54 replies to this topic

[Reformed-Redan]

So, as most of you know I've, along with many others, have been looking for a "great" nootropic. I've spent a whole deal of time and money looking for something that could actually noticeably improve my memory and word recall, mainly for school matters. I had high hopes for PRL; but, the research was based on one iffy paper from long ago. I also hoped ISRIB and IDRA-21 would be potent nootropics; but, they mostly turned out to be duds. They're research was based on rats and animals. So, with college coming up I decided to look at something that was actually tested on humans and had some hard science backing it up. I came across GTS-21 which is the only novel nootropic apart from the good 'ol Piracetam that has some very strong nootropic qualities. Attached is the pdf and I'll include a link here. I hope some people show interest in something that actually will work instead of chasing after large claims. Here is the paper online. 

 

Scroll down to page 546 where it reads: 

 

"The data in this study indicate a clear effect of GTS-21 over placebo on a range of cognitive functions. Table 6 summarizes the results of the ANOVA analysis of the cognitive data. For the primary analysis, statistically significant

 

effects of GTS-21 were observed for at least one measure of all three attention-related tasks (simple reaction time, choice reaction time and digit vigilance), two secondary episodic recognition memory tasks (word recognition

 

and picture recognition), and for the numeric working memory task. Additionally, both the visual tracking tasks and the immediate word recall task exhibited statistically significant improvements in performance fol- lowing dosing

 

with GTS-21. Tasks for which there were no effects on performance as indicated by the primary analysis were the spatial working memory task, the delayed word recall task, overnight face recognition task, and the Bond– Lader

 

self-ratings of mood and alertness. The secondary analysis confirmed the main effects of GTS-21 seen in the primary analysis (Figures 3–5) and, in addition, showed significant improvement for immediate and delayed word

 

recall (Figures 6 and 7) as well as one measure of spatial working memory."

 

Here are some graphs just to see visually how significant the gains were in word recall and other aspects of cognition:

 

The authors of the research paper write in conclusion:

 

"In conclusion, GTS-21 was well tolerated up to doses of 450 mg/day (150 mg t.i.d.) and shows improvements in cognitive behavior in normal subjects. The pharmacokinetics appear to be linear over the range of dose

 

studies and the variability, primarily intersubject, decrease with con- tinued dosing. The data provide important evidence that GTS-21 has the potential to improve human cognitive function. The range of the

 

effects is important, clear benefits being seen to three major cognitive functions (attention, working memory, episodic secondary memory). In addi- tion, there appears to be a relationship between the duration and

 

magnitude of exposure to GTS-21 and/or 4-OH-GTS-21 and the magnitude of effect, with doses between 75 and 150 mg t.i.d. approaching maximal effect. GTS-21 may represent a novel treatment for dementia, and should

 

be investigated further for its potential therapeutic effects in a variety of conditions in which cognitive function is compromised, not least of all Alzheimer’s disease."

 

Large emphasis on the "in normal subjects" as most nootropics discussed around here are based on improving cognition in people already below baseline; while this compounds improves cognition above baseline, which I think any real nootropic should do. Also, the added benefit of improved attention in correspondence with other similar compounds that are being made and geared towards AD(H)D is definitely an added benefit. Anyway, I don't mean to sound harsh; but, I don't really want to f*ck around with other nonsense compounds on which research was based on rats or monkeys when I have the chance to get a real nootropic that has already been tested on humans and has the data to back it up. 

 

So, just wondering if any supplier would be willing to stock this awesome compound. And if possible a show of interest would be great in promoting this compound for not only obvious nootropic qualities; but, also the added benefit of treating positive symptoms of schizophrenia, ADHD, and cognitive decline (as it is prominently neuroprotective). 

 

Thoughts?

 

[Reformed-Redan]

I'd also like to point out to potential suppliers browsing this forum that compounds that actually work will obviously sell better than compounds that have no apparent effects. So, I don't see why you would not want to stock this given it's a surefire best seller. Anyhow, hope not to waste my time and money on pointless and weak nootropics. This seems to be as good as it gets, well also maybe NRX-1074 or Ro 25-6981, in the future along with D-Deprenyl. . .

Edited by yadayada, 04 August 2014 - 05:13 AM.

[Sunifiramses II]

Sorry if this is a stupid question, but I feel I should ask anyway bc I think it might be relevant. What is the marginal benefit of a nicotinic alpha-7 agonist over nicotine itself? [Edit for clarity: I mean nicotine in isolation (via gum or e-cigs), not tobacco of course.]

 

Second, related question: there are other alpha-7 agonists out there, some of which have been tried (I think) by others on this forum. At least that's what I remember from skimming some threads here and there. But I don't recall much about the results. Have they been promising?

 

 

Edited by Sunifiramses II, 04 August 2014 - 06:48 AM.

[Reformed-Redan]

Sorry if this is a stupid question, but I feel I should ask anyway bc I think it might be relevant. What is the marginal benefit of a nicotinic alpha-7 agonist over nicotine itself? [Edit for clarity: I mean nicotine in isolation (via gum or e-cigs), not tobacco of course.]

 

Second, related question: there are other alpha-7 agonists out there, some of which have been tried (I think) by others on this forum. At least that's what I remember from skimming some threads here and there. But I don't recall much about the results. Have they been promising?

Nicotine is a dirty nootropic. It has too many effects apart from the nootropic effects. What the a7n-PAM's or agonists do is target a specific receptor subunit to try and increase cognitive capabilities. I've tried WAY-317,538 at least; but, did not notice prominent nootropic effects. The other nicotinic agonist mentioned in the xks thread did not show strong nootropic effects in the studies I've read. GTS-21 is to the best of my knowledge the best nootropic that is available at the moment. 

[nightlight]

 

Sorry if this is a stupid question, but I feel I should ask anyway bc I think it might be relevant. What is the marginal benefit of a nicotinic alpha-7 agonist over nicotine itself? ...

Nicotine is a dirty nootropic. It has too many effects apart from the nootropic effects. What the a7n-PAM's or agonists do is target a specific receptor subunit to try and increase cognitive capabilities. I've tried WAY-317,538 at least; but, did not notice prominent nootropic effects. The other nicotinic agonist mentioned in the xks thread did not show strong nootropic effects in the studies I've read. GTS-21 is to the best of my knowledge the best nootropic that is available at the moment.

 

Along the same lines, oranges, apples and raspberries are "dirty" vitamins, butter is "dirty" margarine, steak is "dirty" proteins and carnitine, old-fashioned Christmas trees are "dirty" Chinese plastic trees, women are "dirty" blowup sex dolls, humans are "dirty" androids, real world is a "dirty" Matrix.

Edited by nightlight, 04 August 2014 - 11:30 AM.

[medicineman]

Sorry if this is a stupid question, but I feel I should ask anyway bc I think it might be relevant. What is the marginal benefit of a nicotinic alpha-7 agonist over nicotine itself? ...

Nicotine is a dirty nootropic. It has too many effects apart from the nootropic effects. What the a7n-PAM's or agonists do is target a specific receptor subunit to try and increase cognitive capabilities. I've tried WAY-317,538 at least; but, did not notice prominent nootropic effects. The other nicotinic agonist mentioned in the xks thread did not show strong nootropic effects in the studies I've read. GTS-21 is to the best of my knowledge the best nootropic that is available at the moment.

Along the same lines, oranges, apples and raspberries are "dirty" vitamins, butter is "dirty" margarine, steak is "dirty" proteins and carnitine, old-fashioned Christmas trees are "dirty" Chinese plastic trees, women are "dirty" blowup sex dolls, humans are "dirty" androids, real world is a "dirty" Matrix.

I think you are misunderstanding what he means by dirty. Dirty drug in pharmacological context, is a drug with wide range effects (across many receptors, systems)
Nicotine in comparison to a selective a4b2 agonist would be considered dirty.

[Metagene]

While I don't completely agree with yada's argument the data on GTS-21 speaks for itself. 

Edited by Metagene, 04 August 2014 - 02:40 PM.

[ZHMike]

Data looks very promising.  This study is 10+ years old, Taiho pharm would have surely marketed this product if the data was this good...  So the question is why they did not?  Someone should reach out to them, they are still around.  

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[lourdaud]

Probably works great, until tolerance sets in. 

[ZHMike]

hey lourdaud that was my first though

 

[medicineman]

Probably works great, until tolerance sets in.

strangely, agonizing a4b2 causes receptor desensitization. so tolerance may not be an issue.

Edited by medicineman, 04 August 2014 - 03:16 PM.

[Metagene]

 

Probably works great, until tolerance sets in.

strangely, agonizing a4b2 causes receptor desensitization. so tolerance may not be an issue.

 

 

 

 

 

 

DMXBA, like nicotine, enhances auditory gating in mice [78] and in humans [71]. The DMXBA enhancement displays less acute tolerance (i.e., reduced response with successive applications) than does the nicotine effect. 

 

 

http://www.ncbi.nlm....edrugs-04-00255

[Reformed-Redan]

That's actually amazing for a nootropic to get better with repeated doses.

[Reformed-Redan]

Does anyone else realize from the graphs posted above for word recall that retention of words memorized is actually better than the forgetfulness curve... And by a wide margin. Which means that you practically don't forget what you memorize. Personally I find that amazing that you can beat the forgetfulness curve by so much.

[nightlight]

I think you are misunderstanding what he means by dirty. Dirty drug in pharmacological context, is a drug with wide range effects (across many receptors, systems)
Nicotine in comparison to a selective a4b2 agonist would be considered dirty.

 

 

It was perfectly clear what he meant (you merely repeated his explanation, anyway). I parodied his gratuitous use of emotionally charged attributes with negative connotations such as "dirty" (or equivalently "noisy", "messy", "stinky"...). He was obviously parroting the typical pharma-speak about anything they wish to suppress i.e. anything helpful to human health they don't have patent on, such as "dirty" nicotine, or god forbid, the "yucky", "stinky", "carcinogenic" ... tobacco (meaning in pharma-speak  ancient medicinal plant, the original alpha-7 agonist with myriad other benefits and no lifelong damages and side effects of the one dimensional pharma knockoffs).

[Reformed-Redan]

 

I think you are misunderstanding what he means by dirty. Dirty drug in pharmacological context, is a drug with wide range effects (across many receptors, systems)
Nicotine in comparison to a selective a4b2 agonist would be considered dirty.

 

 

It was perfectly clear what he meant (you merely repeated his explanation, anyway). I parodied his gratuitous use of emotionally charged attributes with negative connotations such as "dirty" (or equivalently "noisy", "messy", "stinky"...). He was obviously parroting the typical pharma-speak about anything they wish to suppress i.e. anything helpful to human health they don't have patent on, such as "dirty" nicotine, or god forbid, the "yucky", "stinky", "carcinogenic" ... tobacco (meaning in pharma-speak  ancient medicinal plant, the original alpha-7 agonist with myriad other benefits and no lifelong damages and side effects of the one dimensional pharma knockoffs).

 

Oh, thanks. I guess. 

 

Anyway, any quotes for this nootropic? And when I say "nootropic", I mean nootropic-as shown above. 

[medicineman]

Probably works great, until tolerance sets in.

strangely, agonizing a4b2 causes receptor desensitization. so tolerance may not be an issue.

DMXBA, like nicotine, enhances auditory gating in mice [78] and in humans [71]. The DMXBA enhancement displays less acute tolerance (i.e., reduced response with successive applications) than does the nicotine effect.

http://www.ncbi.nlm....edrugs-04-00255

This isn't specific to a4b2. there are a couple of decent papers on agonists and desensitization specifically with regards to a4b2. nicotine is actually quite potent at desensitizing a4b2. I'm typing on my phone so it is a hassle to link them, but they are easy to find on Google.

[Sunifiramses II]

According to Wikipedia, GTS-21 "binds to both the α4β2 and α7 subtypes, but activates only the α7 to any significant extent." Does anyone (serious question) have reason to doubt this claim? I'm asking because I hear a lot of people talking about the effects on a4b2.

 

Edit: Wiki cites these two studies from 1997. Perhaps these are contradicted by later research?

Edited by Sunifiramses II, 04 August 2014 - 09:12 PM.

[Blomj]

This is very interesting. I did a google search and found a site that sells it (can I link supplier sites here?). Any idea about the long-term benefits?  

 

Also, how is it administered?

Edited by Blomj, 04 August 2014 - 10:51 PM.

[Metagene]

According to Wikipedia, GTS-21 "binds to both the α4β2 and α7 subtypes, but activates only the α7 to any significant extent." Does anyone (serious question) have reason to doubt this claim? I'm asking because I hear a lot of people talking about the effects on a4b2.

Edit: Wiki cites these two studies from 1997. Perhaps these are contradicted by later research?

Good question

GTS-21 (3-[2,4-dimethoxybenzylideneanabaseine, 2-2) is a “functionally”
selective partial agonist drug for α7 nAChR (Ki= 211 nM against [125I]α-bungarotoxin). It is also known to bind to the 5-HT3A (Ki= 0.53 ± 0.9 μmol against [3H]GR65630) and α4β2 nAChR (Ki= 84 nM against [3H]Cytisine).2-4 It was first synthesized in 1993 from anabaseine, a natural product isolated from a marine worm, nemertines and Aphaenogaster ant (Fig. 2.1).5, 6 While anabaseine is a full agonist for α7 nAChR and muscular nAChR, GTS-21 is a partial agonist for α7 nAChR and an antagonist for muscular nAChR and α4β2 nAChR. This α7 nAChR functionally selective agonism of GTS-21has led to interest in the pharmacological effects of α7 nAChR last ten years.

Many preclinical studies documenting its efficacy in cognition, learning and its neuroprotective properties7, 8 set the stage for investigations in humans for the treatment of Alzheimer’s disease to enhance working memory and attention. Its investigation as a drug for the treatment of AD was supported by reports that the α7 nAChR system, not α4β2 nAChR, is intact in the cortex in AD brain.9, 10 In clinical phase I trial for AD, GTS- 21 enhanced cognition in a dose dependent manner without the side effects seen with nicotine itself.

Because of its ability to normalize auditory gating deficit in the rodent model, GTS-21 is also under investigation for the treatment of schizophrenia where it was recently reported to enhance cognitive function in a human study. However, the utility of GTS21 as a drug has been challenged by Tatsumi et al. who comments that GTS-21 “fails to show a satisfactory pharmacokinetics profiles (PK) in the areas of bioavailability and brain permeability.”

In view of metabolism, the phase I metabolism of GTS-21 is known to involve O- demethylation to give three metabolites, 2-OH-GTS-21, 4-OH-GTS-21 and 2,4-diOH- GTS-21 (Figure 2.2). Interestingly, the major metabolite, 4-OH-GTS-21 shows active partial agonistic activity for α7 nAChR which is 10 times greater than GTS-21 itself (Ki= 0.45 ± 0.02 μmol and 23 ± 2 μmol for human SK-N-SH cells, respectively). However, even though the metabolites of GTS-21 are more potent at the alpha-7 nAChR than the parent compound, their brain penetration is not known and consequently the relevance of these metabolites to the therapeutic effects of GTS-21 in humans is not known

http://gradworks.umi...34/3334915.html

Edited by Metagene, 04 August 2014 - 11:32 PM.

[normalizing]

i see a lot of jibba jabba going on here, did anyone try it yet to report and discuss or are we going to continue sucking each others dicks until one of us comes with the goods....

Edited by normalizing, 05 August 2014 - 12:45 AM.

[Reformed-Redan]

i see a lot of jibba jabba going on here, did anyone try it yet to report and discuss or are we going to continue sucking each others dicks until one of us comes with the goods....

LOL! Looking for a supplier. Can I get a show of hands, who's interested for preparing for finals and other exams in a "nootropic" manner,  . Gotta always be ahead of the curve. 

[lourdaud]

 

Probably works great, until tolerance sets in.

strangely, agonizing a4b2 causes receptor desensitization. so tolerance may not be an issue.

 

 

The improvements in working memory and IQ is probably more related to a7n agonism and unfortunately that receptor gets down-regulated very quickly.

 

 

 

Probably works great, until tolerance sets in.

strangely, agonizing a4b2 causes receptor desensitization. so tolerance may not be an issue.

 

 

 

 

 

 

DMXBA, like nicotine, enhances auditory gating in mice [78] and in humans [71]. The DMXBA enhancement displays less acute tolerance (i.e., reduced response with successive applications) than does the nicotine effect. 

 

 

http://www.ncbi.nlm....edrugs-04-00255

 

Nicotine is great for sensory gating issues and tolerance doesn't seem to build up entirely to those effects but it's not of much use for ADHD long-term IME. Same goes for galantamine and nefiracetam (other a7n agonists). I don't see why GTS-21 should be any different.

[normalizing]

 

i see a lot of jibba jabba going on here, did anyone try it yet to report and discuss or are we going to continue sucking each others dicks until one of us comes with the goods....

LOL! Looking for a supplier. Can I get a show of hands, who's interested for preparing for finals and other exams in a "nootropic" manner,  . Gotta always be ahead of the curve. 

 

 

cool. if you find supplier, post. hopefuly someone tries it eventually!

[ocean.soul]

Does anyone know how can i do to get through custums??

where I live it is almost impossible... we have a kind of meeting when something pill-like arrives from another country... So maybe if it is sent to me in something very different than a pill? what do you think? is it too crazy? lol. Any ideas??
 

[Metagene]

i see a lot of jibba jabba going on here, did anyone try it yet to report and discuss or are we going to continue sucking each others dicks until one of us comes with the goods....

 

normalizing keeping it real. 

 

I wanted Superhimik to take a look at this on reddit but I'll post it here too. 

 

http://www.ncbi.nlm....les/PMC1573461/

[crazepharmacist]

Would be absolutely floored if a supplier picked this compound up!

[Nootrapedia]

Does anyone know the half life of this compound? Is the information coming from pg 547 of http://www.readcube..../sj.npp.1300028 this paper?

[nightwolfz]

This sounds very promising. Here's another thread about the same compound http://www.longecity...2-gts-21dmxb-a/

[crazepharmacist]

Any update on the availability of this compound? Pretty eager to try it with the Fall semester getting underway.