Cholinergic toxicity reversed with Forskolin

[Ahmed ELH]

I've been suffering for the last few months of excess acetylcholine symptoms after using B1 for a long time, my symptoms were:

- Excessive Salivation
- Constant Head Pressure during the day, worsening after eating.
- Constantly Tense Gut
- Extreme Fatigue and Headaches after eating (no matter what I eat)
- Insomnia
- Muscle Tensions
- Abnormally High Heart Rate (180 bpm when fast walking)
- Shortness of Breath
- Anxiety
- Excessive Inflammatory responses, after training or sex. (felt like my brain was on fire, with extreme anxious thoughts, I needed 2 to 3 days to fully recover)
- Social avoidance

At first, I thought it was MCAS or histamine intolerance, but all known treatments and supplements for those two didn't work at all.

The only thing that worked for a short period of time was anti cholinergics : DPH and Chlorphéniramine, as well as 5-HT2a and D2 agonists.

I decided last Thursday evening to try Forskolin (250mg Coleus forskohlii extract standardized at 10% forskolin) first thing in the morning to enhance AChE and the results were astonishing.

- The constant head pressure and anxiety vanished, it was replaced by a feeling of well being
- No more excessive inflammatory responses after training or sex
- Stabilized Heartbeats
- Feeling completely refreshed and rejuvenated upon waking up in the morning
- I can easily take deep breaths now
- My MMC is working properly again
- Improved verbal fluency with a desire to interact with others
- Feeling relaxed even in stressful situations
- Extremely motivated and active

I didn't expect it to work so well honestly, I spent too much time trying to increase GABA, dopamine and reduce serotonin without success, thinking they were the problem in my case.

 

[Sitaruîm]

How much B1 were you taking each day and for how long? Would you steer clear from supplementing B1 now or would you just use a moderate dose?

 

[Ahmed ELH]

How much B1 were you taking each day and for how long? Would you steer clear from supplementing B1 now or would you just use a moderate dose?

I started two years ago with 1200mg of Benfotiamine, switched to a product which contained a mix of 4 forms of B1 at the same dose, I had great results and lowered my intake slowly as my absorption and gut issues were improving to 100mg.

The cholinergic symptoms appeared around 6 months ago, I didn't make the connection with B1, I didn't even know it was possible to feel that bad from excess acetylcholine as almost every person on internet is praising its benefits, untill I discovered this forum 2 months ago of people having similar symptoms to mine when exposed to B1 and other cholinergic compounds.

I'd steer clear from B1 for a good moment and in case I take it again it would be no more than 25mg of one of the derivative once in a while.

 

[Logan-]

@mostlylurking

 

[pubh12]

Why do you think this worked compared to taking anticholinergics?

 

[gunther]

@Ahmed ELH
Do you have any brand recommendations?

 

[PeterSN]

I started two years ago with 1200mg of Benfotiamine, switched to a product which contained a mix of 4 forms of B1 at the same dose, I had great results and lowered my intake slowly as my absorption and gut issues were improving to 100mg.

The cholinergic symptoms appeared around 6 months ago, I didn't make the connection with B1, I didn't even know it was possible to feel that bad from excess acetylcholine as almost every person on internet is praising its benefits, untill I discovered this forum 2 months ago of people having similar symptoms to mine when exposed to B1 and other cholinergic compounds.

I'd steer clear from B1 for a good moment and in case I take it again it would be no more than 25mg of one of the derivative once in a while.

I actually took eliott overtons b1 supplements around janurary of 2022, i have been severly short of breath ever since, inability to relax, messed up gut, increase in my autoimmune issues, etc... It has gotten slightly better over alomst 2 years, but i have these symptoms especially the shortness of breath.

 

[mostlylurking]

@mostlylurking

@Ahmed ELH

Here's some info about cholinergic toxicity:

Cholinergic Toxicity - StatPearls - NCBI Bookshelf

"Cholinergic toxicity is caused by medications, drugs, and substances that stimulate, enhance or mimic the neurotransmitter acetylcholine. Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system. Acetylcholine stimulates muscarinic and nicotinic receptors to cause muscle contraction and glandular secretions. Cholinergic toxicity occurs when too much acetylcholine is present in the receptor synapse leading to excessive parasympathetic effects."

"Cholinergic toxicity may result from insecticides, nerve agents, medications, and mushrooms. The most common cause of cholinergic toxicity worldwide is exposure to organophosphate and carbamate insecticides. Exposure to these insecticides may be through inhalation of vapors, ingestion, or direct contact of the chemical with the skin or mucous membrane."

"The underlying mechanism for cholinergic toxicity is excessive cholinergic receptor stimulation which can be caused by substances that mimic, stimulate, or enhance acetylcholine. The symptom complex produced by the agent depends on what type of receptor or combination of receptors is activated. There are three types of cholinergic receptors: central, muscarinic, and nicotinic. Excess acetylcholine at muscarinic receptors will result in symptoms of increased secretions, bronchoconstriction, bradycardia, vomiting, and abdominal cramping. Excess acetylcholine at nicotinic receptors causes muscle fasciculations or paralysis due to activation of the neuromuscular junction. Acetylcholine excess in the central nervous system can cause confusion, headache, or drowsiness.[1]"
-end paste-

It's a fairly detailed article. Thiamine, thiamin, vitamin B1, are not mentioned.

Please note that I was poisoned with organophosphate insecticide in 1993 (30 years ago). Part of the diagnosis on my chart said: Central Nervous System Damage. It nearly killed me and it took over 2 years to recover my brain function. The article I posted above discusses the issue of organophosphate causing cholinergic toxicity. In 1994, part of the protocol that my detox specialist doctor used for my recovery included 16 big b-complex capsules per day; these pills included 100mg of thiamine hcl each which equaled to 1600mg of thiamine hcl per day. I recovered.

I've been taking high dose thiamine hcl, 2 grams/day for 3 years. It has helped me a lot. Although thiamine increases acetylcholine needed for the parasympathetic nervous system, because of my own personal experiences, I do not believe it increases the issue of cholinergic toxicity. But I don't know everything there is to know; a person could have extenuating circumstances that complicate the issue. The cholinergic system is complex. Ray Peat wrote about the dangers of cholinergic toxicity (too much acetylcholine) ; Dr. Derrick Lonsdale wrote about the dangers of not enough cholinergic activity (too little acetylcholine). I think they both are both right.

 

[Ahmed ELH]

Why do you think this worked compared to taking anticholinergics?

The anticholinergics I used worked properly but they didn't last for so long in term of effect as they only antagonise the receptors. Forskolin enhance the breakdown of acetylcholine, which I think was the main problem for me since I used a lot of AChE inhibitors and cholinergic compounds in the past.

 

[Ahmed ELH]

@Ahmed ELH
Do you have any brand recommendations?

I found a brand called EA FIT here in France at my local pharmacy.

 

[Ahmed ELH]

I actually took eliott overtons b1 supplements around janurary of 2022, i have been severly short of breath ever since, inability to relax, messed up gut, increase in my autoimmune issues, etc... It has gotten slightly better over alomst 2 years, but i have these symptoms especially the shortness of breath.

Which one did you take, Thiamax or Thiamega, and at which dosage?

Please note that I was poisoned with organophosphate insecticide in 1993 (30 years ago). Part of the diagnosis on my chart said: Central Nervous System Damage. It nearly killed me and it took over 2 years to recover my brain function. The article I posted above discusses the issue of organophosphate causing cholinergic toxicity. In 1994, part of the protocol that my detox specialist doctor used for my recovery included 16 big b-complex capsules per day; these pills included 100mg of thiamine hcl each which equaled to 1600mg of thiamine hcl per day. I recovered.

I've been taking high dose thiamine hcl, 2 grams/day for 3 years. It has helped me a lot. Although thiamine increases acetylcholine needed for the parasympathetic nervous system, because of my own personal experiences, I do not believe it increases the issue of cholinergic toxicity. But I don't know everything there is to know; a person could have extenuating circumstances that complicate the issue. The cholinergic system is complex. Ray Peat wrote about the dangers of cholinergic toxicity (too much acetylcholine) ; Dr. Derrick Lonsdale wrote about the dangers of not enough cholinergic activity (too little acetylcholine). I think they both are both right.

Thanks for sharing your experience, do you have any idea how you've been poisened? Is it through direct consumption of food grown with pesticides?

At the same time, for B1, I've read studies that show that it actually reduces acetylcholine in high doses and increases it in low doses. : https://journals.sagepub.com/doi/abs/10.3181/00379727-58-14882

As you said the cholinergic system is complex, I've exeperienced both high and low acetylcholine, and being right in the middle is pretty tricky because it involves all the other neurotransmetters, I don't know if you know the braver man test, but I've found a tendency to high Dopamine/Acetylcholine, but a very very low GABA, I don't know how they are related, but lowering Acetylcholine just slightly improved most of the symptoms. I'm waiting for the week end to take a high dose of B1 to see if indeed I'll feel a reduce in acetylcholine with high doses.

Edit: I've just found something interesting "Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate exposure in neuro 2A cells" Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate exposure in neuro 2A cells - PubMed

 

[PeterSN]

Which one did you take, Thiamax or Thiamega, and at which dosage?


Thanks for sharing your experience, do you have any idea how you've been poisened? Is it through direct consumption of food grown with pesticides?

At the same time, for B1, I've read studies that show that it actually reduces acetylcholine in high doses and increases it in low doses. : https://journals.sagepub.com/doi/abs/10.3181/00379727-58-14882

As you said the cholinergic system is complex, I've exeperienced both high and low acetylcholine, and being right in the middle is pretty tricky because it involves all the other neurotransmetters, I don't know if you know the braver man test, but I've found a tendency to high Dopamine/Acetylcholine, but a very very low GABA, I don't know how they are related, but lowering Acetylcholine just slightly improved most of the symptoms. I'm waiting for the week end to take a high dose of B1 to see if indeed I'll feel a reduce in acetylcholine with high doses.

I took thiamax, and the dosage was 1 pill everyday, until the supplement ran out, and I did this with two thiamax bottles

 

[Ahmed ELH]

I took thiamax, and the dosage was 1 pill everyday, until the supplement ran out, and I did this with two thiamax bottles

On it's own or with the other B Vitamins and Magnesium?

 

[mostlylurking]

Thanks for sharing your experience, do you have any idea how you've been poisened? Is it through direct consumption of food grown with pesticides?

I was poisoned by organophosphate fire ant poison that one of my employees poured out all along the exterior edge of the building (just outside my office along the two exterior walls). It was a metal building; there was a drafty opening along the foundation of the the building because of the way it was built.

There were 8-10 other people who worked in the same vicinity. Nobody else got sick. I was vulnerable to it because I had mercury toxicity (from childhood amalgam fillings) which had caused a thiamine deficiency (not known to me at the time) so I was already at my maximum toxin tolerance at the time of the organophosphate exposure.

At the same time, for B1, I've read studies that show that it actually reduces acetylcholine in high doses and increases it in low doses. : https://journals.sagepub.com/doi/abs/10.3181/00379727-58-14882

Thanks for the link; I'll read it. Yes, I believe that's right. Like I said, it's a complicated topic.

As you said the cholinergic system is complex, I've exeperienced both high and low acetylcholine, and being right in the middle is pretty tricky because it involves all the other neurotransmetters, I don't know if you know the braver man test, but I've found a tendency to high Dopamine/Acetylcholine, but a very very low GABA, I don't know how they are related, but lowering Acetylcholine just slightly improved most of the symptoms. I'm waiting for the week end to take a high dose of B1 to see if indeed I'll feel a reduce in acetylcholine with high doses.

I am not familiar with the braver man test, sorry. Have you tried different types of thiamine? TTFD might be a better fit? (Sorry if this info has already been provided in this thread, if it has I missed it.) I couldn't tolerate TTFD myself because my glutathione was deficient from my mercury poisoning. There's also a sublingual type of thiamine that you might consider. The pill is easy to break into 2 or 4 pieces for experimentation. It has become popular in the Parkinson's Disease group. It bypasses the intestine completely so absorption problems are not an issue and a much lower dose is needed. It does work, I tried it, but I went back to high dosing thiamine hcl because I know what dose of that type works for me.

When I started taking higher doses of thiamine hcl, I didn't have a doctor to help me. I spent 4 months slowly increasing the dose. Then I found Dr. Costantini's website and decided to follow his protocol which said my optimum dose, based on my weight, should be 1 gram, 2Xday. I tried that dose and experienced massive improvement in my digestive tract after 2 days. I've stuck with that dose of thiamine hcl, taken orally, for almost 3 years and am doing well on it.

Edit: I've just found something interesting "Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate exposure in neuro 2A cells" Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate exposure in neuro 2A cells - PubMed

Thanks for this.

I looked in my notes about thiamine and acetylcholine from several years ago. I'll paste part of my notes below:
-paste-
In this article, New Page Title Here , Ray Peat explains about acetylcholine and its effect on learned helplessness.

"...chemicals that mimic the effects of acetylcholine, such as the organophosphate insecticides, can impair the ability to think and learn. This suggested to some people that age-related dementia was the result of the deterioration of the cholinergic nerves in the brain."

"The increase of cholinesterase, the enzyme that destroys acetylcholine, during enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by increasing the activity of the cholinergic system, we should expect that a cholinergic drug might substitute for inescapable stress, as a cause of learned helplessness, and that an anticholinergic drug could cure learned helplessness."

I found an interesting study here: Acetyl-CoA and acetylcholine metabolism in nerve terminal compartment of thiamine deficient rat brain - PubMed that seems to shine a light on what is happening in the brain regarding acetylcholine:

Acetyl-CoA and acetylcholine metabolism in nerve terminal compartment of thiamine deficient rat brain

Abstract​

"The decrease of pyruvate and ketoglutarate dehydrogenase complex activities is the main cause of energy and acetyl-CoA deficits in thiamine deficiency-evoked cholinergic encephalopathies. However, disturbances in pathways of acetyl-CoA metabolism leading to appearance of cholinergic deficits remain unknown. Therefore, the aim of this work was to investigate alterations in concentration and distribution of acetyl-CoA and in acetylcholine metabolism in brain nerve terminals, caused by thiamine deficits. They were induced by the pyrithiamine, a potent inhibitor of thiamine pyrophosphokinase. The thiamine deficit reduced metabolic fluxes through pyruvate and ketoglutarate dehydrogenase steps, yielding deficits of acetyl-CoA in mitochondrial and cytoplasmic compartments of K-depolarized nerve terminals. It also inhibited indirect transport of acetyl-CoA though ATP-citrate lyase pathway being without effect on its direct Ca-dependent transport to synaptoplasm. Resulting suppression of synaptoplasmic acetyl-CoA correlated with inhibition of quantal acetylcholine release (r = 0.91, p = 0.012). On the other hand, thiamine deficiency activated non-quantal acetylcholine release that was independent of shifts in intraterminal distribution of acetyl-CoA. Choline acetyltransferase activity was not changed by these conditions. These data indicate that divergent alterations in the release of non-quantal and quantal acetylcholine pools from thiamine deficient nerve terminals could be caused by the inhibition of acetyl-CoA and citrate synthesis in their mitochondria. They in turn, caused inhibition of acetyl-CoA transport to the synaptoplasmic compartment through ATP-citrate lyase pathway yielding deficits of cholinergic functions."

My interpretation/extrapolation: Thiamine deficiency causes deficits of acetyl-CoA which results in unopposed acetylcholine which according to Ray Peat is implicated in learned helplessness.
-end paste-

 

[mostlylurking]

At the same time, for B1, I've read studies that show that it actually reduces acetylcholine in high doses and increases it in low doses. : https://journals.sagepub.com/doi/abs/10.3181/00379727-58-14882

https://journals.sagepub.com/doi/abs/10.3181/00379727-58-14882
-paste-

Summary​

1. The effect of vitamins on the synthesis of acetylcholine was investigated. 2. Vitamin A and K decreased the synthesis of acetylcholine in low and increasing concentrations. Vitamin D did not modify the synthesis in low concentrations and decreased it in higher ones. Vitamin B1 slightly increased the synthesis of acetylcholine in low concentrations and decreased it in higher ones. 3. Riboflavin, nicotinic acid, nicotinamide, calcium pantothenate, p-amino benzoic acid, pyridoxine, and vitamin C did not modify the synthesis in low concentrations and increased it in higher ones. 4. Vitamin E increased the synthesis in low and increasing concentrations.
-end paste-

I want to add that I do take 10,000iu of vitamin D daily; I also take some vitamin K (not high dose). Perhaps the D is affecting my acetylcholine too? I don't know. I feel pretty good on a consistent basis.

 

[pubh12]

The anticholinergics I used worked properly but they didn't last for so long in term of effect as they only antagonise the receptors. Forskolin enhance the breakdown of acetylcholine, which I think was the main problem for me since I used a lot of AChE inhibitors and cholinergic compounds in the past.

Interesting, I may need to try it. I’m also going to try PQQ as it’s needed for the breakdown of choline to betaine.

 

[PeterSN]

On it's own or with the other B Vitamins and Magnesium?

I think there was magnesium stearate in there if I'm not mistaken, I also took ancestral supplements thyroid supplement, but I took a really low dose, around half a pill every other day

 

[Ahmed ELH]

@mostlylurking Thanks for sharing your experience, I really appreciate the quality of your answers as well as your will to find solutions.

I've actually tried all the available forms of B1 in the market, including TTFD and the sublingual form, what's fun is that TTFD has been shown to reduce mercury in the brain, but as you said, the burden on glutathione is not worth it for people with low glutathione status.

I'm wondering if the real problem here is a low AChE activity that can't handle the sudden increase of Acetylcholine resulting from the increase of acetyl CoA after B1 intake, leading to a continuous stimulation of the postsynaptic cell. In this case increasing cAMP should reduce the severity of the symptoms (coffee, forskolin and artichoke)

I'm waiting for the week end to take B1 and try this hypothesis, because I feel like my body needs B1 but can't handle the sudden increase of Acetylcholine when taking it.

 

[Ahmed ELH]

Interesting, I may need to try it. I’m also going to try PQQ as it’s needed for the breakdown of choline to betaine.

Is there any known benefits resulting from breaking down choline to betaine? I'd like to know honestly

I think there was magnesium stearate in there if I'm not mistaken, I also took ancestral supplements thyroid supplement, but I took a really low dose, around half a pill every other day

Magnesium stearate is used as a filler, Thiamax is free of filler, I'm talking about taking B Vitamins and Magnesium supplements which are highly recommended when taking TTFD.

 

[PeterSN]

Is there any known benefits resulting from breaking down choline to betaine? I'd like to know honestly

Magnesium stearate is used as a filler, Thiamax is free of filler, I'm talking about taking B Vitamins and Magnesium supplements which are highly recommended when taking TTFD.

yeah i didnt take any magnesium or other b vitamins, i did try b6 a few months ago, (5p5 form) and that seemed to make my symptoms, particulary the panic and shortness of the breath a lot worse.