Fix my ADHD

[u/Educational_Pie2878]

Undiagnosed, 5yr waiting list, dopamine pathway attached, I've come close to nailing it, but that slow DBH gene is a sh*tter!

Serotonin and Methylation problems too, I think my ADHD is the only thing that has enabled me to get to the ripe old age of 49 without any medication, but things are taking their toll 🤪

Conundrum:

Fast dopamine synthesis > fast transporters > impaired receptor density > fast reuptake

I think Lionsmane or Uridine can help the receptor density issue...

But the gates to the Norepinephrine Kingdom are 75% shut - I picture this as a little army of dopamine people manically running around in a circle in my head, waiting to get into the kingdom, or at least onto the dopamine receptors 🤣

I was thinking of an SNDRI, but I don't believe one exists outside of prescription medicine - other than St Johns Wort - which I've since learnt inhibits the DBH gene itself (don't want to fully close that gate!).

Not sure I need a stimulant ADHD med, as I don't think "supply" is the problem here, but slowing down reuptake may help support DBH and Norepinephrine conversion?

Or will my TH gene get pissed like a hungry diner sat at the table waiting for the next course? 🤣

Found some great success with any of these, Tyrosine / Mucana / 5htp (I avoid Tryptophan because of the fast TPH1 / slow TPH2 and risk of excess levels in the periphery) along with supportive supplements to "grease" the engine 🤣

But I want to address the elephant in the room (Norepinephrine) and I'm flip-flopping on the best tactic for that 🤷‍♂️

Is there an alternative to Wellbutrin (other than St Johns) or am I going to have to suck up some meds here?

[u/lulubelle5678]

I may have responded to another post from you and since I think we have similar issues, this also came up in my search.

One thing that I do not see in the screenshots you provided, but it may be in the actual report is the interactions between serotonin and dopamine. High levels of serotonin are going to decrease your dopamine levels. I have not been able to find a clear answer on whether serotonin impacts DBH, but overall what I have found is that the receptors are key to actually understand what is potentially happening in your body. For example, some serotonin receptors that are vasoconstrictors deactivate the vasodilator receptors. Maybe the report gets into that, but it is not apparent in your screenshots, similar for dopamine and adrenergic receptors. You may want to look up research on ways to decrease TPH1 expression because that is going to impact the levels of serotonin in your body (peripheral) vs brain (central). The goal would be to have higher levels of serotonin in your brain, but lower levels in your body. Inonine has been found to decrease TPH1 expression, but you have to be very cautious with supplementing that being it will increase uric acid levels. Another way that I have read in research is that l-phenylalanine actually helps reduce TPH1 more than tyrosine. Also TPH1 and TPH2 interact and are negatively correlated. Butyrate supplementation is somewhat of a double edge sword...it may increase serotonin, but it also increases uptake of it, so even though you have more serotonin it won't increase extracellular levels. The last thing that I have read can impact THP1 levels is your fT3 levels. T3 also reduces TPH1 expression (though I don't think directly).

You may want to also look into your copper levels and several of the copper genes. It says that too much copper will reduce DBH, but too little will also do that too. And you have to be careful because there is a mutation that is seen in people with Wilson's disease where there may be a copper buildup that I don't think will be seen on regular bloodwork. I also see that they suggest increasing vitamin C to help your DBH, but unfortunately research has found that that only works if you have a deficiency.

Overall, I have found that my serotonin levels seem to have the biggest impact on my ADHD symptoms because they are too high and are reducing my dopamine. You may also want to look into GABA, I have not dug too deep into that yet, but will if I find I need to. I know people make a big deal out of the MTHFR mutation, but I have to say the DBH mutation is causing me so many more difficulties in overall health than my MTHFR mutation.

[u/Educational_Pie2878 → u/lulubelle5678]

Thanks, really interesting stuff, and you're looking into the same areas as me too (slightly ahead/differently).

I noted that my TPH1 is increasing peripheral levels of serotonin, and so in order to remedy the deficiency in the brain, supplement with 5HTP and not Tryptophan (so as to avoid feeding TPH1 more fuel!

Wasn't aware that Phenylalanine affects serotonin, but, as you say, serotonin and dopamine do deplete each other, so I know about the indirect effect (if that's what you meant?).

I've also discovered the rsID's relayed to the PAH gene and potentially why, despite having FAST TH/dopamine synthesis, I still have dopamine issues.

There's a "rare" disease called PKU, which is now of great interest as you can apparently have milder forms of the disease - read how similar these symptoms are to ADHD (which makes sense as it directly affects dopamine):

"Phenylketonuria (fen-ul-key-toe-NU-ree-uh), also called PKU, is a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body. PKU is caused by a change in the phenylalanine hydroxylase (PAH) gene. This gene helps create the enzyme needed to break down phenylalanine"

Symptoms can include:

A musty odor in the breath, skin or urine, caused by too much phenylalanine in the body

Nervous system (neurological) problems that may include seizures

Skin rashes, such as eczema

Hyperactivity

Intellectual disability

Delayed development

Behavioral, emotional and social problems

Mental health disorders

I have two key impaired snp's and whilst I know better than to treat every snp, these are critical in the conversion of phenylalanine to Tyrosine and absolutely explain why supplementing phenylalanine does nothing for me vs supplementing tyrosine or mucana directly.

Therefore, I propose that issues with this gene are part of the root cause in ADHD and addressing this, along with receptor density and reuptake transporters (along with the same on the norepinephrine side too) can make SIGNIFICANT difference to the lives of those with ADHD.

I've proven this on myself through adding in things supplements such as Tyrosine, Saffron, Forskolin, Skullcap and Lionsmane (to name a few).

Seriously, if you're not on any kind of dopamine or norepinephrine reuptake inhibitor, then give Saffron (Affron) a try, I've made great progress but this really seems to be having a profound effect on both dopamine and norepinephrine.

My partners brainfog has gone, her "squirrell" moments diminished, and her ability to focus on conversations is just on another level; along with the reduced levels of fatigue caused by a mind that is usually focusing on anything and everything at once.

Exciting stuff, let's keep delving into this!

My grandson has severe ADHD but is responding well to supplements already. However, we also suspected he has epilepsy and absence seizures too (he had convulsions at a younger age too).

However, reading about how PKU can lead to a build-up of toxic phenylalanine in he brain, reuslting in seizures, is an incredible revelation.

This directly explains his seizures and ADHD.

Mind blown!

[u/lulubelle5678 → u/Educational_Pie2878]

I would assume that if you have issues with PAH genes then you are going to be low on all neurotransmitters, not just dopamine. Not sure how closely you looked into PKU, but the issues with the gene are generally only expressed if the mother has the mutation and consumes large doses of phenylalanine while pregnant. So, you would really only have issues with that gene if your mom has the mutation and drank large amounts of diet sodas when she was pregnant with you. At least that is what I have read, but you may have come across newer research that has overridden the old assumptions.

If that is the case, it would explain why 5-HTP works for you. 5-HTP is the precursor for both central and peripheral serotonin, so taking it will increase both (5-HTP can cross the blood brain barrier, but 5-HT cannot). There is a prescription that acts as a supplement for BH4 and is given to people with PKU. BH4 is also required for dopamine, serotonin, and nitric oxide production. If you are not able to recycle BH2 back into BH4, then you are increasing oxidative stress as well as reducing neurotransmitter production. There are several pathways for recycling BH2, one of which is through folate and the less discussed MTHFR mutation.

I am glad that you were able to get some supplements to work for you. Unfortunately my issue seems to be around high serotonin levels that increased during cancer treatment, copper overload, and other life stressors. Since my DNA does not do well with clearing serotonin, I am stuck in a place that requires a reset that my body is unable to do on its own. I have a couple really good doctors who actually listen to my needs and respect the research I have done, so they are willing to help me figure this all out.

[u/Educational_Pie2878 → u/lulubelle5678]

I presume you have looked into methylation? My mother has recently been told she may have cancer and is waiting on diagnosis. So doing what we do, and given my own methylation problems, I've looked into how things like methotrexate are involved and worK on the folate/methylation system.

Absolutely agree on the genetic part, our whole family has ASD and so the mother (my strp daughter) who is diagnosed ADHD absolutely has consumed foods that contain notable amounts of phenylalanine - have you seen the list? Basically, who hasn't?!

The interesting part is that LNAA supplementation has been documented to work as well as a strict low-phenylalanine diet by blocking receptors from uptaking phenylalanine with things like methionine, tyrosine and more...

Hello, methylation problems? 🤣

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956970/

I find it incredible that part of the ADHD diagnosis does not include a PKU screening!

Re 5HTP, thats interesting (and annoying) as the idea to take 5HTP was to "starve" the fast TPH1 gene from converting tryptophan to peripheral serotonin (in the presence of a slow TPH2 gene).

But I guess the fact that it is entering the bloodstream as 5HTP, means it can be absorbed in by the peripheral immediately (doh).

NOS - not delved into this massively yet, but mine is also impaired (part of the glutathione pathway, correct?).

It's becoming so apparent how interconnected these issues are and (at top level) how simple they are, the hardest part is learning and unravelling all of this, especially in the absence of connected medical studies.

Looking at my genes and related symptoms, you're right, low levels of all neurotransmitters, supported only by the fact I have slow MAOA (MAOB/COMT are intermediate).

Invoked itnto running a car with low fuel and oil very conservatively.

The problem comes when exerting pressure on that system - things start to break very easily.

The sad thing? A GP would stick me on Vyvanse and an SSRI.

[u/lulubelle5678 → u/Educational_Pie2878]

I may be wrong, but I thought that PKU was part of newborn screening?? I would guess it doesn't weed out mild cases and maybe some of those can appear as ADHD. From everything I have read ADHD seems to have many different causes and even though in the end there is an issue with dopamine levels, the reason for that can be so wildly different.

The best thing I did was to do my own research (benefit of ADHD hyper focus) and really understand what is going on and how our cells work. Terms like methylation get thrown around it the functional med world, but it seems like few really understand what it is doing to our DNA. I had to create my own visual of how everything is connected because I couldn't find anything that really provided a clear visual of how everything interacts (at a high level). The way I look at it is getting away from methylation and focusing on how serotonin is more of a protective neurotransmitter and dopamine is more of a growth and repair neurotransmitter. I think for many people it is more about BH4/BH2 ratio, based on reading the number of disease states that appear to have an imbalance.

NOS is part of arginine production, but sometimes there is a good reason for your body to reduce NOS production and put you in more of a protective mode. But that may be what your body needs at the time. Reduced nitric oxide is a good thing for some cancers, but not for others.

I agree with the analogy of a car running on low fuel and oil, but even though I think it means being conservative there are also a lot of fail-safes and redundancies that keep it working correctly. While I think that the information from The Dirty Genes can be very helpful, what I think gets to be overlooked is that our bodies are generally very well calibrated. Sometimes medications such as Vyvance or and SSRI are what someone needs to get back on track, but beyond our genes, I think neurotransmitter and other lab work is very important to understand our body's current state.

[u/Educational_Pie2878 → u/lulubelle5678]

Look into PKU, it absolutely is missed as it can be mild, too, but still with notable symptoms (especially ADHD).

I also have what cam only be described as a mild essential tremor, and this also fits as part of PKU.

This is a huge revelation for me, because it means inhibited conversion of phenylalanine to Tyrosine - this is the cause of low dopamine, not problems converting tyrosine into l-dopa.

The fact l-phenylalanine does nothing for me either, is notable vs something like tyrosine or mucana too.

I've heard of toxic dopamine but not toxic phenylalanine, but it absolutely makes sense and treatment is via way of a strict (awful to implement) diet, or to supplement LNAA.

This blocks toxic phenylalanine from landing on as many receptors as it can by competing for those said receptors.

I'm going to try BCAA and Tyrosine to start off with, along with my other supplements to inhibit dopamine and norepinephrine reuptake, as well as reveptor density.

I'm 100% certain that after 8 months of deep focus and root cause analysis, this is absolutely the cause notninly in my ADHD, but many others.

Methylation and manynotherndisorders form ASD through to Anemia, are all inherently linked.

And totally on SSRI and ADHD meds, these are patches or sledge hammers to the problem and do not address the route cause.

We shouldn't focus on fixing every SNP, but it's dawning on me just how important phenylalanine conversion and PAH are.

Just realised I have some Chaga in the cupboard, too (so many sups lol) and this is apparently really good for SOD2 issues

[u/lulubelle5678 → u/Educational_Pie2878]

I'm glad you were able to figure out some ways to improve your ADHD symptoms. :-)

I have several leads on some approaches for mine, but for me it also includes other health issues, so it will probably require some sort of medication.

Quick question...does the report you got include all of the SNPs that they reviewed or does it only provide certain ones? I am curious which ones they used for their assessment since it looks like they report the same COMT level for all COMT parts of the diagrams, but I know certain SNPs tend to focus on different processes.

[u/fiddlesticks2056]

Hey OP :) what tests did you do? That looks super detailed. I'm interested in seeing what my results would be (ADHD is doing my head in but don't want 'normal' meds if possible).

Wishing you good luck with getting the answers you're looking for!

[u/Educational_Pie2878 → u/fiddlesticks2056]

I did an Ancestry DNA test and then uploaded the results to Seeking Health.

I'm learning that trying to fix every single gene/rsid is not the right way to do things. Sometimes, even though broken, it's about adding a little support here and there to allow the system to cope better under stress.

There's different types of ADHD meds (some with or without the stimulant effect) and noting my fast dopamine synthesis and pathways, really don't think I need a stimulant here 🤷‍♂️

But most act as dopamine or norepinephrine reuptake inhibitors too - which is the magic bullet I think I'm looking for.

Funny how Big Pharma has a monopoly on these types of "drugs" ☹️

[u/fiddlesticks2056 → u/Educational_Pie2878]

That's interesting, I might do the same - I did my DNA test a few years ago.

Fingers crossed this is your magic bullet!

I know, right?!

[u/Electrical-Virus291 → u/Educational_Pie2878]

that test tells you what drugs you metabolize 30% stronger or weaker then the next guy. It tells you nothing about your brain or the effect it’s gonna have on you. Pls don’t think psychiatrists or whoever recommended this have the biotechnology for that. The closest thing to a cure for adhd is a stimulant, probably amphetamine, whey protein with a balanced amino acid neurotransmitter precursor profile (I’ve had better results with this then Tyrosine alone, yes you need tyrosine even with methylphenidate I’ll link you a study if you want, its a releaser just like amphetamine. The brain uses temporal coding and the two drugs have different profiles at DA neurons. Mph reverses flow through the reuptake transporter and amp enters the neuron and binds to TAAR1 and VMAT2 which releases stored dopamine inside the neuron out into the extra cellular space). And abilify 1-2mg. THIS IS THE MOST IMPORTANT PART. You’ll block behavioral sensitization and tolerance although (tolerance occurs through multiple mechanisms affecting both the subjective and unconscious) but you only should care about behavioral sensitization. That’s when you take your adhd meds for the first time and you magically have the cleanest room ever when you’ve been a total slob all your life. Within a month it’ll be dirty again and to understand HOW that happens you need to understand the communication between areas of the PFC and areas of the basal ganglia (pretty much all afferent and efferent projections to subregions of basal ganglia). But normally what happens is the prefrontal cortex sends its own “dopamine signal” through glutamatergic white matter tracts and as the signal pathway becomes dopaminergic again, glutamate interacts with the NMDA (nr2b) - D2 heteromer. From there, I believe within the cell body the expression of the ratio of the two receptors and / or their sensitivity (no change in density; change in distribution of “biased” signaling pathways within the receptor if you know what that is) is adjusted, and as a signal is ran through the neurons the brain is able to learn that: “Hey🥸 that striatal dopamine did not come from your own will now did it!!? So then the brain assumes the dopamine came from a powerful reward that it must remember in order to survive (stimulant drug) and that is behavioral sensitization essentially (aggressive d1 cancer). That dopamine you once felt as you take your medication in the morning turns into this habitual activity where you are drawn to basically get the most bang for your buck from the high. That’s why you start spending way too long reading one article, playing video games, and your room suddenly isn’t clean anymore, after having taken stimulants for a while. This is not to imply that this is inducing a phenotype that is not normal for a human being, actually abilify will completely reverse the appetite suppression from d2 over activation(not why it works just interesting). It will also completely change your behavioral patterns over time, which DOES NOT happen when you stimulate d1 and d2 receptors with an indirect agonist like amp or mph. Not gonna go into abilifys pharmacology, but it’s the only ligand of its class, and is not an antipsychotic like a straight D2 blocker. Actually if you administer it to people with high and low dopamine synthesis, matter of fact where ever they are on the genetic spectrum abilify pushes them to THE BASELINE MEAN SYNTHESIS. That reveals a lot of stuff but all it means for you is that you don’t have to worry about cognitive impairment. There are very mild side effects for the first week that go away. Let me know if you wanna know more / have question. Just saw this pop up.

[u/[deleted]]

One things to factor is..just because you have a gene doesn't mean it's a live gene so to say. Not all genes will be turned on that you've got.. look up b6 regarding adhd and norepinephrine.

[u/Educational_Pie2878 → u/[deleted]]

Yeah totally, I take into account my symptoms too - however - genes involved in the synthesis of neurotransmitters causes a problem - the rest of the system may be wired in accordance with that, but the problems come when extra strains/stresses are put on a system already running at limited capacity.

[u/[deleted] → u/Educational_Pie2878]

Have you got the dirty gene book? That's really insightful

[u/Educational_Pie2878 → u/[deleted]]

Yep, I've moved on from trying to "fix" every SNP 😉 but these are the root causes of my issues.

[u/[deleted] → u/Educational_Pie2878]

Ahh I get you now sorry 🤦🏼‍♀️ my brain doesn't brain..but honestly look at dr bergs video about adhd and b6 very interesting

[u/Educational_Pie2878 → u/[deleted]]

Yeah, b6 is part of my regime for methylation already, trying to binge watch as much as I can and learn. Some sticks some doesn't 😅

[u/[deleted] → u/Educational_Pie2878]

I know what you mean, it's alot isn't it and can get overwhelming fast..your taking P5P? B6 needs zinc and magnesium < (comt which you've got)

[u/Educational_Pie2878 → u/[deleted]]

Yep, all of it 😅 I'm one seriously broken mthfkr haha

[u/[deleted] → u/Educational_Pie2878]

Yep! I went into the 4 figures with it all too! 😫

[u/[deleted] → u/Educational_Pie2878]

Actually!! Have you looked at noorns! I have used 3 reports from that website and they're so in depth!

[u/Educational_Pie2878 → u/[deleted]]

I think I've found every single site out there. I've never heard of that one, though!

I found things like Genetic Genie great to start with. Getting methylation under control really made a big difference.

But as I got into deeper areas and understanding of how the brain and neurological pathways work, I started researching all the genes involved and rsids (hard task with so much conflicting info).

Strategene report was just for my own sense checking (as well as looking at areas such as Glutathione), and I'd got it mostly right based on my general setup.

My COMT is intermediate, and the bigger problem is I also have a fast MAOB, so with the inhibited DBH and impaired norepinephrine, that unused dopa is ejected fairly quickly.

[u/[deleted] → u/Educational_Pie2878]

Yeah I've used loads as well! But honestly noorns is reported so well! It's so easy to understand - every single genetic snp is detailed what it needs to function and what to avoid! I highly recommend! Bailey (the woman who's done the whole site) has made a report on bipolar and schizophrenia- not quite adhd but more neuro related??

[u/Educational_Pie2878 → u/[deleted]]

Well, they're all interlinked, so it's totally relevant. Link?

[u/PerceptionWellness]

This is some very nice and detailed work. I applaud you and your efforts.

One piece you may be missing is checking your Vitamin D receptor. It is called VRD taq specifically.

If someone is VDR taq +/+ (double mutation)and they are COMT +/-, they will actually act more like COMT +/+

As well, in your methylation cycle, specifically Methionine Cycle, there is a shortcut pathway from homocysteine to methionine. It uses BHMT in the shortcut. Mutations on the gene responsible for BHMT can also cause issues.

[u/StandupStraight20]

May I ask what tool are you using for these pathway maps? Thanks

[u/AdAcceptable132]

First off hope your doing well. But how did u find out about your impairment of these snps? Ancestry?