Epigenetics, Methylation, MTHFR & the Brain, Made Easy...er

8/11/2015

Courtney Snyder, MD

Before I delve at length into the amazing process of methylation and its impact on personality and mental health, I'll lay some groundwork. For those who don't need or want such background, I've tried to make it easy for you to hit the highlights or jump ahead to your own starting point.

GENETICS

Genetics is basically the study of how parents pass some of their characteristics to their children. Genes are the units by which this occurs. The job of a gene is to make a specific protein. We have two of each gene - one from our mother and one from our father. Every cell in the body has the same genes, but only some of those are used/expressed in each cell. This selective expression is what allows our brain to be a brain and our liver to be a liver and not the other way around.

Despite our incredible diversity, we all generally have the same genes as others of our same sex. We are only about 0.1% different from one another. SNPs or Single Nucleotide Polymorphisms are genetic mutations that developed over thousands of years. Of more than 10 million SNPs identified in the human genome, most of us have more than (but closer) to one thousand. Those that are expressed explain some of our differences including our unique vulnerabilities to certain health conditions. If you’ve ever looked at your SNPs, this can be a bit frightening. For many, doing so can cause more harm than good. Most of these mutations or SNPs are never expressed and have no significant effect. Walking around thinking you are destined for a serious or fatal health condition when you're not, can be a problem.

EPIGENETICS

Until recently we believed our genes and mutations were written in stone. We now know that during pregnancy, chemical bookmarks (methyl groups) can attach to DNA to enhance or inhibit gene expression in each tissue. Environmental insults in utero can produce deviant bookmarks resulting in more serious conditions or birth defects. Throughout our lives, a severe environmental insults can alter these bookmarks and produce an epigenetic disorder. Such insults can be psychological/emotional (inadequate or disrupted attachment, trauma, severe stress) or physical (exposures to toxic metals, radiation, chemicals). This field of research is called "Epigenetics" and it is revolutionizing our understanding of cancer, heart disease, developmental disorders such as autism and psychiatric disorders all which seem to be epigenetic in nature.

With this comes good news - we have a degree of control over the expression or the turning on or off of our SNPs. Many disorders previously thought of as genetic and untreatable, are actually epigenetic and treatable using certain nutrients and/or lifestyle changes that powerfully affect gene expression.

METHYLATION

The most dominant factor in epigenetics is methylation. This is a biochemical process, which occurs a billion times every second, and involves the addition of a methyl group to an atom or a molecule. Meet methyl with it's carbon and three hydrogen atoms:

I'm including a "simplified" diagram below, only to make two points about the process of methylation:

#1 - Its complicated

#2 - There are a number of genes (in colored boxes) which collectively determine how much methyl someone has. Certain genes, including the infamous MTHFR, if expressed can result in undermethylation (not enough methyl), while others, such as CBS, if expressed can result in overmethylation (too much methyl).

The most important methylation gene is MTHFR. While having a mutation at the C677T location can result in someone having undermethylation, this isn't always the case. It is possible (though less likely) to be homozygous (have both genetic mutations) for MTHFR C677T, and have normal methylation or even be overmethylated. The presence of the genes matter less than whether or not they are expressed. What matters most is the net sum of all of the expressed methylation genes.

Accurate diagnosis of someone’s methylation status is essential for treatment. A convenient and simple marker for methylation status is the whole blood histamine test. This is because methyl is the primary mechanism for breaking down histamine. If you have a low histamine level, your methyl is too high. If your histamine is high, your methyl is low.

Aside from playing a role in whether or not our genetic mutations are expressed, methylation is essential for almost every system in our body, including:

repairing DNA
replenishing of compounds that our body uses to detoxify (to eliminate toxins from our body)
keeping inflammation (the bodies innate immune response) in check
maintaining a stable mood and influencing our personality. This is due to the relationship between methylation and neurotransmitter activity.

METHYLATION IMBALANCES

A database of 30,000 people by Dr. William Walsh, PhD (referred to by some as the father of methylation) found that 60-70% of people have normal methylation, 22% undermethylation (too little methyl) and 8% overmethylation (too much methyl). Abnormal methylation doesn’t translate to mental illness. Many highly successful CEO’s and athletes are undermethylated and many talented artists, writers and musicians are overmethylated. Of individuals with behavioral or mental disorders, however, 70% have a serious methylation imbalance. This is due to the impact of methylation on both genetic expression and on neurotransmitter activity.

Nutrient therapies for methylation imbalances aim to normalize methylation, which normalizes neurotransmitter activity, which can alleviate symptoms. For example, methionine and SAMe are serotonin "reuptake inhibitors" and thus increase serotonin activity at the receptor site. Folate reduces synaptic activity of serotonin, dopamine and norepinephrine at the receptor site. For me, as a psychiatrist, this is incredible. For many struggling with brain related disorders, addressing methylation can mean never needing to start on medication. For others, treatment of a methylation imbalance can mean coming off or being on less or fewer medications. In some cases, such as when there is toxicity, such as mold toxicity, methylation treatment may not be tolerated until this is addressed first.

What has been both fascinating and satisfying for those of us who have trained with Dr. Walsh, is being able to often predict someone’s methylation status even before seeing lab results.

UNDERMETHYLATION: [Think low methyl, high folate , high histamine and low neurotransmitters (serotonin and dopamine) activity.]

Symptoms & Traits:

Obsessive compulsive tendencies, ritualistic, perfectionistic, dietary inflexibility (likely related to low serotonin)

Very strong willed, competitive at sports
Calm demeanor (likely due to lower neurotransmitters) with high inner tension
High accomplishment or family history of high accomplishment
Seasonal allergies and high fluidity in eyes and mouth (remember - high histamine)
Good response to serotonin reuptake inhibitors, ie. Prozac, Paxil, Zoloft, Celexa (again because of low serotonin)

The Incidence of Undermethylation:

98% of those on the Autism Spectrum
95% of those with Antisocial Personality Disorder
90% of those with Schizoaffective Disorder
85% of those with Oppositional - Defiance
62% of those with Anorexia
38% of those with Depression

Treatment:
Nutrient therapies, which include methionine and/or SAMe, aim to increase methionine and increase serotonin activity. Because folate reduces neurotransmitter activity and these individuals are already low in neurotransmitter activity, folate should be avoided. In fact for better brain health, these individuals do better on a high protein diet (and thus high in methionine). They should avoid supplements that contain folic acid.
******Because multivitamins usually contain folic acid, they're problematic for many individuals with mental health symptoms. They contain copper and copper overload too, is very common in brain related disorders.

OVERMETHYLATION: [Think high methyl, low folate and high neurotransmitter (serotonin, dopamine and norepinephrine) activity.]

Symptoms and Traits:

High artistic or musical ability
Hyperactivity, high energy, verbose (likely due to high neurotransmitter activity)
High empathy for others, good neighbor, noncompetitive in sports
Food and chemical sensitivities, but absence of seasonal allergies and dry eyes and mouth
Adverse reaction to SSRIs (Prozac, Paxil, Zoloft, Celexa, etc.) as well as Methionine and SAMe (there is already too much neurotransmitter activity)

The Incidence of Overmethylation:

64% of those with Panic Attacks
52% of those with Paranoid Schizophrenia
28% of those with ADHD
18% of those with Depression

Treatment:
Nutrient therapies aim to increase folate and thus lower what is high neurotransmitter activity. Most important is folic acid, which reduces neurotransmitter activity. Niacin/niacin-amide also lowers dopamine activity. These individuals will do better with a high folate diet (veggies and fruit) as opposed to a high protein diet.

THE FUTURE OF PSYCHIATRY

Knowing that someone is depressed or psychotic or manic doesn’t tell you if they are undermethylated or overmethylated. It also doesn't tell you if they have copper overload, metal toxicity or pyrrole disorder - the other common biochemical imbalances. If everyone with depression took an antidepressant that raises serotonin activity, those with undermethylation would likely have significant benefit, however, those with overmethylated would likely get worse. Tragically for some, this can mean suicide or even homicide. Currently in conventional psychiatry, there's no specific way to know who those people are. Dr. Walsh's biochemical approach removes that guess work. His database and research informs physicians on how to evaluate and treat methylation disorders (and other nutrient imbalances) using targeted nutrient therapies.

The fact that many conventionally trained psychiatrists are testing for MTHFR C677T and using the highly promoted methylfolate (Deplin) show that the psychiatric field is starting to grapple with these important concepts. However, adding Deplin to an antidepressant is missing the mark. Some may benefit; many will not and some will get worse. Again a mutation at the MTHFR gene doesn't tell you someone's methylation status. Also, if someone is undermethylated and depressed and likely low in serotonin, they can become more depressed if given more folate. To quote Dr. Walsh (from an interview on the ACN website)

"... blindly using methylfolate (Deplin) for patients with C677T MTHFR or other weakened enzymes can produce negative results in patients afflicted by low serotonin activity. Folate supplements including Deplin tend to drive serotonin activity even lower.... The bottom line is that methylfolate and other folate supplements are very effective in enhancing methylation for autism and other conditions that are not dominated by low serotonin activity." (apathetic depression and anxiety typically involve low serotonin activity)

***
Thank you for sticking with this lengthy post. My hope with some of these early articles (ie. on the microbiome, nutrient therapies and copper overload) is to provide resources and background for those wanting to better understand these complicated issues. Having done this, I look forward to more specific and shorter posts.

If you'd like to go deeper into these topics, I recommend the following book and youtube videos:

Nutrient Power: Heal Your Biochemistry and Heal Your Brian - book by William Walsh, PhD

The Role of Methylation and Epigenetics in Brain Disorders - video presentation by William Walsh, PhD

"MTHFR and Mental Health: Understanding the Overall Effect of Individual Genetic Mutations SNPs" - video presentation by Dr. Albert Mensah

If you're looking for a physician trained in this area or are a physician interested in training, visit the Walsh Research Institute.

51 Comments

Ronan Brown

8/10/2015 02:05:48 am

Thanks Courtney. I actually read your article. Based on what I think I understand, I may fall into the OVERMETHYLATION column. Fruits & veggies; not a strong part of my diet. Alot of protein is. Going to experiment and switch these things. Will let you know.

Love,
Ronan

Courtney Snyder link

8/10/2015 07:48:26 am

Thanks Ronan - hope that's helpful. If you want to maximize the higher folate veggies, they would be things like spinach, asparagus, broccoli, brussel sprouts, okra, romaine lettuce. Higher folate fruits are strawberries, cantaloupe, banana and orange.

Andrew

8/11/2015 10:06:21 pm

This is so interesting! Is there a more comprehensive list of folate containing foods? Many thanks!!

Courtney Snyder, MD link

8/12/2015 01:06:16 am

Hi Andrew - a good place to look is http://nutritiondata.self.com
You can plug in any nutrient and they will list the items in order. Highly processed and enriched foods, which I don't recommend, will also be listed. Some nuts and beans/lentils are also high in folate but for some with copper overload which isn't uncommon, an overconsumption of these can be problematic. Though I mention diet as a factor, Dr. Walsh would say that, for most people with biochemical imbalances, dietary changes alone usually isn't enough, which is why we use nutrient protocols. A diet that goes against someone's methylation status however, could be making things worse .

Andrew

8/11/2015 10:03:41 pm

Wonderful article!! With regard to the high protein diet; Which proteins are most suitable and what percentage of the diet should comprise of these? Also, where does this leave us with regard to fats and carbohydrate? Many thanks!

Courtney Snyder, MD link

8/12/2015 08:28:08 pm

Thanks Andrew. I don't have a percentage because like many things it can depend. Though I'm focusing on methylation here, the micro biome also matters a great deal and it seems to benefits from fiber - so vegetables and fruit remain important. Because methylation relates more to methyl (think protein) and folate (think veggies and fruit), fats and carbs don't factor in so directly. In general healthy fats seem to benefit brain health - ie. olive oil, coconut oil, butter and animal fat. Carbs ie. in the form of refined carbs (ie. sugar, white bread, pasta, etc.) are considered problematic. Some believe that all grains even whole grains are problematic for brain health, but I think this can depend on the individual. For most the best way to increase protein and/or veggies and fruit is to use them to replace some of the grains.

Thomas F. Pequignot DDS, CCN

4/4/2016 11:49:52 am

Dr. Synder--what few people realize is that the human microbiome is not just in the gut but occupies the entire body. We are a walking Petrie dish of bugs. Most of the diseases of aging are caused by stealth infections of L-form bacteria.

beverley steffert link

1/1/2017 11:50:27 am

why is the dimension of attention (or not) to detail, due to under or overmethylation - what neurotransmitter is involved for example?

Courtney Snyder link

5/12/2017 01:05:52 pm

Beverly. Apologies for my very delayed response. In under methylation, there is a decrease activity at the serotonin, dopamine and norepinephrine receptors. Low activity at the dopamine receptor would contribute to inattention. In over-methylation, there is an increase in the serotonin, dopamine and serotonin activity at the receptor site. If there is inattention here, it often relates to racing thoughts, high anxiety etc.

Frederick Bertram

4/15/2017 03:58:49 am

Hi I believe my schizophrenia is caused by overmethylation, I can't seem to find any journals about folate reducing neurotransmitter activity I'v only done a search with google so far, are those journals published and available on google? Alternatively is there some database of case studies i can read of people treated with folate for overmethylation? Kind Regards Frederick

Courtney Snyder link

5/12/2017 01:09:35 pm

Fredrick. If you haven't already checked these out, I would refer you to Dr. Walsh's book, Nutrient Power as well as the Walsh Research Institute link: http://www.walshinstitute.org/the-walsh-theory-of-schizophrenia.html.

Laurel

6/9/2017 03:10:37 pm

Hi, my 3 year old suffers from a lot of anxiety, aggression, ODD-like behaviors at times. I was concerned about underlying causes and her MD ran some blood work. He only checked her B6 and B12 but they were both extremely high despite no multivitamin for a full week prior to the test and paleo diet with no fortified foods. I had read about MTHFR and thought she was maybe under-methylating and not able to use the vitamins correctly. However, her Red Blood Cell count, hemoglobin, hematocrit were all elevated as well. After reading about over-methylation on your site I'm wondering if she may actually be over methylating. Do you know if high RBC can indicate over-methylation since b12 is so key in making RBCs? Thank you for this post.

Courtney B Snyder link

6/26/2017 04:40:48 pm

Hi Laurel. To my knowledge, there is not a relationship between a high RBC and overmethylation. When I do see abnormal blood cell indicators in people with brain related symptoms, I wonder about mast cell issues (you may want to look into Mast Cell Activation Syndrome and the work of Dr. Larry Afrin - he is a hematologist and really the pioneer in the area of mast cell activation). This can cause high levels of histamine (and other immune mediators) which can cause behavior and cognitive changes as well as physical symptoms. Often such individuals are very reactive to a range of things - ie. certain foods, chemical sensitivities, even bug bites, etc. It looks different in different people. Separately, there is some debate about the benefit of B6 and B12 levels and I'm not sure how much is known about levels in 3 year old. There are some who will argue that such elevations actually indicate an intracellular deficiency, rather than an excess. I don't regularly check levels for either of these, though I do use them in my nutrient protocols.

Pam link

7/6/2017 08:13:24 am

Hi, My daughter is 11 and has been having some PANDAS/PANs / tourettes like symptoms over the last year. She has been tested for the the MTHFR mutation and is positive for ONE copy of the C677T variant. Her symptoms are tics that change over time, throat clearing, nose sniffing, deep breath with shoulder shrug, occasional eye blinking, and some mild OCD tendencies. She has had tons of blood work done over the last year. No specific diagnosis has been made but a functional doctor is leaning towards PANDAS/PANS. Some of the irregularities that stand out: anti streptomycin O remains high after months, VEGF, elisa test is Low, anti nuclear AB titer high (although coming down), zinc was very low but has come up with supplementation, m. pneumoniae AB (IGM) remains high (but coming down). I (mom) am homozygous for MTHFR...but don't know the details because it was a test done long ago without anymore details.

My question is ~ would that make by daughter UNDER mentholated?

Courtney B Snyder link

7/6/2017 01:29:27 pm

Hi Pam. Not necessarily, but possibly. There are multiple genes involved in methylation. While MTHFR is seemingly the most significant, having a mutation doesn't equate to undermethylation, which is why we use a whole blood histamine or a methylation profile along with history of symptoms. Usually individuals are born with their methylation status, so longstanding traits or symptoms can be helpful in this regard. There are other things that can cause, for example, OCD tendencies, including PANDAS/PANS, but usually there is a more acute onset of symptoms. With PANS, I think about things like strep, m. pneumoniae, lyme, bartonella, candida and mold which is seemingly more common than previously realized.

Meaghan

7/6/2017 11:24:30 am

So if I'm giving my child who is on the under end a multivitamin with methyl, then that's ok?

Courtney B Snyder link

7/6/2017 01:37:59 pm

Hi Meaghan. I really can't say what's okay from this distant perspective and it does depend on the person's symptoms. In this blog post, I am focusing on brain related symptoms. There are for example individuals who are undermethylated and do not have low serotonin activity who do fine with methlyl folate, but we wouldn't recommend any form of folate to someone who is undermethylated and depressed. For someone who is depressed and undermethylated, other forms of methly (without folate)- things like methyl b12, methionine and SAMe work well. In what I do, I'm not usually recommending multivitamins, because they usually have folate/folic acid (and undermethlyation is common in brain related disorders) and because they often have copper (and again elevated copper is very common in brain related disorders).

Morgan

7/7/2017 12:32:42 am

Hi Dr. Snyder. Thank you so much for this information. I'm looking forward to reading your other posts to continue learning more. My daughter, age 5, is homozygous C677T, has been diagnosed with severe generalized anxiety as well as OCD(triggered be the trauma of me being in the hospital for a month last year) and has some attention difficulties. She is also extremely strong-willed and often has a calm demeanor but is internally tense and anxious almost constantly. Physiologically, she has moderate to severe eczema, a few food allergies and many environmental allergies. According to your information, it appears so is undermethylated, correct? My concern is I cannot find a doctor who is knowledgeable in MTHFR and knows how to help her. I'm not sure what my next step should be. Blood tests for histamine levels, heavy metals, vitamin levels etc and treat accordingly? Request further methyl genetic testing? Any advice on how to proceed is welcomed. Thank you!

Courtney Snyder link

3/5/2018 02:51:47 pm

Morgan -
I thought I had responded to you questions - perhaps I did by email, but in the event that I didn't, you can find practitioners on the Walsh Research Institute site that could probably help you. Some do telepsychiatry in the event that there is not someone local. Another option is to use DHA lab - you can request the lab tests (which would include a whole blood histamine which would help assess methylation) and a consultation with Dr. Albert Mensah.
Best to you and your family,
Courtney

Elaine

8/14/2017 06:37:54 am

This is very confusing to me because my daughter is homozygous for the c6777 mthfr gene she is also diagnosed with Adrenal fatigue, She was also diagnosed with general anxiety and depression.Her doctor prescribed very high doses of folate along with seeing a Psychologist who prescribed through her M.D. the drug Zoloft.
After 3 mths on Zoloft she had a manic episode, they then took her off the Zoloft saying she is Bi-polar and would not respond well to Zoloft. I notice that the higher the dose of folate she takes the more likely the manic behavior. She has anxiety, sleep issues, low weight , OCD, paranoid issues and nausea. I was told because of the MTHFR gene mutaion she would need a lot of folate, the doctor recommended 15mg deplin, after I read about people having adverse rections to higher doses I wasn't willing to put her on that high of a dose so we started her on about 1500mcg and moved her up to 3.5 Metanex but as soon as she starts to take that much it seems like her anxiety,insomnia and not eating returns. I am very confused what to do, she is 20 and insists on following what the doctor advises and wants to stay on the metanex. I also do not believe she is Bi-polar, I think the manic episode is the first she ever had and was caused by the Zoloft, she also takes two 200mg SAME per day. She had some more blood tests done and her Doctor wants her to be evaluated by a Pshychiatrist. Can you give me any advise? We are close enough about an hour and a half from Louisville. Thank you

Courtney Snyder link

8/14/2017 08:45:45 am

Hi Elaine - I understand your confusion. It's more common that physicians are recommending folate for MTHFR, but as I indicated above, that is not the approach those of us trained by Dr. Walsh are using for individuals who have depression. Know also, there are other factors beyond methylation that can impact someone's ability to tolerate SSRI's - for example - mast cell activation. One of the challenges of writing this blog, is that it requires me to write about these topics as if they are separate entities. Most of the people that I see have a number of things going on simultaneously - not only methylation. I have some individuals that I see for example, who are under-methylated and have mold toxicity, and we can't start treatment approaches for methylation until we address the mold toxicity (they can't tolerate the treatment for methylation). Before you consider calling my office, you may want to see if there is a doctor closer to you who is trained in this area via the Walsh Research Institute research list. (http://www.walshinstitute.org/clinical-resources.html). If you are interested in more information about my evaluation and treatment process, feel free to call my office and Courtney (the adminstrative assistant) will be happy to give you that information. Best to you and your daughter.

Tom

8/19/2017 01:26:56 pm

Dr. Snyder, thank you for the information you share. Do you ever test for food/environmental allergies via scratch test, blood test, etc. if someone has high histamine levels? Does high histamine necessarily mean the person's behavioral and neurological symptoms are caused by methylation imbalance or could an allergic response causing inflammation be the cause? I'm wondering especially if this could happen even without typical symptoms of allergies like hives, mucous, etc. Would love to hear your thoughts. Thanks.

Courtney Snyder, MD link

10/16/2017 12:50:59 pm

Hi Tom - Apologies for my very late response.

Yes - I would say, one can be undermethylated and not have allergy symptoms.

I don't do scratch testing, though I will do some IgG testing for food sensitivities, but not frequently. Mostly I try to get as much of that information through history.

For many people, there are likely multiple factors contributing to their elevated histamine levels - methylation impacts one's ability to break down histamine (as well as impacting the epigenetic expression of receptors for neurotransmitters), a DAO mutation impacts one's ability to break down histamine in food, there are other mutations that impact histamine breakdown as well systemically. Mast Cell Activation (which can be triggered by a number of things including stress and mold toxicity) can also increase histamine levels, as can food/environmental allergies and sensitivities. For some, I try to impact as many of these that are at play.

There are many, however, who respond very well to simply addressing methylation. I have seen a number of people who's environmental allergies went away and they stop needing antihistamines.

Usually I'm also impacting the gastrointestinal tract as well which can lower inflammation, food sensitivities, etc. Though I write about these imbalances separately, usually people have more than one, so I am not treating methylation alone, but also often low zinc, high copper, low Vitamin D, etc.
I hope some of this is helpful.
Courtney

Kelly

9/17/2017 09:06:00 am

Thank you Dr. Snyder for the wonderful info. I recently had a genetic test stating I had a "A1298C" mutation. Majority of symptoms with overmethylation apply to me, but of course not all. I have starting supplementing with L-5-Methylfolate and my doctor prescribed viibryd as well due to my rejection history of SSRI's. I'm also supplementing with B complex, zinc, Vit. C, Vit. E, and Magnesium. My main question is I am already on 60mg Dextroamphetamine and 250mg of Nuvigil. I have and always have had a high drug tolerance with many different classes of medications. Seeing as Nuvigil works with our histamine to promote wakefullness, could this be causing overmethylation to stay the same or get worse? Nuvigil really does absolutely nothing for me. Dextro. works, but my tolerance has built up to it and it's not as effective. I seem to have a few "idiopathic" issues that this new genetic finding may hold a key to helping. My biggest medical issue is idiopathic hypersomnia w/long sleep. I'm 40 and it's been an issue all my life...and getting worse. If you're aware of Nuvigil being a better med. for undermethylation as opposed to over, I would greatly appreciate your feedback. I'm fortunate enough to have a dr. who was willing and able to help with the genetic tests, but as you stated it's still not all that well understood yet. I appreciate your time and effort in trying to help some of us understand this genetic mutation. Thank you, Kelly

Courtney Snyder, MD link

10/16/2017 01:04:41 pm

Hi Kelly - It's hard for me to comment on your specific situation.

I should mention that there are other factors beside methylation that can cause brain related symptoms - for example mast cell activation (which I haven't written about, yet), copper overload, pyrrole disorder, food sensitivities, yeast overgrowth, mold toxicity). I have seen a number of people with MTHFR snps who had other factors causing their symptoms and not necessarily a methylation imbalance.

Typically when we think of pure overmethylation, we don't recommend stimulant medication or SSRI medication and when someone is depressed and undermethylated, we don't recommend any folate or folic acid supplementation. My experience has been that there is usually more than one thing going of for most people.
Best,
Courtney

Martha

10/6/2017 12:50:39 pm

My 16-y-o daughter has struggled for years with depression, anxiety and BPD. the depression and anxiety have not responded well to a long series of SSRI drugs. (now using combination of prozac, wellbutrin and abilify). genetic test recently revealed heterozygous C677T in MTHFR gene. have spent a month slowly increasing folate as directed by doctor. up to 5 mg daily and just now added methylated B12. absolutely no improvement and possibly worse. have not had blood levels checked for histamines. is it possible this is the wrong treatment? might she benefit from methionine and SAMe? and how much of each is advisable? thank you.

Courtney Snyder, MD link

10/16/2017 12:23:16 pm

Hi Martha - I really can't make recommendations regarding what your daughter should take or even what doses, as I have not evaluated her.
But what I can say is that when it appears that someone who is depressed is undermethylated, we (those of trained through the Walsh Research Institute) do no use folic acid, methlyfolate, deplin, etc. Instead, we avoid folic acid and use things like SAMe or methionine - usually one or the other, but sometimes both. DHA does make the Whole Blood Histamine Test available without a doctor's order and you can request a physician consult to discuss the result if you'd like. We usually are not checking the whole blood histamine in isolation, but also check copper, zinc, Vitamin D, pyrroles, because each of these can be contributing and usually people have more than one imbalance going on at a time. I hope some of this information is helpful.

Christie

10/20/2017 06:21:08 pm

Thank you so much for this information. I have pyrrole disorder and I'm undermethlayted. Before I was feasted I had someone helping me that thought I was low histamine. She told me to take many supplements that had folate in it. When I finally got tested I had been on my period for 7 weeks. I quit taking everything at that time and now I've been on my period for 11 weeks. I'm exhausted and tired of trying to figure out the cause of this. Could it may be too much folate?

Courtney Snyder link

3/5/2018 02:57:30 pm

Christie - I hope you were able to find the help that you were seeking. Usually we associate copper with excessive menstrual bleeding. As it sounds like you are aware, for someone with undermethylation, we would recommend they be off folate and folic acid..if they have had symptoms of low serotonin - depression for example.

Laurie McCloud

10/29/2017 09:55:07 am

Hello! I just stumbled across this article in my search for a better understanding of methylation. My histamine level is 65 and my practioner thinks I'm over methylated. He started me on a hydroxy b12/folate combo and it knocked me flat. Thinking it was the hydroxy b12, he put me on methyl b12 by itself. I didn't react as severely yet overall, my symptoms of fatigue, depression, anxiety, trichotillomania, intolerance to foods and vitamins/minerals increased. My practioner wanted to add folate so I added 400 mcg to the methyl b12 and within 12-18 hours I experienced whole body inflammation aka weakness, fatigue, pain, puffiness. I'm beginning to think that I'm under methylated instead. Can you offer your opinion? :) Thank you!

Courtney Snyder link

3/5/2018 03:01:50 pm

Hi Laurie-
I hope you were able to get your questions answered. Though I use the Walsh approach and find it to be very impactful, there are many other variables I consider as well, including things like mast cell activation, underlying infections, biotoxicity, hormonal dysregulation, and so on. For some people, addressing methylation needs to be put on hold until other issues are addressed first. I hope you have found some relief from your symptoms.
Courtney

Ora

12/3/2017 09:27:40 pm

HI,
I am a medical provider, currently getting additional training in psych. I've come to your page as I review what to do for some of my patients with MTHFR SNPs seeking a more holistic path.

Labs this year that may be of interest: (Genesight, others) I was found to be homozygous for 677T, CYP2C9 Poor Metabolizer, UGT1A4 Ultrarapid Metabolizer, COMT MET/MET, ADRA2A C/C. My folate level has always been above register (> 25.2 ng/ml). I've never had a histamine level drawn, that I know of (possibly done by allergist). Serum copper is 107 ug/dl, zinc 85 ug/ dl, Serum B1 173 nmol/L, homocysteine was 12.3 in Feb 2017 and 6.6 umol/L in June 2017. Immunoglobulin E, ANA, Sed rate, T4 and TSH WNL.

I have several skin prick test confirmed multiple environmental/ seasonal allergens. I am on daily antihistamine, aspirin, Vit D, multivitamins (hx of VSG), lexapro 10 mg, and Adzenys 12.6 mg.
Personal history of fibromyalgia, eczema, environmental allergies, Vit D deficiency, anxiety, PEs, Factor V Leiden, cochlear hydrops, PTSD, sleep hallucinations, depression, ADHD (inattentive), IBS-D, morbid obesity (now improved after VSG), OSA (CPAP) and osteoarthritis. I'm almost 40. I attempt to eat a higher protein diet due to the VSG.

I have a family history significant for narcolepsy, Tourette's syndrome, severe OCD, probable autism spectrum, hoarding, depression, and ETOH.

I have sent off my 23andMe kit and will get the raw data once it is available.

According to your list above, I have symptoms of both under and overmethylation.
Obsessive compulsive tendencies, perfectionistic but also messy
Very strong willed at times
Calm demeanor with high inner tension
High accomplishment
Seasonal allergies
Good response to escitalopram
...
High artistic or musical ability
High empathy for others, good neighbor, noncompetitive in sports
chemical sensitivities

Based on my MTHFR, I was Rx'd Deplin, but went with Methylpro instead. I had diarrhea on the 15mg dose for a few days, so I halved it for a few days and still had issues. I stopped it, and resumed 2 weeks later, this time at about 1/4 of the 15 mg capsule sprinkled onto applesauce. After the second day, i vomited several times. I called the company and they said they had never heard of anyone reacting badly. Now, several months later, I mentioned this to my preceptor in psych, who suggests I give Deplin a try. However, after reviewing some of Dr Walsh's information, I may not need to add folate at all. Please make any suggestions to my above treatment plan. Also, please explain how high or normal serum folate is associated with homozygous 677T / MTHFR. Correct me if wrong: A high serum folate does not equate to bioavailable methylfolate, which can be utilized to build dopamine, serotonin, and norepinephrine.
If undermethylation+ low serotonin ??= adverse response to folate (what is the usual adverse response? ) but l-methylfolate is needed to build serotonin, what is the cause for the poor response?

Courtney Snyder link

3/5/2018 03:14:03 pm

Hi Ora -
I'm not sure I understand your question. People who are undermethylated can benefit from methylation, unless they have low serotonin activity. This is less about the level of serotonin and more about the genetic expression of the receptors for neurotransmitters. So for someone who is undermethylated and has symptoms c/w low serotonin, our goal would be to limit folic acid and use supplements like methionine or SAMe to help with increasing not the neurotransmitters themselves, but the expression of the genes for the serotonin receptors. The adverse response thus to folate for an undermethylated individual can be worsening of their depression. I hope that answers your question.
Courtney

Liz

9/22/2018 03:25:57 am

I have MCAD/POTS/HEDS, homozygous C677T MTHFR, depression/anxiety. Whew! In addition to the Whole Blood Histamine test, what other labs (via standard labs covered by insurance) would you recommend to determine methylation and nutrient deficiencies?

Thanks so much for the information you have provided. It’s been invaluable and helped me move my treatment in the right direction.

Courtney Snyder link

7/18/2020 04:34:54 am

Hi Liz. This response is likely way too late to be helpful (I apologize, but still want to respond as other too may also have that question). I don't know of any other methylation tests that are covered by insurance. There are specialty labs that we use that measure various aspects of the methylations, but they are not covered by insurance. Thank you for your kind comment, I'm glad the information was or has been helpful to you. Best to you, Courtney

Colleen

8/5/2020 06:59:33 pm

Hi! I am in the middle of a b12 deficiency horrible dizziness/pressure in back of head andleg weakness/tingling. The b12 makes me very anxious. The same thing happens when I take at Johns wort,Zoloft, compazine and reglan. I suspect I overmethylate. However my copper serum level was 254 and then went down to 178 (still high). So I’m not sure what to treat or what to do. The dizziness is horrible I went from fully functioning very active to doing NOTHING.

Courtney Snyder, MD link

8/9/2020 08:15:31 am

Hi Colleen. If you haven't, you may want to read my last post about mast cell activation. Though my own functional medicine training started out very much focused on the Walsh nutrient levels, I have found that for a number of people, there are deeper roots to their nutrient imbalances beyond genetics. Mold toxicity for example seems to worsen copper overload. It also causes mast cell activation which makes people often highly reactive to various medications, supplements, sometimes certain foods, etc. I have another post on that as well. I wouldn't consider dizziness a symptom of high copper or a methylation imbalance, but it could be related to mast cell activation and/or mold toxicity.

Amber

11/18/2020 07:12:58 pm

Hey, so I recently gave birth to my second child 3 months ago. Since giving birth ive had high hemoglobin & hematocrit, high b12 & folate, & POTS like symptoms, minus the drop in blood pressure but everything else fits to a t. My anxiety has been thru the roof since getting pregnant. My hematologist has no idea what’s causing the high hemoglobin, my jak2 was negative. Wondering if it could do with mthfr mutation, & how do I go about getting tested? Do I test for overmethylation? Also what can I do to stop feeling like I’m dying constantly. Do I change my diet & take supplements? I’ve been told a low histamine diet but I fear that’ll affect my milk production too much.

Courtney Snyder link

11/27/2020 05:14:54 am

Hi Amber,
I'm sorry you're struggling. While methylation could certainly be at play, we more often would associate symptoms (especially high anxiety) that are worsening during pregnancy and post-partum with high copper. Relatively low progesterone postpartum can also be at play. POTs and abnormalities in a CBC make me think about mast cell activation which could be exacerbated by high copper, high anxiety (and further worsen anxiety) and further by high histamine foods. I have posts about copper overload and mast cell activation. To your question - knowing someone's MTHFR status, doesn't necessarily indicate that they are definitively undermethylated or not, as there are other genes involved and just having a mutations doesn't tell is whether it is being expressed or not. Typically we use a whole blood histamine as a screener for methylation or a methylation profile. I'm unable to give medical advice without doing an evaluation. If you are intersted in seeing a doctor in your area with experience with methylation, the Walsh Research Institute has a website resource map (otherwise a functional medicine doctor in your area). I do hope something here is helpful for you. Warm Regards, Courtney

Terri

1/7/2021 12:22:00 pm

Thank you for an excellent article!! I have read hundreds of books and studies on mental illness. Your explanation of methylation is outstanding! Now I get it!! Thank you.
My son was diagnosed with schizophrenia 12 years ago. As you mention in the article, he has been prescribed so many medications that have been ineffective! Dr. Mensah and DHA labs have been very helpful in finding an accurate diagnosis and a prescription of supplements. I am wondering about oils. Would oils such as MCT, flax, and fish oil be beneficial or not? He has been diagnosed with undermethlylation & pyrrole disorder.

Courtney Snyder link

1/10/2021 01:22:01 pm

Hi Terri. Thank you. I'm glad it was helpful. I would defer to Dr. Mensah, as he has more information and knows your son. Generally we try to avoid Omega 3's (fish oil is rich in omega 3's) when someone has especially high pyrroles (in the high twenties or above), and instead use Omega 6's usually in the form of Evening Primrose Oil. I do feel MTC can be beneficial for brain functioning for a number of reasons, but again I'm not in a position to know what would be best for you son. Thank you again for commenting.

Gianna

7/19/2021 04:09:26 pm

Hi Courtney! I am so interested in this article because I have been diagnosed with adhd and bipolar II. Yet I feel like I am not sure which category I would fall into and I haven't been responding to medication. I am desperate to figure out what is going on.

With my adhd symptoms, they fit mainly under the under-methylation category. However, here is where the contradictions come in. I have tried the following medications and this is how they affected me:
- Zoloft = hypomanic at low dose, took 2 weeks
- Sertraline = hypomanic at low dose, took 1 week
- Lamotrigine = currently taking, might be helping, unsure
- St. Johns Wort = hypomanic after 2 weeks
- Wellbutrin for adhd = Not doing anything but raising heart rate and causing some irritability (300 mg)
- Adderall = Did close to nothing, even at FDA rec. max dose of 60, and (it seems I am an outlier). If anything I became more depressed.
- Ritalin = Made me tired, angry, panicky
Now from my understanding, overmethylation would be hypomania. Yet, if I was undermethylated this wouldn't have occurred? I am also not responding to stimulants that act on dopamine, etc.
-- I had OCD when I was younger, and trich (still struggle with fidgeting - almost constant).
-- Depression since high school, worsened last year and began SSRIs.
-- Have always had moderate levels of anxiety, especially when over-stimulated. This is not accompanied by racing thoughts, yet I am prone to anxiety attacks, only when very anxious (passed out once from one).
-- Feel bored most of the time, often sit and do nothing because I have little motivation and energy

I apologize for the length but I would love to know your thoughts. Is there anything I can do/take to test myself, so I could know which category I fit into? I have recently bought some SAM-e -- will my response to that dictate my category?
Thank you very much, I am really looking forward to a response!

Courtney B Snyder link

7/30/2021 01:53:47 pm

Hi Gina,
Keep in mind there are many other factors that can be at play. When someone is unable to tolerate SSRI's there are other things beyond overmethylation to consider - such as mast cell activation (I have a post on this). SSRI's have been shown to have antifungal properties, so yeast and or mold are other things I consider when someone has reactions to SSRI's (a "die off" phenomenon). From a Walsh perspective, when someone has been diagnosed with Bipolar II, we typically consider pyrrole disorder before considering overmethylation. You might also look at that post. It is not uncommon to be undermethylated, have pyrrole disorder and mast cell activation (these can relate in different ways which is difficult to elaborate on here). All this to say methylation may not be the highest priority at the moment. Courtney

Gianna

8/19/2021 01:42:06 pm

Thank you very much for the response Courtney! I do not think I have mast cell activation and I do not think for me yeast was the cause, however pyrrole disorder seems to fit my symptoms. I had a blood test done to test my homocysteine levels and they were normal, although I did a promethease gene report and it said I was at risk for high levels (homozygous for C677T of MTHFR = 10-20% efficiency in processing folic acid). I know that pyrrole disorder can be tested for via urine, but is there any way I can see if I have it myself? I have had blood work done in the past, and I read that for this disorder it is common to have low levels of magnesium, zinc, and vitamin B6. I tested low for all of those. My copper was slightly higher than my zinc, but still low. When I say low, they were in the green (normal) but close to the yellow mark, which is not normal.

--- Are there any other markers that you can think of?
--- I have SAM-e that I bought but have not used yet. Is that helpful or unhelpful for people with pyrrole disorder? I am assuming no?

If you are unsure it's okay, just curious as to what you know about it! If there are any books on the subject you'd recommend that would be great. No worries if not. Thank you so much!

Courtney B Snyder link

8/19/2021 05:02:21 pm

Hi Gina,
DHA labs offers testing that individuals can order themselves (insurance doesn't cover even when ordered by a physician). SAMe isn't specific to pyrrole disorder, but rather, undermethylation. Regarding resources for pyrrole disorder - Trudy Scott has written and spoken a lot about pyrrole disorder and it is discussed in multiple areas in Dr. Walsh's book, Nutrient Power or on the Walsh Research Institute - or my post which you may have already read. Courtney

Gianna

8/20/2021 06:17:17 am

It's okay : ) And thank you! This was all very helpful.

Courtney B Snyder link

8/19/2021 05:36:15 pm

Apologies - I'm just realizing I've misspelled your name twice!

Shanna

7/27/2021 09:26:43 am

I found this incredibly interesting. I was wondering, is it possible for an individual who is in a cycle of overmethylation to have an intolerance to protein? I find that my anxiety skyrockets shortly after a high protein meal. I have some food sensitivities and never understood why this would be the case as meat has gotten a green light on every gut diet I've ever tried. I was also wondering how hormones might impact this cascade. I have very low free testosterone, but when I try to supplement I have the same reaction as to meat. Have you happened to study how hormones might impact methylation (if they do at all)? Thank you for an excellent and informative read.

Courtney B Snyder

7/30/2021 01:42:26 pm

Hi Shanna. Thank you for your lovely comments. Depending on one's overall seeming methylation status, a reaction to protein could be due to other factors, such as histamine in the protein source (certain proteins fall into the high histamine food category) and/or problems with breaking down protein and even a sulfate metabolism issue (usually the later is felt the next day). Also too much protein in someone with yeast can create acidity which can increase yeast. Any of those could trigger inflammation which can cause brain related symptoms. I don't know of a direct relationship between testosterone and methylation, however, it's possible that there is something in your supplement that is triggering inflammation. I'd be curious what is in that supplement. Thank you again, Courtney

Shanna

7/30/2021 02:05:29 pm

Interesting that meat can increase yeast. This is counter-intuitive so I'm grateful to have it pointed so. I would have thought that yeast would increase more with foods that get easily broken down into sugar and that acidity would help (maybe thinking of vaginal yeast and how a low pH is typically helpful). Regarding your curiosity on the testosterone supplement, I've tried 3 different types. Custom compounded cream (I now have just Estrogens in the cream and don't have a problem), pellets (awful), and Axiron in a teeny tiny dose. They all do the same thing so I don't think it has anything to do with something inactive in the supplement. I had always heard that Testosterone is supposed to help with sleep and mood, but no matter how little I use I always feel worse. I know that testosterone increases tryptophan in the body which is a serotonin precursor. I have learned that meat does this as well and was wondering if the two are triggering the same mechanism. It's all very complex and difficult to solve. I imagine there are a bunch of people walking around with mental health disorders who actually are having issues physiologically instead of psychologically. Thank you very much for your response!

Sam

8/5/2022 09:13:43 am

Hello
For MTHFR mutations I thought folic acid is toxic and only the active form of folate is recommended and should be given for this gene mutation? I’m confused.
Sam

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