Excess acetylcholine & methylation

[jwat87]

I have a problem with excess acetylcholine buildup I've been struggling to understand. I suspect it has something to do with a messed up methylation cycle.

For those who aren't familiar with acetylcholine, too much can cause depression https://www.pnas.org/content/110/9/3573

I will reach a point where I have symptoms of excess acetylcholine- depression/anhedonia, poor working memory, fatigue. Diphenhydramine (Benadryl)
relieves these symptoms and allows me to feel normal again. Benadryl is an anticholinergenic. I've come across others on the internet who have this problem.

Some people have success with racetams (piracetam, aniracetam, etc) to use up excess acetylcholine, but these don't work for me. The only thing that helps is an anticholingernic drug such as benadryl, dramamine, or doxylamine.

I've received comments skeptical of the anticholinergic action, asking "How do you know it's not the antihistamine effect, or benedryl's effect on serotinin?" I know because other antihistamines with minimal anticholinergic activity do not help my symptoms at all. Also bendryl's effect on serotonin is extremely weak, and other supplements that effect serotonin do not help me at all.

There are several genetic mutations that influence how you break down acetylcholine. They can be found on 23andme. These articles list all of the mutations and go into detail.
https://www.geneticlifehacks.com/bche-nightshade-sensitivity-anesthesia-risk-and-more/
https://www.geneticlifehacks.com/choline/
https://sites.google.com/site/annerwright/avoiding-cholinesterase-inhibitors

Strangely, I've looked up the mutations listed, and mine are all normal.

Acetylcholinesterase (AChE) is the enzyme responsible for breaking down acetylcholine. If you take AChE inhibitors (such as huperzine, used for memory enhancement) it can cause buildup of excess acetylcholine. I've found that almost every herbal/plant extract out there has some degree of AChE inhibition. Plants have many components & chemicals in them, so it's likely at least one of the components in the extract has been shown to inhibit AChE to some degree.

These are some of the supplements, I've found to inhibit AChE and/or boost acetylcholine through some other mechanism, and make me feel worse:
black cumin seed oil
turmeric/curcumin
ginger
sulforaphane
fish oil
rhodiola
ginko bilboa
olive leaf
berberine
cbd oil
cannabis

Which is a shame because a lot of them also have antidepressant properties that initially make me feel good before the accumulation of choline occurs.


Excess methylation caused by taking too many methyl donors will cause acetylcholine overload. TMG and B12 (both hydroxy and methyl) cause me problems. I avoid TMG and only take hydroxyb12 is very small amounts when needed. I am careful not to get too many methylated B-vitamins.

Some people reported that taking niacin/niacinamide to slow down methylation has fixed their "excess choline" problem. This hasn't worked for me, though.

I have 2 Homozygous mutations: MTHFR A1298C and MAO-A R297R (warrior gene). I take small amounts of methylfolate and B2.

I've seen several reports of "Rebound problems" after taking methylfolate and methylb12, people feeling great the first day then it stops working, and they feel increasingly worse the following days. There are many causes for this (depending on individual genetics), but I believe acetylcholine overload is one of the overlooked factors involved in this.

 

[drmullin30]

Hello @jwat87 do you have any thyroid issues are you taking anything for that? Thyroid problems can cause problems with neurotransmitter balance and synthesis and many of the the supplements that you list have dramatic effects on thyroid function.

Also, have you looked into your oxalate status? Oxalates can cause many different issues including brain issues.

I also have the homozygous mthfr1298 among my many SNPs and I need a very large dose of folate, B2 and b12 to function properly as well as carnitine, iodine, molybdenum and many other vitamins and minerals that are all essential to methylation.

I had to detox ammonia, mercury, copper and aluminum and get my biopterin Bh4 levels up before I saw any improvement in health. After several years of dealing with this illness I have come to realize that detoxification and mineral balancing is vital and it's hard to understand how your body will react to supplement protocols while your physiology is still dominated by toxicity. In the beginning, pretty much anything I did made symptoms worse because of detox pathways opening up.

 

[jwat87]

@drmullin30
My TSH range: 2.080 uIU/mL (standard: 0.450 to 4.500 uIU/mL0.450 - 4.500 uIU/mL)
Dr said my thyroid is normal.

I haven't looked into oxalates, but diet changes never really made a big difference for me.

 

[drmullin30]

Maybe this article will help: https://mybiohack.com/blog/acetylcholine 83+ Ways To Increase Or Decrease Acetylcholine There's also a video embedded:

7 ways to reduce AC naturally.


It lists the following to help decrease: I used Kava Kava for years to control glutamate and ease anxiety. It works really well for me and many people in these forums find Alpha Lipoic Acid to be an essential supplement.

• Luteolin R
• Kava,
• Lipoic Acid
• BCAA lowered ACh in animals (I use this one "LHECMA" for 20% off) R
• Mercury compounds
• Nicotine R
• Butyrate R R
• Botulin
• Forskolin,
• Piracetam, R
• Glycine R
• Curare
• Clonidine R
• Centrophenoxine R

 

[YippeeKi YOW !!]

Maybe this article will help: https://mybiohack.com/blog/acetylcholine 83+ Ways To Increase Or Decrease

Good link, and thank you for posting it ....

 

[xebex]

interesting, I have also been noticing issues with acetylcholine i took benedryl ONCE for (something else) and had 4 days of considerably higher function - other antihistamines also do not have that effect, but then i had a nasty crash after, and when i took the benedryl again it didn't work. I also feel worse with rhodiola, turmeric and cbd although thc does seem helpful. I had an awful reaction to andrographis and I get highly irritable and sound sensitive after just two days of taking NT factor (phosphatidylcholine) and it happens every single time. I have not tried any of the ACh lowering supplements in the list yet, this certainly gives me some food for thought in what could help, maybe i'll try luteolin first.

 

[Cnew2this]

This is very interesting. I have been back and forth for years on whether I need more acetylcholine or less. When I first read Dr. William Walsh’s book (Nutrient Power), I thought he had all the answers and that I was in the Undermethylated Depressive category and needed to avoid all forms of choline supplements, and folate. And that SAMe was the best methylating agent. Then I tried his Low Folate Depression protocol, with no benefit. Then Dr. Amy Yasko’s recommendations – supplementing with lots of choline, phosphatidylcholine, and moderate folate, and B12. Incidentally, she likes SAMe for everyone. I can’t decide if SAMe is good or bad for me, but it sure seemed that it brought my homeocysteine down quickly at one point.

But there is more info in these threads that makes me think that I may have been taking supplements throughout my experiments that were increasing my acetylcholine. I haven’t read what is on all of the links provided yet, but wanted to pose a couple questions:

I believe I discovered at one point that PS (phosphatidylserine) supplements typically contain phosphatidylcholine, even if that isn’t shown on the label. I use a no soy PS (typically Jarrow), which uses sunflower lecithin (I think all non-soy brands of PS do) and I’m pretty sure I read that any such product will contain phosphatidyl choline, inositol, and ethanolamine, in addition to serine. Unless the manufacturer purposely removes the first 3. I can’t find those notes now. Has anyone else heard of that?

And any thoughts on supplementing with regular choline, or purposely eating a diet high in choline, like mushrooms (for muscle health)? Could this lead to acetylcholine buildup?

I found the list of AChE inhibitors above to be very interesting, and troubling. Fish oil really caught my eye. I wonder if that is huge doses, or normal supplementation?

 

[xebex]

And any thoughts on supplementing with regular choline, or purposely eating a diet high in choline, like mushrooms (for muscle health)? Could this lead to acetylcholine buildup?

I eat 2 eggs every day and i have tried to eat liver regularly but its disgusting and hard to find a clean source but i don't notice any adverse effects from eating them - liver was helpful i think mainly for the b12. Choline foods can help to build acetylcholine as its a precursor, but in my case i don't think it causes the issues i was having with supps that directly increase acetylcholine.

 

[drmullin30]

I have PEMT, MTHFD and BMHT homozygous SNPs so I need really large amounts of choline to keep my liver and methylation going. I also have liver damage so choline is really important for healing the liver. I take about 800 - 1000 mg of PC a day, 240 mg a day of bitartrate choline. I eat on average two eggs a day and I eat about 200 g of organic grass fed beef liver once a week. All of that keeps me from losing all ability to concentrate and staves off the depression. I have no experience with excess ACh or with SNPS that hinder the AChE enzyme. I have never had symptoms of excess ACh.

I'm pretty sure @Cnew2this that you're right about PC and PS. They are always together I think even in soy lecithin. I don't like using soy derived PC but any other kind of lecithin gives me a reaction.

I also take a pretty standard dose of fish oil every day so maybe that counteracts some of the effect of all that choline in my diet.

 

[Cnew2this]

Thank you for the replies @xebex and @drmullin30. I’m torn whether to experiment again with reducing acetylcholine and this time paying attention to all supplements that could be contributing. I’ve become so frustrated with such experiments. And, I didn’t keep good notes on the details of what I have tried.
I have been taking the PS for years, just because I got it in my head many years ago that it is a good brain support supplement. I’ve never gotten the impression that it is helping (but afraid to stop in case it is).

@drmullin – you mentioned that you have a reaction to sunflower lecithin. What kind of reaction? I have a soy allergy, so need to stay away from soy lecithin. I’m probably getting a pretty high dose of sunflower lecithin through several supplements. Plus eating sunflower seeds?
Regarding regular choline supplements – I have been taking a choline supplement daily on/off (off during times of concern about acetylcholine) for a couple years, because I probably don’t get enough choline through my diet. The only meat I eat is fish (mostly salmon), and I have an egg allergy. My most significant IgE food allergies (highest scores), from a blood test 12 years ago are: garlic, dairy, peanut, green bean, soy, egg, and almond. And then I have many, many IgG allergies. I’m disgusted with myself that when I looked back at those results I see that almonds had a high enough score (0.07) to be concerned about, but I guess I conveniently drew the line just above almonds (on which foods to eliminate). I have been consuming a lot of almond butter in the last year or so. Again, disgusted …

For what it is worth, my SNPs are:
The ones NRI/Yasko are concerned about:
MAO A R297R +/+ TT
MTHFR C677T +/- AG
MTHFR A1298C +/- GT
MTRR A66G +/- AG
CBS C699T +/- AG
PEMT, from the original 23andMe report:
PEMT G634A T CT +/-
PEMT T17020543A A AT +/-
PEMT T17023592G T GT +/-

Any other thoughts for me?

 

[drmullin30]

Hi @Cnew2this I react to sunflower lethicin because it's all gluten contaminated during processing and I'm a hyper sensitive celiac. I haven't been able to find a certified gluten free version. Luckily for me, no soy allergy but I try to minimize my intake none the less. The only place I get soy, is in my PC supplement.

@Cnew2this Are you taking methyl folate and methyl b12?

Methylation is crucial for choline metabolism and liver metabolism and with your SNPs, you're likely to need some mb12 and folate. With proper methylation, your body will manufacture some PS on its own and will also help with ACh synthesis, uptake and recycling.

 

[jwat87]

From https://chrismasterjohnphd.com/blog/2019/03/01/start-here-for-mthfr-and-methylation
"
The low activity of the MTHFR enzyme is a result of its lower ability to use riboflavin, and an extra 1.6 milligrams of riboflavin per day helps bring the activity back up closer to normal. It isn't clear whether enough riboflavin will make the enzyme work just as well as in someone with the genes for high MTHFR activity, but it might. Therefore, getting enough riboflavin should be central, but we should still work on the assumption that your methylfolate production is lower than it could be.

Because you are less good at making methylfolate, you use choline as an alternative methyl donor more often.

Methylfolate is the off-switch for the glycine buffer system, so low levels of methylfolate make you methylate glycine more often, even when you shouldn't. This makes you waste methyl groups and can deplete your glycine levels."

Pic
So, The cycle goes around and around to produce SAMe, which acts as a negative modulator on some of the enzymes. Meaning if too much SAMe gets produces its going to down regulate things to keep everything in balance. Same thing applies when its too low. One reason for it being low is a lack of 5-Methylfolate, so the mitochondrion will convert available choline (4methyl groups) into TMG(3 methyl). Next Tmg donates a methylgroup to homocysteine and converts it to methionine with the enzyme BHMT. As you can see on the pic, thats a shortcut, and its basically a backup and its jot meant to operate at 100% at all times. Since it shortcuts it leaves folate methylated and the cell loses its supply of THF which is needed for some reactions like synthesis of glycine. However, if you supplement TMG, the cell starts taking the shortcut and now choline isnt being used up. This builds up the levels to the point where extra ACh is synthesized and you feel depressed. I assume supplementing folate takes off the load of BHMT and therefore choline gets spared.

"Choline is converted into TMG (betaine) and then DMG. The latter two AAs (tmg & dmg) are the main causes of depression from choline. If your methylation is messed up, usually due to issues in the methionine synthase / reductase cycle , your body will try to use the shortcut pathway for methylation, BHMT. . . How do they cause depression? They fuck up your methylation cycle, either by overmethylating you or by depleting homocysteine that's also needed for glutathione synthesis and other sulfur based AAs. Another effect of this is for those of us who are sensitive to methyl donors due to certain genetic mutations (Eg: COMT/CBS). Choline has 4 methyl groups, if it's used for acetylcholine synthesis by the body, then it doesn't increase methylation, but if it is, then it becomes a strong methyl donor in converting to tmg and dmg, sarcosine, and eventual serine and glycine. I've personally tested both TMG and DMG and I have gotten the same depression I get with choline. "

After discovering that B2 lifts "folate-trap," I only take B2 and methylfolate in small amounts. I don't require extra B12. Once I fixed the B2 deficiency, B12 and methyfolate became much more potent. Even a small amount of B12 will trigger acetylcholine overload, so will TMG and creatine. What are the possible causes of this? Low homocysteine? BHMT pathway overactive? What should I be taking/avoiding?

A few people online reported they got excess acetylcholine from being overmethylators, and they fixed it by supplementing niacin. It's possible that I'm an overmethylator (despite having MTHFR), but folinic acid doesn't work very well for me, even when coupled with B2.

 

[drmullin30]

What are the possible causes of this? Low homocysteine? BHMT pathway overactive? What should I be taking/avoiding?

That might be it. I have very down regulated BMHT pathway (multiple homozygous SNPs) so I can handle all of that choline I take plus the gram or so of TMG I take daily. If you don't have these SNPs or they are upregulated that could be an explanation. Also, since I started the advanced protocol, I have had more mental concentration than I've ever had. Maybe this is because I'm using less choline as a methyl donor and creating more ACh?

Other things that will supposedly increase the flow through the BMHT shortcut are Phosphatidylcholine, TMG, Phosphatidylserine and Zinc.

Unfortunately I haven't had as strong a response to riboflavin. It's certainly essential in my regimen and I notice a reduction in b12 effectiveness without it but it has never allowed me to reduce my methyl folate dose.

 

[jwat87]

Another explanation - methylation may not be good for me, anything that increases methylation boosts neurotransmitters which initially fixes my depression, but it also boosts ACh production which then blunts all other neurotransmitters causing anhedonia. Maybe increased ACh is some rebound defense mechanism in response to overproduction of neurotransmitters. I might be an overmethylator, but niacin just makes me feel down. I've tried glycine, but it doesn't seem to do anything. Maybe the answer is to go on pharmaceutical antidepressants instead.

 

[Cnew2this]

Thanks for the replies @drmullin30 and @jwat87. I need to read, and reread what @jwat87 wrote. A lot to absorb and there is definitely some new info there that I had not read about. Your info regarding choline causing depression is something I had read about (Walsh and others), and is why I go back and forth on whether to supplement with choline and PC. After I read, and reread I’m sure I will have more questions for you.

I do know from the reading I have done that the methylation topic is very complex and there are many experts who disagree with each other on the best approach for supplements.

@drmullin30 - That is interesting that sunflower lecithin is almost always gluten contaminated. Probably not a problem for me. I avoid gluten, but don’t have celiac. I sure sympathize with Celiacs, with so many hidden dangers.

I took methyl folate for years and then a couple years ago decided it was causing me problems. Anxiety and headaches that I am pretty sure were from taking it (but possibly I got that wrong). Since then I have taken folinic acid supplements (not folic acid, which I definitely avoid) and I eat lots of leafy greens.

For B12, I take 1,000 mcg of methylated and 1,000 mcg hydroxo. For a time I took a lot more, of just mB12, but started to suspect it might be causing the same problems I suspected from mfolate. I read a lot on the forums here of people who can’t tolerate either mfolate or mB12. At some point, I will probably experiment with mfolate again. Now, I just take a very small amount of SAMe and methionine daily, which are good methylating agents for people who are in the “Undermethylated Depression” category, according to Walsh and Yasko thinks that everyone can benefit from some SAMe, and includes it in her Ultimate B supplement. I did a couple tests 2 years ago through Yasko (Holistic Health) and got comments back from Yasko. She recommended a pretty high dose of SAMe for me, but I suspect it may contribute to my anxiety, so I have gone with a very small dose.
Thanks again to both of you, and I will be back with more questions.

 

[Cnew2this]

Ok – I’ve read and reread the post by @jwat87. Thanks for providing the link to the longecity forum. That was interesting – and entertaining. They are not as cordial over there as the PR Posters. Too bad that thread appears to be dead. Looks like the last post was 2 years ago.

One thing you discussed is how B2 (riboflavin) can lift the “folate trap”. I hadn’t heard of that. I have been taking what I consider to be a huge dose of B2 for at least a year, after reading that it is supportive for my MAOA SNP and for migraines. I have been taking 10 mg of R5P (activated form of B2) and 50 mg regular B2. What have you read on recommended doses for “lifting the folate trap”?

I was also interested in your statement about creatine causing acetylcholine overload. I think that I knew that at one time and forgot. I should pay more attention to how it affects me.

Some of what I read in the longecity forum agrees with Walsh’s (Nutrient Power) theory on methylation vs acetylation but I think suggests that Walsh tried to oversimplify it. It has been awhile since I read his book, but my understanding is that he thinks most undermethylated people need more methylation and less acetylation and that folate (in any form) is not the way to do it (for people with depression due to undermethylation). For these people, he thinks SAMe and methionine are the best methylating agents and to stay away from all forms of choline (as well as manganese, copper, and DMAE). When I read his book, it made sense, and I was hopeful that this was the answer for me. But, after trying his protocol for many months I finally decided that I was doing no better.

I have to say that of all the research I have done on improving my health, methylation (and SNPs) have been the most maddening. I feel like after so much time devoted to it, I’m really nowhere.
I do know that back when I was taking what I now realize were massive doses of methylfolate, prescribed by a doctor, I was doing terribly. And, I’m pretty sure I later concluded that even small doses were not a positive for me.
And I had persistently high homocysteine for years (even when I was taking the massive doses of methylfolate) and what seemed to bring it down (very quickly) was SAMe. I haven’t had the homocysteine checked in 2 years – which is when I got fed up with the doctor I was seeing, and doctors in general. I am interested in knowing where my homocysteine is at now that I am taking only a very small amount of SAMe and methionine. But with the COVID situation, I don’t see myself going to a doctor, or even a lab for a blood draw, anytime soon.

Thanks for taking the time to share info.

 

[drmullin30]

I do know that back when I was taking what I now realize were massive doses of methylfolate, prescribed by a doctor, I was doing terribly. And, I’m pretty sure I later concluded that even small doses were not a positive for me.

Hi @Cnew2this massive doses of methyl folate always require massive doses of methylb12 to work and not cause general degeneration. In general you won't see any benefit from folate unless it's taken with b12 and there's a certain minimum ratio required as well. More b12 than folate is usually what most people need.

I take 30-45 mg of methyl folate per day (needed due to multiple homozygous MTHFR, DHFR, MTRR and MTHFS SNPs) and I also have to take large does of b12 with it to prevent all kinds of problems.

SAMe will drive methylation far harder than methyl b12. I can't tolerate it at all because of COMT, CBS and GAD SNPs. I think somewhere Fredd and Rich talk about how b12 and and maybe folate are safer than SAMe because they don't "drive" methylation it's more like they remove blocks not sure if that's correct though.

 

[jwat87]

@Cnew2this I believe I found the info about B2 & folatetrap in these threads:
https://forums.phoenixrising.me/threads/how-b2-really-affects-folate.48416/
https://forums.phoenixrising.me/thr...g-cant-find-the-missing-cofactor.76310/page-3

The amount you require is gonna be different for eveyrone. You may want to check out Chris Masterjohn's stuff as he has a different approach. I never found Walsh's approach to be useful.

 

[Cnew2this]

Thanks for that @drmullin30 - I will try to read more on b12/folate, including your Fredd and Rich references. Wow - that is a lot of mfolate that you take. But then you do have several homozygous SNPs that would point toward you needing it. How much B12 do you take with it?

 

[Cnew2this]

Thanks for that @jwat87 I will keep reading. I get discouraged, and overwhelmed, at times but I need to press on.