysteine: 10.5
folate, b12, b6, Mg, Zn, all them ok at blood test.
may thanks
Unfortunately Pedro, you are one of the more complicated cases. Your situation could be due to a number of problems including trauma. Feel free to read my latest blog post about how do I know if I have trauma. It is also possible that there is heavy metal toxicity or another underlying cause.
Dear Dr. Winkelman,
Thank you so much for all the useful information. I assume being an overmethylator (high folate, high vitamin b6 and b12 and low homocysteine). I tend to do bad on folate and folic acid but feel that I tolerate betaine quite well (not sure if it was the betaine I took or something else, I did not identify yet). Does this all make sense or would you consider betaine as adverse for overmethylators?
Thank you very much for your time and consideration.
Best, Charlotte
Biochemically, it doesn’t make sense but that doesn’t mean to not take it. There are several possibilities related to your situation. You may actually be an UNDERMETHYLATOR. But I’m not sure I could say without knowing more.
Hi,
I’ve been reading that social anxiety is caused by elevated serotonin. As an undermethylator, wouldn’t my serotonin be low? I don’t quite understand the connection between methylation and neurotransmitters. Does methylation turn off the reuptake genes– so low methylation would mean low reuptake?
Thank you!
Sarah
You are correct. Serotonin would be low because it is being reuptaken too quickly. The total amount of neurotransmitters may or may not be important with regards to anxiety.
I react very badly to methylfolate and any methylated B vitamins, however I have recently started injecting 5000mcg of hydroxocobalamin, do I need to try other forms of folate or can I just continue with the b12 alone? What are the reactions I should be aware of regarding the need to supplement folate while using b12? Some say even sub methylators need folate when they supplement b12 but I’m scared because I have very severe anxiety, insomnia and depression and the methylfolate always makes it worse! Thanks!
You probably get enough folate in your diet. In general, we need to add B12 when giving folate but not necessarily the other way around.
I am Val/Val Homozygous for the Val allele of the COMT gene Val158Met polymorphism. I also have Homozygous T allele of the C677T polymorphism in the MTHFR. What vitamins do I need? I am taking antidepressants and they make me have extreme anxiety. Have been on at least 7 throughout the past 2 years and nothing has helped.
Without knowing more, I couldn’t tell you. I do not use the genetic tests for treatment, at least not to start.
I was taking all the methy forms, plus all the b’s . I am on a antidepressant and have bad anxiety still. Very tired all the time. I do have the genes one of each for MTHFR. I also am a slow and fast metabolizer with certain cypt genes. Should I not methyl anymore? Any info appreciated.
Without knowing more, I couldn’t tell you. But the MTHFR gene may or may not be the right information with regards to whether one should methylate or not.
I tested for MTHFR, can’t take 5mthf as it makes me depressed (most likely undermethylated, reading your article) and rapidly lowers my b12 level. Folic acid increases my homocystein and cyanocobalamin gives me skin issues.
My husband tested for MTHFR and COMT, becomes very tired from methylated vitamins.
My child tested for MTHFR and COMT. Unfortunately he has to use medical nutrition, which has a lot of folic acid and cyanocobalamin. Could I use hydroxocobalamine and NAC for him as an ‘antidote’?
It’s hard to tell you what to take without knowing more information. That folate raises homocysteine is very curious though.