NB: This article was modified March 2024. I am offering two new courses about this. The short course covers the specifics of folate, what to do, how to figure out if there’s an issue, and a decision tree to determine what to do if you have trouble with folate. The longer course goes into other problems related to anxiety and other mental health issues
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 the full impact of methylated folates. 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 the methylation cycle, DNA, and why genetic tests may not be the right approach.
Undermethylators are one of the primary subtypes described by the Walsh Protocol. To understand why folate is a problem for them, we should discuss undermethylation.
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 reactions and one of them is to turn off DNA.
How does it do this?
Though we are not exactly sure, methyl groups change the charge of chromatin, making it bind tighter to histones. What does this mean? The DNA is less accessible for transcription, so turning off those genes. Acetylation has the opposite effect. Here DNA becomes more available and turns genes on. Folate appears to increase acetylation of chromatin, though the mechanism is unknown.
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, serotonin levels will be low. If you have too little reuptake, serotonin will be too high. (Yes, you can have too much serotonin in your body and some people do.)
Undermethylators with anxiety or depression are vulnerable to folates. The folates turn on the serotonin reuptake gene that is already not downregulated because of 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.
This gets further complicated when you add in high S-Adenyl-Homocysteine (SAH) a substance that regulates the enzyme methyltransferase. (This is a topic beyond the scope of this article for the moment. But the plasma methylation test is a wonderful way to determine if one is an undermethylator and the best treatment approach.)
NOTE: If you are a pregnant woman, it is advisable to have your folate levels measured to determine the amount of folate to take.
What about Methylated Folate?
What about methylated folate? Isn’t that supposed to help undermethylators? Many providers prescribe it because folate is intimately involved with recycling homocysteine into methionine. This drives the production of methyl in the 1-carbon cycle in the body. But Dr. Walsh has shown something odd about this. All folates turn on the serotonin reuptake gene so that serotonin levels drop and you have a recipe for problems. Likely, this happens because the DNA responsible for the production of the SERT gene has greater exposure to transcription factors. Increasing methyl causes this to reverse so there is less transcription of the gene.
Having said that, many undermethylators show temporary improvement because of taking methyl folate. After two to three months, the person devolves again. The methyl donation from the methyl folate 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 everyone. Undermethylators respond slowly; some people may not get a benefit for almost a year after treatment starts.
To learn more about methylation, I’m planning a course that goes into greater detail about the topic and how to recognize the differences between overmethylation, undermethylation, and another underlying issue. A deeper course covers more information Or 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.)
when you say folate do you mean methylfolate as well
Where do you get your information? I cant find anything about folate increasing SERT.
Conversations with Dr. Walsh. There’s also research out that excessive folate may decrease methylation in two ways. Shutting down the one-carbon cycle and turning off methylase enzymes.
Avoid folate or methyl-folate or are you using the terms interchangeably here? Thank you.
For the purposes of what we are discussing there is no difference. But if you take folate for other reasons the form of the folate can make a difference.
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
As someone who is undermethylated with a long history of psychosis, I have found high protein low car diet helpful. Specifically wondering how this pertains to veggies.. I do a lot of root vegetables which are great… But what about green leaf vegetables like kale, broccoli, mustard greens. If they’re high in folic acid and I have very low seratonin wouldn’t it make sense to stay away from those greenies altogether? Or am I just speaking hogwash?
Generally, people do fine with natural folates in food. The body can control the production of folic acid in the liver and making it bioavailable.
I have been Histamine tested (95) and have undermythelation. I should avoid folic acid. Should I avoid foods high in folic acid/folate or just avoid folic acid supplementation?
It depends if you have symptoms with it. Most people consume too much folate (regardless of methylation status.) It’s best to get in diet only but you can check levels
Dr Winkelman,
I am on SSRI’s and that really helps my severe anxiety issues. This probably can mean that I have a high serotonin reuptake activity at the synapse. This would mean lower serotonin levels at the Serotonin receptors.
The SSRI medications work but have side effects. I do have a few mutations in MTHFR, MTHFD, BHMT, CBS, COMT etc. I react negatively to sulfate, SAMe, L-Dopa, Copper sulfate.Am I over methylation or under?
Thanks,
Hard to know from this. Generally, patients who do well with SSRIs also do well with SAM-e and are undermethylated. The reaction to SAM-e may be because your homocysteine is high and therefore the body doesn’t know what to do with it.
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.
So how do you your levels up if you’re a undermethylator with low folate ?
You can take folate, eat more leafy green vegetables, or take methylfolate. The thing is that if you are an undermethylator you still need folate. It’s just good to limit intake 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.
Dear Dr.,
In my case, I have the common behavior profile of a overmethylator and react highly to l-glutamine, whey, and also methyl-b12 was not good for me. My reaction is with insomnia or very bad sleeping.
But I also react to histamine (fermented foods, etc) with the profile of histamine intolerance (I have Dao levels ok). Histamine in blood in the upper limit but ok. Excercise or stress are also triggers. Homocysteine 9.3, within limits (53 years old)
Is overmethylation the main problem or is the histamine?
Should I try methylfolate?
Thanks a lot
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.
Which methylation status test(s) do you recommend to determine whether someone is an under or over methylator? Thanks 🙂
The Plasma Methylation Test can help you figure out if you’re an undermethylator. There isn’t one for Overmethylation but it is relatively rare since we’ve added folate to food.
It is extremely disheartening to hear that if you are suffering immensely that you might not feel better for A YEAR. That is horrific. I think some people might fall into great despair hearing such a thing. Perhaps it might be better to say “not fully improve”. Unless you think a person just has to spend up to a year suffering before they can feel better. That’s a lot to put on someone.
It’s not that I want someone to suffer. It’s just that it can take that long for the effects to be felt. It’s more a suggestion to stick with it. Most people find relief sooner than that but the methylation process can take time to correct.
Dear all,
I one fits the undermethylator profile excepting the anxious character of the over-methylators and have:
– close to upper limit homeocysteine (11.99). => under-methylator profile…
– histamine intolerance (histamine rich foods affect sleeping, and also issues with oxalate rich ones) but histamine blood levels ok, => under-methylator profile…
– zinc low limit, copper ok.
– vit d low (20.3)
– b12 (340) and folate (10) blood tests ok
– too sensitive to methyl-donors, I tried methyl-b12. One single dosage -> insomnia, => over-methylator profile…¿?
– good for sleeping with niacinamid when histamine is too high due to foods. However niacimamide depletes methyls. => over-methylator profile…¿?
how can one identify in which range he/she is according to these values?
NAC ? TMG ? what to try to lower homocysteine?
thanks!
Generally we do a plasma methylation test to figure this out. Just because you have insomnia from the methyl-b12 does not mean you’re an overmethylator. There are other factors that can cause this issue.
Methyl-B12 does Overmethylation Symptoms.
After Methyl-B12 My body goes in Overmethylation Mode. I don’t know what to do Some Say B3 helps but it didn’t.
Magnesium and Riboflavin help 50% and Yes Lithium also
But my body is not getting normal
Thank you so much for this post. I am MTHFR hetero for both and +-CBS. My folate serum level is high (>24) and homocysteine is normal (7). Does that mean I’m an overmethylator or undermethyltor? Also, my iron and ferritin are low. Could my high folate indicate a B12 deficiency (pernicious anemia)? I appreciate any help you can provide.
High folate could be masking B12 deficiency. From the information one cannot determine if one is an under or overmethylator. It is based on symptom profile and a plasma methylation test.
Hello Dr. Gill,
I am an overmethylator with an homozygous A1298c. Normally I respond well with a low dose of methylfolate 2X daily and B12, B6 and B2. Since I began this regimen over 2 years ago I noticed that my body reacts badly to a number of supplements such as glycine, L arginine, citrulline, magnesium, DHEA and few others that I know of. Is this unusual or am I doing something wrong?
Thanks,
Paul
I couldn’t say without knowing more. They could be two unrelated issues.
I Have MTHFR and my GP advised me to take folate for my depression and anxiety. The point is a have all possible side effects on just 2 drops (yes, liquid form) of methylfolate. Besides, I`m not formally diagnosed with any auto imune disease but I have bouts of inflammation in the body. My face is always puffy. Is insisting on methylfolate a good strategy or avoid it considering my anxiety and depression?
Methylation issues are generally not solved by methylfolate. And just because you have MTHFR does not mean you need it either. Taking methylfolate (even if you’re an undermethylator doesn’t necessarily cause problems either.)
You can check out my course about this topic.
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.
Hello
While everything was normal at first, my life turned into a nightmare with the PPI given for low back pain. I had very serious neurological conditions with Lhermitte and many doctors could not find the cause. Later, my blood test showed that my B 12 level was very low, the doctor said that might be the reason for what I was experiencing and suggested an injection of cyanocobalamin. . After 11 injections the level increased from 201 to 334. In my research, I found hydroxycobalamin to be more beneficial and switched to this. After 1 injection, the level rose to 504. I continued this once a month for 5 months, but paresthesias started again with the 5th injection. I used about 15 methylcobalamin pills but did not see any immediate benefit. I started cyanocobalamin injections again. after the injections ended, the decreased paresthesias started to increase again. I also have undermethylation properties. I want to continue cyanocobalamin injections and try to consume folate-rich foods. I would like to know what your thoughts are.
thanks in advance
Just from this, I couldn’t say what’s causing it. Generally, B12 helps the parsasthesias. It’s a water soluble vitamin so it’s out of the system fairly fast. It could be you’re struggling with something else that the B12 is moving.
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.
“What’s interesting is that some undermethylators can tolerate folates while others can’t. ”
Which TOTALLY destroys your hypothesis. Not to mention the fact that there is no such thing as an ‘undermethylator’ or an ‘overmethylator’…
It’s a continuous process that happens millions of times a second. Sheesh…
It doesn’t. What it is saying is that some undermethylators don’t tolerate folates because it affects the SERT gene and lowers serotonin in the synaptic junction. The thing about methylation is that it prioritizes in ways we don’t understand. The Walsh Protocol really only looks at this from a mental health lens. But methylation affects every system in the body. The other confusing aspect of this which you allude to in your comment is that the term is used in multiple ways. Methylation does refer to the one-carbon cycle. But an undermethylator per se is someone who developed without enough methyl in their system. How the chromatin forms in the nucleus can then be impacted by folate, SAM-e etc. But that varies from person to person.
If you want more information, please sign up for my online course (still in progress at this time but should be released in 2024) at https://askdrgil.com/methylation_training_program/
Hi Loriann, how long after stoping the methylfolate and b12 did you start improving the depressive symptoms, I have been taking folate for 8 months and I think it might have led me into a deep depression unexpectedlly, really deep depression, it been a week I stopped it completly? I am from Brazil.
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.
Dr Gill what are your thoughts on l-glutathione? Do you think it helps histamine regulation?
Maybe indirectly through detox pathways. But I don’t think of it as an antihistamine.
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.
I have been breaking out in hives for 3 years. I figured that I am histamine intolerant. I started taking antihistamines and found that I get terrible leg cramps. I just found this article about undermethylation, and think that this might be my problem. I also notice if I take methylfolate I break out in hives.
I am currently trying to stay on a low histamine diet and taking multiple natural supplements to remove histamine but I still break out in hives. I was also thinking that it might be a TH2 (T-Cell) problem. I spoke to my allergist and he dismissed both.
What test do I need to figure this out?
I’m sorry to hear that; that sounds horrible. There definitely could be an immunological component. As for the test, do you mean for undermethylation? The Plasma Methylation Test can determine that. For the entire picture, I don’t think there’s one test that would figure this out, honestly. But you might want to start with Zinc, copper, ceruloplasmin might give some insight. Honestly, your case is challenging enough that I would recommend an appointment with either me, or a functional medicine doctor.Feel free to email gil@askdrgil.com to schedule.
I am currently on Remeron for anxiety and depression. It has antihistamine action so if I took the test to see if I am over or under methylator would this med affect the true outcome of my results?
Also is a non methyl B12 and non methyl folinic acid combo ok to take?
If you did a whole blood histamine test, it most likely would affect it. But if you are very high in the histamine it might still be abnormally high. You could do the plasma methylation test which isn’t affected in the same way.
As for the non methyl B12/folate, I couldn’t say. Some undermethylators struggle with ALL types of folate. Some do fine with it.
Hello, thank you so much for this insightful article! So thankful for doctors like you who take the time to detail all this for us 🙏
I am homozygous for A1298C and have had two miscarriages since February. All labs for recurring miscarriage came back normal. I was taking high doses of a B-complex with folic acid in the past and added 800mcg of folinic acid on top of that at the advice of my NDs, during my second pregnancy in July. I was taking around 1600mcg of folate without realizing it, including the B complex. Within 6 weeks, my OCD was through the roof and I couldn’t stop the thoughts no matter how hard I tried.
By this time, I had already suffered our second miscarriage, so I stopped taking all of it for another 6 weeks and felt my mental state get better.
Recently I tried adding back in the folinic acid alone, and within a week was experiencing high anxiety/OCD again, felt like I couldn’t turn my brain off and was crying non-stop.
My homocystein is on the lower end, zinc is on the higher end, b12 was also high at one point (just taking cyanocobalamin), and my folate when taking the B complex was over 20…
What is the answer for someone like me who wants to get pregnant, but seems to be so sensitive to folic acid/folinic acid?? Can I rely on just food sources of folate?
You should be able to rely on the food sources for folate. The challenge is the pregnancy but I would bet there is something else going on with regards to the miscarriages. I would need a lot more information though to figure that out.
With regards to the OCD, often undermethylators who take too much folate have that experience.
Hi, I was about to get gene testing done, because im looking into b vitamin issues with treatment resistant depression.
I was diagnosed with lowish b12 and put on shots a month ago, which got me researching into folic acid, and then methylation.
Youre saying to not get the gene tests, but to get a plasma methylation test instead?
My blood test that got me put on b12 also tested serum folate, and it is at 15.6, with anything over 5.4 being normal. On that blood test there is a note that says to take the b12 shots and folic acid. Why would my doctor tell me to take folic acid if it is at 15.6 and normal is anything above 5.4?
THANKS
The gene test doesn’t appear to give us the correct information. Plasma Methylation test is great for figuring out if you’re undermethylated but may not be as helpful for overmethylation. Fortunately, OM is less common. I can’t answer the other question regarding folate injections.
As a note, treatment resistant depression is often zinc/copper in balance and/or pyrrole disorder. Check out https://askdrgil.com/portfolio/walsh-protocol-2/
What does it mean if your DNA comes back that you do not uptake L methyl folate or methyl folate? I have been taking for severally months now (deplin) and feel terrible.
DNA tests are generally not useful to figure out methylation. Many people take methyl folate and feel worse because they are actually undermethylator and the folate turns on the serotonin reuptake gene. I make be creating a course on this soon. Please check out. https://askdrgil.com/methylation_training_program/
I used to take a B complex which contained 100% RDA folic acid and 100% RDA methylcobalamin. My blood tests showed my folate and B12 levels were normal. I stopped taking my b complex as was having other medical tests done which required me to stop all supplements. My recent blood test for active B9 and B12 showed I am B9 deficient (just), but B12 is normal (though on the low end and gone down since the last time I had a blood test when I was taking B complex).
If my folate levels were normal when taking folic acid, could that mean I am under or overmethylation, or would it show that I do not have a problem converting folic acid to folate if my levels of folate are normal when I supplement with folic acid? I have seen so much information online about folate vs folic acid, cyanocobalamin vs methylcobalamin, etc and I just want to make sure I’m taking the correct forms.
Thank you!
Hi Matt,
I do not necessarily trust B vitamin blood tests for a variety of reasons. Maybe I’ll do a podcast on that soon. Having said that, folate is probably normal in your case. But I couldn’t tell you if you are an UM or OM based on that test.
Experiencing mood shifts post-surgery, I rely on Bariatric Multivitamins. The serotonin reuptake gene connection is fascinating. Dr. Winkelman, how can Bariatric Multivitamins be tailored to support mental well-being, especially for undermethylators?
Hi Rhonda,
Thanks for your message. I have no experience with bariatric vitamins. But there is a possibility that we could work to get something compounded. Without knowing more I couldn’t answer but if you wanted to call or schedule please do so.
Hi, I am intrigued by all of your knowledge!!! After getting my genetics test back, I am starting to put some puzzle pieces together as to why I’ve felt so poorly for so long. I am COMT met met, and MAOA slow….
Recently, my B12 and folate bloodwork came back really high B12 1500, and Folate level of 25. I assume I’m an undermethylator and I should stop the Folate, and I’m worried I’m not absorbing B12.
I’m scheduled for a histamine and MMA test next week… if I’m on Prozac, and clonazepam, will that affect my histamine test?
I probably need an appointment with you. I haven’t been able to shake my anxiety and depression for years, and I feel horrible every day… Maybe the high folate is causing my Prozac not to work as well as it should… just another thought
Also, I just ordered your multivitamin without folate or B12, and I hope I can get this figured out.
Anything you can offer would be helpful!!
Thank you so much,
Christy A
Hi Christy,
Thank you. It’s my goal to help people. An appointment would be helpful to go through this. Please feel free to call the office 503-894-7437 and I can get you scheduled.
As for the testing Prozac and Clonazepam both affect histamine levels (lowering them.)
I have suffered with what’s been deemed anxiety and depression for about 7 years now. No trauma just randomly started one morning when I was in college which resulted in a trip to the ER. On and off antidepressants. None help. Just recently got swabbed and have mthfr C677T homozygous T. Just started taking 15mg L methyl folate 5- MTHF plus methyl b-12. 2 days later I feel absolutely horrible. Mental health is as bad as it’s ever been. Am I taking what I should take? Should I take something different? Only 28 years old. Not on anything else currently but just got off a steroid pack this morning after a bad poison ivy outbreak.
Hi Jacob,
Most likely you should not be taking what you are taking if you felt horrible that quickly. Having said that 15 mg is a massive dose for most people. The MTHFR test tells us little with regards to methylation status. I will be doing a course about this (https://askdrgil.com/methylation_training_program/)
If you are interested in working iwth me fill out the form at http://www.askdrgil.com/schedule
Hello,
I’m a health practitioner myself. I have Raynaud’s phenomenon and when checked was low in B12. I’m trying to get pregnant and took methyl b12 and methyl folate. I presume I undermethylate and reacted horribly to the vitamins (muscle aches all over, anxiety, restlessness and increased HR). Would hydroxo B12 and folinic acid be a safer option for me and still work in the methylation cycle to also increase NOS (helping my Raynaud’s)? Should I just start slow since I’m sensitive to the supplements?
Hi Hope,
The B12 form shouldn’t make a difference with regards to undermethylation. Folinic acid is better tolerated by some UM folks. Definitely start slow if you’re sensitive. But I would suggest working with someone on this (I’d be happy to do so.) There may be a different issue going on that has less to do with methylation but I wouldn’t be able to speculate what without knowing a lot more.
Hi,
A few years ago I was diagnosed with MCAS (I also have POTS, EDS, Hashimotos, and homozygous c667t MTHFR mutation) We have never been able to get my MCAS under control. Recently another doctor tested me for overmethylation and found that my histamine and basophils were very low. Can someone still have MCAS when overmethylating or is that an incorrect diagnosis now? From what I’ve read, most people who experience mast cell issues are undermethylators. Anti-histamines never worked for me except high doses of Benadryl, which I now think only helped because of its depressing of the CNS. My issue now is that while my reactions have gone way down, I’m still having some. Is there a supplement or medication that helps with acute reaction attacks? My “MCAS” symptoms are mostly edema, GI discomfort, neurological symptoms, nerve pain, and vomiting.
Hi Paula,
This is a very complicated case and one that I work with. I would not want to suggest anything without knowing more. Generally MCAS is related to undermethylation but often goes hand-in-hand with Ehlers-Danlos Syndrome. As I said, your case is very complex.
Hello,
Are all forms of folates bad for undermethylaters?
Folic acid, methylated folic acid, folinic acid, … ?
Usually the pyrrole disorder should be no longer detectable in the urine after supplementation. How long does this take? 3 weeks?
Thanks
The detection of pyrroles in the urine isn’t necessarily a great measure. I am more interested in how one feels. The pyrroles can fluctuate without supplementation. But in general people see improvement in 3-4 weeks.
Folates (all forms) can exacerbate problems with anxiety and depression in undermethylators. But that doesn’t mean it is a problem for everyone. If you check out my webinar and course on the topic. https://askdrgil.com/methylation_training_program/
Hello doctor, I am writing to you from faraway Bulgaria. I have been struggling with anxiety-depressive disorder for a year, during which time I changed 5 antidepressants and nothing worked as it should. I also did a genetic test, which found a mthfr c677t and a1298c mutation. I included high dose methylfolate 7-10mg. The first 2-3 months I felt pretty good, with my combination of wellbutrin and methylfolate, everything was fine. But at the beginning of the third month everything turned upside down, depression and anxiety returned. I stopped methylfolate and tried sam-e a few days later but it got worse. Also tried months ago methylcobalamin which for hours increase my anxiety tremendously. Here in my country there is no person who has knowledge in this field. I’ve done everything in world psychiatry and it doesn’t work. All my blood tests are normal, homocysteine, ceruloplasmin, b12, D3, complete blood count. I have only mildly low zinc levels and little elevated folate.I consider myself an extremely low methylator and nothing works for that. Maybe have pyrolle disorder, because all mental symptoms are exactly like mine, also many of undermethylaton. Now i take P5P, zinc, B1, probiotics, enzymes, magnesium threonate and vit C (with wellbutrin 150mg). I also have critically low levels of serotonin in my blood, according to one of many tests. I will be extremely grateful if you share your opinion in my case!
I know Dr. Walsh and his protocol focuses on mental health.
My question is can supplemental folates or dietary folates in excess cause or contribute to chronic fatigue in an undermethylator?
Hi Lori,
Yes folates can contribute to increased fatigue. Though if you’re asking about chronic fatigue there may be other causes related to it. Undermethylation has been implicated in various diseases, autoimmune conditions, cancer etc. The research though is still Lin early stages.
My 12 year daughter was put in 400 ug methyl folate and 400 ug B12.She developed anxiety almost after a month of taking it.We have now stopped the supplement.Will the anxiety go down on its own slowly?
It should go away on its own.
Hi,
I am an undermethylater and want to try folinic acid. Methylated folic acid was really bad for me.
In my theory folinic acid + more methyl groups (betaine, methyl B12, …) should work and I should not get depressed. Is that true?
At first I want to check my folic acid blood status. Maybe I don’t need to take it. I am not sure because of all the supplement and health marketing in my environment.
If folinic acid makes me also depressive in a few weeks, … how long will it take to feel good again, if I stop taking it and only follow my personal Walsh protocol again?
Hi Dr! I took an MTHFR test that I couldn’t decipher the meaning of. But I started taking L methyl folate and it caused shaking, sweating, and anxiety. So I stopped it. Then I tried b12 and had anxiety and tried b complex and had rolling panic attacks. Any ideas what causes this reaction? My doctor is stumped about the reaction to b vitamins.
Hi Mira,
There are many reasons this could have happened. I would need to do an intake to figure out. But I am offering a new course that might answer the question too.
https://askdrgil.com/methylation_training_program/
Hi Dr. Gil,
What’s your take on methylB12 supplementation for undermethylators? (Assuming one is following the core treatment protocol with methionine zn ca b6 etc)? Does B12 help or hurt undermethylators? Thank you
Hi Cara,
Generally B12 should be fine and I often recommend for UMs. But it isn’t a particularly strong methylating agent which is very interesting.
I have had genesight test done.. Even with methfolate and extensive TESTING.. I still have depression and anxiety and 5 other things not including medical conditions.. CAN you help??
Yes. Feel free to call the office or use the form on the Schedule button link.
The gene tests do NOT give enough insight into what is happening in the body.
Hi Dr. Gil – what should I do if I am trying to manage OCD/anxiety/depression and also needing to take a prenatal multivitamin for TTC in the next few months? I’m currently taking one with Methylfolate and I’m really nervous that’s it’s going to make things worse in a couple of months. As far as I know, every prenatal has some form of folate, and it’s important for pregnancy. Should I get tested to see if I’m over or undermethylated? Should I only be getting folate from food? Thanks!
Also, when you said it can take almost a year for undermethylators to improve, does that mean after taking methylfolate, or just recovering from anxiety and depression in general?
That’s or undermethylators. But methylfolate is NOT the treatment for undermethylators.
I suggest working with someone (I’m happy to do so.) You need testing though you don’t say if you are or are not pregnant. The research suggests that folate is critical in the first 4 weeks of gestation. After that too much may be an issue. Interestingly, it is also critical for the father to be taking folate prior to conception. (Or have a good level of folate.)
What I’m finding with my research is most people take too much folate. You can check out my course, Why Folates Make Me Anxious for more information too.
I am not pregnant currently, but am hoping to try to concieve in a few months. They say you need to build up your folate/folic acid levels before pregnancy to help prevent birth defects, which is why I’m conflicted on whether I should take a prenatal with some form of folate or not. Do you think a food based one would be safer as far as anxiety and OCD go?
Hi Renee,
I would suggest getting tested to see where your levels are before taking it. Also, if taking folate doesn’t cause OCD or anxiety then it’s generally fine. Generally speaking, food sources are better than supplements. Most people do not eat enough leafy greens though and/or have issues with their liver preventing the conversion of folate into tetrahydrofolate. That is why methylfolate is recommended.
Hi Dr. Winkelman. I was taking folinic acid and hydroxo b12 along with some b complex and after a while started feeling bad anxiety and more depression. At first, it seemed so helpful though.
I realized that I did better in mood while I was taking NMN (now NMNH is claiming superiority) – but don’t remember if I took it together or not – with the folate.
Is there a possibility that the NMn was helping me with emotional symptoms while taking in tandem with folate or just on its own? Can you please put light to this possibility? Thanks
There are definitely differences in quality of supplements along with changes in fillers, capsules etc. There might have been something else in there that your body did or didn’t like.
Good day
I am desperate. I am trying to conceive and ever doctor recommends Folic acid. Every time I take it, I become a different person. I am highly emotional, agitated and quite frankly depressed. I have mentioned this to health care practitioners who have never heard of these side affects, but the change that occurs in me within 24hrs is so obvious. I have tried to research if others feel this way and there doesn’t seem to be any literature supporting my side effects. Is there an alternative drug I can take to help during pregnancy?
Hi Vanessa,
So sorry to hear this. I have a course that covers what do to with Folic Acid problems. https://askdrgil.com/methylation-mini-course/ . I suggest getting your folate levels without supplementation. We do want to be sure the numbers are good before you get pregnant. Issues with folate causing problems is very common actually and there is data about this. Also, too much folate can cause many problems for the fetus too. https://holisticprimarycare.net/topics/naturopathic-perspective/folic-acid-too-much-of-a-good-thing/ Is an article I wrote about the topic.
I’d be happy to work with you if you want to schedule. One thing that occurred to me is you don’t say if you’re having fertility issues.
Hi Dr. Gil, I have been taking a non-methylated form of folate, folinic acid and a non-methylated form of B-12 as well, as I am sensitive to methyl, However, its my understand it still converts to folate, but it takes different steps or pathways, anyway, when I have been taking these non-methylated supplements, it greatly increases my dopamine and serotonin levels, and in turn makes my histamine levels much worse! maybe folate is also increasing my norepinephrine? I had an OATS urine test done recently, shows high dopamine and serotonin, I will therefore only eat my folate and B-12 and not take supplements, I should have pulsed my DOSE!! as well, Lesson learned, your comments please, thank you Lori
I don’t know if the OATS test is reliable for the neurotransmitters. I don’t like to look at NTs because the effects are short lived and in a tight space (the neural gap junctions.) OATS and other tests measure total NTs so we don’t necessarily get a good view of what is happening.
As for the pathways with methyl vs non-methyl, that’s not completely correct. The body prioritizes them in different manners and sometimes will methyl the vitamins (if unmethylated) for other functions. Generally though Methylfolate is used in the methylation cycle but too much shuts that down. (and turns off other methyltransferases). Long story short, too much folate is not good for us.
Hi Dr. Gil,
Based on Chris Masterjohn’s choline calculator, it shows that I need 8 egg yolks worth of choline everyday to compensate the methylation deficiency caused by MTHFR and other gene SNP’s I have.
Choline pathway is an alternative pathway for methylation cycle, do you think taking choline supplements or eating choline rich foods also have the same Serotonin Reuptake gene activation problem in undermethylators?
Hard to say for sure. Betaine (a form of choline) can recycle homocysteine to methionine. That doesn’t mean that the body will prioritize to the methylation cycle. MTHFR by itself and the SNPs do not cause undermethylation. They are only tendencies. without knowing more it’s hard to say if that would help someone. As for it’s affect on the SERT gene, I would say there is no direct effect because that is related to methylation.