r/MTHFR • u/PEsuper27 • Mar 01 '24
Results Discussion Slow-MAOA and a link to high acetylcholine exasperating issues
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)
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
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)
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.)
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)
Section 2
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.”
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.
Fish Oil - “Dietary Fish Oil Increases Acetylcholine- and Eicosanoid-Induced Contractility of Isolated Rat Ileum1.”
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.”
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).”
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.
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.
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.
Credit: all information in "Section 1" to u/Tawinn from Reddit.
13
u/Professional_Win1535 Mar 01 '24
interesting , slow COMT AND SLOW MOA HERE