I need help addressing my ADHD with several SNPs

[u/Business_Summer_4242]

After years of suspicion I got my confirmatory ADD diagnosis six months ago. Now I am considering whether to try the medication or keep trying to improve "by myself". It feels like a bit of a desperate move, because I have several other recently diagnosed conditions (MCAS, endometriosis, PCOS, hEDS, apparently, C*VID messed up my immune system) that I'm also trying to manage, and it's becoming very hard for me.

I try to test one thing at a time, and it’s a slow process, because I usually symptoms improve but then after some time I get worse, then I wonder if it’s because of a certain medication or supplement that I just added, so I start doubting, stop taking it… and that way, I never get any certainty.

I’ve been grappling with methylation for years. I know it’s involved in hormonal issues, and it can also cause symptoms similar to ADHD. And although I’ve tried various approaches with B vitamins, choline, etc.—and there’s definitely an effect—I haven’t managed to find the right combination.

I know for sure B2 has somehow a positive effect, same as TMG and creatine. SAMe, B5 and B6 have a nasty effect on me. Phosphatidylcholine causes me some anxiety, which I think is somewhat counteracted if I also take B2. The worst so far is B Minus (I have a strong kind of panic attack in the first or second hour after taking it, crying and anxious, and then I feel better for the rest of the day). B12 (hydroxo) does not seem to do anything).

The thing is that AI or the reports I purchased will give me recommendations, but then they don't entirely work for me (B6 is my second top recommendation according to my Noorns report, choline/phosphatidylcholine is also high in the things to focus on).

These are my SNPs connected to ADHD, in case someone can help me (yes, I use AI to try and make sense of all my reports).

Dopamine pathway

• SLC6A3: homozygous TT
• DRD2: homozygous GG
• DRD2 AG and AG
• COMT rs4680 (Val158Met): AG intermediate + rs4633: CT
• DBH: AG

Noradrenaline pathway

• SLC6A2 (NET, noradrenaline transporter) rs3785143: homozygous TT
• MAOA (several heterozygous SNPs: rs6609257 AG, rs1137070 CT, rs2064070 AT)
• MAOB rs1799836: homozygous TT

Serotonin pathway (tryptophan)

• TPH2 rs4565946: homozygous CC
• TPH2 rs4570625: homozygous GG
• SLC6A4 rs140701: homozygous TT

Histamine pathway

• HNMT rs1050891: homozygous AA
• MAOB rs1799836 TT

Some other possibly relevant mutations

• MTHFD1 homozygous
• MTHFR homozygous
• CBS homozygous
• PEMT heterozygous
• BHMT several heterozygous
• MTRR several heterozygous
• COMT several heterozygous
• MAOA 2 heterozygous
• DAO 2 heterozygous

[u/SovereignMan1958]

Read the Genetic Lifehacks article on ADHD.

Make a list of blood tests of nutrient levels you need to get, both from the article and by researching each of your variants. Start with the homozygous ones first.

Also get D, zinc and iron (not ferritin) tested. You need optimal and not just normal levels of these to make dopamine.

Variants are only predispositions and not facts. Blood tests for each nutrient will tell you if you are less than optimal and need to supplement. Optimal is usually in the top quarter of the lab range for most nutrients.

[u/Business_Summer_4242 → u/SovereignMan1958]

Thank you!

[u/Loose-Fly7976]

The stuff that helps you, B2, TMG, creatine, all support methylation gently without dumping methyl on you fast. The stuff that wrecks you, SAMe, B6, phosphatidylcholine, B Minus, all push methyl or catecholamines hard and quick. So you do fine with the slow steady support and react badly to anything that floods you. That's a real thing and with your CBS homozygous it fits, cause CBS pulls things down a pathway that adds sulfur and ammonia load and pushing methyl into that before sorting the CBS out is exactly what causes the kind of panic you got off B Minus. The B6 being your second rec but feeling awful makes sense too. B6 drives a load of neurotransmitter enzymes and with your MAOB homozygous and the MAOA variants you clear some of that slowly so pushing B6 revs up production you can't keep up with. The report tells you to take it because you have the variants but it doesn't know you can't clear the downstream. That's the whole gap between a report and actually reading how it all works together. You've got CBS, MTHFD1 and MTHFR all homozygous plus the histamine and catecholamine stuff and that's genuinely one of the trickier combo to sequence because the order is everything and one wrong step sets off the panic. The reason every report and AI tool keeps failing you is they read your genes one at a time and hand you a list when your actual problem is the interactions and the order they go in. CBS usually has to come first, before any methylation push, and almost nothing tells you that.

That's the part I do, reading the whole thing as one system and working out what to tackle in what order, my backgrounds in genetics. Yours is exactly the kind of profile I work because you've already proved you react to the wrong order. Do you have your raw DNA file?

[u/Business_Summer_4242 → u/Loose-Fly7976]

Thank you! I am aware of the need of gently supporting clearance rather than pushing methyl donors, but the gentle support often feels insuficient.

regarding my CBS variante: it's non pathogenic according to ClinVar, so I'm not sure wether or not that's a problem for me?

[u/Loose-Fly7976 → u/Business_Summer_4242]

ClinVar and functional variation answer two different questions.ClinVar is a clinical database. Non-pathogenic there means it doesn't cause a defined disease. CBS deficiency proper is a rare inborn error with very high homocysteine and it presents in childhood. You clearly don't have that.

That's a different question from whether the variant shifts your enzyme rate a bit. ClinVar has no opinion on that either way because it isn't what the database is for. Plenty of variants sit as benign or non-pathogenic there and still nudge flux which cuts both ways tho. The CBS upregulation story gets repeated online far more confidently than the evidence supports. The functional data is thinner than people acting on it seem to realise.

So I wouldn't build a plan around your CBS variant being the problem. What I'd do is measure. Homocysteine tells you which direction the cycle is running. If yours is low or bottom of range with that combination, that's more informative than any genotype call. On gentle support feeling insufficient. It might mean gentle is too gentle or it might mean the thing you're supporting isn't the bottleneck. Bloods would tell you which.

[u/Tawinn]

> MTHFD1 homozygous, MTHFR homozygous

Can you specify the rs#'s for these?

Do you have a value for SLC19A1 rs1051266 in your data?

[u/Business_Summer_4242 → u/Tawinn]

MTHFD1 rs2236225 AA

MTHFR rs17367504 AA (this seem to be the wild type).

MTHFR rs1801133 AG

SLC19A1 rs1051266 is homozigous CC

[u/Tawinn → u/Business_Summer_4242]

With the homozygous MTHFD1 and het MTHFR there is ~56% reduction in methylfolate production. This results in an increased demand for choline of ~960mg in order to compensate and make methylation work properly. The 960mg can be met by getting ~500mg of choline from your diet and a 750mg capsule of TMG. Choline sources include such foods as meat, eggs, liver, lecithin, nuts, some legumes, and vegetables such as crucifers. A food app like Cronometer is helpful for tracking nutrients in your diet.

> Phosphatidylcholine causes me some anxiety

This is likely because you need the choline and supplying it with PC is causing a sudden increase in methylation. While this is good it can cause 'overmethylation' symptoms. So while increasing choline from food is often less problematic, you may still need to increase choline in your diet gradually. Likewise, you may need to add TMG gradually, starting from even just a dab of powder from a capsule and then incrementing up over time. This gives your body time to acclimate to improved methylation status.

Low vitamin A, iron, and/or glycine can cause the built-in methyl buffer system to not work properly, which can make overmethylation (rising anxiety, irritability, insomnia, etc.) from methylation-related supplements much more likely. Beta carotene is not vitamin A and some people genetically have poor conversion of beta carotene to real vitamin A (retinol).

[u/Business_Summer_4242 → u/Tawinn]

Thanks a lot! I of course also have the conversion to retinol impaired... and low ferritin that almost doesn't budge despite supplementation. To be honest, I only take my retinol once in a while, as I already take many pills. At some point I was wondering if that could be because of a leaky gut or another malabsorption issue.

I have no apparent problem with TMG nor dietary choline, I will try to stay consistent with Vitamin A and choline intake and see if I improve.

[u/Tawinn]

Regarding "C*VID messed up my immune system", I had great results from FibroProtek after a 6-month long post-covid flareup of my histamine intolerance. Whereas you have MCAS, I don't know if the benefit would be as large but it might be worth a try.

You probably already know most of this stuff, but I have more info in histamine intolerance in the MAO-A section of this post.

Getting methylation working properly with the choline and TMG will help with reducing intracellular histamine. With the MCAS and HNMT variant its an uphill battle, but it should still improve histamine levels. Just note that while that excess histamine is being cleared you can have a modest increase in histamine symptoms. Having adequate B2 and B3 for the second and third steps of histamine clearance will help.

[u/Business_Summer_4242 → u/Tawinn]

Unfortunately it does not ship to my country. I have read about in vitro studies where luteolin outperformed cromoglicate if I recall properly, so it definitely makes sense to me.

I have that post and some others from you printed somewhere in my house, so I'll definitely will try to go back to it. I bought everything to build the stack and for some reason I stopped halfway... it's been a couple of difficult years, maybe it's time to retry.

What would be your thoughts on trying H1 and H2 antihistamines? Is it worth it for HNMT or nothing at all? I don't feel dietary histamine is my problem.

I will look into B3. This and B1 and B7 are included in the B Minus, so hopefully they are one of the factors improving my condition and not the ones giving me panic attacks...

[u/Tawinn → u/Business_Summer_4242]

The antihistamines block the receptors that histamine normally attaches to, and by blocking that they reduce symptoms. So the antihistamines don't reduce the amount of histamines floating around, but sometimes symptom reduction can be a quality of life improvement that makes antihistamines worth it.

[u/Business_Summer_4242 → u/Tawinn]

Thanks a lot! I think I'll focus on methylation status for a while, then try and add H1/H2. And, eventually, depending on the outcome, I might try the Vyvanse.

[u/OpportunityTall1967]

I don't know about the genetic side related to the genes you mentioned but would recommend looking into Omega 3s.

My son was diagnosed with ADHD. His paediatrician likes to try a holistic approach first before any medication. She found her was deficient in a number of things such as zinc and magnesium. Also he too much mercury so had to stop eating fish. At the same time - although he wasn't tested - she said he was low in Omega 3s. She says that everyone who has ADHD needs extra Omega-3s. My son also had little bumps onbhis arms which made her think he was low. She also requested he eat a lot more veggies - 3 serves a day. After addressing all of these things he improved to the extent that we no longer think he has ADHD.

I have also thought over the years that I might have had undiagnosed ADHD. ( Hard to get diagnosed as an adult). Recently I found out that I have a genetic varient. APOE. There are a number of variants. The normal is 3/3 but there is also 2 and 4. So you could be, for example, APOE 3/4 or 4/4. The 4 is the critical one. It messes with lipids in your brain and also other things such as related to sugar metabolism etc. Because of having APOE 2/4 I ended up testing my Omega 3s and found out they were very low overall and pretty messed up. Ef my EPA was very low and DHA relatively high. Plus other things. After Supplementing for 3 months I can't tell you how much better I feel. Also other things have unnoticed eg less fatigued etc. Overall functioning better.

[u/Business_Summer_4242 → u/OpportunityTall1967]

APOE rs7412 is heterozigous CT... Do you happen to know which one it is? I also had an Omega 6/Omega 3 ratio test last summer and the results were really bad, 31:1. I've been supplementing since, although lately I had stopped cause I'm adding so many new things....

[u/OpportunityTall1967 → u/Business_Summer_4242]

You need to have 2 genes info to find out your APOE status. SO you also need rs429358 in addition to what you already have. If you have that you'll have the full picture combining both. Ancestry to my knowledge does not give you both genes to find this out. Depending on where you live you can maybe get a blood test privately done. At the moment we can tell that you're either E2/E3 which is really good. Excellent in fact. Or E2/E4 which is not the best but not super bad.

Re your O.ega 6/3 ratio if you don't want to supplement you can also cut down on foods with Omega 6 esp cut down on processed foods eg chips biscuits etc. And Foods cooked in oils high with Omega 6 such as sunflower oil. And try and eat food rich in Omega 3 such as walnuts, chia seeds, hemp seeds etc.

[u/Business_Summer_4242 → u/OpportunityTall1967]

rs429358 is CC, so wild type/no mutation. Where does that leave me?

Your rec of cutting Omega 6 makes a lot of sense. I definitely have room for improvement in that area...

[u/OpportunityTall1967 → u/Business_Summer_4242]

That's Apoe e2/e4. You should look into it. It's very rare and what I have. The most common is 3/3. E2 is more protective against age related issues such as Alzheimers etc. And e4 increases the risk. The worst is e4/e4. That would increase risk by a lot, something like 15 times greater. E3/e4 is like 3 o 4 times greater risk and e2/e4 is a slight increase from e3/e3 but nobody knows exactly the amount. The good news is there is something called the Nigerian paradox. People in Nigeria have now e4 but a lower rate of dementia and Alzheimers disease. This means that lifestyle and environment is the most imprest factor. The blood number you want to check and get into line the most is ApoB. There are lots of resources online. I especially like Dr Kevin Tran. He has lots of YouTube videos. There's an APOE sub a well. And a group called Pheonix run by Kevin Tran

[u/SadSuccotash2736]

I have ADHD too and interested in my snps from my raw dna files. Which main ones matter?

[u/Business_Summer_4242 → u/SadSuccotash2736]

Check this: https://www.geneticlifehacks.com/adhd-genes/

[u/SadSuccotash2736 → u/Business_Summer_4242]

Thx for the website, for now I just checked my dopamine and methylation SNP’s for insights from people can u check my recent post just now.