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The search for a safe Alpha7 Nicotnic Receptor Agonist?


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#1 dubcomesaveme

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Posted 02 August 2010 - 02:57 AM


 Alpha 7 nicotinic receptor agonists appear to be a very promising target for cognitive enhancement.

Someone sent me a link to an article within the past few days: http://articles.balt...-cognition-acid

"University of Maryland discovery may lead to 'smart pill'". It is not very well written so here is a a related research paper that is much  mroe substantive: http://www.ncbi.nlm....pubmed/20336058

"Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior."  Basically by reducing kynurenic acid production( which antagonizes alpha 7 nicotinic receptor) they increase alpha 7 nicotinic receptor activity. Alpha 7 nicotinic receptors have also been under research for quite some time as treatment for schizophrenia, parkinson's, and cognitive enhancement.

I know galantamine is popular here and has nicotinic effects, but according to this paper it effects alpha 7 nicotinic in only a very narrow concentration range: http://www.ncbi.nlm....pubmed/15834443 . I know Aniracetam which is also popular here and has nicotinic effects, but according to this paper aniracetam\nefiracetam only potently effects alpha4\beta2 and actually mildly antagonizes alpha 7: http://www.ncbi.nlm....pubmed/11259610

I think alpha7 nicotinic could be one of the best possible targets for a nootropic. The wikipedia article lists a few in development: http://en.wikipedia....otinic_receptor . I am considering investigating the chemicals listed and seeing if any has an exceptionally safe pharmacologically safe profile, and possibly doing a guinea pigging a low dose log if so. If anyone has more knowledge in this area or is interested in continuing this investigation please feel free to share!  

Edited by dubcomesaveme, 02 August 2010 - 02:59 AM.

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#2 chrono

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Posted 02 August 2010 - 06:41 AM

Good thinking! This is definitely a promising target. The list of agonists on the Wiki isn't very encouraging, though...as a rule, drugs which can only be identified by a string of alphanumerics probably don't have enough human testing to be considered 'safe,' and are probably very hard to obtain without custom synthesis. A-582941 sounds interesting. But galantamine isn't listed, so it's only a partial list.

I don't think galantamine is very popular here. I can only think of one or two people I've seen talking about it this year, and AFAIK they stopped taking it. It was a bigger topic 4-5 years ago when LifeMirage was all about it. It might be worth trying to figure out what dosage/schedule would land us in the right concentration for nAChR agonism.

Another thought is to try reducing KYNA directly, or somewhere upstream. See this thread: Reduction of kynurenic acid shows promise for improving learning.
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#3 bacopa

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Posted 02 August 2010 - 07:25 AM

Good thinking! This is definitely a promising target. The list of agonists on the Wiki isn't very encouraging, though...as a rule, drugs which can only be identified by a string of alphanumerics probably don't have enough human testing to be considered 'safe,' and are probably very hard to obtain without custom synthesis. A-582941 sounds interesting. But galantamine isn't listed, so it's only a partial list.

I don't think galantamine is very popular here. I can only think of one or two people I've seen talking about it this year, and AFAIK they stopped taking it. It was a bigger topic 4-5 years ago when LifeMirage was all about it. It might be worth trying to figure out what dosage/schedule would land us in the right concentration for nAChR agonism.

Another thought is to try reducing KYNA directly, or somewhere upstream. See this thread: Reduction of kynurenic acid shows promise for improving learning.

I've read about these new nicotinic agonists and since the cat is out of the bag and I do have schizoaffective I could surely use one or more of these promising cognitive modulates. I tried galantamine although for only a short period. My cognition turns to shit whenever I have to abstract think, problems solve, which includes the former, and rote memorization which I'm terrible at. Please keep me posted on potent nicotinic receptor modulates.

"Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior." yes I've read about this too. Perhaps what's most sad is that my subjective conscious waking/thinking experience that used to feel so full and alive, like I was attached to all my cognitive senses is now flat and it feels like I'm a "copy of a copy of a copy." This is extremely frustrating as I don't feel at all human, more like the life force of my brain has been sucked out. I know this is a hard and nebulous image to imagine, but I can assure you it's terrible, and I have heard of NMDA receptor modultates in the pipline along with glutumate ones.

I also read that article on reduction of kynurenic acid in mice models and it sounds promising. Lets hope this isn't another example of promising research never reaching clinical lab trials, as in the famous Sharon Begeley, "Valley of Death" article. I WANT so bad for these promising in vitro and animal studies to translate to human clinical trials. :mad:

Edited by dfowler, 02 August 2010 - 07:31 AM.


#4 NR2(x)

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Posted 02 August 2010 - 09:57 AM

I got that impression that some of the alpha 7 nicotine agonist where in fact allosteric modulators of a more common protien. I was thinking adaptins, that memantine, amphetamine, ibogaine bind to. Might be wrong.
Promising target, i heard that there is a contraindication between these alpha 7 N and sigma-1 agonist, due to an emergant toxiticity.


I WANT so bad for these promising in vitro and animal studies to translate to human clinical trials.

You need to conduct your own trails if you want the good stuff. This is because we have capitistic health care in a rather totalarian world. (without making it a subject, Fluorine halves the number of bright children) Why would you expect that you would be handed cognitive enhancers?
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#5 Galantamine

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Posted 02 August 2010 - 03:55 PM

Obviously, nicotine, and endogenous acetylcholine, are substrates for the receptor.

I'm also a fan of galantamine, but it needs to be titrated up to avoid GI problems. (from 4mg to 8mg +)

Galantamine + aniracetam is a potent stack, although aniracetam has bioavailability problems (oral admin: ~11% absorbed), and so needs to be ran high and dosed frequently (~2-3 hr half-life).

Since piracetam binds to a different subunit on the glutamate receptor, combining piracetam with galantamine and aniracetam should make an even better stack.

#6 aLurker

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Posted 29 August 2010 - 03:08 PM

Since I found this thread very interesting I'll practise some necromancy and raise it from the grave.

An article mentions another nicotinic acetylcholine receptor agonist called ABT-418 which binds with high affinity to alpha-7 among others. This wiki article about nicotinic agonists lists even more drugs.

In the meantime though: let's start to speculate in what dosage range Galantamine might be the most efficient when it comes to modulating nicotinic receptors! I like this post about this research.

If you read it it says that galanatamine enhances dopaminergic activity through allosteric potentiation of nicotinic acetylcholine receptors and this is the most interesting part:

Galantamine's effect on prefrontal dopamine efflux was significant at 0.1 mg/kg but not 1.0 mg/kg, an observation that parallels our electrophysiological data showing that 0.1 mg/kg of galantamine increased both firing rate and burst firing of dopaminergic neurons. Thus, it appears that galantamine enhances dopaminergic activity most effectively at a dose that results only in minor AChE inhibition (Geerts et al, 2005), and the effect may therefore rather be due to allosteric potentiation of nAChRs.


So the most effective range for these effects might be quite narrow. This study used rats and injected the galantamine subcutaneously, hard to tell what that says about oral doses for humans. Anyone who knows of any others studies that might give us ANY clue as to what the optimal dosage range is for these effects?

It might be a good idea to start at a low dose of galantamine and increase the dose slowly and document the subjective effects. I don't know how acute the effects of galantamine are though so there are a couple of problems with this approach. First: the obvious problem of subjectivity although perhaps a battery of tests could help there. Second: if the effects are gradual rather than acute it might take a long time to investigate the dosage range. Also, a higher dose could seem better if one responds better to higher levels of AChE inhibition rather than the nicotinic and dopaminergic aspects.

Any opinions on galantamine?

Edited by aLurker, 29 August 2010 - 03:51 PM.


#7 yowza

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Posted 29 August 2010 - 10:34 PM

Since I found this thread very interesting I'll practise some necromancy and raise it from the grave.

An article mentions another nicotinic acetylcholine receptor agonist called ABT-418 which binds with high affinity to alpha-7 among others. This wiki article about nicotinic agonists lists even more drugs.



I really looked into nicotinic agonists a couple of years ago. If interested you can check out www.targacept.com. They list a number partial nicotinic agonists that are currently in the pipeline (most of these drugs are outsourced to a larger pharmaceutical company called Astrazeneca that's been doing more expensive tests on targacepts compounds). "Chantix" (a drug maybe developed by targecept and outsourced to shire pharmaceutical?) was the first nicotinic partial receptor agonist released on the market. The problem is it's useless for cognition enhancement (just makes you get sick when stimulating nicotine receptors through cigarette smoking).

Besides targacept, Abbott pharmaceutical seems to be the other major company trying to develop these compounds (what the ABT stands for in the acronym). ABT-418 was unfortunately cancelled it appears. I did find a few biochemical research suppliers that make this but would have to dig up the information. Anyway, it appears that now the compound Abbott is trying to develop for ADD (among other conditions) is ABT-089 (although this is for a different section of the nicotine receptor than alpha 7 I'm pretty sure). Supposedly it was set to undergo phase 3 clinical trials. Not sure what's going on with it now.

Update: Abbott has 2 lead partial nicotine agonists at the moment:
ABT-894 (developed through Abbott/NeuroSearch)
ABT-089 also known as pozanicline (developed through Abbott)

Any opinions on galantamine?




I've always wanted to try galantamine. The only problem with it is that it stops the enzyme Acetylcholinesterase (not acetylcholine but the enzyme that breaks this neurotransmitter down from building up too much). While maybe taking it every once in a while for cognition enhancement may work, this could be a problem in terms of continuous usage.

Edited by yowza, 29 August 2010 - 10:50 PM.


#8 aLurker

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Posted 29 August 2010 - 11:01 PM

I've always wanted to try galantamine. The only problem with it is that it stops the enzyme Acetylcholinesterase (not acetylcholine but the enzyme that breaks this neurotransmitter down from building up too much). While maybe taking it every once in a while for cognition enhancement may work, this could be a problem in terms of continuous usage.


As said previously, galantamine enhances dopaminergic activity most effectively at a dose that results only in minor AChE inhibition, so perhaps some desirable effects could be obtained at quite low doses compared to what has been used in clinical trials.

Why is the AChE inhibition such a problem btw, what are the hypothetical dangers of long-term use here? Furthermore wouldn't something like Piracetam in conjunction help decrease the acetylcholine levels and thus acting in synergy? There are probably problems here I don't know about and I'd love for someone to point some of them out to me.

#9 yowza

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Posted 30 August 2010 - 12:06 AM

As said previously, galantamine enhances dopaminergic activity most effectively at a dose that results only in minor AChE inhibition, so perhaps some desirable effects could be obtained at quite low doses compared to what has been used in clinical trials.


I'm just going by memory as it's been a while since I looked into this.

It's not so much the nicotine receptor stimulation (that leads to the dopaminergic enhancement) but a seperate effect (the AChE enzyme inhibition) I'm talking about.

Perhaps at lower dosages, a regimen would be more easier to control (as I beleive there's somewhere around an 8 hr half life unlike the 70 hr half life of aricept) that would make low dosaging easier. However, enzyme levels still need to rebound back to normal once the drug begins to wear off, which could make taking Galantamine on a daily basis hard to do without the amount of acetylcholine in the brain skyrocketing due to being without the brain's homeostatic control mechanism (the acetylcholinesterase) to keep it in check.

On a seperate note: I'm not saying taking supplements that increase acetylcholine is bad. Just that there are different ways to increase acetylcholine. The most direct way to do this would be to decrease the amount of acetylcholinesterase (the enzyme that keeps this in check) but this could be risky. If you feel sickly/weak then you may know you have too much acetylcholine in your system without the bodies natural way to control it. I can dig up some more info. on this subject if your interested, I'm just going by general memory here.


Why is the AChE inhibition such a problem btw, what are the hypothetical dangers of long-term use here? Furthermore wouldn't something like Piracetam in conjunction help decrease the acetylcholine levels and thus acting in synergy? There are probably problems here I don't know about and I'd love for someone to point some of them out to me.


Acetylcholine could act as a sort of excitatory toxin if too high in the brain.

Galantamine is sold both as a supplement and as a pharmaceutical (like Reminyl). Piracetam could be taken with the supplement form of galantamine perhaps...















One of the less talked about roles I think partial nachr agonists could play in pharmacology:

I believe that these compounds would fill a gap in pharmacology. People with temporal lobe issues may benefit from this (although they'd probably have to take a drug like this with an anticonvulsant in combination to avoid burning out).

A temporal lobe disruption may effect visual and auditory pathways; able to hear and see but not able to integrate this fluidly into cognitive systems feeling abit of detachment even though responsive to visual and auditory cues. People with these sort of issues often are undiagnosed and taking stimulants like dexedrine just leads them to internalize more rather than feel more integrated and fully aware. From this perspective, our perceptual systems--->attention--->memory--->thinking.

Partial Nicotine Agonists could play a promising role in a niche market if they'd ever come out. Not everybody responds best to classical stimulant drugs.

Anybody agree with me?

Edited by yowza, 30 August 2010 - 12:47 AM.


#10 yowza

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Posted 30 August 2010 - 01:50 AM

Sorry to doublepost but I'd just like to back up my final comment abit (feel free to comment on my previous comment and ignore this one if you choose but this is just way to interesting not to post hopefully some of you will have more insight into this):

One of the less talked about roles I think partial nachr agonists could play in pharmacology:
I believe that these compounds would fill a gap in pharmacology. People with temporal lobe issues may benefit from this (although they'd probably have to take a drug like this with an anticonvulsant in combination to avoid burning out).

A temporal lobe disruption may effect visual and auditory pathways; able to hear and see but not able to integrate this fluidly into cognitive systems feeling abit of detachment even though responsive to visual and auditory cues. People with these sort of issues often are undiagnosed and taking stimulants like dexedrine just leads them to internalize more rather than feel more integrated and fully aware. From this perspective, our perceptual systems--->attention--->memory--->thinking.

Partial Nicotine Agonists could play a promising role in a niche market if they'd ever come out. Not everybody responds best to classical stimulant drugs.

Anybody agree with me?


Following up on what I just said (these comments are just in general regards to the nicotine not to any specific area of the nicotine receptor; partial nicotine agonists could target different areas that could have different effects so please bear this in mind) :

I found an interesting map of how the eyes connect to the mind. This isn't so much a map of the visual pathway as a map of the sensory pathway the eyes are connected to.

On the picture below, note the paths stimulated by red colored light (stimulating effect) and blue colored light (calming effect) and corresponding areas of the brain responsive to this; some people feel more aware under certain kinds of lighting (or even lack of lighting).

What this picture is meant to get across is that our 1) perceptual systems stimulate and guide our 2) attention that's backed up by our 3) memory (for storage and retrieving what we attend to) that allows for 4) thinking clearly.



Attached File  Eye Connection with Brain.jpg   26.23KB   53 downloads


On a seperate note, there's an interesting study that I found in regards to nicotine's effect on the visual pathway (seen here http://www.cell.com/...%2802%2901004-8).

This abstract is from a study done at the "medical college of wisconsin" (milwaukee, wi):


  • Abstract:

  • Understanding nicotine's neurobiological and cognitive mechanisms may help explain both its addictive properties and potential therapeutic applications. As such, functional MRI was used to determine the neural substrates of nicotine's effects on a sustained attention (rapid visual information-processing) task. Performance was associated with activation in a fronto-parietal-thalamic network in both smokers and nonsmokers. Along with subtle behavioral deficits, mildly abstinent smokers showed less task-induced brain activation in the parietal cortex and caudate than did nonsmokers. Transdermal nicotine replacement improved task performance in smokers and increased task-induced brain activation in the parietal cortex, thalamus, and caudate, while nicotine induced a generalized increase in occipital cortex activity. These data suggest that nicotine improves attention in smokers by enhancing activation in areas traditionally associated with visual attention, arousal, and motor activation.


Interesting to see that some of the brain areas mentioned in the study correlate with the map picture I posted above.

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When finding info. on this sort of stuff I thought nicotine was the best nootropic out there.
The problem with nicotine (besides the harmful carcinogens/smoke) is it's effects (from cigarett's) don't really last. Tolerance builds extremely fast and the initial hit (the one you feel right after finishing a cigarette) isn't going to last very long. There's no drug out on the market that prolongs and intensifies this effect selectively. This is where the partial nicotine agonists may be helpful not only with cognition enhancement but also to help people quit smoking.

Edited by yowza, 30 August 2010 - 02:15 AM.

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#11 aLurker

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Posted 30 August 2010 - 01:30 PM

Partial Nicotine Agonists could play a promising role in a niche market if they'd ever come out. Not everybody responds best to classical stimulant drugs.

Agreed.

About nicotine
Interesting information there about nicotine yowza.
Well the good news is that the problems you mention aren't really that problematic if you use the right means of administration. Anything with tobacco is obviously awful to your general health and therefore by far the worst method. The metabolites of nicotine by itself has been shown to potentially be dangerous too so that rules out oral consumption. However, with an extended release nicotine patch one could get a slow and steady dose of yummy nicotine!

I looked at the possibility of using this but there seems to be two problems even with this.

First of all it is still very very addictive, which is a minor problem, at least until you decide to quit. The second problem is that nicotine is a vasoconstrictor. Some speculate this could lead to circulatory problems and clots. Whether or not this is a real world problem at low doses remains unknown to me but there doesn't seem to be any way around the fact that it is a vasoconstrictor :/
Here is a thread about it.

Even so, nicotine might be safer than galantamine, I don't know. Far more addicting though and I still get cravings for coffee even though I quit months ago.

More about galantamine
Here is a post by chrono I found informative.

Galantamine is selective for AChE (with an negligible affinity for BuChE). A 10mg dose only inhibits 36-55% of AChE, doesn't accumulate in the body even after months of treatment, and nearly all AChE inhibition disappears by 30h after the last dose [1] [2]. It sounds like it obviates some of the concerns about Hup A's over-inhibition in the thread I linked above.


The thread he refers to is about the dangers of AChEIs like Huperzine-A (and to a lesser degree therefore also galantamine).

I'd love to find a graph how galantamine's inhibitory effects on AChE are dependant upon dosage.

I found an interesting study done on rabbits (Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning) that includes goodies such as these in the discussion:

Among the many cognition-enhancing drugs we have tested in 4-month-old rabbits (BMY-21502, donepezil, GTS-21, nefiracetam, nimodipine), Gal is the only drug that has facilitated learning in young rabbits.


These findings are consistent with a report (32) that also demonstrated a similar effect of chronic Gal therapy on nicotinic receptor density. Although Barnes et al. (32) did not find a significant improvement in spatial memory in their aged rats, they did find a significant positive correlation between the durability of long-term potentiation and the B max of nicotinic receptors within the hippocampus that was induced by chronic Gal therapy. Taken together with the results of the current study, these data suggest that chronic Gal therapy can effectively and consistently increase the density of nicotinic receptors in selected brain regions that are involved in learning and memory. It is our conclusion that this increase in nicotinic receptor number, and the resultant changes in electrophysiological indicators of neural plasticity (32), may underlie aspects of the cognitive benefits produced by long-term therapy with Gal in humans with AD.


As the nicotinic effects of galantamine seem to be more prominent at low doses (according to the research in my previous posts), perhaps a chronic low dose of galantamine could have beneficial effects upon cognition while mostly avoiding the problems of AChE inhibition. The million dollar question here is HOW low since messing with AChEIs seems kind of questionable in the first place.

Edited by aLurker, 30 August 2010 - 01:34 PM.


#12 yowza

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Posted 31 August 2010 - 02:46 AM

Galantamine is selective for AChE (with an negligible affinity for BuChE). A 10mg dose only inhibits 36-55% of AChE, doesn't accumulate in the body even after months of treatment, and nearly all AChE inhibition disappears by 30h after the last dose [1] [2]. It sounds like it obviates some of the concerns about Hup A's over-inhibition in the thread I linked above.




I wonder whether Chrono was referring to the pharmaceutical or supplemental form of galantamine?

I remember seeing a chart somewhere that mentioned Reminyl (pharmaceutical form) as inhibiting the lowest relative percentage of ACHe compared to aricept and rivastigmine. Plus, galantamine doesn't share the same negatives as aricept (70 hr half life on top of everything which would be impossible to control dosaging levels without acetylcholine levels skyrocketing in the brain) and rivastigmine (rivastigmine also inhibits butylcholinesterase; a liver enzyme which automatically negates it as a cognition enhancer).

However, if you look at what Chrono posted closely, it can be seen that a 10 mg dose inhibits 35-55% of AChE for 1 day.
The half life of galantamine seems to be on average about 7 hours (although it could be slightly more depending on metabolism); so assuming that one were to take the first dosage at 8 a.m. on day 1, they'd most likely be almost up to about 4 half-lives the following day when taking dose 2 (therefore, there would only be a slight build-up of galantamine in the system for the first several weeks before reaching a steady state); 30-48 hours seems to be the time it would take for a single dosage to be totally absent from one's system it seems.

The half-lives however, don't factor in how long it would take AcHe levels to rebound to normal after taking it. Taking Galantamine every now and then may work but not on an everyday basis I'm thinking, it may begin to take a toll on the mind. Once you reach a steady state, I'm guessing one's Acetylcholinesterase levels would remain relatively low. This sort of information probably wouldn't be reflected in a graph citing how acetycholinesterase levels are dependent upon dosage as this would only suggest how one would be effected on average from the first dose as opposed to taking it on a day to day basis.




Among the many cognition-enhancing drugs we have tested in 4-month-old rabbits (BMY-21502, donepezil, GTS-21, nefiracetam, nimodipine), Gal is the only drug that has facilitated learning in young rabbits.


Interesting list... I wonder what seperates Galantamine from these other compounds...




As the nicotinic effects of galantamine seem to be more prominent at low doses (according to the research in my previous posts), perhaps a chronic low dose of galantamine could have beneficial effects upon cognition while mostly avoiding the problems of AChE inhibition. The million dollar question here is HOW low since messing with AChEIs seems kind of questionable in the first place.



This is a very good question. At 10 mg 36-55% is being inhibited. It would seem logical that 5 mg would be half of this % range; however, medications don't always work like this.

Besides this, there's also the other factor to consider; how long, on average, it takes the body to naturally replace acetylcholinesterase once it's been inhibited.

Without having good solid info. on these aspects, all any of us can do is take a guess at how low a healthy person could take this. I tried looking up the normal prescriptive dosages for galantamine (usually people with some sort of dementia) and 8-12 mg twice daily (24 mg is the max any person should take) seems to be the normal range; although some take two 4 mg amounts.

Considering this, a healthy person probably wouldn't want to take more than 2-4mg/day if they were going to take it every day as opposed to every once in a while. I'm not sure if it would be better to take this amount in a single dosage (could feel a bit of a crash later in the day maybe?) or a double dosage (can't really get into a steady state anyway at such a low dosage so it probably doesn't matter). Although I don't really think messing with AChE inhibitors is the best idea in the first place.



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Back to Nicotine:

Well the good news is that the problems you mention aren't really that problematic if you use the right means of administration. Anything with tobacco is obviously awful to your general health and therefore by far the worst method. The metabolites of nicotine by itself has been shown to potentially be dangerous too so that rules out oral consumption. However, with an extended release nicotine patch one could get a slow and steady dose of yummy nicotine!


From personally trying a cigarette vs. trying nicotine gum (as well as reading anecdotal reports of people who've tried the nicotine patch), I'd guess the problems I mentioned still hold.

The initial hit you feel right after smoking (although as mentioned, this effect doesn't last long and builds quick tolerance, which is the problem)
isn't felt while chewing nicotine gum. As a cognition enhancer nicotine gum just doesn't have that dramatic of an effect it seems; I'd venture a guess
that this is because the nicotine is entering the body via a more indirect route vs. smoking where the effect can go right to the brain instantly...

As you mention, the patch takes care of some issues in regards to at least having a steady stream/long lasting effect (which may or may not guard against quick tolerance) but still doesn't seem to be the answer even if one were to disregard the vasoconstriction and addictive quality. For the patch, (just going by anecdotal reports I've heard from people who've tried it), I'd guess the same issue holds true as with nicotine gum. The patch may require a prescription (unlike nicotine gum which is sold over the counter) but this is probably more due to the addictiveness of getting a steady stream supply throughtout the day and not so much because it would provide the same sort of cognition enhancement you may feel a few seconds after smoking a cigarette (at least this is my impression).


Partial nicotine agonists appear to be the answer to these problems. Not only are they formulated to last longer than a few seconds but are also offer a variety of options in terms of how to selectively stimulate only certain parts of the nicotine receptor; which means a possibly more intensely selective than the diluted one gained from plain nicotine. They're able toplay with the cognition enhancing properties of nicotine and exploit these effects towards different target markets (depending on the area of the nicotine receptor aimed at). The alpha 7 and a4b2 seem to be the most commonly aimed at areas for cognition enhancement from what I remember. Too bad none will ever be released on the market for the foreseeable future.









On a seperate note, glad you appreciated what I could find in regards to where I think Partial Nicotine Agonists could fit in the market. One of the main effects I noticed from smoking is that in a way, it seemed to make my surroundings more vibrant. It seems to effect the sensory system in a very unique way unlike traditional stimulants (regular stimulants directly effect "attention" as opposed to the sensory systems underlying one's ability to attend...) A person's sensory system can become disrupted a number of different ways due to TBI, prolonged periods of intense emotion or stress, seizures, ect. A stimulant used to enhance ones sensory system would go a long way towards laying the foundation towards a heightened form of cognition. It's a possibility that partial nicotine agonists could do this...

Edited by chrono, 07 September 2010 - 05:07 PM.
fixed a double-quote of aLurker's post

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#13 aLurker

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Posted 31 August 2010 - 07:32 AM

Thanks for your reply.

However, if you look at what Chrono posted closely, it can be seen that a 10 mg dose inhibits 35-55% of AChE for 1 day.

I disagree although I could very well be mistaken since I couldn't download the original study. Here is the abstract in case anyone missed it:

Stereoselectivity of cholinesterase inhibition by galanthamine and tolerance in humans.

The effect of galanthamine (GAL) and its 2 major metabolites on human cholinesterases has been explored. Epigalanthamine, a diastereomer of GAL, was 130-times less potent in vitro in its effect on acetylcholinesterase (AChE) in erythrocytes than the parent compound, and it did not differ significantly from the ketone galanthaminone. In vivo, the maximal 36-55% inhibition of AChE was approached 30 min after oral administration of 10 mg GAL. The duration of the catalytic inhibition corresponded to an elimination half-life of approximately 5-7 h. GAL was well tolerated in 8/8 healthy volunteers, and 3/4 Alzheimer patients tolerated the drug up to a daily dose of 40 mg.


Reading that it seems pretty clear to me that 36-55% is the maximal inhibition that was achieved after only 30 min and not something sustained during an entire day, contrary to your claim. Was it an honest mistake on your part or did I forget to factor something in here?

At 10 mg 36-55% is being inhibited. It would seem logical that 5 mg would be half of this % range; however, medications don't always work like this.

Half? Is that a figure based on inherent truthiness or some pharmacological rule of thumb I'm unaware of?

Besides this, there's also the other factor to consider; how long, on average, it takes the body to naturally replace acetylcholinesterase once it's been inhibited.

Yes. Any information here would be much obliged.

Though chrono said that at 10 mg nearly all AChE inhibition disappears by 30h after the last dose. He probably read the studies since this isn't mentioned in any of the abstracts he cites. That factoid is pretty significant though since it would mean that there is a good chance of the levels returning to normal within 24 hours if you take a single low dose daily. Altering the AChE back and forth on a daily basis might still be a very bad idea in the first place though and there is also the risk of up-regulating AChE in response to the inhibition.

Without having good solid info. on these aspects, all any of us can do is take a guess at how low a healthy person could take this. I tried looking up the normal prescriptive dosages for galantamine (usually people with some sort of dementia) and 8-12 mg twice daily (24 mg is the max any person should take) seems to be the normal range; although some take two 4 mg amounts.

Considering this, a healthy person probably wouldn't want to take more than 2-4mg/day if they were going to take it every day as opposed to every once in a while. I'm not sure if it would be better to take this amount in a single dosage (could feel a bit of a crash later in the day maybe?) or a double dosage (can't really get into a steady state anyway at such a low dosage so it probably doesn't matter). Although I don't really think messing with AChE inhibitors is the best idea in the first place.

What made you say 2-4 mg? Even if it is just guesswork I'd like to know your thought process.

On a seperate note, glad you appreciated what I could find in regards to where I think Partial Nicotine Agonists could fit in the market. One of the main effects I noticed from smoking is that in a way, it seemed to make my surroundings more vibrant. It seems to effect the sensory system in a very unique way unlike traditional stimulants (regular stimulants directly effect "attention" as opposed to the sensory systems underlying one's ability to attend...) A person's sensory system can become disrupted a number of different ways due to TBI, prolonged periods of intense emotion or stress, seizures, ect. A stimulant used to enhance ones sensory system would go a long way towards laying the foundation towards a heightened form of cognition. It's a possibility that partial nicotine agonists could do this...

Yep. The dream lives on :)

Regarding galantamine it still seems up in the air as to what levels of AChE inhibition are reached at lower doses and how fast our bodies bounce back from that. Assumptions aside I'd love some data on that. Perhaps someone with access to the studies chrono cite might enlighten us.

Edited by aLurker, 31 August 2010 - 07:36 AM.

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#14 KimberCT

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Posted 31 August 2010 - 10:14 PM

Obviously, nicotine, and endogenous acetylcholine, are substrates for the receptor.

I'm also a fan of galantamine, but it needs to be titrated up to avoid GI problems. (from 4mg to 8mg +)

Galantamine + aniracetam is a potent stack, although aniracetam has bioavailability problems (oral admin: ~11% absorbed), and so needs to be ran high and dosed frequently (~2-3 hr half-life).

Since piracetam binds to a different subunit on the glutamate receptor, combining piracetam with galantamine and aniracetam should make an even better stack.


I stumbled across this today.  Something to look forward to.


Memogain is a galantamine pro-drug having dramatically reduced adverse effects and enhanced efficacy.

Abstract

Memogain (Gln-1062) is an inactive pro-drug of galantamine, the latter being a plant alkaloid approved for the treatment of mild to moderate Alzheimer's disease. Memogain has more than 15-fold higher bioavailability in the brain than the same doses of galantamine. In the brain, Memogain is enzymatically cleaved to galantamine, thereby regaining its pharmacological activity as a cholinergic enhancer. In animal models of drug-induced amnesia, Memogain produced several fold larger cognitive improvement than the same doses of galantamine, without exhibiting any significant levels of gastrointestinal side effects that are typical for the unmodified drug and other inhibitors of cholinesterases, such as donepezil and rivastigmin. In the ferret, dramatically reduced emetic and behavioral responses were observed when Memogain was administered instead of galantamine. Based on these and other preclinical data, Memogain may represent an advantageous drug treatment for Alzheimer's disease, combining much lesser gastrointestinal side effects and considerably higher potency in enhancing cognition, as compared to presently available drugs.


PMID: 19669943

Edited by KimberCT, 31 August 2010 - 10:17 PM.


#15 yowza

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Posted 01 September 2010 - 01:27 AM

However, if you look at what Chrono posted closely, it can be seen that a 10 mg dose inhibits 35-55% of AChE for 1 day.
The half life of galantamine seems to be on average about 7 hours (although it could be slightly more depending on metabolism); so assuming that one were to take the first dosage at 8 a.m. on day 1, they'd most likely be almost up to about 4 half-lives the following day when taking dose 2 (therefore, there would only be a slight build-up of galantamine in the system for the first several weeks before reaching a steady state); 30-48 hours seems to be the time it would take for a single dosage to be totally absent from one's system it seems.


I'm not trying to pretend to be an authority on this subject, just going by general memory and what I managed to find specifically to back this up to try and help people out by presenting what info. I could find.

I hit enter after highlighting "1 day" so it may have thrown my point off abit (the above quote is all supposed to be 1 paragraph). By "1 day" I just meant each day one would take a dosage of Galantamine (not literally that the peak effect lasts 24 hours; if that were the case then no one would claim it has a 7 hour half life). My main point was that there could be slight (probably negligible) increase in AChE inhibition beyond what one experiences from the initial dose if taking it on a daily basis as opposed to just 1 day. The 30-48 hours I posted is roughly 5 half lives (depending on how fast one metabilizes the drug), which is considered indication that the drug has cleared the system. Therefore, there could be very slight build-up going by half-lives and possibly a bit more as there may be some residual acetylcholinesterase inhibition after the half-lives are done and over with.

Irregardless of this small technical detail, I think the main question should be what factors go into how a younger person would handle inhibiting the enzyme that controls their acetylcholine levels on a daily basis.


Half? Is that a figure based on inherent truthiness or some pharmacological rule of thumb I'm unaware of?


I wasn't presenting any "pharmacological rule of thumb". As can be seen from the part you quoted me at, I mentioned medications don't work that way, which makes finding an answer to your "million dollar" question difficult to answer. More information is needed.

Do you have a link to an article discussing Galantamine as having negligible effects at a "chronically low dose"?

Besides this, there's also the other factor to consider; how long, on average, it takes the body to naturally replace acetylcholinesterase once it's been inhibited.

Yes. Any information here would be much obliged.

Though chrono said that at 10 mg nearly all AChE inhibition disappears by 30h after the last dose. He probably read the studies since this isn't mentioned in any of the abstracts he cites. That factoid is pretty significant though since it would mean that there is a good chance of the levels returning to normal within 24 hours if you take a single low dose daily. Altering the AChE back and forth on a daily basis might still be a very bad idea in the first place though and there is also the risk of up-regulating AChE in response to the inhibition


You pretty much ended on the exact point I was trying to make. That's the kind of information I was trying to put forth.

What made you say 2-4 mg? Even if it is just guesswork I'd like to know your thought process.


It's educated guesswork at the very least.

The thought process was quite simple. The lowest dosage for an elderly person that I could find was two 4 mg dosages of Galantamine/day making the total 8 mg. I doubt a doctor would prescribe Galantamine for it's FDA approved usage to an elderly person at a dosage amount that would have an insignificant effect on AcHE levels. If your suggestion is accurate (That galantamine could have insignifant effects on AcHE levels at low dosages while maintaining a nicotonergic effect) then I think it pretty safe to reason that these would be subclinical dosages (or chronicly low as you put it) so it would definitely be below 8 mg.
Based on there being some companies that make Galantamine in 4 mg tablets (hopefully there is one that still does; although there should be some liquid dosage form too); this would make breaking the tablet in half or in quarters quite easy. A 1-4 mg range would therefore, seem somewhat easy to control.


Regarding galantamine it still seems up in the air as to what levels of AChE inhibition are reached at lower doses and how fast our bodies bounce back from that. Assumptions aside I'd love some data on that. Perhaps someone with access to the studies chrono cite might enlighten us.


If you have some studies suggesting negligible AChE inhibition at lower dosages this would be enough. If this holds true for Galantamine, then maybe it would also hold true for "memogain" (thanks for bringing this up KimberCT). The following article seems to mention it as having superior transport to the brain (found it at http://www.galantos....16dc5b53a8807bf); this would make exploiting nicotonergic activity possible at even lower dosages (although it may be impossible to feel an effect off this while still having a small amount of AChE inhibition).

One other compound to look into... Ever hear of Lobeline? Yaupon Therapeutics is developing this as a treatment for ADHD (in the past it's enjoyed commercial usage for smoking cessation). One of it's effects is on a dopamine transporter protein within a cell (helping recovery from prolonged periods of taking amphetamines or methylphenidates; typical ADHD drugs). It also has some effects on nicotine receptors too.

I know this thread is specific in regards to alpha 7 partial nicotine agonists so I don't want to take things off track but, as this can be acquired, it would be interesting to hear from anyone whose tried this to see if it has any usage as a nootropic...?

Edited by yowza, 01 September 2010 - 01:55 AM.


#16 aLurker

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Posted 02 September 2010 - 06:05 AM

Okay, thanks for clearing that up. It seems we're on the same page regarding galantamine.

The Lobeline ADHD trial should have finished August 2010 so keep your eyes open for that one!

The more I look into nicotine the better it looks, which paradoxically kind of worries me.

First of all, addiction might be less of a worry than I previously thought. Nicotine is far more addicting combined with combined MAO A and B inhibition. Thus, without the MAOI effects of tobacco, in the form of a patch; it is far less addictive.

Secondly: I could find a LOT of information on the positive effects nicotine has on cognition in healthy non-smoking individuals. This meta-analysis on acute effects contributed more to making nicotine look cool to me than Clint Eastwood ever did.

I've been considering whether to try either galantamine or nicotine and the effectiveness of nicotine weighs heavily in it's favour since I couldn't find any evidence that galantamine improves cognition to a significant degree in healthy individuals, even though such studies actually exist I haven't found any favourable ones yet, let me know if you do. On the other hand there seems to be some evidence that combining the two would be an awesome synergistic crime-fighting duo.

I'd really appreciate some more input on this though since nicotine doesn't seem like something that should be underestimated. Regarding galantamine I still need to do more research on how low doses affect AChE inhibition and the nicotinic effects. I'm also a little concerned about insulin resistance from long-term nicotine use although this doesn't seem to be an acute effect. The more pressing matter is of course the vasoconstriction since I don't know of a really good way to counteract it (B-complex, even more exercise, capcasin and Piracetam?). It would also be nice with some kind of comparison on exactly how much of a vasoconstrictor nicotine really is in comparison to other vasoconstrictor stims such as amphetamine and methylphenidate, and how constricting it is in different doses. So many questions and so hard to find answers, the search goes on.

Edited by aLurker, 02 September 2010 - 06:07 AM.


#17 yowza

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Posted 06 September 2010 - 03:24 AM

Okay, thanks for clearing that up. It seems we're on the same page regarding galantamine.

The Lobeline ADHD trial should have finished August 2010 so keep your eyes open for that one!


I'll maybe post more on Lobeline in a seperate thread. I see it's referred to as a partial nicotine agonist through some sources even though this term seems to usually be reserved for pharmaceutical chemicals being developed specifically for this purpose as opposed to a naturally occurring chemical derived from a plant.


My previous post I tried to reason as best I could what dosage could be effective (to get nicotonergic effect while minimizing ACHe effect). However, I just found more exact information in regards to your million dollar question:


http://www.ionchanne...act/pm/16641937
Galantamine enhances dopaminergic transmission in vivo (meaning with whole living organism) via allosteric potentiation

Clinical studies suggest that adjunct galantamine may improve negative and cognitive symptoms in schizophrenia. These symptoms may be related to impaired dopaminergic function in the prefrontal cortex. Indeed, galantamine has been shown to increase dopamine release in vitro. Galantamine is an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) and, at higher doses, an acetylcholine esterase (AChE) inhibitor. We have previously shown that nicotine, through stimulation of nAChRs in the ventral tegmental area (VTA), activates midbrain dopamine neurons and, hence, potentiation of these receptors could be an additional mechanism by which galantamine can activate dopaminergic pathways. Therefore, the effects of galantamine (0.01-1.0 mg/kg s.c.) on dopamine cell firing were tested in anaesthetized rats. Already at a low dose, unlikely to result in significant AchE inhibition, galantamine increased firing activity of dopaminergic cells in the VTA. The effect of galantamine was prevented by the nAChR antagonist mecamylamine (1.0 mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1 mg/kg s.c.), and it was not mimicked by the selective AChE inhibitor donepezil (1.0 mg/kg s.c.). Our data thus indicate that galantamine increases dopaminergic activity through allosteric potentiation of nAChRs. Galantamine's effect was also prevented by the alpha7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-D-aspartate antagonist CGP39551 (2.5 mg/kg s.c.), indicating a mechanism involving presynaptic facilitation of glutamate release. In parallel microdialysis experiments, galantamine was found to increase extracellular levels of dopamine in the medial prefrontal cortex. These results may have bearing on the enhancement of negative and cognitive symptoms in schizophrenia.


My Summary/Interpretation from reading this:
This study helps confirm that, indeed:
1) Galantamine at lower dosages is unlikely to result in significant AchE inhibition.

2) The nicotonergic mechanism was also seperated from Galantamine's Acetylcholinesterase properties. The data supports this since a nicotonergic antagonist prevented it's effect but not a muscarinic antagonist meaning we know galantamine's "allosteric modulation" is nicotonergic and not muscarinic. Also the "allosteric modulation" and not the AChe inhibition causes the nicotine receptor stimulation since donepezil (Aricept; just a ACHe inhibitor and not an "allosteric modulator") doesn't do this.

Measurement of Galantamines Nicotonergic mechanism:
Nicotine Receptor stimulation leads to dopamine release. For Galantamine, nicotine receptor stimulation (happens through "allosteric modulation") would therefore, also lead to dopamine release. In order to measure the effects of this mechanism (dopamine release caused by nicotonergic effect) from Galantamine, without it's acetylcholinesterase inhibiting properties getting in the way, the researchers, therefore had to pick dosages that would fall below this threshold.

The dosage range selected was 0.01-1.0 mg/kg s.c (.01-1.0 milligrams per kilogram subcutaneous I think is what this stands for). This seems like a chronically low dosage and seems to have been administered by injection (therefore, even if we calculate mg/kg for human body weight we'd still have to factor in that by injection there may be a possibility of the dosage being lower than if taken orally). Another obstacle to interpreting this is that this was used on rats as opposed to humans. But, I suppose it's something. Anyone calculate out what this may be?


On the other hand there seems to be some evidence that combining the two would be an awesome synergistic crime-fighting duo.


A very long article by a Bulgarian Psychologist Silvia Petrova also seems to like this combo (although she specifies it for alzheimers disease as opposed to nootropic purposes). I found a short excerpt from it that's on-topic):

http://www.alzforum....ova/default.asp
"Galantamine, with its dual mode of action as cholinesterase inhibitor and allosteric modulator of nAChRs, covers many aspects of cholinergic dysfunction and deficiency"

1) Allosteric Modulation compenet is what Increases Nicotine Receptors:
"Scientific studies find that nicotine induces an upregulation of nAChR sites in human brains, including brains of AD patients."

"Nicotinic receptors go against the generally accepted paradigm in that overexposure to agonists produces receptor downregulation, and overexposure to antagonist produces receptor upregulation. In particular, long-term exposure to nicotine results in an increased number of nAChRs in the brains of humans."

While the "allosteric modulation" on nicotine receptors serves to stimulate nicotine receptors, we don't know to what extent this would be at below ACHe inhibiting level dosages (the author seems to be mainly focusing on Alzheimers patients who would obviously not be taking low dosages below the ACHe inhibiting level).


In any case it appears the general reason given for why nACHR receptors in the brain upregulate is due to increasing nerve growth factor.

"Nicotine has a neuroprotective effect against Ab deposition and increases the expression of high-affinity nerve growth factor (NGF)."

"High-affinity NGF receptor (TrkA) levels are decreased in AD brains as compared to age-matched control brains. Nicotine increases the expression of high-affinity nerve growth factor receptors both in vitro and in vivo. Rats with chronic indwelling intravenous catheters were continuously infused with nicotine to a total dose of 12 mg/kg over 24 hours. This treatment resulted in a 44 percent increase in TrkA receptor expression in the hippocampus. The increase in TrkA expression produced by nicotine was shown to be related to its cytoprotective actions. These results suggest that nicotine's neuroprotective actions might also be mediated through its interaction with central a7 nAChRs and a subsequent increase in TrkA receptor expression"


2) Allosteric Modulation of nACHR (nicotine receptor) is what sensitizes them:
"What does galantamine do to improve the symptoms of AD patients? Gordon Wilcock has said that "to halt the disease, you have to stop the brain cells from being killed." Galantamine rescues brain cells from death. It was found that a few cholinesterase inhibitors, including galantamine, produce beneficial effects even after drug treatment has been terminated.29 These effects assume modes of action other than mere esterase inhibition and are capable of inducing systemic changes. Allosterically potentiating ligands sensitize nicotinic receptors by increasing the probability of channel opening induced by acetylcholine and nicotinic agonists and by slowing down receptor desensitization.30 Allosteric modulation of nAChR is a novel approach which circumvents the development of tolerance. "

3) Allosteric Modulation of nACHR can act as a nuerotransmitter enhancer:

"NAChR activation modulates the release of a number of neurotransmitters such as ACh, dopamine (DA), GABA, and glutamate. "

Edited by yowza, 06 September 2010 - 04:24 AM.

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#18 yowza

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Posted 06 September 2010 - 05:14 AM

Clarification to my previous post: There are different types of "allosteric modulation" of the nachr. Galantamine's effect (that produces nachr upregulation, sensitivity, neurotransmitter enhancement) is on the following:

a) Noncompetitive allosteric activator site. Compounds that bind to this site are termed channel activators, as they enhance channel opening and ion conductance.






Combining nicotine with galantamine for alzheimers patients.

What could be expected if nicotine and galantamine were applied in combination, but in a consecutive, periodical or cyclic way, similar to contraceptive hormones? At the beginning, application of nicotine (as patches, gums, vaporization, or maybe, in the future, tablets) for a three-to-four-week period is expected to increase the density of nAChRs. Consecutive application of galantamine for about 30-60 days (as applied in Bulgaria for more than 40 years) is expected to have an enhanced effect by its dual mode of action on the cholinergic system, and that effect will be facilitated by an increased number of AChERs, induced by nicotine. Consecutive application of both substances will avoid cumulative cholinergic side effects. Such a therapeutic cycle probably has to be repeated several times, and the necessity of medication-free intervals of four to six weeks between therapeutic courses may prove to be of interest.


It's an interesting strategy. Although, probably abit dangerous to do for a healthy person; the concerns I already wrote down about just taking galantamine would seem to be enhanced if taking it along with nicotine (not to mention the issues with just taking nicotine by itself).

Another interesting quote from Dr. Petrova about the benefits behind just taking nicotine:

A specific CNS effect of nicotine includes EEG desynchronization, increased cerebral blood flow, and increased cerebral glucose utilization through stimulation of nAChRs. In humans, nicotine increases arousal, visual attention, and perception. It improves the speed and accuracy of motor function, as well as performance in complex psychomotor tasks such as driving a car.


While the benefits seem to be pronounced (very interesting to see visual perception/sensorimotor function as these underlie certain forms of attention disorders as talked about earlier), it's not like drastic quality of life gains can be experienced from just nicotine. There needs to be partial nicotine agonists that come out to exploit this effect along with offering better means of administration.

The extent of "EEG desynchronization" (an excited state; I'm guessing this alludes to encouraging disproportionate EEG frequencies) the extent of which probably depends on dose and underlying condition/individual response. I think it's due to nicotine's short acting/non-selective effect (I'm talking the chemical nicotine and not the general enhancement of nicotine receptors) not to mention that it's excitatory in nature.

Edited by yowza, 06 September 2010 - 05:19 AM.


#19 Rational Madman

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Posted 07 September 2010 - 09:48 AM

Dosage should be determined by tolerability, and symptoms indicative of reduced nicotinic receptor expression/population. Start at 4mg (TID), and keep titrating until optimal dosage is reached. Frankly, I'm not convinced of the perils of acetylcholinesterase inhibition, since there is plenty of evidence supporting the safety of this pharmacological target in healthy subjects. If you spend hours at PubMed, you'll find contradictory findings on any subject, but I'm convinced that the Imminst population spends an inordinate amount of time obsessing about the contrary findings and hypothetical risks---which as a consequence, perpetuates many neuroses. In sum, take a deep breath, suppress your fears, and conduct a careful empiric trial. If adverse events arise, consider mitigating strategies, which I can elaborate on, but should already be apparent. If you find the substance intolerable, or undesirable, simply cease use. Seriously, I find it highly dubious that your chemistry will be permanently altered through long term use. Indeed, I find the dosage guideline to be exceedingly timid---especially considering the aggressive progress of neurodegenerative disorders that influence acetylcholinesterase. Finally, let me impart some sage advice that will undoubtedly be ridiculed and ignored....
The success of all serious endeavors is contingent on taking risks, and if there are palpable symptoms or evidence of altered nicotinic receptor expression, then it's a risk worth undertaking. Risk has a considerable multiplier effect, and if we desire progress, we must expose ourselves to it with calculated zeal. Most importantly, I should be emphatic about the notion that all risks can be managed with carefully devised strategies. Seriously, though, I don't expect the towering wisdom of my advice to be enlightening or revelatory, but it's certainly worth iterating.
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#20 aLurker

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Posted 07 September 2010 - 06:10 PM

...


Yes, I spend hours on pubmed and I'm certainly one of those who spend a lot of time obsessing about hypothetical risks. Yet I'm still definitely prepared to take risks, otherwise I wouldn't be here and taking nootropics. All I'm trying to do is find out what risks I'm taking in order to have a clear risk/benefit analysis so I can make a reasonably informed decision, well that and also try to minimize the risks.

An empiric trial wouldn't tell me anything about the long-term risks I might be taking here. In this particular case it might be a good idea though since it is by far the easiest and most reliable way to figure out the benefit part in my risk/benefit analysis and the acute risks seem to be very low. In order to use this long-term however I'd certainly want to research it more thoroughly. I might order some to see if the benefits are noticeable enough to make it worthwhile though so thanks for your input.

#21 chrono

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Posted 07 September 2010 - 07:09 PM

Nice, there was some awesome discussion in this thread while I was preoccupied with irrelevant mundanities this week.

@yowza: It's great to see you back here. Hope you'll stick around ^_^ Your thought about the connection between nicotinic receptors and sensory-attention-cognition is pretty awesome, and certainly could use more discussion.

I wonder whether Chrono was referring to the pharmaceutical or supplemental form of galantamine?

I haven't done a very thorough review yet, but none of the papers/abstracts I've read thus far have mentioned this distinction. I'm only aware of a few sources of galantamine (the "supplemental" variety, I suppose), but my impression was that the extraction process is fairly selective. For example, GalantaMind lists the ingredient only as 4mg galantamine, rather than a % composition of an herbal reduction (like the L-DOPA product I have). Are there products I'm unaware of which are a more "soupy" mix of plant materials, and do you think they're significantly different than pure extracted or pharmaceutical galantamine in terms of effect?

I don't have the full texts of the studies I cited above, but I'm assuming they used a pure material from a chem supplier.

The half-lives however, don't factor in how long it would take AcHe levels to rebound to normal after taking it. Taking Galantamine every now and then may work but not on an everyday basis I'm thinking, it may begin to take a toll on the mind. Once you reach a steady state, I'm guessing one's Acetylcholinesterase levels would remain relatively low.

This is an excellent point, and one I hadn't considered. Do you happen to know anything about the resynthesis rate of this esterase? Couldn't find any good papers directly, but now I'm looking for examples of recovery rates with various AChEIs.

However, aLurker brought up another great point: if 5mg inhibits 17-27% of AChE (convenient assumption for 1/2 the 10mg effect), these levels are almost certainly maintained for a shorter period than the 5-8h elimination half-life. I wonder if there is data for the shape of the inhibition/time curve? Since the primary clinical usage is for AChEI, it seems possible (I've concentrated most on nAChR studies so far).

Though chrono said that at 10 mg nearly all AChE inhibition disappears by 30h after the last dose. He probably read the studies since this isn't mentioned in any of the abstracts he cites.

This was mentioned in a review, which cited the first paper (Stereoselectivity of cholinesterase inhibition by galanthamine and tolerance in humans) as the source. I'm way overdue for a trip to the library to get some of these full texts.

There were a few other points that I wanted to touch on, but I need to do a little more research first.

#22 chrono

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Posted 07 September 2010 - 07:46 PM

Dosage should be determined by tolerability, and symptoms indicative of reduced nicotinic receptor expression/population. Start at 4mg (TID), and keep titrating until optimal dosage is reached.

Galantamine is a positive allosteric modulator, not an agonist, so it probably doesn't regulate nicotinic receptor expression. Feel free to correct me if this is wrong, but I thought the benefit of PAMs was that they exert their effect outside the homeostatic loop.

You also may have missed our discussion about nAChR modulation occurring at lower dosages, and not at higher ones. Starting at what is probably an effective dosage for this effect and titrating upward based on tolerability is almost certainly counterproductive.

Frankly, I'm not convinced of the perils of acetylcholinesterase inhibition, since there is plenty of evidence supporting the safety of this pharmacological target in healthy subjects.

General tolerability and safety in no way implies that everything is optimal (or even without adverse effect) on a more minute scale. Though it doesn't appear to be as large a concern with the dosages of galantamine we're talking about here, inhibiting the mechanism by which the brain regulates levels of a neutrotransmitter certainly has the potential to throw a wrench into the works. When we're talking about optimizing levels and function of such NTs toward the goal of cognitive enhancement, such concerns would seem to be highly salient.

And as aLurker rightly observes, the approach you advocate really doesn't tell you anything beyond its subjective effects (those that are grossly apparent, anyway).

If you spend hours at PubMed, you'll find contradictory findings on any subject, but I'm convinced that the Imminst population spends an inordinate amount of time obsessing about the contrary findings and hypothetical risks---which as a consequence, perpetuates many neuroses. In sum, take a deep breath, suppress your fears, and conduct a careful empiric trial.

So studies should be used as justification of general safety, but fears should be "suppressed" when research points to potentially adverse effects? That sounds like wishful thinking to me (especially when consideration of research and risk assessment are characterized as neurosis), but in the interest of safety I tend to apply a somewhat lower requirement for evidence to things that can potentially screw me up. Based on most of your previous posts, I'm frankly shocked to hear you saying something like this.

Not to be indelicate, but you seem to have missed the point of this thread. We're discussing the pharmacological research of a very interesting substance, toward the goal of increasing our understanding of its effects. This in no way precludes the "just do it" approach you seem to be advocating here, but rather allows it to be undertaken with better probability of a good, sustainable result. The hypothetical risks here are pretty small, and stated as such.

But really, I think your advice is a little out-of-place in such a theoretical discussion, and I'm pretty sure that no one involved in this conversation really needs to be told any of that. I'm not trying to say that your opinion is invalid, but rather that a stimulating discussion should not be minimized in such a "you guys are thinking about it too much" way. If you have something to contribute toward our understanding of these issues, feel free.

Edited by chrono, 08 September 2010 - 12:06 AM.

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#23 aLurker

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Posted 07 September 2010 - 09:11 PM

Nice, there was some awesome discussion in this thread while I was preoccupied with irrelevant mundanities this week.

@yowza: It's great to see you back here. Hope you'll stick around ^_^ Your thought about the connection between nicotinic receptors and sensory-attention-cognition is pretty awesome, and certainly could use more discussion.


Great that both of you are here to keep me company in this thread, I fear it would be lonely without you.

Are there products I'm unaware of which are a more "soupy" mix of plant materials, and do you think they're significantly different than pure extracted or pharmaceutical galantamine in terms of effect?

Indeed there is: Pro-Galantamine is a product marketed towards the lucid dreaming community and it contains natural galantamine hydrobromide from the Red Spider Lily, with a purity over 96%. You can also extract galantamine from other plants such as the Snowdrop (that also contains other alkaloids).

There were a few other points that I wanted to touch on, but I need to do a little more research first.


I'll start by sharing what I've got so far and perhaps you can help me fill in the blanks:

The following is from "Beyond in vitro data: a review of in vivo evidence regarding the allosteric potentiating effect of galantamine on nicotinic acetylcholine receptors in Alzheimer's neuropathology.":

In summary, the available in vitro data suggest that relevant concentrations for allosteric potentiation by galantamine are in the 0.5–1 µM range. This is slightly less than the range of IC50 values for AChE inhibition(0.9–3 µM)[14,111]. As the measured levels of in vivo AChE inhibition in Alzheimer’s patients are around 30%–40% for a 24-mg daily dose [28,51], using a mass balance equation, this leads to a functional brain concentration between 0.4 µM and 1.5 µM.
This is clearly in the range of the observed relevant concentrations for the APL effects of galantamine.



And the following from an earlier study from 2000 called "Galantamine is an allosterically potentiating ligand of the human alpha4/beta2 nAChR." Admittedly this is not about the alpha 7 receptor but I'm assuming the concentration interval doesn't differ too much.

Gal enhances the ACh-induced response in a window of concentrations between 0.02 and 2 μM, with
maximal enhancement displayed around 0.7 mM. At higher concentrations, the APL effect of Gal is superseded by non-competitive inhibition of the nAChR.


From the graph in the full study we can see that the interval between 0.1 and 1 μM gives us a pretty significant APL effect. So a pretty low concentration of galantamine could result in a significant allosteric potentiation of nicotinic receptors.

Question now is: does anyone know how to calculate the mass balance equation here to convert the relevant μM brain concentrations into oral doses in mg (like they did in the first study I quoted in this post) and what degree of AChE inhibition would this correspond to?

Edited by aLurker, 07 September 2010 - 09:28 PM.

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#24 KimberCT

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Posted 07 September 2010 - 09:44 PM

 

Galantamine is a positive allosteric modulator, not an agonist, so it probably doesn't regulate nicotinic receptor expression. Feel free to correct me if this is wrong, but I thought the benefit of PAMs was that they exert their effect outside the homeostatic loop.

My understanding is that, PAMs increase the effect when a separate agonist binds to the receptor.  For example, benzodiazepines are GABA-A PAMs.  They cause the ion channel to open wider and/or for a longer period of time only when GABA or another agonist binds to the receptor.  In the case of benzos, this potentiation of GABA causes rapid downregulation of the receptor.


edit: The above is just an example of one group of PAMs.  This doesn't necessarily mean that galantamine will cause downregulation of nicotinic receptors.

Edited by KimberCT, 07 September 2010 - 09:46 PM.


#25 chrono

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Posted 07 September 2010 - 11:53 PM

My understanding is that, PAMs increase the effect when a separate agonist binds to the receptor.  For example, benzodiazepines are GABA-A PAMs.  They cause the ion channel to open wider and/or for a longer period of time only when GABA or another agonist binds to the receptor.  In the case of benzos, this potentiation of GABA causes rapid downregulation of the receptor.

Yes, definitely. Though from my past experience with benzos, I'm not sure if there's really rapid downregulation. In doing some quick pubmedding just now, it seems like the BZD/GABA situation might be a somewhat special case with regard to tolerance: "...These changes might be mediated by a unique homeostatic mechanism regulating the expression of GABA(A) receptor subtypes that maintain specific functional features of GABAergic function in cortical cell layers." [1] (and a few more details [2] [3]).

I think this is where I got the idea that regulation doesn't occur for nAChR PAMs:

Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease.
Maelicke A.
Laboratory of Molecular Neurobiology, Johannes Gutenberg University Medical School

Impairment of the central cholinergic system has a pivotal role in the cognitive decline observed in patients with Alzheimer's disease (AD). One of the most prominent cholinergic deficits is the reduced number of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are important for memory and learning, enhancing nicotinic neurotransmission is a promising treatment strategy for AD. The two most common approaches to correcting these cholinergic deficits are to increase the synaptic availability of acetylcholine (ACh) by inhibiting acetylcholinesterase (AChE), or to mimic the effects of ACh (nicotinic agonists) by acting directly on nicotinic receptors. Clinical studies suggest that AChE inhibitors produce only short-term symptomatic improvement. Similarly, long-term use of nicotinic agonists may induce desensitization of nicotinic receptors, leading to tolerance and therefore limiting the duration of efficacy. Allosteric modulation of nAChR is a novel approach, which circumvents the development of tolerance. Allosteric modulators bind to a site on nAChR that is different to the binding site of the natural agonist, ACh. This allosteric interaction amplifies the actions of ACh at post- and presynaptic nAChR. In particular, presynaptic nAChR are capable of modulating the release of ACh and other neurotransmitters, such as glutamate, serotonin and GABA, which may contribute to symptoms of the illness. Allosteric modulation of nAChR could therefore produce significant therapeutic benefit in AD. One of the most potent of these allosteric modulators is galantamine. As well as modulating nAChR, galantamine inhib- its AChE. The extent to which the clinical benefits of galantamine are attributable specifically to its nicotinic effects is uncertain and requires further investigation. However, galantamine maintains patients' level of cognitive and daily function for at least 1 year, which has not been reported for other AChE inhibitors. Galantamine's modulatory effects on nAChR may influence transcriptional regulation, resulting in an increased synthesis of nAChR. This may account for galantamine's sustained efficacy.

PMID: 10971047 [PubMed - indexed for MEDLINE]

This assertion seems based more on principle than observation, though I don't have the full text. So I guess tolerance might be possible, but definitely should not be assumed. Will certainly keep an eye out as I'm reading.

@aLurker: I think what you just posted may be something I had a hard time finding back when I first looked into this: a correlation between oral dosage and resulting brain concentration. I remember trying to find a conversion factor to extrapolate this from the data on rats, rabbits and dogs, without any luck. ~_~ I just finished reviewing nicotine vasoactivity, so I'm not sure if I have my oomph left in me tonight, but I'll post some more thoughts soon.

Edited by chrono, 08 September 2010 - 12:14 AM.

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#26 John Barleycorn

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Posted 08 September 2010 - 08:44 AM

My understanding is that, PAMs increase the effect when a separate agonist binds to the receptor.  For example, benzodiazepines are GABA-A PAMs.  They cause the ion channel to open wider and/or for a longer period of time only when GABA or another agonist binds to the receptor.  In the case of benzos, this potentiation of GABA causes rapid downregulation of the receptor.


I keep quoting a post out of this thread here: http://www.imminst.o...mpa-modulator/. The concern is with piracetam's supposed increased excitotoxic effect at glutamate receptors, but it also has potential relevance to sensitisation and tolerance in general. There are positive but resensitising modulators like aniracetam which theoretically delay tolerance, at least at the particular receptor concerned. Downstream effects could, however, be a different matter. I guess one obvious concern would be the relationship between nicotinic receptors and DA receptors in the limbic system.

Here are non-scientific categories of what are called "positive allosteric modulators" (compounds that enhance the activity of a channel without binding at the same place as the agonist):

"Sensitizer": increases affinity of normal agonist for the receptor, allowing it to activate at lower concentrations of agonist. This type of modification is common. Benzodiazapines work this way for GABA receptors (although not with ion channels).
"Permeability enhancer": allows more calcium "per shot." In theory, this should not cause excitotoxicity. Even increasing the amount of calcium per channel opening by an order of magnitude doesn't involve much calcium.
"Resensitizer": prevents the receptor from desensitizing, allowing it to open and close repeatedly. This kind of modulator might cause excitotoxicity if stimulated excessively. It doesn't have to be "all-or-nothing" - you could have a "partial resensitizer" or a "sensitivity delayer."
"Open channel stabilizer": keeps the channel open even when the agonist is not present, either for a longer period of time than normal (slows closing) or all the time (usually a toxin). Some drugs work this way (for example, valproic acid and other mood stabilizers keep sodium channels open). This is an extraordinarily BAD idea for calcium channels.

The concern with piracetam, I guess, is that it might lead to too much calcium. But it binds to glutamate receptors rather weakly and has subtle effects. Some new structures that have been released show piracetam binding at multiple sites of the "ligand binding domain" of glutamate receptors, so it's possible that it has more than one mechanism.


Edited by John Barleycorn, 08 September 2010 - 08:53 AM.

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#27 aLurker

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Posted 08 September 2010 - 05:51 PM

Combining nicotine with galantamine for alzheimers patients.

What could be expected if nicotine and galantamine were applied in combination, but in a consecutive, periodical or cyclic way, similar to contraceptive hormones? At the beginning, application of nicotine (as patches, gums, vaporization, or maybe, in the future, tablets) for a three-to-four-week period is expected to increase the density of nAChRs. Consecutive application of galantamine for about 30-60 days (as applied in Bulgaria for more than 40 years) is expected to have an enhanced effect by its dual mode of action on the cholinergic system, and that effect will be facilitated by an increased number of AChERs, induced by nicotine. Consecutive application of both substances will avoid cumulative cholinergic side effects. Such a therapeutic cycle probably has to be repeated several times, and the necessity of medication-free intervals of four to six weeks between therapeutic courses may prove to be of interest.


It's an interesting strategy. Although, probably abit dangerous to do for a healthy person; the concerns I already wrote down about just taking galantamine would seem to be enhanced if taking it along with nicotine (not to mention the issues with just taking nicotine by itself).


The Silvia Petrova interview was very interesting, thanks for that. What are the benefits of cycling between nicotine and galantamine compared to concurrent administration? Concurrent administration obviously yields some synergy since together you can get a response at doses that by themselves doesn't. Is the cycling to avoid tolerance to nicotine or am I missing something here?

What concerns are you referring to that would be enhanced by nicotine? The only concern about galantamine I've got is the potential danger of AChE inhibition. Of course you are right that nicotine on its own has issues though.

Edited by aLurker, 08 September 2010 - 05:52 PM.


#28 KimberCT

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Posted 08 September 2010 - 06:44 PM

Combining nicotine with galantamine for alzheimers patients.  

What could be expected if nicotine and galantamine were applied in  combination, but in a consecutive, periodical or cyclic way, similar to  contraceptive hormones? At the beginning, application of nicotine (as  patches, gums, vaporization, or maybe, in the future, tablets) for a  three-to-four-week period is expected to increase the density of nAChRs.  Consecutive application of galantamine for about 30-60 days (as applied  in Bulgaria for more than 40 years) is expected to have an enhanced  effect by its dual mode of action on the cholinergic system, and that  effect will be facilitated by an increased number of AChERs, induced by  nicotine. Consecutive application of both substances will avoid  cumulative cholinergic side effects. Such a therapeutic cycle probably  has to be repeated several times, and the necessity of medication-free  intervals of four to six weeks between therapeutic courses may prove to  be of interest.


It's an interesting strategy.  Although, probably abit dangerous to do for a healthy person; the concerns I already wrote down about just taking galantamine would seem to be enhanced if taking it along with nicotine (not to mention the issues with just taking nicotine by itself).


The Silvia Petrova interview was very interesting, thanks for that. What are the benefits of cycling between nicotine and galantamine compared to concurrent administration? Concurrent administration obviously yields some synergy since together you can get a response at doses that by themselves doesn't. Is the cycling to avoid tolerance to nicotine or am I missing something here?

What concerns are you referring to that would be enhanced by nicotine? The only concern about galantamine I've got is the potential danger of AChE inhibition. Of course you are right that nicotine on its own has issues though.


I'm glad this topic is being discuss, as the above is where I'd like to go.  Use nicotine as I do caffeine along side chronic, though lowish, galantamine dosing.

#29 chrono

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Posted 09 September 2010 - 01:49 AM

Therefore, there could be very slight build-up going by half-lives and possibly a bit more as there may be some residual acetylcholinesterase inhibition after the half-lives are done and over with.

I don't have time to post any good research tonight, but I wanted to mention something about this point. In one of my last posts I asked about the resynthesis rate of AChE after inhibition...which was a pretty big brain fart, as galantamine (and all other AChEIs we discuss here, I believe) is a reversible inhibitor. (Which is a good thing, as resynthesis period is measured in weeks). From a review I read about Hup A, I think this means the molecule attaches directly to AChE, and prevents it from binding to ACh, and detaches when it naturally leaves the brain/body—returning the enzyme to normal functioning at that point. So, what I think this means is that there wouldn't be any residual inhibition after clearance of the drug from the brain. This is a small but potentially critical point in trying to figure out if any kind of increased steady state level is reached wrt AChEI effect.

Do you guys agree with this, or is one of these assumptions incorrect?

Will still be examining the research closely to try to get more specific answers about the levels, but in looking just now, there are about 350 papers on AChE inhibition to look through, so it's probably going to be a somewhat involved project.

Galantamine and nicotine: This seems like the very definition of synergy...the allosteric potentiation effectively means that the same amount of agonist (nicotine) will have a greater effect at the receptor, and (possibly?) without the downregulation that would come with the greater amount of agonist needed to achieve this effect without the allostery.

I'm also curious what concerns yowza had about the combination. In reading about the allosteric modulation, I seem to recall mention that direct agonism of nAChRs, perhaps at certain levels, had a potentially undesirable effect. Regardless, cycling is still probably a good idea, as nicotine is subject to tolerance at nAChR and downstream dopamine, and as Mr. Barleycorn mentions, galantamine's downstream effect on dopamine is almost certainly going to cause downregulation, even if its PAM does not. I also thought someone raised the possibility of rebound upregulation of AChE levels with on-off galantamine dosing, but I can't seem to find it just now. If so, it might make sense to use galantamine in longer cycles, and nicotine either short-period or as-needed.

Edited by chrono, 09 September 2010 - 02:05 AM.


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#30 John Barleycorn

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Posted 09 September 2010 - 06:13 AM

Aren't some nicotinic receptors a rare example of when agonism actually results in upregulation - and so the obvious question is does this apply to the alpha 7s?




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