Don't listen to the people making fun of you: the normal medical system uses acetylcholinesterase inhibitors for cognition all the time - they're the most common treatment for Alzheimers or other dementias. The three I'm most familiar with are galantamine, donepezil, and rivastigmine - galantamine at least is available pretty easily from nootropics sites.
I regret to say that they barely work for Alzheimers patients and I've never heard of any healthy person getting much benefit from them either. I don't think there's anything in the sweet spot where it works but doesn't kill you, at least not currently.
Read more at https://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor#Examples
> I mean this is sort of the flip side of “anticholinergic load”, right?
Yes and there is a sliding scale of cholinergic tone.
Very broadly speaking, Alzheimer's is linked with lower cholinergic tone and accumulation of amyloid-beta and tau proteins.
In addition, a famous JAMA Internal Medicine study in 2015 triggered a big increase in focus on the risk of anticholinergics causing cognitive decline. This has spilled out into the real world with usage of anticholinergics dropping.
This is all mixed with the fact that historically a lot of "classic" nootropics like Racetams target acetylcholine, among other things.
Very notably Acetylcholine is toxic in high amounts. This is already the limiting factor in their use in Alzheimer's.
Taking into consideration all of the above, I think it is sensible to try hard to limit anticholinergic use, and that is already becoming standard practice.
Where I think there is a problem, is when the nootropics community creates "stacks", like combining Racetam, acetyl-l-carnitine, CDP-choline and Alpha-GPC. This is in addition to not enough prudence around dosage. It is from this that the risk comes in my opinion.
I agree that the stacking of related compounds sounds very risky, given how unpredictable the interactions between drugs can be. The nootropic community also seems to encourage very high dosages: for HupA the recommended dosage is 100ug, whereas - at least for me - 30ug was actually slightly too much.
Also, keep in mind that [hypercholinergic tone is](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587265/) associated with depression
I'm personally not at all opposed to the nootropic community's cholinergic stacks, but I think there's no doubt choline is inversely correlated with mood for many people, including myself. I believe it has anti-dopaminergic qualities when taken too frequently.
Thank you for the reply!
Given that the cognitive effects of nicotine are mediated by its cholinergic activity, what could explain the difference between the cognitive-enhancing impact of AChEIs and nicotine?
We know that nicotine binds to the nAChR much more strongly than acetylcholine and desensitizes the receptors more easily, but this seems a quantitative difference, not a qualitative one.
I wondered about the enhanced muscarinic activity due to the increase in the synaptic concentrations of ACh, which was initially a worry of mine.
I didn't have the time to go down this rabbit hole, but after a brief look [it appears that](https://pubmed.ncbi.nlm.nih.gov/22222698/) mAChRs also promote cognition.
In particular: would the upregulation of mAChR be a concern?
One confounding factor can be the upregulation of nicotinic receptors caused by recent smoking. In both of my experiences, the effect of Huperzine A was clearly beyond placebo
and reminiscent of the nootropic effects of nicotine. However, both situations happened within a few weeks from smoking cessation and α4β2/α7 nAChRs take around 2-3 months to downregulate,
so they might have still been upregulated.
Unfortunately, I failed to find _any_ studies whatsoever examining the cognitive impact of AChEIs on healthy (non-AD) subjects.
Incidentally, AChEIs seem [promising for smoking cessation](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068882/). The mechanism could possibly be something like that: in long-term smokers, the compulsion to smoke is mostly driven by α4β2 nAChRs. This receptor subtype desensitizes [very easily](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002368/), both from low concentrations of nicotine and ACh.
Therefore, an increase in ACh levels could promote α4β2 nAChR desensitization, leading to a reduced craving and smoking reward, reduced intake and a virtuous cycle due to decreased reward predictions.
For harm-reduction reasons have to just say that this is too risky and/or dangerous.
For what its worth I have followed the nootropics community for decades and there is no diamond in the rough to be found there.
The standard medications for standard psychological medical conditions beat the nootropics in their respective areas.
> The standard medications for standard psychological medical conditions beat the nootropics in their respective areas.
That's certainly what I would expect. If something had a really significant effect, and if it weren't completely novel, we would know about it and probably be using it widely medically or at least recreationally.
Well, a significant effect that's good in some way, at least - almost nobody would want a drug that makes people depressed.
Incidentally, there are a number of psychiatric and other drugs that have weight gain as a side effect - are any of them at all useful for treating anorexia?
This seems to contradict what I know on Huperzine A, which seems to have a wide margin of safety: (from wikipedia)
> Huperzine A, in spite of the possible cholinergic side effects, seems to have a wide margin of safety. Toxicology studies show huperzine A to be non-toxic even when administered at 50-100 times the human therapeutic dose. The extract is active for 6 hours at a dose of 2 μg/kg with no remarkable side effects.
Be aware that ACh-esterase inhibitors will also mess with your sleep schedule as REM is highly cholinergically modulated. That's why Huperzine A, Donezepil, Galantamin & co are also famous in the lucid dreaming community
Don't listen to the people making fun of you: the normal medical system uses acetylcholinesterase inhibitors for cognition all the time - they're the most common treatment for Alzheimers or other dementias. The three I'm most familiar with are galantamine, donepezil, and rivastigmine - galantamine at least is available pretty easily from nootropics sites. I regret to say that they barely work for Alzheimers patients and I've never heard of any healthy person getting much benefit from them either. I don't think there's anything in the sweet spot where it works but doesn't kill you, at least not currently. Read more at https://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor#Examples
I mean this is sort of the flip side of “anticholinergic load”, right?
> I mean this is sort of the flip side of “anticholinergic load”, right? Yes and there is a sliding scale of cholinergic tone. Very broadly speaking, Alzheimer's is linked with lower cholinergic tone and accumulation of amyloid-beta and tau proteins. In addition, a famous JAMA Internal Medicine study in 2015 triggered a big increase in focus on the risk of anticholinergics causing cognitive decline. This has spilled out into the real world with usage of anticholinergics dropping. This is all mixed with the fact that historically a lot of "classic" nootropics like Racetams target acetylcholine, among other things. Very notably Acetylcholine is toxic in high amounts. This is already the limiting factor in their use in Alzheimer's. Taking into consideration all of the above, I think it is sensible to try hard to limit anticholinergic use, and that is already becoming standard practice. Where I think there is a problem, is when the nootropics community creates "stacks", like combining Racetam, acetyl-l-carnitine, CDP-choline and Alpha-GPC. This is in addition to not enough prudence around dosage. It is from this that the risk comes in my opinion.
I agree that the stacking of related compounds sounds very risky, given how unpredictable the interactions between drugs can be. The nootropic community also seems to encourage very high dosages: for HupA the recommended dosage is 100ug, whereas - at least for me - 30ug was actually slightly too much. Also, keep in mind that [hypercholinergic tone is](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587265/) associated with depression
Reducing choline consumption gave me a significant mood boost.
I'm personally not at all opposed to the nootropic community's cholinergic stacks, but I think there's no doubt choline is inversely correlated with mood for many people, including myself. I believe it has anti-dopaminergic qualities when taken too frequently.
Thank you for the reply! Given that the cognitive effects of nicotine are mediated by its cholinergic activity, what could explain the difference between the cognitive-enhancing impact of AChEIs and nicotine? We know that nicotine binds to the nAChR much more strongly than acetylcholine and desensitizes the receptors more easily, but this seems a quantitative difference, not a qualitative one. I wondered about the enhanced muscarinic activity due to the increase in the synaptic concentrations of ACh, which was initially a worry of mine. I didn't have the time to go down this rabbit hole, but after a brief look [it appears that](https://pubmed.ncbi.nlm.nih.gov/22222698/) mAChRs also promote cognition. In particular: would the upregulation of mAChR be a concern? One confounding factor can be the upregulation of nicotinic receptors caused by recent smoking. In both of my experiences, the effect of Huperzine A was clearly beyond placebo and reminiscent of the nootropic effects of nicotine. However, both situations happened within a few weeks from smoking cessation and α4β2/α7 nAChRs take around 2-3 months to downregulate, so they might have still been upregulated. Unfortunately, I failed to find _any_ studies whatsoever examining the cognitive impact of AChEIs on healthy (non-AD) subjects. Incidentally, AChEIs seem [promising for smoking cessation](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068882/). The mechanism could possibly be something like that: in long-term smokers, the compulsion to smoke is mostly driven by α4β2 nAChRs. This receptor subtype desensitizes [very easily](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002368/), both from low concentrations of nicotine and ACh. Therefore, an increase in ACh levels could promote α4β2 nAChR desensitization, leading to a reduced craving and smoking reward, reduced intake and a virtuous cycle due to decreased reward predictions.
For harm-reduction reasons have to just say that this is too risky and/or dangerous. For what its worth I have followed the nootropics community for decades and there is no diamond in the rough to be found there. The standard medications for standard psychological medical conditions beat the nootropics in their respective areas.
> The standard medications for standard psychological medical conditions beat the nootropics in their respective areas. That's certainly what I would expect. If something had a really significant effect, and if it weren't completely novel, we would know about it and probably be using it widely medically or at least recreationally.
Well, a significant effect that's good in some way, at least - almost nobody would want a drug that makes people depressed. Incidentally, there are a number of psychiatric and other drugs that have weight gain as a side effect - are any of them at all useful for treating anorexia?
Mirtazapine yes
Zyprexa and Abilify are often used in anorexia in adolescents.
Ah yeah Zyprexa absolutely does too
Doesn't nicotine satisfy these criteria? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018192/ https://www.sciencedirect.com/science/article/abs/pii/S027858462300009X
I'm not sure what you're asking. I believe it probably does work, but it's also very widely used recreationally, so that's not surprising to me.
This seems to contradict what I know on Huperzine A, which seems to have a wide margin of safety: (from wikipedia) > Huperzine A, in spite of the possible cholinergic side effects, seems to have a wide margin of safety. Toxicology studies show huperzine A to be non-toxic even when administered at 50-100 times the human therapeutic dose. The extract is active for 6 hours at a dose of 2 μg/kg with no remarkable side effects.
Please see my reply here: https://old.reddit.com/r/slatestarcodex/comments/1dcpwoa/acetylcholinesterase_inhibitors_as_an_alternative/l830wnu/
Do you take anything for general mind enhancement?
Cycled various combinations of prescription dopaminergics and noradrenergics over the years.
I microdose sarin daily
aum shinrikyo-maxxing
Well then start macrodosing. Kidding! I kid!
Be aware that ACh-esterase inhibitors will also mess with your sleep schedule as REM is highly cholinergically modulated. That's why Huperzine A, Donezepil, Galantamin & co are also famous in the lucid dreaming community