22 replies to this topic

[creier]

I made the terrible discovery when reading stuff about myelin :

Organophosphates, a class of chemicals which are the active ingredients in commercial insecticides such as sheep dip, weed-killers, and flea treatment preparations for pets, etc., will also demyelinate nerves.

Organophosphates are strong AChE inhibitors yet they cause destruction of myelin?
I have been using huperzine A during several months, I am scared I have done any permanent damage to myself.
I made more research on the web and some studies seem to confirm demyelination :

Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures.
Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination.

So this is it, too much choline cause destruction of myelin?
Shouldn't we stop taking cholinergic drugs? I have taken lots of cholinergic drugs, huperzine A, phosphatidylserine, choline citrate, ETC...
I thought it was enhancing my brain but in fact it is destroying it.
Anyone with AChE inhibitor long term usewho has experienced demyelination?

[dear mrclock]

i was wondering the same thing but people keep recomending cholinergic supplements/drugs for enhanced mental acuity and so far there are no substitutes for those. what else can there be ? i guess it has to be really potent and be done over very long term regularly (maybe 1-2 years of regular high dose) to finally cause some serious mental problems ? i assume this is so because a lot of the people using them have reported safe results short term.

[creier]

I cannot post links here but I will quote, you can look on google for quotes.
I have found that demyelination by organophosphates is because "neuropathy target esterase" is irreversibly inhibited by the drugs :

The pathogenesis of OPIDN is presumed to be
due to phosphorylation and ageing of an enzyme in
axons called neurotoxic esterase or neuropathic target
esterase (NTE). Inhibition of NTE causes degeneration
of predominantly long axons, with loss of myelin and
macrophage accumulation in nerves leading to motor
axonal neuropathy.
4,

A possible treatment for this :

The use of thiamine and high dose methylprednisolone
has been shown to be beneficial in experimental animals.

Too much cholinergic stimulation can cause downregulation :

Type II paralysis or intermediate syndrome is a
distinct clinical entity having incidence of 8-49% and
it usually appears 24 to 96 hours after poisoning.
3
The pathogenesis is presumed to be dysfunction of
neuromuscular junction caused by downregulation of
presynaptic and postsynaptic Nicotinic receptors due
to release of excessive Ach and Ca2+ respectively.
3

[color=#000000][font=arial, helvetica, clean, sans-serif][size=3]Phosphatidylcholine treatment results in a down-regulation of muscarinic receptors in certain brain areas which appears to be related to an increase in phosphatidylcholine concentration.[/size][/font][/color]

That let me think that chronic cholinergic intake can be detrimental and can cause myelopathy long term or after withdrawal.

So I think cholinergics should be carefully taken and maybe stop using them some days to avoid syndrome.
I have found that caffeine upregulates muscarinic receptors, read the study :

Chronic Caffeine Alters the Density of Adenosine, Adrenergic, Cholinergic, GABA, and Serotonin Receptors and Calcium Channels in Mouse Brain
[color=#000000][font=Georgia, 'Times New Roman', serif][size=4]Densities of cortical muscarinic and nicotinic receptors are increased by 40–50%.[/size][/font][/color]

But strangely there is a study saying :

[b]	Inhibition of acetylcholinesterase by caffeine, anabasine, methyl pyrrolidine and their derivatives.[/b]

[color=#000000][font=arial, helvetica, clean, sans-serif][size=3]Most of the compounds had moderate inhibitory activity with I50 values in the range of 87-480 microM.[/size][/font][/color]

I don't understand?

i was wondering the same thing but people keep recomending cholinergic supplements/drugs for enhanced mental acuity and so far there are no substitutes for those. what else can there be ? i guess it has to be really potent and be done over very long term regularly (maybe 1-2 years of regular high dose) to finally cause some serious mental problems ? i assume this is so because a lot of the people using them have reported safe results short term.

I think 1 or 2 years is already too much.
Some receptors can downregulate very fastly others can take some weeks but not years.
About mental problems I hope there is no such thing, I have used huperzine A for months but I am not sure my brain is demyelinating or not. I hope it isn't.

Another warning

Interactions of Abeta(1-40) with glycerophosphocholine and intact erythrocyte membranes: fluorescence and circular dichroism studies.
Deposition of amyloid beta peptide in human brain in the form of senile plaques is a neuropathological hallmark of Alzheimer's disease (AD). Levels of a phospholipid breakdown product, glycerophosphocholine (GPC), also increase in AD brain. The effect of GPC on amyloid beta(1-40) peptide (Abeta) aggregation in PBS buffer was investigated by circular dichroism and fluoresence spectroscopy; interactions of Abeta and GPC with the intact erythrocyte membrane was examined by fluoresence spectroscopy. Fluorescamine labeled Abeta studies indicate GPC enhances Abeta aggregation. CD spectroscopy reveals that Abeta in the presence of GPC adopts 14% more beta-sheet structure than does Abeta alone. Fluorescamine anisotropy measurements show that GPC and Abeta interact in the phospholipid head-group region of the erythrocyte membrane. In summary, both soluble Abeta and GPC insert into the phospholipid head-group region of the membrane where they interact leading to beta-sheet formation in soluble Abeta which enhances Abeta aggregation.

Alpha GPC can increase amyloid buildup in brain!

Edited by creier, 08 January 2013 - 05:34 AM.

[nightlight]

I cannot post links here but I will quote,..

Probably because of < pre > tags in your quotations. Those are quite annoying to the readers anyway, wasting their time on horizontal scrolling within the ugly boxes with raw html tags made visible (preview the post before submitting).

Regarding the main topic, the dose makes poison. Even the plain, clean water, at the right dose, will deplete your electrolytes and damage your organs (including brain) or kill you. The cholinergic toxicity examples you cited all seem to fall into heavy overdose region compared to nootropic doses (such as 50 mcg of HupA/day).

[dear mrclock]

^ but long term use of cholinergics even at moderate to low dose will still cause brain problems either stopped suddenly or not. cholinergics are a stupid outdated class of drugs, and i call for a better take on nootropic category

Edited by dear mrclock, 08 January 2013 - 07:15 PM.

[renfr]

^ but long term use of cholinergics even at moderate to low dose will still cause brain problems either stopped suddenly or not. cholinergics are a stupid outdated class of drugs, and i call for a better take on nootropic category

What a huge load of BS.
Choline isn't even a "drug", it's a vitamin (vitamin Bp) and each and every day choline is needed as it is essential in our diet.
It's not even outdated, it's not a drug developed in order to make profit, it's something already exisiting in our bodies and needed for our proper function, would you say vitamin C is outdated too?
Phospholipids are vital for our bloodstream, liver health, cell health and brain health, just look at the damage caused by the use of statins (drugs that reduce LDL cholesterol), neuropathy, nerve damage, inhibition of myelin production, etc...
If you don't put choline in your diet you are way more likely to develop brain damage than someone who takes the recommended amount of choline.
Every cell of our body is made of a phospholipid membrane, if that isn't vital for you...
Also cholinergics can prevent or inhibit neurological disorders and bring a better balance in our brain by decreasing concentrations of dopamine, serotonin, norepinephrine, ...
This can help restoring proper neuroreceptor levels after extreme downregulation.

I have used soy lecithin (3,5g of phosphatidylcholine) a day for a bit more than one month, effects haven't decreased at all on the contrary. Then I withdrew cold turkey during one week and no severe side effects were experienced, therefore downregulation seems to be very long and doesn't seem to cause a major problem (from my withdrawal experience it seems to be fastly reversible).

Concerning what has exposed creier, we have to consider the fact that we are talking about demyelination caused by organophosphorus compounds which are POISONS.
Nothing in those abstracts says that demyelination is caused by excessive agonism (it could certainly be but there's no proof).
Besides the polyneuropathy seems to be delayed, probably this may be due to an extreme withdrawal after strong cholinergic transmission.
It could also be due to an extreme inhibitor of AChE which cause a massive AChE rebound which inhibits strongly cholinergic neurotransmission.
It's clear that you are going to have issues if you're going to take enormous amounts of cholinergics for a very long time and then withdraw cold turkey but that certainly won't happen for someone who takes a dose of choline within the UL intake.
Organophosphate poisoning is way too extreme to be compared with nootropic doses of cholinergics.

[dear mrclock]

"it could also be due to an extreme inhibitor of AChE which cause a massive AChE rebound which inhibits strongly cholinergic neurotransmission.
It's clear that you are going to have issues if you're going to take enormous amounts of cholinergics for a very long time and then withdraw cold turkey but that certainly won't happen for someone who takes a dose of choline within the UL intake."

yes of course i agree with this. not sure why you called what i said a huge BS since its the same shit ? but let me add this; all cholinergics prescribed for any mental disorder like Aizheimer are very high doses with prolonged use. for any nootropic effect, i would not think low to moderate dose will work on healthy individuals at all. not recomended.


now, on another note you missed the point here by arguing for choline being essential and a vitamin. same with phospholipids. they arent actual cholinergics, actual drugs and strong agonists in any way. they are just essential for MAINTAINCE OF ALREADY NORMAL AChE LEVELS. why the hell did you put them in here and start this argument is beyond me.

Edited by dear mrclock, 08 January 2013 - 11:49 PM.

[renfr]

"it could also be due to an extreme inhibitor of AChE which cause a massive AChE rebound which inhibits strongly cholinergic neurotransmission.
It's clear that you are going to have issues if you're going to take enormous amounts of cholinergics for a very long time and then withdraw cold turkey but that certainly won't happen for someone who takes a dose of choline within the UL intake."

yes of course i agree with this. not sure why you called what i said a huge BS since its the same shit ? but let me add this; all cholinergics prescribed for any mental disorder like Aizheimer are very high doses with prolonged use. for any nootropic effect, i would not think low to moderate dose will work on healthy individuals at all. not recomended.


now, on another note you missed the point here by arguing for choline being essential and a vitamin. same with phospholipids. they arent actual cholinergics, actual drugs and strong agonists in any way. they are just essential for MAINTAINCE OF ALREADY NORMAL AChE LEVELS. why the hell did you put them in here and start this argument is beyond me.

What I called BS is saying choline is outdated and that it causes brain problems. Yes it causes brain problems, if you take too much of it like anything else.
Cholinergics does have an effect on me and on several people who use it even at low doses and the doses used for Alzheimer's aren't really that high.
In fact those who supplement galantamine use the same dosage as an Alzheimer patient would. Piracetam is also a cholinergic and the dosage used in patients is far lower than the dosages some people use around here.
What's that again? Choline is not cholinergic? Yes it is, it increases ACh receptors neurotransmission so yes it's a cholinergic, phospholipids such as phosphatidylcholine also increase neurotransmission...
By the way, choline is not an AChEI, it is part of the neurotranmission itself so I don't see your point.
AChEIs might be dangerous long term but that doesn't mean other cholinergics are...
No offense but no wonder why you have the lowest rating on this forum.

[dear mrclock]

you have no idea who is the lowest rating on this forum, but well done being so sure in what you said.

"What's that again? Choline is not cholinergic? Yes it is, it increases ACh receptors neurotransmission so yes it's a cholinergic, phospholipids such as phosphatidylcholine also increase neurotransmission..." any good studies, proof on this or are you just gathering random reports from people ?

"By the way, choline is not an AChEI, it is part of the neurotranmission itself so I don't see your point." yes it is. in normal conditions you dont need it. it doesnt work on healthy individuals. same with phospholipids. they are useless for someone who is already within normal range hence why so many reports on this forum (open your eyes again and check) that do report zero results from taking choline and soy lecithin. i can find you a dozen problems, side effects with choline use. just recently the choline in eggs was associated with problems, not the cholesterol. but that should be separate topic regarding choline and its natural sourcing. this thread is more about potent drugs affecting the cholinergic system.

Edited by dear mrclock, 09 January 2013 - 05:37 AM.

[renfr]

you have no idea who is the lowest rating on this forum, but well done being so sure in what you said.

"What's that again? Choline is not cholinergic? Yes it is, it increases ACh receptors neurotransmission so yes it's a cholinergic, phospholipids such as phosphatidylcholine also increase neurotransmission..." any good studies, proof on this or are you just gathering random reports from people ?

"By the way, choline is not an AChEI, it is part of the neurotranmission itself so I don't see your point." yes it is. in normal conditions you dont need it. it doesnt work on healthy individuals. same with phospholipids. they are useless for someone who is already within normal range hence why so many reports on this forum (open your eyes again and check) that do report zero results from taking choline and soy lecithin. i can find you a dozen problems, side effects with choline use. just recently the choline in eggs was associated with problems, not the cholesterol. but that should be separate topic regarding choline and its natural sourcing. this thread is more about potent drugs affecting the cholinergic system.

No, those aren't only reports from people, it's studies. I'm not going to do the work for you, go on pubmed and make your own research, if you find contradictory information then expose it.

In normal conditions? What are normal conditions for you? Even cavemen had choline coming from their food, meat for example is a good source of choline and not only meat :
http://www.whfoods.c...=50#foodsources
Would you mind showing those reports? Some people are naturally deficient in choline, others are not. Food doesn't explain everything, genetics also do.
Some people get extremely depressed when they take choline, probably because they already have too much of it, others don't and that's my case.
Just recently? Show me where. Despite what you say, a lot of people on this forum still supplement cholinergics.
Funnily, one of the longest threads in this category is about cholinergics. (GPC choline, uridine, DHA)
More potent drugs? yeah sure, it's just about harmless deadly organophosphates... Poisons can't be compared with supplements, AChEIs can't be compared with other kind of cholinergics...

Also, I was interested by the term "secondary demyelination" used in the study :
"Secondary demyelination is defined as changes of the myelin secondary to neuronal or axonal degeneration associated with ischemia, infection or metabolic/toxic disease"
In other terms, secondary demyelination means that firstly neurons or axons are damaged then due to that myelin is damaged. This is extremely different from primary demyelination.
Organophosphate demyelination is in fact caused by destruction of neurons not by destruction of myelin and that changes it all.
Choline has not been shown to cause neuron necrosis therefore it cannot be accused of possibly causing secondary demyelination.
Also organophosphate necrosis can likely be due to respiratory failure.

Recent studies have shown that large toxic doses of
organophosphorus compounds cause early
convulsive seizures and subsequent encephalopathy,
leading to the necrotic death of brain neuronal cells,
whereas small doses produce delayed apoptotic
death.


Necrosis: in addition to breaking down the blood
brain barrier and producing early seizures, large
toxic doses of organophosphorus compounds result
in the activation of the glutamatergic system.


Accumulated ACh, resulting from acute inhibition
of AChE by organophosphorus compounds, leads
to the activation of glutamatergic neurones and the
release of the excitatory L-glutamate amino acid
neurotransmitter that is a major agonist of NMDA
receptors and a major excitatory neurotransmitter in
the central nervous system, as well as being a potent
excitotoxin.
http://www.aerotoxic...urotoxicity.pdf

See? Damage seems to be in fact caused by glutamate excitotoxicity resulting from extreme ACh agonism.
Daily supplementation of choline doesn't cause extreme agonism and is unlikely to cause glutamate excitotoxicity.
Organophosphates are extremely powerful cholinergics, choline is just a little guy among them.
Again as I said, it's just about taking enough of it but not too much of it.
Choline can also cause cholinergic syndrome and damage if extreme doses are taken (over 4g).
500mg of choline a day (recommended intake) is hardly going to kill you.
In fact even choline is added to baby food as it is necessary for a proper development of the brain.

I don't know who has the lowest rating on this website but you're the worst I've ever seen.
No wonder why when we see your deluded and totally lunatic minded posts, you should rather spread your "scepticism" on ATS or Godlikeproductions.

Edited by renfr, 09 January 2013 - 06:25 AM.

[dear mrclock]

i stand by what i said. i did what you suggested on ncbi and i didnt find anything positive associated with supplmentation with basic choline as choline bitartrate and/or soy lecithin or any phospholipids. all it says is "nutrients that are required for normal growth". there is a reason so many prescription only chlolinergics are produced out there since the vital nutrients for acetylcholine production are just too weak and/or you need too much for any significant results but with all the side effects.

and most importantly dont always try to personaly pick on people (saw it with few others too) by defining, in my case, if im the worst or not. try to keep personal insults aside from the discussions on this forum ? you strike me as someone really emotional. try to be focused on the topic at hand and not call me the worst, and/or the other silly rantings you give me.

Edited by dear mrclock, 10 January 2013 - 12:34 AM.

[renfr]

That's your own experience, it's not a scientifical study.
If you have studies then alright show them, if you don't then don't scaremonger people with unvalidated theories.
You could say nicotine is dangerous (it is) but choline there's no study claiming that.
It's not because it's Rx that it's necessary more powerful, choline recommended dose is 500mg-1000mg, overdose starts at 4000mg, I would rather call that quite powerful.

[dear mrclock]

no actually i did take high doses of choline and nothing. b vitamins seem to give a more potent punch in combinations. but when i find decent articles in more depth of choline i will post indeed. cheers

[renfr]

did you try vitamin B5 alone? pantothenic acid is needed for acetylcholine formation.

[dear mrclock]

isnt royal jelly a very rich source of it ? then i have. but maybe i need a huge dose ? cuz the capsules i had for a while didnt really do much. or maybe most royal jelly out there is crap :(

[LBGSHI]

Without wading into the thick of this topic, I will address the focal point by taking a look at one of your responses:

"By the way, choline is not an AChEI, it is part of the neurotranmission itself so I don't see your point." yes it is. in normal conditions you dont need it. it doesnt work on healthy individuals. same with phospholipids. they are useless for someone who is already within normal range hence why so many reports on this forum (open your eyes again and check) that do report zero results from taking choline and soy lecithin. i can find you a dozen problems, side effects with choline use. just recently the choline in eggs was associated with problems, not the cholesterol. but that should be separate topic regarding choline and its natural sourcing. this thread is more about potent drugs affecting the cholinergic system.

Here you have quoted renfr, when he stated that choline is not an acetylcholinesterase inhibitor. You then responded that choline is in fact an acetylcholinesterase inhibitor. This is not correct, and I think this is why you are confusing choline supplementation with acetylcholinesterase inhibitor supplementation.

As you likely know, choline is a precursor to acetylcholine, a critical neurotransmitter (specifically, choline acetyltransferase synthesizes acetylcholine from choline and acetyl coenzyme A).

Acetylcholinesterase is an enzyme which breaks down acetylcholine in the brain (specifically, to choline and acetate). This is necessary to regulate the amount of acetylcholine in the brain. Acetylcholinesterase inhibitors block this action from occurring, thus increasing the total amount of acetylcholine present in the brain, as more acetylcholine is produced and released while existing acetylcholine is not broken down normally.

Choline itself is merely a precursor to acetylcholine, and does not in any way inhibit its breakdown via acetylcholinesterase. In summary, choline is not an acetylcholinesterase inhibitor.

In response to the remainder of this thread, I will concur with renfr. You're referring to deadly organophosphates, not nootropic levels of acetylcholinesterase inhibitors. Not only does this topic not pertain to choline supplementation (as explained above), but it also doesn't pertain to relatively small doses of inhibitors such as huperzine A, which are relevant to the nootropic community. Certainly, Parathion (as discussed in another thread...unfortunately initiated by a troll, as it turned out) and similar permanent/semi-permanent acetylcholinesterase inhibitors are very harmful and should be avoided, but comparing acetylcholinesterase inhibitors of the nootropic type to organophosphate poisons is like comparing sleeping pills to lethal injection.

That being said, this is a community of scientific inquiry. Please refer to studies pertaining to nootropic acetylcholinesterase inhibitors at reasonable dose causing myelin degradation, and we will discuss seriously the possibility that supplements such as huperzine A should be avoided or kept to a very low dose...but this discussion will not include choline supplementation, as choline is not an acetylcholinesterase inhibitor.

[dear mrclock]

LBGSHI, so is it a good idea to take whatever it is required for precursor of acetylcholine (in high enough doses for a result) and then while you do this, you add acetylcholinesterase inhibitors like huperzine a ?? in theory, this is going to be a power trip.

[renfr]

I don't suggest huperzine A at all, it is more an insecticide than a nootropic, why do you think the doses are only at the mcg level?
http://www.ncbi.nlm....ubmed/11804518/
I think royal jelly has 5mg of B5 however my B5 supplement has 70mg and usually you can use high doses of it.

[Bwints]

One day I will understand and grasp all of what is being discussed here. Reading this good spirited debate full of mind boggling chemistry was worth the time spent.
In the mean time: Believe nothing, no matter where you read it or who has said it, not even if I have said it, unless it agrees with your own reason and your own common sense.

[jillin]

I am just going to point this out, AChE-I's like Huperzine-A or Donepezil are completely different from AChE-I's like organophosphates. To say organophosphates are "strong" AChE-I's is erroneous, organophosphates are irreversible non-competitive and highly selective inhibitors, whereas Donepezil and the likes are only reversible non-competitive inhibitors. Now, one can label AChE-I's like Donepezil as "strong" as it is a selective inhibitor, yet still reversible; however organophosphates are in a different class altogehter. The enzyme kinematics/kinetics between a reversible and irreversible inhibitor is really light and day. Why Huperzine-A and Donepezil are administered at low dosages and not recommended for chronic recreational use is because while they are reversible inhibitors -- at high dosages or prolonged use leading to ACh build up, one can achieve the same detrimental effects seen with organophosphates.

There is an example of this topic in my book but I am too tired to be asked to scan it for citation purposes. However, a quick google search gave me a pretty good replacement: http://www.pharmpk.c.../PK2006164.html

Edited by jillin, 11 January 2013 - 05:44 AM.

[LBGSHI]

LBGSHI, so is it a good idea to take whatever it is required for precursor of acetylcholine (in high enough doses for a result) and then while you do this, you add acetylcholinesterase inhibitors like huperzine a ?? in theory, this is going to be a power trip.

No. I don't recommend acetylcholinesterase inhibitors, much less taking them alongside choline supplements (that seems like a bit of overkill). However, it would be incorrect to represent them as analogous to organophosphates. Nootropic acetylcholinesterase inhibitors have their place, are probably useful for rare cases in which a person's acetylcholinesterase levels are too high, and are, after all, just one of two ways of tackling the "not enough acetylcholine" problem. Personally, I think choline supplementation (via alpha-GPC, preferably) is quite sufficient for this purpose.

Edited by LBGSHI, 11 January 2013 - 05:05 PM.

[dear mrclock]

LBGSHI, so is it a good idea to take whatever it is required for precursor of acetylcholine (in high enough doses for a result) and then while you do this, you add acetylcholinesterase inhibitors like huperzine a ?? in theory, this is going to be a power trip.

No. I don't recommend acetylcholinesterase inhibitors, much less taking them alongside choline supplements (that seems like a bit of overkill). However, it would be incorrect to represent them as analogous to organophosphates. Nootropic acetylcholinesterase inhibitors have their place, are probably useful for rare cases in which a person's acetylcholinesterase levels are too high, and are, after all, just one of two ways of tackling the "not enough acetylcholine" problem. Personally, I think choline supplementation (via alpha-GPC, preferably) is quite sufficient for this purpose.

why not ? i find the idea alluring. you build naturally your acetylcholine with supplements and then you inhibit its deterioration with other supplements. why is it not a good idea ?

[dear mrclock]

hmm found out that thc from cannabis is a potent acetylcholinesterase inhibitor. never knew this before but it explains some of its psychoactive activity i used to experience where i become really concentrated on various tasks. wonder if you take pure thc as pill, it will be good nootropic without the side effects and other crap cannabis has in smokable form.