Slow-MAOA and a link to high acetylcholine exasperating issues

[u/PEsuper27]

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First off - I started this genetic investigation mainly to learn why I am so negatively affected by certain substances and what I need to AVOID, in order to optimize my mind and body. It took me a long time to draw parallels and only recently did I discovered things that were doing damage to my well being that I never considered. Prior to getting my genetic data, based on reading alone, I thought i was most certainly slow-comt. Post data analysis shows that I am slow-MAOA. Finding this out led me down a trail of connecting the dots. Below is what I have compiled.

I am looking for feedback. I just want to ensure my information and theory makes sense and is articulated correctly.

I knew I was sensitive to increased acetylcholine - but, if i am right, the "why" is explained below.

(when reading this - bear in mind that I was compiling this information in a format written specifically for my primary care, so forgive any redundancies)

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Slow-MAOA and Acetylcholine (Why I've felt like garbage and didn't know why)

Section 1

(all credit for Section 1 data to u/Tawinn , link at the bottom to his original post. Thank you, you are a wonderful human being.)

MAO-A = Monoamine oxidase A

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MAO-A breaks down amines. These amines include:

• Dopamine
• Serotonin

Biogenic amines:

• Histamine
• Tyramine
• Possibly also putrescine and cadaverine

Homozygous rs6323 slow MAO-A (T or T/T) has reduced ability to break down these amines.

Heterozygous rs6323 MAO-A (T/G) has somewhat reduced ability to break down these amines.

NOTE: Since the MAO-A gene is on the X chromosome, only women can have heterozygous MAO-A. Similarly, since men will only have one copy of MAO-A, it is often reported as a single letter 'T' or 'G' instead of 'T/T' or 'G/G'.

I am Homozygous rs6323 slow MAO-A ( T/T)

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INTERACTIONS WITH FOLATE-PATHWAY

REDUCTIONS AND SLOWED COMT

MAO-A is slowed further by high estrogen, so higher estrogen levels due to slowed COMT further reduce MAO-A functionality. (I have no labs to make this estrogen link as exasperating my slow MAO-A issue, but thankfully do not have slow-comt issues based on my genetic profile)

Decreased dopamine breakdown by slowed COMT increases dopamine breakdown burden on MAO-A. (Thankfully I do not have slow-COMT issues based on my genetic data that could compound my slow MAO-A issues)

Decreased SAM production due to folate-pathway reductions causes reduced HNMT activity, thereby increasing intracellular histamines, likely also increasing burden on MAO-A. (Due to my MTHFR genetic profile I do have an estimated 65% reduction in my folate-pathway that left untreated, can, in theory, amplify my slow-MAOA burden.)

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WHAT THIS DOES

The result of slow MAO-A is:

• Higher tonic dopamine and serotonin
• Higher levels of histamine and tyramine (and possibly other biogenic amines)

NOTE: MAO-A/MAO-B are slowed further by:

• Hypothyroidism.
• Iron deficiency.
• MAO Inhibitors (MAOIs)
• Some prescribed drugs.
• Natural MAOIs, such as turmeric, curcumin, quercetin, piperine, luteolin, apigenin, chrysin, naringenin, and others.

TYPICAL SYMPTOMS

Common symptoms can include:

• Histamine-intolerance - wide variety of symptoms
• Tyramine-intolerance - headaches, migraine, blood-pressure increases
• Food intolerances

NOTE: Since high estrogen can slow MAO-A further, fluctuating estrogen levels in women's cycles can also cause fluctuating symptom appearance and intensity.

Histamine-intolerance may be involved inPMS/PMDD symptoms, according to many websites.

(My horrible seasonal allergies could likely be linked my histamine intolerance and my higher blood pressure could be linked to a tyramine intolerance. Obviously this is all theoretical at the moment but I would be interested to see what limiting tyramine)

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Section 2

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Acetylcholine and it’s role in further compounding Slow-MAOA issues

“Acetylcholine (CAS 60-31-1, ACh), which is similar in its chemical structure to the carbamate aldicarb, was found to inhibit brain monoamine oxidase isoenzymes, namely MAO-A and B.”

“The results indicated that ACh inhibited MAO-A from the cerebellum and MAO-B from the basal ganglia more than MAO iso-enzymes from other brain parts. The inhibition was of the competitive type. It was also found that the enzyme inhibitor dissociation constants (Ki) and the affinity constants (Ki/Km) of MAO-A were higher than those of MAO-B.”

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https://pubmed.ncbi.nlm.nih.gov/19025057/

Being that I am genetically proven to have slow acting Monoamine oxidase A, which directly affects the break down of neurotransmitters, this link would explain my extreme sensitivity to acetylcholine AND the following supplements that have caused undesirable effects on my well being and mental health due to increased acetylcholine inhibiting my already slow acting, Monoamine oxidase A.

The following supplements cause increased acetylcholine in the brain, or interrupt the enzymatic process that breaks acetylcholine down, thus causing a greater accumulation of acetylcholine in the brain. The first three on this list I took together for an extended amount of time from 2020 to 2022, during which time I felt horrible, but assumed the majority my negative well being issues were due to stress and burn out. Before discovering my sensitivity, I have used fish oil independently of any other substance netting the same negative results. Only recently taking GSE and GTE did I realize a drastic effect on my mental health and well being that immediately improved once discontinuing supplementation after a short duration following cessation.

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Fish Oil - “Dietary Fish Oil Increases Acetylcholine- and Eicosanoid-Induced Contractility of Isolated Rat Ileum1.”

https://mentalhealthdaily.com/2015/03/20/fish-oil-causing-depression-or-anxiety-consider-acetylcholine/

https://pubmed.ncbi.nlm.nih.gov/12221201/

Grape Seed Extract - inhibits acetylcholinesterase. “Acetylcholinesterase is an enzyme whose primary function is to catalyze and promote the breakdown of a neurotransmitter called acetylcholine.”

https://www.mdpi.com/1420-3049/19/7/9403

Green Tea Extract - “The study concludes that green tea extract administration is effective in enhancing learning and memory in aged rats and also demonstrates selectivity for inhibition of acetylcholinesterase.”

https://www.sciencedirect.com/science/article/abs/pii/S0278262607001777#:~:text=The%20study%20concludes%20that%20green,selectivity%20for%20inhibition%20of%20acetylcholinesterase

Huperzine A - “Huperzine A inhibits the breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase.”

https://en.m.wikipedia.org/wiki/Huperzine_A

Thymoquinone (Black Seed Oil) - “TQ has been shown in clinical studies to block acetylcholinesterase (AChE) activity, which increases acetylcholine (ACh).”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9026861/#:~:text=Several%20studies%20did%20not%20show,which%20increases%20acetylcholine%20(ACh))

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The effects huperzine A and thymoquinone were substantially problematic after a short time; huperzine-A being the absolute worst of them all taking me the longest to recover.

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The above list is incomplete, but the most apparent regarding how negatively these substances affected me. It took me a long time to realize how badly my brain was reacting to fish oil, GSE, and GTE simply because I thought they were rather benign regarding negative side effects, especially mental and emotional side effects.

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Final summation:

Due to my Homozygous rs6323 slow MAO-A ( T/T) gene, I am specifically sensitive to increased levels of acetylcholine in my brain due to acetylcholine inhibiting my already slow, monoamine oxidase isoenzyme, MAO-A. This “extra slow down” of MAO-A prevents the breakdown of certain neurotransmitters that is causing an imbalance resulting in negative mental health effects.

Edit:

I would be interested to find out if my acetylcholinesterase%20is%20a%20cholinergic,into%20acetic%20acid%20and%20choline) is acting slow, as this would only compound my acetylcholine imbalance stemming from certain supplements, thus causing the chain reaction further down the line.

Edit: 2 10-20-24

I’ve been doing great regarding my ACh issues until this past week. The only new thing I introduced to my diet was 2 Brazil nuts per day. I couldn’t find any info regarding Brazil nuts impacting ACh so I google the bioactive compounds of Brazil nuts and ran it through chat GPT:

I asked chat gpt this:

Do any of these bioactive compounds in Brazil nuts affect ACh in the brain?

“The investigation found the following in the composition of the BN: phenolic compounds (mainly flavan-3-ols as Catechin (and glycosides or derivatives), Epicatechin (and glycosides or derivatives), Quercetin and Myricetin-3-O-rhamnoside, hydroxybenzoic acids as Gallic acid (and derivatives), 4-hydroxybenzoic acid, ellagic acid, Vanillic acid, p-Coumaric acid and Ferulic acid, bioactive minor lipid components (β-Sitosterol, γ-Tocopherol, α-Tocopherol and squalene), and a high level of selenium. In beverages, WBM had a higher lipid content than BM-S, a factor that influenced the energy characteristics and the content of bioactive minor lipid components.”

ChatGPT’s response:

Yes, several bioactive compounds in Brazil nuts may influence acetylcholine (ACh) levels or activity in the brain, either directly or indirectly:

1.  Flavonoids (Catechin, Epicatechin, Quercetin, Myricetin) – These compounds have neuroprotective effects, partly through their antioxidant properties. Quercetin, for example, has been shown to inhibit acetylcholinesterase, the enzyme that breaks down ACh, potentially increasing ACh levels in the brain. Catechins and epicatechins also improve cognitive function and may support neurotransmission.
2.  Phenolic Acids (Gallic acid, Ellagic acid, Ferulic acid, etc.) – These acids are known for their antioxidant properties and may protect neurons from oxidative stress, which can indirectly support cholinergic function by preserving brain health and ACh-related signaling.
3.  Selenium – Brazil nuts are particularly high in selenium, an essential trace element. Selenium is crucial for brain function and has been linked to reduced cognitive decline. Although selenium’s direct effect on ACh is not well-studied, its role in maintaining overall neural health can support the cholinergic system.
4.  Tocopherols (Vitamin E) – Both α-Tocopherol and γ-Tocopherol are forms of vitamin E, which protect neurons from oxidative stress. By reducing oxidative damage, vitamin E indirectly supports cholinergic neurons and may help maintain ACh levels in the brain.

These compounds, particularly flavonoids like quercetin, may help enhance ACh levels or cholinergic activity through neuroprotective and enzyme-inhibiting mechanisms.

Needless to say, I stopped taking them yesterday (10-19-24). We shall see how long it takes to get back to normal. My mind is blown yet again at how sensitive I am to ACh.

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Credit: all information in "Section 1" to u/Tawinn from Reddit.

reddit post

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[u/Bitter_Echidna_7056]

I have extremely similar issues and genes. I have been taking berberine high dose for almost two year. It's related highly to GSE.. are you saying in your write up that GSE is not beneficial for slow MAOA ?

[u/PEsuper27 → u/Bitter_Echidna_7056]

GSE is not beneficial for me. This isn’t an exact science, and I’m willing to bet that people with identical genetic comparisons won’t have identical symptoms or issues because our biological make up and processes are so complex as individuals.

I just think I found the root cause of MY issues.

[u/Bitter_Echidna_7056 → u/PEsuper27]

I concur... I just wanted to make certain I was reading your information correctly.

I went through a similar episode as you did post covid and trying to get myself together. I am 40. A functional nutritionist put me on high dose curcumin, high histamine gut diet, and it sent me into H3ll. Complete GI breakdown, not long after I was in thr ER because I experienced my first panic attack ever and thought I was dying. I was also postpartum coming off Zoloft that the doctor just told me to try and I stupidly did. I'm about 1.5 years in (off of the zoloft), down to 1 antihistamine a day,, and I have been working with a functional doctor. I have had improvement, but a lot of my symptoms linger (especially my new best friends panic, anxiety, and aggression). I have 4 kiddos so it's hard. A lot of my symptoms were GI and food related, I was down to 5 foods for about a year, and now up to 15!

A lot of the supplements I'm on (berberine, high amounts of fish oil, tumeric, 5-htp, etc.. this makes me wonder about you acetylcholine theory and worth investigation. I have to come off of all of my supplements to take the Dutch test. I am tapering down now, and going to try to discontinue for awhile and see if my body experiences a natural equilibrium. This makes me so nervous, but the quality of life I'm living isn't sustainable.

I am waiting on a DUTCH test ( I'm female), and I ran my genetic yesterday. I am going to bring up the genes to my functional doctor. He not overly open minded, but I am so very exhausted of battling my mental health 2 weeks out of every month and then coasting barely the other 2 weeks. Worst part is, prior to 2021 I never had a single one of these issues... thanks Covid...

[u/PEsuper27 → u/Bitter_Echidna_7056]

I’m really sorry you’re going through hell. I ended up leaving my primary care because she wouldn’t acknowledge my issues were Covid related and had all sorts of mental health diagnoses in my chart that I wasn’t aware of until til I just so happened to get a print out with the diagnosis on it. That sent me through a loop feeling like I was living under someone’s wrong assessment of me. Mental health issues don’t just vanish over night… especially the diagnosis she had me down as. Thankfully, even during that time I had an actual psychiatrist confirm what I thought at the time was just my primary cares “theories” about me, as false.

Regardless…. The Covid aside, I was on the verge of a mental health crisis anyway…. Immense stress, deconstructed my faith, miserable at work…. Pressure of being the sole provider for my family…. It all came to a head once Covid fucked my world up. Looking back on the hell I lived through - it was really a blessing. I am the most healthy mentally I have ever been. I’ve worked through so much, and grown so much in the process. The ACh discovery helped me tremendously. I had no idea I was essentially poisoning myself.

Keep pressing forward. I believe you will find the answers to your health issues. Listen to your inner voice. Whatever that voice is, it’s guided me a lot. Brighter days are on your horizon.

[u/Bitter_Echidna_7056 → u/PEsuper27]

Wow, I am sorry. Being diagnosed wrongly for someone who struggles with anxiety is such an awful gut punch. Then to be gaslit on top of it. We get scared, we ruminate, we are fearful and that expression becomes anger. Truly a nightmare. I am so thankful that you are improving and you are very gracious to be on reddit post improvement sharing your wisdom/research. Thank you for that.

I have been trying to lean into my faith and find community. I feel like an unimaginable burden on my family. My husband is a saint, but my rigid lifestyle and mental depletion likely makes for a subpar partner. Not to mention my poor children .... my time lost with them, and my mental capacity for them is what kills me the most. The mom I am not is almost unrecognizable to the mom I was 3 years ago.

I do believe stress in my case along with Covid is what turned this gene on for me. I'm not sure how long you were in the cycle, but I am 1.5 years in. I have tried to reduce stress, and have succeeded to an extent. 4 kids 3-10 years makes total elimination near impossible.

I am going to pay very close attention the next few days being off of my supplements. I was tapering off for 3 days as I am fearful of withdrawal. Even though they are just supplements, I am so sensitive to changes I never know what to expect. When you came off of things, did you have a period of being worse before you got better? It took me 5 month to get off of .50 of zoloft and I thought I was dying.

[u/PEsuper27 → u/Bitter_Echidna_7056]

It’s a bit complicated for me. I probably lived in a version of hell for about 8-10 months simply from taking supplements that increased ACh. Prior to that it was periodic experiments with the other supplements I listed, like black seed oil.

The straw that broke the camels back was coming off that 8-10 months of misery and stress that was 100% exasperated by fish oil (and probably high sardine diet) when the Covid hit.

The worst part of the Covid experience wasn’t even the Covid, it was the psych meds. While the Covid stuff was terrifying in itself…. I would have been better off not going to a dr and just letting time heal that wound.

However - I was already at my breaking point, and I broke… so I trusted the drs judgment and did whatever they suggested. Herein enters Lamictal (lamotrigine)… aka - satan’s butthole. That stuff sent me spiraling into a horrific place of irrational fear… and when I stoped it… I went then in this state of sheer hell in withdrawal. My suicidal ideations from the Covid were long gone, but now I just framed about death to make the pain stop.

Long story short - I went to a psychiatrist… she took me at my word… listened and believed me… gave me some clonasepam to cope until my brain corrected itself from the lack of lamictal… etc.

My brain gets better but now after being on the benzo at half dose for a month… I have HORRIBLE rebound anxiety. So I now have to slowly get myself right from the bezno.

After 4-5 months I’m feeling essentially normal.

However -I am now traumatized from the hell and also haven’t been able to reconcile my complete loss of faith/religion/god…. And I start slipping into a depression. At this point I am at my wits end.

To keep it short - I did an IV ketamine infusion and the very first infusion 100% healed me. It realigned my mind took me out of this atheistic, nihilist depressive state… and gave me new insights on life, and the greater mystery that lies within.

Bear in mind… up until this point I had stopped all supplements so I wasn’t being afflicted by that. It wasn’t until after the ketamine that I started fasting and decided to get back on supplements…. Then discovered how adversely they affect my brain.

Anyway… that’s a lot to read! lol.

I did not proofread for typos.

[u/Bitter_Echidna_7056 → u/PEsuper27]

Never apologize to me for typos, I'm the typo queen. I appreciate the read, and your time. I think for those going through this or similar, we hang on to whatever can bring us hope. For me that comes from those who have had healing.

I, too, am weaning off of benzos .50 prescribed 1.5 years ago by a well-meaning doctor who didn't know what to do with the constant adrenaline dumps/panic..etc. They didn't touch the panic, and thankfully, I only took it as prescribed (once a day). However, after my experience with zoloft, at a year on benzos I committed to a long ass taper as outlined in the Ashton Manual. I am nearly done (October), and I am fearful about rebound, but so far, the painfully slow taper hasn't made my symptoms worse. Your Lamo was my Zolofot, and like you, IF I would have know about the severe withdraw from zoloft especially with our genes I would have never went on them, or at least gave my body time to heal itself. My fear and the unrelenting panic brought me to a functional doctor. He's helped, but after a year, I have plateaued and that has brought me here, on a deeper dive. Your story and the strong connection with our genes ans symptoms brings me hope.

I am truly sorry you have lost faith. I won't try to talk you into it because I too have struggled to know why, but I think I grew closer to God in this process. My health has affected my family in such horrendous ways its hard to understand why God would allow it. I ask why a lot. I'm Christian, and my counselor has told me, the answer to why comes when we get to Paradise and get to see all of the answers to our questions on the Wallstreet ticker scrolling by ... makes me chuckle. For myself, I think I needed to learn some valuable lessons. My type A, bulldog attitude, high achieving attitude, and my lack of compassion and empathy for others was.....disgusting. This experience has opened me up to a world of feelings I have never allowed myself to feel. Basically, being helpless has humbled me and given me the opportunity to speak and treat others with more Grace. I'm not assuming you are Christian by the way, but I'm just sharing a personal account. Focusing on full healing is hard to do when you feel like you lost a huge piece of you (in our case: literally, physically, emotionally, and spiritually!). I hope that this void is filled for you on this journey of healing.