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.
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.