Too Much Neurotransmitter Activity (1 of 2) Focus on Overmethylation

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Courtney Snyder, MD - Holistic Psychiatrist

Күн бұрын

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@trypolarity 7 ай бұрын

Low dose Niacinimide will quench methyl groups and quickly help with overmethylation.

@courtneysnydermd-holisticp3072 6 ай бұрын

We do use niacinamide as part of the overmethylation protocol to help clear the high catecholamines and also use B12 and folate. Thank you for commenting.

@Diego.Domene 4 ай бұрын

@@courtneysnydermd-holisticp3072 Can you use niacin instead of niacinamide? I think I read that Dr. Walsh uses both in his protocol. And what about vitamin B9, folic acid or folinic acid? I would appreciate the answer

@nelacivic1950 Ай бұрын

If you suplement with Creatine is it posible to go overmethylation?

@vrillion7588 3 ай бұрын

You guys Never Try to Find Out Why Methylated b12 and b9 Causing Overmethylation For Long Term ? If you find this you can treat many of us Which ho have Overmethylation for a Months

@ladibyrd 10 ай бұрын

Hello Courtney, illuminating podcast, thank you for sharing your knowledge. I am studying to be a doctor too this stuff is facinating! Currently in the midst of working through my own methylation issues. Very cool that you point out COMT gene's estrogen and methylation role in issues - I have heterozygous in COMT from memory.. I have estrogen issues and have many of the symptoms of overmethylator - Diagnosed with Pyroluria, artistic, musical, sleep issues ( potassium gluconate has helped a lot with sleep!) I've got to dust off my DNA test.... things are becoming clearer. I'd love to get in touch and get some treatment with you and learn through how you treat me! :)

@courtneysnydermd-holisticp3072 10 ай бұрын

Thank you very much. I have information on my website courtneysnydermd.com if you do decide to reach out. Best to you in your health and studies.

@aznauk Жыл бұрын

That is me! Undermethylation with high neurotransmitter activity due to variants in COMT and MAOA. I did everything wrong. Ate high protein because I worked out in the gym. Took lots of painkillers because I bust my disc. I suffered for decades. But after working with a functional medicine doctor who put me on the supplements you suggested, most, if not all that inner turmoil, stress, irritability and a general ‘Argh! Get me off this planet!’ has quietened and softened. I can breathe again and feel much happier these days. This level of medicine should be mainstream nowadays! Thank you gif your great informative videos. I have just found your podcast and following 👍🏼🫶🏼

@courtneysnydermd-holisticp3072 10 ай бұрын

Thank you for your comments and for sharing your experience with this. That's great that you were able to find what you needed and are doing so well.

@reesecup6915 5 ай бұрын

This is my issue as well. What supplements did you take that helped?

@melanellopea 11 ай бұрын

COMT +/+ & MAOA +/+ here. I over methylated once with too much b12 and it was a NIGHTMARE. Complete psychosis, hallucinations, horrific dreams, paranoia. I wouldn’t wish it on my worst enemy.

@courtneysnydermd-holisticp3072 9 ай бұрын

Really sorry to ready that. Thank you for sharing. I'm imaging that you were using a methylated B12? I find many people do well with the hydroxoB12.

@melanellopea 9 ай бұрын

@@courtneysnydermd-holisticp3072 Actually no, I have another gene mutation which doesn’t allow me to process methyl B12 (coincidentally), otherwise I would easily overmethylate on it. I did however overmethylate by taking too much adeno and hydroxy B12 (capsules). Now I take a liquid form of hydroxy in small doses so I can have more control over it.

@KevinMooney-k4z 7 ай бұрын

How long did it take for you to be normal again? Did you just let your body run it course or did you take anything to help it? I am only asking because I am experiencing the same situation.

@melanellopea 7 ай бұрын

@@KevinMooney-k4zI stopped the B12 right away and I think it took maybe a week to come out of the psychosis? It was a while ago that it happened but that’s my memory of it. Within that week, each day was more and more improved.

@KevinMooney-k4z 7 ай бұрын

@@melanellopea That makes me feel a lot better! Thank you for replying!

@ladibyrd 10 ай бұрын

I am in the situation right now ( I think, i understand i need to get a whole body blood histamine blood test now) of overmethylating. I am 36 years old, i was diagnosed with pyroluria age 25 and have been taking zinc, p5p and magnesium for years, but after eating 1 teaspoon - yes! only 1 teaspoon of saurkraut 6 years ago, tinnitus started in me pretty much straight away and i've had bad histamine issues since. (But i grew up with dermographism, so i've always had histamine issues). Once I took DMG and I had a very bad time - uncomfortably awake for 3 days, I wrote to my ND asking for help and she replied - take niacinamide but i didn'tunderstand _why_ it helpedd so much (the half life of niacinamide being 4 hours is very true! It's so frustrating that niacinamide raises histamine, the histamine makes it harder to sleep.

@courtneysnydermd-holisticp3072 10 ай бұрын

Thank you for commenting on this. If you aren't already familiar, you might look into mast cell activation and DAO insufficiency, as that might provide other tools. Separately some people with undermethylation (and a slow COMT and/or MAO) also benefit from niacinamide. While the whole blood histamine is helpful,, by itself it isn't reliable as it can be impacted by a number of things. Symptoms are perhaps more important on this particular imbalance.

@SueT55 Жыл бұрын

Would the Organic Acid Test by The Great Plains Lab showing low Tryptophan neurotransmitter metabolites be a helpful indicator of overall low serotonin?

@courtneysnydermd-holisticp3072 8 ай бұрын

I would go more based on someone's symptoms and methylation status than on neurotransmitter metabolites, which I don't find to be reliable.

@teresagonzalez8226 2 жыл бұрын

Thank you, Thank you. This is so extremely interesting. I’m so glad to have found you. I have a question and would love to hear your take on this.. Is measuring the homocysteine levels alone, a sufficient method of knowing if you’re under/ over methylating? And at what levels would you say under/ over happens? Thanks again for sharing all your knowledge.

@courtneysnydermd-holisticp3072 2 жыл бұрын

Thank you. I'm glad you found this interesting. Regarding your question - I wouldn't use a homocysteine level to determine someone's methylation status, though I do understand why you would ask that. Instead, I would look to their symptoms as well as a whole blood histamine level (from LabCorp) and/or a methylation panel (from Doctor's Data).

@courtneysnydermd-holisticp3072 10 ай бұрын

Thank you for your comments and question. A homocysteine is not sufficient for knowing if you are under or overmethylating. It can be high with either. I'm glad you found this video interesting.

@miketermaaten26 9 ай бұрын

it's called a Methylation profile ..not panel ..when looking at the Doctor's data website.

@courtneysnydermd-holisticp3072 9 ай бұрын

@@miketermaaten26 Thank you for clarifying that.

@wallowinthehallows Ай бұрын

Would love to know your holistic approach and insights for supporting and treating nonverbal profound autism in individuals who are aggressive. Thank you.

@courtneysnydermd-holisticp3072 Ай бұрын

Really important question - I would consider the same issues that I would for someone who is verbal and even nonautistic, who has aggression - I would evaluate for pyrroles, high copper, low zinc and methylation (using the Walsh optimal ranges, as opposed to typical lab ranges). I would also wonder about candida, mold, mast cell activation. Thank you for this question.

@amitabh15 10 ай бұрын

This is exceptionally helpful information. This explains my overmethylated profile. Adverse reaction to Benadryl, bad effects from 5htp and serotonin syndrome from SSRI. That triggered a functional neurological disorder (PPPD, Visual snow syndrome, massive ptsd). No practitioner believed me that I could be so adverse to Benadryl, 5htp and low dose SSRI. Overmethylated profile is a complete replica of me: all of it. Why did I take SSRI? I developed panic disorder out of the blue after chronic stress. Now that I’ve bumped into your research, I’m trying to figure out how I can get help being stuck in perpetual fight-flight and associated FND/Conversion disorder. Thankfully excessive agitation, pacing back and forth has gotten better. Dr. Snyder, are you able to recommend anyone in the Calgary, Canada region? Where I can get help with the research that you work with?

@courtneysnydermd-holisticp3072 10 ай бұрын

So glad you found this helpful. If you go to the Walsh Research Institute website, they have a resource map with doctors who are trained in treating overmethylation. There is also other helpful information on that site. Thank you for sharing your experience.

@paulinelee3334 5 ай бұрын

There used to be an orthomolecular Dr in Calgary but he's gone.

@rebeccacurtin6006 2 жыл бұрын

Great talk. Thank you! I have a question though... I tick alot of the overmethylation symptoms boxes. Anxiety, panic attacks, insomnia etc. I had a naturopath put me on b12 and folate and b6. I became so manic, my heart wouldn't stop racing for days on end and I couldn't sleep at all. Once I stopped these I improved. Blood levels indicated really high b12 levels and toxic b6 levels after only taking them a month or so. I also do great on a plant based diet, much more relaxed. However I have the symptoms of histamine intolerance, particularly hives. Antihistamines don't really help the hives but they actually help my anxiety. So can I be an overmethylator and have a histamine intolerance/MCAS?

@soulheights823 Жыл бұрын

Yeah great question! Someone should answer this poor woman🤨

@mystrength5640 Жыл бұрын

@@soulheights823Apparently some people don’t Absorb B12.. that’s why it says it too high?? 😮

@johnjacob442 Жыл бұрын

I caused myself to have histamine problems because I took too much zinc and caused my copper to lower. The enzyme used to breakdown histamines uses copper but don’t just take copper to try that look into dessicated oyster or dessicated liver that will raise levels up naturally if that is the problem

@vykis88 Жыл бұрын

What's your body type, do you have seasonal alergies? if your skinny and have allergies, you might be undermethylated

@lisathebeautician6489 Жыл бұрын

My body calmed way down once I stopped eating sugar and starchy foods.

@misterchoc123 Жыл бұрын

Quick question about copper overload. Could it be that a severly copper toxic person, who is also an undermethylator, would temporarily need an overmethylator program (e.g. niacinamide and folic acid) simply to reduce their crazy high norepinephrine? From what I have seen, copper detox can lead to crazy anxiety attacks and bringing down someone's catecholamines during such a dump seems like a good idea to me. Would love your take on this.

@courtneysnydermd-holisticp3072 Жыл бұрын

For some reason my response is now gone, so here goes.... Really interesting question - From my perspective - copper detox should not lead to "crazy anxiety attacks." If it is - the protocol is being started to quickly. It really is about meeting the body where it is at and not "pushing through" something. I usually build up a nutrient protocol to the full dose over 4 weeks. Using folate would have the potential to drive down serotonin activity, which could cause depression if the person is undermethylated and has had low serotonin symptoms (such as depression), which many do. Niacinamide would bring down dopamine activity (which is already low due to the high copper). Thank for that question.

@Andrew.the.Philosopher Ай бұрын

Zinc. You need lots of zinc. If you wish to study the topic of copper toxicity, then reference information about Wilson's disease. Your problem might not be Wilson's disease, but it's where you'll find all the information you need. Copper excess is extremely dangerous. If you don't have Wilson's disease, then you're most likely a vegan. Cut it out with the eating disorder before you kill yourself or destroy your brain.

@1truthseeking8 Ай бұрын

@@courtneysnydermd-holisticp3072 I don't see my original comment either now about 5 minutes later... I just remembered after seeing the titles of your video about "pyrolle" that I have struggled with MANY issues when I was in gross anatomy labs due to the mostly phenol they used in place of the traditional formaldehyde...i would apparently "hold"/fail to breakdown or expell the phenol and end up with severe Brain Fog & short term memory loss which seems to have caused long term looking back (and I used to have a pretty functional *perfect visual recall* like page numbers every word on page diagram, chemical pathways, words spoken...it was such a hopeful moment in life back then having come from a rough upbringing... Also suffered gastric issues and GERD .. seems to have been THE START of the Achlorhydria.... a depressed like feeling of zombie like day to day just passing like blurs, loss of positive or really any emotion... Also,if I ever drank coffee I would get a cold sweat and a headache?!?... Also, perfumes give a headache, and if I get close to or walk down the lawn chem or detergent/Cleaner aisle I feel the fumes like a heat on my skin/body and a general unwell feeling ... So I stay several aisles away ... Also very sensitive to whatever the chemicals they are putting in the plastics in children's toys in the last 5 years...I forget the name/type (it is actually a banned substance, some type of known carcinogen/neurotoxic substance) but it's a known thing that our political overlords have decided to turn a blind eye to ..so I avoid getting close to the toy aisle at Walmart and try to get in and out as fast as I can in places like harbor freight where the fumes are in HIGH concentration.

@aidanbrooks6626 9 ай бұрын

Hi Courtney, with homozygous c677t and bloods (low histamine) and symptoms (panic) implying overmethylation ... is there a step by step protocol available for these people?

@courtneysnydermd-holisticp3072 9 ай бұрын

Hi. Thank you for this question. I wouldn't use panic and a whole blood histamine alone to imply someone has overmethylation. Panic is also seen with high copper and also mast cell activation or a biotoxin (like mold). Overmethylation, undermethylatyion, high copper, mast cell activation and mold toxicity - each have different protocols, often people are dealing with more than one of these. There is not a one size fits all approach.

@moss534 Жыл бұрын

WOW I feel confused! My sons doctor told me he has pandas and overmethylation and that he is not getting enough protean and suggested he drink a whey protean shake daily. I have been looking up video on this and came across yours which says they need a low protean diet. So that confused me a lot. I will say a lot of things has cleared up since taking the supplaments including daily shake and meds she prescribed him and his energy increased (he had low energy) and his mood is so much better. He was so irritably before it was starting to scare me, but his brain fog is getting much worse and we dont know why. Mabey you could give me your insight into this.

@courtneysnydermd-holisticp3072 Жыл бұрын

I can certainly see why you would be confused. It would hard for me to comment without knowing what supplements and meds that he was also starting on - I think that can always be the first things to determine - is there something that is creating or making certain symptoms worse. Separately, I would wonder what the diagnosis of overmethylation was based on - histamine, methylation panel, symptoms. I would wonder if you feel overmethylation as opposed to undermethylation is more fitting (given symptoms).

@moss534 Жыл бұрын

@@courtneysnydermd-holisticp3072 He was diagnosed with PANDAS and Overmethylation. Looking at the notes says his histamine is low which is why she said overmethylation. His Vit D wasvery low. (He had a lot of lab work) Low Bun and she says that means he dosnt get enough protein. High RBC and hemoglobin she said that means he needs to drink more water. His copper and Zinc looked great. Does this help? Thank you for responding.

@moss534 Жыл бұрын

@@courtneysnydermd-holisticp3072 Sorry I also forgot to add what he is taking. Ok so hes taking Vit D, Neuroflam, amoxacillian, n-acetyl-l-cysteine, rosita cod liver oil, probiotics, and whey protein powder. He has been taking these for almost three months.

@shreyshah50 5 ай бұрын

Does the flush niacin help with overmethylation ?( I was on Methyl B12 for 2 months which made me crazy maniac). Also can glycine be helpful to buffer excess methyl? Thanks

@courtneysnydermd-holisticp3072 5 ай бұрын

Usually for overmethylation (from a Walsh perspective), we use niacinamide, along with folic acid and cyanoB12, though I will often use hydroxoB12. I've not used glycine in that way.

@Tiffany-l2c 7 ай бұрын

Great video! I have the slow COMT and slow MAO and a number of health issues I believe these genes have directly played a part in creating. Do you think these genes can ever be turned off or expressed less through some means?

@courtneysnydermd-holisticp3072 7 ай бұрын

Thank you! I hope you also heard the part 2 video where I address COMT and MAOA and the various things that seem to impact our genetic expression and slow down or speed up the functioning of these enzymes. Here is the link, in case you haven't seen it: kzbin.info/www/bejne/hXbIkIqVZ9WIjK8

@robertviggiano Жыл бұрын

I have histamine issues (hives and fat lips) and respond well to SSRI. Does this mean I am an undermethylater?

@courtneysnydermd-holisticp3072 Жыл бұрын

Those symptoms sound more mast cell related than undermethylation, however it is not uncommon to have both. Mast cells can be highly reactive for various reasons and they can release histamine and other inflammatory mediators. Since methylation is needed to break down histamine (as are a number of other pathways), undermethylation can exacerbate the histamine issue. If you haven't already, you might look at my mast cell post or video. Thank you for your question.

@robertviggiano Жыл бұрын

@@courtneysnydermd-holisticp3072 Thank you Courtney. Possibly MCAS. I have MTHFR genes 1298 GT +/- and 677 AG +/-. So combination likely. I have lots of eye symptoms, eye pain, depression and fatigue.

@newbermuda Жыл бұрын

Such a great video, thank you!

@courtneysnydermd-holisticp3072 Жыл бұрын

Thank you

@AsOfYetUnnamed Жыл бұрын

If one has bipolar disorder with a lot of cycling, with comt and maoa favoring higher dopamine, and has to take antihistamines for allergies, and took 800 mcg of methylfolate that calmed person down, but also made the person's ocd worse so person quit taking the methylfolate. Not asking for medical advice! But would be interested in how the neurotransmitters work in conjunction in more depth, especially since this video is about neurotransmitters.

@courtneysnydermd-holisticp3072 Жыл бұрын

Great point. Yes.....there are always multiple factors to consider. First - from a Walsh perspective, I tend to think about three forms of bipolar - it is rarely this simple. Rapid cycling is most associated with pyrrole disorder (which has it's own impacts on neurotransmitters), undermethylation - predominant depressive symptoms and overmethylation - predominant manic episodes. So normally with bipolar disorder, I'm considering pyrrole disorder as well as methylation and snps like COMT and MAO. If someone has worsening of OCD with folate, that makes me think about undermethylation (as added folate in someone who has low serotonin symptoms can cause a decrease in serotonin and dopamine activity - (per the work of Dr. William Walsh and the Walsh Research Institute). And it's not uncommon at all to have pyrrole disorder and undermethylation. None of which answers the question as to how folate would be calming for someone with symptoms of undermethylation (?getting the MAO and COMT to work better? or ?promoting detoxification?). Perhaps someone reading will have some thoughts on this. (I have a podcast and blogpost on pyrrole disorder and undermethylation if you aren't already familiar) Thank you for commenting.

@AsOfYetUnnamed Жыл бұрын

Thank you for the insightful reply! I just ordered Dr. Walsh's book, Nutrient Power.

@AsOfYetUnnamed Жыл бұрын

I hope you see this. When I said I was calmer, I meant less manic and excitable. I think that explains how the methylfolate reduced my dopamine as well as my serotonin (which increased my OCD).

@courtneysnydermd-holisticp3072 Жыл бұрын

@@AsOfYetUnnamed I'm unable to know (or give specific recommendations in your case), but I do know that Dr. Walsh has described for some people a need to have a somewhat fluid protocol and using their symptoms as a guide - meaning someones nutritional needs can change depending on their symptoms. Dr. Ben Lynch also speaks to this idea.

@Michael-bt6ht 4 ай бұрын

Do you recommend methyl folate for over methylation in general? I know there’s more factors in play here but in general?

@courtneysnydermd-holisticp3072 4 ай бұрын

Using the Walsh nutrient protocols, we avoid methyl in those who are overmethylated and instead use folic acid (which you won't hear use in other functional medicine approaches for other methylation issues)

@nikolaussoundso 11 ай бұрын

Where is the video for too little neurotransmitter activity? low serotonin, low dopamin, low norepinephrine but rather high methylation

@courtneysnydermd-holisticp3072 11 ай бұрын

Really interesting question. I would wonder what the "high methylation" is based on - symptoms? and/or a whole blood histamine level? Normally the low neurotransmitter activity is associated with undermethylation (which I have a couple of episodes on). There can be other variables at play beyond methylation.

@nikolaussoundso 10 ай бұрын

@@courtneysnydermd-holisticp3072 I have middle range blood serum histamin, no allergies, low homocysteine (8), and low basophils and high MCV (Chris Masterjohn said high MCV is indicative to do better on folinic acid instead of (methyl)folate), which sounds like overmethylating). According to the Bravermann personality test, I'm low in GABA, Acetylcholine and Dopamin. My serotonin levels are usually the last to go if I'm in a mental crisis. I like dopamine raising stimulants, while serotonin boosting supplements/drugs feel neutral. I never had any of the excessive Dopamin/Serotonin/GABA/Acetylcholine symptoms, which could be indicative of low glutamate levels or a weak NMDA-system whose task is to upregulate all the other receptors if I understood that right. I think the misconception to methylation might be that high methylation is not necessarily high Biopterin 4 methylation, but fast COMT and MAO, the neurotransmitter degrading enzymes. I find the personality profile of under/overmethylator confusing, because I want to be an undermethylated Type a personality but I'm probably perceived as a type B personality (overmethylating). And this is different from overmethylators who are okay with their lack of drive and willfully prioritize their relaxed and nurturing lifestyle.

@Borka642 6 ай бұрын

I also have low dopamine, norepinephrine and overmethylation. It is confirmed with the DUTCH Test. My androgens are also very low. My worst symptom is insomnia which started after taking a high dose b complex 1.5 years ago. Since then I’m no longer able to tolerate methyl vitamins. What can be the reason? @@courtneysnydermd-holisticp3072

@isa-manuelaalbrecht2951 11 ай бұрын

Mediterranian diet is my favest...🎉

@manojlogulic4234 7 ай бұрын

Hello doctor, i recently did some blood test and checked my histamin and homocisteyn levels, histamin was 0,9 ng/mL and homocystein was 12 μmol/L but i don't know how to interpret those numbers, would you please help me, is this mean I am high metilated or low? I still didn't test my COMT, MTHFR genes I'm planing to do that as well but based on those numbers from histamin and homocystain can you tell something? I'm trying to find cause for my blood pressure, I resolve all my mental problem with high fat and protein diet and low to non sugar, my body do very well in clearing sugar from blood I gain back my insulin sensitivity but for some reason my blood pressure is still high. Thank you in advance.

@courtneysnydermd-holisticp3072 7 ай бұрын

There are so many considerations, I won't be able to comment on your situation specifically, but will share some general comments that may be helpful. The only lab we find reliable for a whole blood histamine or histamine determination is LabCorp. Unfortunately, I wouldn't know how to interpret the a histamine level you shared. Symptoms and traits are often the bigger determinant of methylation, as there are many medications that can impact the histamine level and even with LabCorp, it's not so precise. There is a methylation test by Doctor's Data, but it needs interpretation. From a Walsh perspective, we like to get the homocysteine down to below 10 prior to starting an undermethylation protocol. I'm glad you are finding benefit from the dietary changing. If you feel you have a mix of symptoms, you might look at the followup video - COMT and MAOA, which cause high neurotransmitter states (but can be in the presence of undermethylation). Thank you for commenting. Best to you.

@manojlogulic4234 7 ай бұрын

@@courtneysnydermd-holisticp3072 Thank you very much for giving some direction. I forgot to mention i don't use any drugs and medication, except some suplementation from time to time, NAC, Q10, Berberine and ALA. I'll check all my genes soon and will have more clear picture of my genetics. In the meantime, can you tell me how to lower the hystamin under 10 and what Walsh protocol mean, it's some sort of medication to use or change in lifstyle? For the record, I changed my lifestyle completely, i'm now fit, going to the gym 3-4 times a week, running short and long distance...but high blood pressure is still present. Maybe my body needs time to restore completely health but somehow i think my blood pressure has somethign with my methylation. Once more, many thanks for responding to my comments and share your thoughts, appricciate your time and effort.

@ericajoseph7245 Жыл бұрын

Can vaccines turn on genes?

@courtneysnydermd-holisticp3072 Жыл бұрын

This is a great and complex question. I don't have an expertise on vaccines. The way I think about it - Our epigenetic expression is constantly fluctuating and being impacted by a number of external and internal factors. Some of this is more fluid and in some cases this is more of a dramatic shift. We know vaccines ability to impact the expression of certain genes is part of how they work. "More recently, attention has focused on the ability of non-carcinogenic infections, as well as vaccines, to modify the human epigenome and modulate the immune response." www.ncbi.nlm.nih.gov/pmc/articles/PMC7574386/ I think, however, more related to your question - is a presentation by Dr. William Walsh. If you start at slide 18, he talks about how environmental insults (he includes vaccines as one example) can impact genetic expression in those who are are vulnerable. www.walshinstitute.org/uploads/1/7/9/9/17997321/an_epigenetic_model_of_autism_and_a_warning_regarding_risperdal.pdf

@Andrew.the.Philosopher Ай бұрын

Beware of them.

@jozefk93 8 ай бұрын

If overmethylation is to much methyl and to low folat and folate is needed to recycle homocysteine in methyonin why we and up with low level of homocysteine it should be opposite or not??

@courtneysnydermd-holisticp3072 8 ай бұрын

This is a really interesting question that I won't be able to do justice here. Not everyone who is overmethylated has low homocysteine, just as not everyone who is undermethyated has high homocysteine. There are multiple points within the methylation cycle that can be impacted genetically. Using the Walsh perspective, we are looking at the sum impact of multiple genes that impact methylation. Please feel free to leave a followup question if I haven't answered your question.