57 replies to this topic

[Florian Seichert]

Hey, 

 

I was bored over the last couple of hours so I tried to figure out how NSI-189 might work. 

 

--------------------------The following work might not represent its real mechanism of action-----------------------------

 

I ran the compound through some target prediction algorithms and got the following output. 

 

 

 

The algorithm uses a database of molecules and compares the structure the compound to similar already known bioactive molecules and calculates the target probabilities. 

 

Modulation of JAK-STAT pathway?

The first 4 matches are the most interesting in terms of "neurogenesis". They indicate that NSI might interact with the JAK-STAT pathway which is really interesting. It may have modulating or inhibitory effects on the Tyrosine-protein kinase JAK/Janus kinase. 

There are structure similarities NSI and the JAK inhibitor Momelotinib. 

There is an evidence that inhibition of JAK and JAK-STAT regulation promotes neurogenesis. The hole subject in damn complex so I skip the part of explaining how, why and when. Maybe I will post some more information the next days...

https://www.ncbi.nlm...les/PMC4360852/

https://www.ncbi.nlm...pubmed/20979137

Moreover I found a paper that connects JAK and its inhibition to major depressive disorder.

 

https://www.karger.c...icle/PDF/442613

Just an example: 

 

Jak-3 inhibitors increase hippocampal neurogenesis

In the next series, we determined whether stress has a direct impact on the phosphorylation status of Jak-3 (Fig. 3). Phosphorylation of Jaks is a measurement of the activity of these kinases [19]. Further, we analysed whether Stat-3, a target of Jaks [19], is phosphorylated and thereby activated after stress and whether the Jak-3 inhibitor prevents this phosphorylation (Fig. 3). These data demonstrate that stress induces phosphorylation of Jak-3 in the hippocampus, which is prevented by treatment with the Jak-3 inhibitor IV (Fig. 3A). Phosphorylation of Stat-3 was not altered after stress, nor after treatment with the Jak-3 inhibitor, indicating that Stat-3 does not serve as target of Jak-3 after stress in hippocampal neurons (Fig. 3B)

Sounds like this could be part of NSIs neurogenic effect. Please let me know if you wish more detailed explanation. 

 

Interaction with serotonin and dopamine receptors

According to the target prediction report there is a nameable interaction potential with the serotonin/5-ht 1a receptor supposedly as an agonist/partial agonist science you  get a moodlift or immediate antidepressive/anxiolytic effect. 

There is also an interaction potential with dopamine D2 and D3 receptors probably agonistic (like most compounds with similar structure) which would explain the stimulating effect. 

 

Activation of Multidrug resistance protein 1

In short for this context: The Multidrug resistance protein 1 is a kind of transporter which pups drugs out of the cell. Once the transporter is activated drugs are carried out and are no longer able to operate correctly. I have made the personal experience that taking NSI while on a medication like Dexedrine or Vyvanse the NSI cancels or diminishes their effect. This could be the explaination why. 

 

All right. If you have any more information or ideas how NSI could work please let me know

Florian

Attached Files

•  TargetPredictionReport.jpg   185.96KB   19 downloads
•  Screenshot_20161228_144624.png   531.33KB   17 downloads

Edited by Florian Seichert, 28 December 2016 - 05:02 PM.

[Florian Seichert]

Yes GABA is somehow neuroprotective (but not neurogenic i think) against exotoxicity but i don't believe its GABA related. If it was there would be signs of tolerance by the time but the neurogenic effect takes place over time. It must be far more complex. 

 

If it triggers partial seizures in an epileptic it could be indeed glutamatergic in some way. Maybe some sort of glycine reuptake inhibitory effect. There are other piperazine compounds (like Bitopertin) working like this. 

[Mind_Paralysis]

MOST interesting data! May I ask what the program and algorithm you used, is called? It would be very interesting to run other molecular structures through it, and see what some of the other exotic molecules used by the Nootropics-community would show probable affinity for.

 

Btw, curious that you find NSI-189 to dampen the effects of Vyvanse, because me and several others seem to find it the other way around! Well, at first at least - it seems to synergize with Vyvanse, causing even MORE stimulation than Vyvanse alone - this effect then seems to dampen, possibly then from downregulation of D2-receptors? Does some people simply have a natural resistance towards MRP1 and MRP3 then? Or does it take a certain time before the effects of MRP is felt?

[Florian Seichert]

Sure, the target prediction report is cut from a web-based analysis (http://www.swisstargetprediction.ch/). I additionally set up a webserver with MyChemBl to compare the data. 

 

When it comes to Vyvanse: I think in the first period of time the Stimulating effects of Vyvanse will be added to those of NSI. But later it felt like it would dampen the effects of Vyvanse and several other meds (Maybe due to D2 Downregulation and/or MRP activity).

The MRP1 (also called p-glycoprotein) pumps substances out of the brain. The activity of MRP1 differs individually. Thats one reason why person A feels a drug for 1-2 hours while person B about 2-4 hours. The important thing is it does not affect plasma clearance. Thats also why so many substances have a long half-life but the subjective effects only take place in a small period of time. A lot of people say that they feel the (short time) effects of NSI several hours while half life is from 17.4 to 20.5 hours. That could be some reason for this. 

Maybe it really takes some time before the transporters get adjusted. 

[Florian Seichert]

On another forum I found a post which underlines my assumption about the MRP-thing: 

 

Cut from: http://forum.biohack...si-189-tipss/p1

 

Interestingly, NSI-189 seems to reduce addiction/drug-seeking behavior. 

For example, NSI-189 blunts the effect of nicotine, stimulants, modafinil, etc. for me. I wonder what underlies this effect. 

 

The reduction of drug-seeking behavior is something I can confirm. In the past I combined NSI with some recreational drugs (Not my intention but it was still in my system). Mostly research chemicals like 3MMC, 5MAPB, Diphenidine/Methoxphenidine NMDAR-antagonists)). 

In any case the effects of all of them were strongly reduced or even cancelled out. 

 

A quick report what NSI did for me: 

After this short period of drug abuse I just realized how much NSI did for me, my brain and my family. 

I was able to feel emotions (again) wich was so fantastic cause I am on autism spectrum disorder (Asperger). I experienced this like never before. For me it was like MDMA without MDMA. Empathy, fears, guilty , love and so on. Music feels so nice. Things which are not common for me. (Maybe it has to do with 5HT agonism and neurogenetic effects in combination)

Moreover my Depression was completely gone for weeks and I got back all my ambition and I could clearly see my perspectives. It was the feeling I can reach everything I want. So much positives thoughts. So unbelievable. 

I could Strongly feel the nootropic effects. My concentration was high and I could read without glases, huge memory boost, faster thinking. There was just one down side. My psychotic symptoms got a little bit stronger (currently on Abilify 15mg). Possibly because of D2-receptor agonism and BRP activation.

 

More reports will follow connecting the effects with it MOA. 

[Sciencyst]

Holy cow I can't believe I missed this amazing post!!! You sir, are amazing. It's funny, I was trying to figure this stuff out but it was a bit like fumbling in the dark - I had never tried predicting binding properties but my search led me to SwissDock... which I used to compare WAY 100,635 and NSI-189's docking to the D₄ receptor. I really should have looked around the site more, I didn't notice the target prediction! I'm going to have to spend a lot of time messing around with it though. Such a cool tool!

 

Here's a picture of the side by side results. WAY is on the left, NSI on the right. I don't know how to interpret them, but I would expect D₄ binding might occur at normal doses.

 

 nsiwaybinding.png   324.13KB   10 downloads

So, your results indicate some 5HT_1A partial agonist activity. I think this explains the itching and paresthesia some have experienced on NSI-189. From the Wikipedia page on WAY 100,635 "Paradoxically, chronic administration of the very high efficacy 5-HT_1Aagonist befiradol results in potent analgesia following an initial period of hyperalgesia, an effect most likely linked to desensitisation and/or downregulation of 5-HT_1A receptors (i.e. analogous to a 5-HT_1A antagonist-like effect)."
 

So maybe downregulation of 5HT_1A by NSI-189 is causing hyperalgesia.

I wonder if we should be concerned about dopamine receptor downregulation from NSI-189. Enough people have anhedonia on here as is, I hope it doesn't make it worse.

Oh, and what do you think about NSI-189's metabolism? Piberaline and befuraline share the same BZP/ketone structure of NSI, and both of these are pro-drugs for BZP. I did notice on one night a strong intensification in stimulating effects about 18 hours after dosing. Could this be from BZP metabolism?

[Mind_Paralysis]

Holy cow I can't believe I missed this amazing post!!! You sir, are amazing. It's funny, I was trying to figure this stuff out but it was a bit like fumbling in the dark - I had never tried predicting binding properties but my search led me to SwissDock... which I used to compare WAY 100,635 and NSI-189's docking to the D₄ receptor. I really should have looked around the site more, I didn't notice the target prediction! I'm going to have to spend a lot of time messing around with it though. Such a cool tool!

 

Here's a picture of the side by side results. WAY is on the left, NSI on the right. I don't know how to interpret them, but I would expect D₄ binding might occur at normal doses.

 

nsiwaybinding.png

So, your results indicate some 5HT_1A partial agonist activity. I think this explains the itching and paresthesia some have experienced on NSI-189. From the Wikipedia page on WAY 100,635 "Paradoxically, chronic administration of the very high efficacy 5-HT_1Aagonist befiradol results in potent analgesia following an initial period of hyperalgesia, an effect most likely linked to desensitisation and/or downregulation of 5-HT_1A receptors (i.e. analogous to a 5-HT_1A antagonist-like effect)."
 

So maybe downregulation of 5HT_1A by NSI-189 is causing hyperalgesia.

I wonder if we should be concerned about dopamine receptor downregulation from NSI-189. Enough people have anhedonia on here as is, I hope it doesn't make it worse.

Oh, and what do you think about NSI-189's metabolism? Piberaline and befuraline share the same BZP/ketone structure of NSI, and both of these are pro-drugs for BZP. I did notice on one night a strong intensification in stimulating effects about 18 hours after dosing. Could this be from BZP metabolism?

 

I doubt it, mainly because most people report that NSI-189 is only stimulating in the first few days of use - then it becomes either neutral or quite sedating! I myself also have the disease known as SCT, and I did not find NSI-189 stimulating at all, nor did I find that it improved ADHD-like symptoms - in fact, I think I was MORE hyperactive on it!

 

However, hyperactivity is actually also a feature of ANXIETY, and I definitely had more anxiety while on the drug - interestingly enough, once you reach adulthood, hyperactivity is actually more associated with anxiety than with adhd.

 

BZP is reported to have similar effects to Amphetamine, which enhances focus and treats ADHD - alas, I did NOT notice any such effects, following prolonged use of the drug. In theory, the BZP-metabolite would be much more noticeable after prolonged use - but I, and many others, do not find it more stimulating with prolonged use.

Of course, there's also the small note that BZP, even though users report it as such, is NOT AMPHETAMINE - it actually seems to affect serotonin far, far more than Dopamine or Norepinephrine, as such, the stimulant effects of BZP may be completely and utterly useless for the treatment of ADHD or SCT.

 

I think there IS some concern for dopamine receptor downregulation - the fact that Amphetamine salts are first potentiated by NSI-189, but then WEAKENED, could well indicate downregulation... However, there have not been any big reports of anhedonia while on the drug, nor any such persistent effects upon discontinuation either, so it remains a bit ambiguous.

 

It think we can safely say it has D2 and D3 -agonistic properties though - but perhaps it's only partial agonism?

 

 

Interesting note regarding the potential D4-agonistic properties - because the D4-receptor is theorized to be the MOST important D-receptor when it comes to cognition, and faulty D4-receptors is believed to be the source of the inattentive symptoms of ADHD - however, once again, one must ponder how strong this effect is... because I have not, nor have others, noted any enhanced effects on penile erection (this is a feature of most D4-agonists, such as the legendary A-412,997), and the effects on ADHD-like symptoms are... inconsistent, to say the least.

Edited by Stinkorninjor, 13 March 2017 - 09:28 AM.

[Finn]

Neuralstem has released summary of  their de novo screening and DISCOVERX KinomeScan results, there doesn't seem to be any overlapping with those computer simulation results. Computer simulations have their limits, producing the substance and running actual screenings on it are often necessary for better results.

 moa – kopio.jpg   148.88KB   17 downloads

Edited by Finn, 13 March 2017 - 10:59 AM.

[Florian Seichert]

Interesting. Opioid are receptor involved. Nice

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

[Florian Seichert]

Can you provide a link?

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

[Finn]

Can you provide a link?

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

http://investor.neur...l-presentations

 

Took it from March 2016 presentation there, can also be found in some of the other presentations there.

[Florian Seichert]

2016? Can't go down to march 2016 only up to september

Gesendet von meinem ONEPLUS A3003 mit Tapatalk
Or did you mean 2017?

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

[Finn]

2016? Can't go down to march 2016 only up to september

Gesendet von meinem ONEPLUS A3003 mit Tapatalk
Or did you mean 2017?

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

 

Hmm, I can't see any representation from September on that page.

 

Here is direct download link to,

 

June 2016 Corporate Presentation MOA Insight

 

It has that same data on page 12, and, not surprisingly, more focused on MOA than other presentations.

 

 http://phx.corporate...FR5cGU9MQ==&t=1

Edited by Finn, 13 March 2017 - 11:29 AM.

[Mind_Paralysis]

Interesting. The Opioid receptors are involved. Nice

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

 

Well... I don't know about that!

 

I mean, there's a magnitude of 15 TIMES greater affinity to the NET according to that table, and 7 times or so, greater affinity towards the 5HT3-receptor.

 

Hmm... does it say anywhere whether or not this effect is agonistic or antagonistic?

The most logical conclusion towards the NET is that it's a terribly weak NRI, since no NRE has ever been recorded in existence, nor have DRE ever been recorded, and the only compound known to have SRE-effects is Tianeptine, a compound vastly different in chemical structure to NSI-189 - so, purely from a statistical stand-point, it's probably an NRI.

But what can we conclude from the 5HT3-effects?

 

Is it an agonist or antagonist? As far as I can tell, the only 5HT3-selective antagonists known are antipsychotics or antiemetics (often both) - selective 5HT3-antagonists are currently being researched as hyper-atypical antipsychotics, with particularly good results on negative symptoms - interestingly enough also in PARKINSONS PSYCHOSIS, and not just in schizotypal psychosis.

 

Hmm... the strange lapses in rage and anxiety seem a bit at odds with an antipsychotic effect though... not sure if I, or anyone else, would notice any antiemetic effects either. (we wouldn't know to look for it)
 

Could those of you with greater knowledge and understanding of drug design have a look at the drug design-section on 5-HT3-antagonists and see if there are ANY structural hints from the different classes of 5-HT3-antagonist out there, and see if they correlate at all with NSI-189's molecular structure?

 

https://en.wikipedia...ist#Drug_design

 

I'm too tired to truly learn this and discern it for myself, alas.

 

 

Regarding 5-HT3-agonists, I must also admit towards complete ignorance - what do we know of any known 5-HT3-agonists? There doesn't appear to be as much research put into the actions of these... many of the reported compounds are definitively PRO-psychotic though! Ethanol, BZP (interesting coincidence there... certainly lends credence to the idea that NSI-189 is a 5-HT3-AGONIST...!)  and others all cause psychosis - but they have such diverse and complex mechanisms, that one can't say it's because of 5-HT3-agonism, more like a combination of actions. It should be noted that one selective 5-HT3-agonist has memory-enhancing properties though, which is certainly interesting.

 

 

Otherwise... this disclosure mentions nothing about JAK-STAT, which could be deliberate on Neuralstem's part - that COULD still be the effect which the drug has, which they don't want to disclose, it also fits the bill for not being a neurotransmitter pathway, and would technically be true in their disclosure on binding-affinity testing.

[PeaceAndProsperity]

 

Is it an agonist or antagonist? As far as I can tell, the only 5HT3-selective antagonists known are antipsychotics or antiemetics (often both) - selective 5HT3-antagonists are currently being researched as hyper-atypical antipsychotics, with particularly good results on negative symptoms - interestingly enough also in PARKINSONS PSYCHOSIS, and not just in schizotypal psychosis.

 

 

Interesting that you should mention this. Here I was asking myself whether the 5ht2a receptor is the only serotonin receptor known to cause psychosis (in terms of positive symptoms, hallucinations, delusions, thought disorder).

 

But I can say for certain that antipsychotics do not deal with the deficit symptoms of psychosis more than a very tiny part and that's almost certainly due to catecholamines or the 5ht2a receptor.

[Finn]

 

Interesting. The Opioid receptors are involved. Nice

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

 

Well... I don't know about that!

 

I mean, there's a magnitude of 15 TIMES greater affinity to the NET according to that table, and 7 times or so, greater affinity towards the 5HT3-receptor.

 

Hmm... does it say anywhere whether or not this effect is agonistic or antagonistic?

The most logical conclusion towards the NET is that it's a terribly weak NRI, since no NRE has ever been recorded in existence, nor have DRE ever been recorded, and the only compound known to have SRE-effects is Tianeptine, a compound vastly different in chemical structure to NSI-189 - so, purely from a statistical stand-point, it's probably an NRI.

But what can we conclude from the 5HT3-effects?

 

Is it an agonist or antagonist? As far as I can tell, the only 5HT3-selective antagonists known are antipsychotics or antiemetics (often both) - selective 5HT3-antagonists are currently being researched as hyper-atypical antipsychotics, with particularly good results on negative symptoms - interestingly enough also in PARKINSONS PSYCHOSIS, and not just in schizotypal psychosis.

 

Hmm... the strange lapses in rage and anxiety seem a bit at odds with an antipsychotic effect though... not sure if I, or anyone else, would notice any antiemetic effects either. (we wouldn't know to look for it)
 

Could those of you with greater knowledge and understanding of drug design have a look at the drug design-section on 5-HT3-antagonists and see if there are ANY structural hints from the different classes of 5-HT3-antagonist out there, and see if they correlate at all with NSI-189's molecular structure?

 

https://en.wikipedia...ist#Drug_design

 

I'm too tired to truly learn this and discern it for myself, alas.

 

 

Regarding 5-HT3-agonists, I must also admit towards complete ignorance - what do we know of any known 5-HT3-agonists? There doesn't appear to be as much research put into the actions of these... many of the reported compounds are definitively PRO-psychotic though! Ethanol, BZP (interesting coincidence there... certainly lends credence to the idea that NSI-189 is a 5-HT3-AGONIST...!)  and others all cause psychosis - but they have such diverse and complex mechanisms, that one can't say it's because of 5-HT3-agonism, more like a combination of actions. It should be noted that one selective 5-HT3-agonist has memory-enhancing properties though, which is certainly interesting.

 

 

Otherwise... this disclosure mentions nothing about JAK-STAT, which could be deliberate on Neuralstem's part - that COULD still be the effect which the drug has, which they don't want to disclose, it also fits the bill for not being a neurotransmitter pathway, and would technically be true in their disclosure on binding-affinity testing.

 

 

Not sure if it is terribly weak.

 

From Neuralstem March 2016 presentation

 

Norepinephrine transporter IC50 (µM) for NSI-189 1.1 μM

 

Bupropion and hydroxybupropion are weaker, IC50 values of 1.9 and 1.7 μM, of course bupropion dose is larger than NSI-189 dose, but bupropion's bioavailability is believed to be pretty poor, so their net NET effect could be relatively close.

 

http://molpharm.aspe...t/66/3/675.full

 

Racemic bupropion and hydroxybupropion inhibit [3H]norepinephrine (NE) uptake with similar potency (IC50 values of 1.9 and 1.7 μM, respectively)

 

 

 

http://www.rxlist.co...harmacology.htm

 

 

The absolute bioavailability of WELLBUTRIN in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.

 

 

 

 

When it comes to agonist or antagonist:

 

 

Object of any size can block the keyhole opening, but not all objects can fit the keyhole and act as a key. To act as antagonist, it just has to attach to the receptor and block "natural" agonists from activating the receptor, to act as agonist, it has to attach to the receptor and act on it somewhat like "natural" agonist. So pretty much always when lots of receptors are listed without specification, it is antagonist activity, I can't come up with any substance that is broad spectrum agonist and not antagonist for anything.

Edited by Finn, 13 March 2017 - 05:39 PM.

[Mind_Paralysis]

 

 

Is it an agonist or antagonist? As far as I can tell, the only 5HT3-selective antagonists known are antipsychotics or antiemetics (often both) - selective 5HT3-antagonists are currently being researched as hyper-atypical antipsychotics, with particularly good results on negative symptoms - interestingly enough also in PARKINSONS PSYCHOSIS, and not just in schizotypal psychosis.

 

 

Interesting that you should mention this. Here I was asking myself whether the 5ht2a receptor is the only serotonin receptor known to cause psychosis (in terms of positive symptoms, hallucinations, delusions, thought disorder).

 

But I can say for certain that antipsychotics do not deal with the deficit symptoms of psychosis more than a very tiny part and that's almost certainly due to catecholamines or the 5ht2a receptor.

 

 

Hold your horses now - you, nor hardly anyone else, has actually used a selective 5-HT3-antagonist - have a look at the trials for those - they really do show some very good results - particularly, they seem to help a lot with side-effects such as extrapyramidal ones.

 

Have a look at Ondansetron, that compound is seemingly, proving you wrong.

 

https://en.wikipedia...setron#Research

 

5-HT3-agonists also definitively cause psychosis - for instance, BZP is far more selective towards serotonin than it is dopamine or norepinephrine, yet it's still one helluva' drug in that regard - definitively not a drug you want to underestimate if you have schizoidal features.

 

Many times, more recent data on the inner workings on the brain and the drugs which affect it, have shown things in a new light - the 5-HT3-receptors potential role in psychosis is another one of these recent findings - much like how neurogenesis is the true effect of antidepressants, and how serotonin down-regulation is the true effect in anxiolysis.

 

NO-ONE would have guessed that, with our previous understanding of the brain, but now these findings are putting things in new light.

[PeaceAndProsperity]

 

 

 

 

 

Hold your horses now - you, nor hardly anyone else, has actually used a selective 5-HT3-antagonist - have a look at the trials for those - they really do show some very good results - particularly, they seem to help a lot with side-effects such as extrapyramidal ones.

 

Have a look at Ondansetron, that compound is seemingly, proving you wrong.

 

https://en.wikipedia...setron#Research

 

5-HT3-agonists also definitively cause psychosis - for instance, BZP is far more selective towards serotonin than it is dopamine or norepinephrine, yet it's still one helluva' drug in that regard - definitively not a drug you want to underestimate if you have schizoidal features.

 

Many times, more recent data on the inner workings on the brain and the drugs which affect it, have shown things in a new light - the 5-HT3-receptors potential role in psychosis is another one of these recent findings - much like how neurogenesis is the true effect of antidepressants, and how serotonin down-regulation is the true effect in anxiolysis.

 

NO-ONE would have guessed that, with our previous understanding of the brain, but now these findings are putting things in new light.

 

I just learned that Risperidone does not target these receptors.

 

I guess my experience that serotonin-increasing agents tend to worsen affective blunting (but sometimes paradoxically the opposite), possibly independently of the 5ht2a receptor, may have to do with the 5ht3 rceptors.

 

In pharmacology, does targeting a receptor mean you automatically target all subreceptors, such that a 5HT2 antagonist is also an antagonist of all subreceptors, 5HT2A,B,C ...?

 

Anyway, I guess by the time a drug is developed to target these new disease models, and it actually gets approved in the European Union, and then used in my country, I will either have killed myself or genetic engineering would have become a thing.. I'm talking 20-40 years from now.. sigh.

 

[Sciencyst]

IC50 means the dose at which a receptor is inhibited by 50%. It's proper meaning is Half Maximal Inhibitory Concentration. So all values in that presentation are inhibition of the receptors. Whether this means inverse agonist, neutral antagonist, or partial agonist is unknown. The opposite is EC50 - half maximal effective concentration. We don't know EC50 values for NSI-189, but I have a feeling it might act as an agonist at some oher 5HT subtypes. The opioid receptor inhibition explains the hyperalgesia, and also explains why cannabis persistently prevents the hyperalgesia in my experience.

Edit: I suppose I should also add that I do have experience with ondansetron, a selective 5HT3 antagonist used for nausea. All I can really say about it is that it's slightly relaxing and helps a lot with nausea lol. I've noticed that green tea which is steeped for too long hasn't made me nauseous since starting NSI 189, but it usually did before.

Edited by UltraCitron, 15 March 2017 - 07:38 AM.

[AOLministrator]

Is there any metabolic simulator?

 

It might still be that some NSI-189 metabolizes into piberaline, which partly metabolizes into BZP.

 

Regardless of whatever NSI-189 does by itself.

 

 

The simulator seems to be pretty good though. Its almost entirely accurate with most drugs, but then weirdly fails with simplest stuff like GHB.

Edited by AOLministrator, 15 March 2017 - 05:28 PM.

[Florian Seichert]

Unfortunately there is no simulator for metabolism I know about. You can predict its metabolites by comparing similar compounds where the metabolism is known.
But I think we have to wait for more Infos by neuralstem.
They indeed know about metabolism and they would have thrown it already if there was an evidence that it metabolizes into psychoactive and potentially harmful bzp analogous I think.

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

[Sciencyst]

Unfortunately there is no simulator for metabolism I know about. You can predict its metabolites by comparing similar compounds where the metabolism is known.
But I think we have to wait for more Infos by neuralstem.
They indeed know about metabolism and they would have thrown it already if there was an evidence that it metabolizes into psychoactive and potentially harmful bzp analogous I think.

Gesendet von meinem ONEPLUS A3003 mit Tapatalk

 

As much as I love NS, they are still a pharmaceutical company.. and there are abundant examples of pharma co's suppressing or "glossing over" information to get those sweet dollar bills. This is for the sake of discussion.

Trazodone, for example, metabolizes to mCPP, a BZP analogue that is significantly more harmful than straight-up BZP. It causes long-term anxiety in rodent models. And if you look at the structure, they would have needed to be totally blind to not notice the mCPP sub-structure. 
 

On a related note, I tried oral dosing yesterday at 50mg, and the effects were very, very different from sublingual administration. I'm thinking about getting a reagent test to see if I can detect BZP in my urine. Because I don't really want BZP in my system lol. Again.. this is speculation, I'm not saying it does or doesn't actually metabolize into BZP.

I also discovered that a small insufflated dose of 5-10mg rapidly assists in raising the flag pole, so to speak. From nada to fully raised in about 5 minutes. I'm not sure if there's just a short time window after dosing, or if it's just the ROA. I'll need to experiment further. 

Attached Files

•  Trazodone.svg.png   25.94KB   11 downloads
•  MCPP.svg.png   8.15KB   11 downloads

[Florian Seichert]

All right, keep us updated about the test

Gesendet von meinem Pixel C mit Tapatalk

[normalizing]

ultracitron, what are you references regarding this; Trazodone, for example, metabolizes to mCPP, a BZP analogue that is significantly more harmful than straight-up BZP. It causes long-term anxiety in rodent models

 

so, if long term use of trazodone is stopped suddenly it will cause anxiety, but i would think that is similar to the anxiety being there in the first place. i havent heard of trazodone worsening it so far, but antidepressants in general have withdrawal problems, if thats what you are referring to.

[Florian Seichert]

IC50 means the dose at which a receptor is inhibited by 50%. It's proper meaning is Half Maximal Inhibitory Concentration. So all values in that presentation are inhibition of the receptors. Whether this means inverse agonist, neutral antagonist, or partial agonist is unknown. The opposite is EC50 - half maximal effective concentration. We don't know EC50 values for NSI-189, but I have a feeling it might act as an agonist at some oher 5HT subtypes. The opioid receptor inhibition explains the hyperalgesia, and also explains why cannabis persistently prevents the hyperalgesia in my experience.

Edit: I suppose I should also add that I do have experience with ondansetron, a selective 5HT3 antagonist used for nausea. All I can really say about it is that it's slightly relaxing and helps a lot with nausea lol. I've noticed that green tea which is steeped for too long hasn't made me nauseous since starting NSI 189, but it usually did before.

 

 

So if IC50 is related to antagonistc properties then it should be an opioid receptor ( mu and delta) antagonist right?

Why then it synergise with tianeptine. Shouldn't it cancel tianeptines opioid-like effects out? 

Or binds tianeptine stronger to the receptors?

[Sciencyst]

ultracitron, what are you references regarding this; Trazodone, for example, metabolizes to mCPP, a BZP analogue that is significantly more harmful than straight-up BZP. It causes long-term anxiety in rodent models

 

so, if long term use of trazodone is stopped suddenly it will cause anxiety, but i would think that is similar to the anxiety being there in the first place. i havent heard of trazodone worsening it so far, but antidepressants in general have withdrawal problems, if thats what you are referring to.

 

Well, I read a study a long while ago claiming that mCPP caused long-term anxiety in rodents when administered chronically or at a young age. Unfortunately, I'm having trouble finding that study. But I do have several complementary studies, and some human anecdotal evidence:

 

An amalgam of mCPP & anxiety studies

 

• Evidence that mCPP-induced anxiety in the plus-maze is mediated by postsynaptic 5-HT2C receptors but not by sympathomimetic effects
   
• Serotonin function in anxiety. II. Effects of the serotonin agonist MCPP in panic disorder patients and healthy subjects.
  
   
• Moreover, administration of mCPP has been shown to elicit, and/or aggravate, anxiety attacks in patients with panic disorder, obsessions in patients with obsessive compulsive disorder (OCD), elation in alcoholics and cocaine addicts, and positive symptoms in schizophrenic patients (see Murphy et al. 1991; Kahn and Wetzler 1991; Krystal et al. 1993; Buydens-Branchey et al. 1993; Krystal et al. 1994). from Effects of mCPP on the Extracellular Concentrations of Serotonin and Dopamine in Rat Brain - http://www.nature.co...l/1395253a.html

• mCPP-induced anxiety in the light-dark box in rats--a new method for screening anxiolytic activity
   
• Bluelight Post about mCPP induced anxiety: 
  

   

   

  I am making this post as both a warning and an inquiry.
  
  My entire life, I have been both mentally and physically fairly healthy. For about ten years now, I have responsibly used MDMA and psychedelics mostly, with an occassional fray into weed and opiates, but very rarely. I have never once experienced any significant aftereffects from use of these substances. 
  
  I decided to try out some of the piperazines. mCPP and TFMPP to be exact. I used mCPP about 8 times in a 3 month period and TFMPP twice (in conjuction with mCPP). The effects were ok mostly, once very good, but during the onset I would feel a bit of panic each time. The TFMPP gave me a 5 hour long panic attack each time. I think that these substances somehow set something off in me that has left me open to anxiety.
  
  I have not touched any of these substances for about a month and a half now, but I'm still experiencing anxiety atleast half of the day and I have a lot of trouble getting to sleep. The only thing I have done since then is one MDMA session. Not surprisingly, the MDMA cleared up my anxiety for three days but then it returned to where it was. The anxiety is pretty bad and I sometimes feel like I am going to seizure or die of irregular heart beat...which is irrational I know, but it seems real to me then. I also sometimes get really odd thought patterns, similar to what I got on mCPP, and will space out and forget what I was thinking about 30 seconds prior and why I am thinking of what I am thinking of now (if that makes any sense). I will go to the doctor if this keeps acting up but I think it might be slowly letting off.
  
  I have seen these substances noted as panicogens in literature before and am just putting this out as a warning to anyone that is interested in trying them, if you have any history of anxiety disorders or even if you don't, these substances could possibly give them to you. I don't have any literature to back this up but only my personal experience. 
  
  Anyone else know why these substances might cause this? (BZP, mCPP, TFMPP) any of them? Just would like something that substantiates my warning is all.

  
  I'll continue looking for the original study I have in my mind and update if I find it.

 

IC50 means the dose at which a receptor is inhibited by 50%. It's proper meaning is Half Maximal Inhibitory Concentration. So all values in that presentation are inhibition of the receptors. Whether this means inverse agonist, neutral antagonist, or partial agonist is unknown. The opposite is EC50 - half maximal effective concentration. We don't know EC50 values for NSI-189, but I have a feeling it might act as an agonist at some oher 5HT subtypes. The opioid receptor inhibition explains the hyperalgesia, and also explains why cannabis persistently prevents the hyperalgesia in my experience.

Edit: I suppose I should also add that I do have experience with ondansetron, a selective 5HT3 antagonist used for nausea. All I can really say about it is that it's slightly relaxing and helps a lot with nausea lol. I've noticed that green tea which is steeped for too long hasn't made me nauseous since starting NSI 189, but it usually did before.

 

 

So if IC50 is related to antagonistc properties then it should be an opioid receptor ( mu and delta) antagonist right?

Why then it synergise with tianeptine. Shouldn't it cancel tianeptines opioid-like effects out? 

Or binds tianeptine stronger to the receptors?

 

Yes, this could possibly explain the hyper-algesia (pins and needles, painful tingling, neuropathy) that some people have reported in the main thread. This is also an effect I experienced when I tried a thrice-per-day (TID) dose. Cannabis, which indirectly influences opioid receptors, totally removed the itchiness for me. Tianeptine apparently binds to a rather odd array of opioid sub-types, so I'm not sure how to explain that. Maybe NSI-189 creates the paresthesia through a different mechanism. And maybe normal doses don't reach the IC50.

But to test, we would want someone to take a known, classic opiate like morphine and take NSI-189 alongside and report the effects. To see if Tianeptine's effects are mainly through opioid receptors, we would want to have someone test naloxone in combination with it. Theoretically.

[Sciencyst]

Okay, so I found some additional info on IC50. It appears that agonists can be measured by IC50 because they do indeed inhibit other ligands from binding while activating the receptor. This was found in relation to an mCPP analogue which is a very selective 5-HT₃ receptor agonist. The abstract denotes an IC50 for the agonist: https://www.ncbi.nlm.../pubmed/2144822

Also, I think 5-HT₃ antagonism would explain the anti-drug effects of NSI-189. I have also noticed that recreational substance effects have been substantially reduced. Cannabis is less intense, and I've lost most interest in alcohol. When I do drink, it hardly does anything. 

I highly recommend reading this review about the 5-HT₃ receptor's role in addiction and abuse and how it affects dopaminergic neurotransmission. Unless there's still some super-secret super-potent MoA, I think this article explains a lot of NSI-189's effects: 

The Role of 5-HT3 Receptors in Drug Abuse and as a Target for Pharmacotherapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878195/
   

[Florian Seichert]

But to test, we would want someone to take a known, classic opiate like morphine and take NSI-189 alongside and report the effects. To see if Tianeptine's effects are mainly through opioid receptors, we would want to have someone test naloxone in combination with it. Theoretically.

 

 

 

I could try to combine it with methadone the next days. See what happens...

[Florian Seichert]

From my experiences there is really a chance that it metabolizes partly into BZP. I am on Venlafaxine (Effaxor) and dosed the NSI for a short period of time around 120 mg. 

In the firs 4 hours I experienced the normal NSI effects like HD vision, incredible memory recall, strong anidepressant effects and the ability to feel emotions. 

Four hours after initial dose the effects changed. I got stronger colors, wired feeling and general diziness. I always thought it was in terms of the venlafaxine which I thought was potentiated by NSI. But it could also be the 2HT2A agonism of BZP and serotonergic effect of BZP mixed with still left but weaker NSI efffects. 

The clue is I didn't had such a drugged feeling from venla before. 

 

What do you think?

 

Edited by Florian Seichert, 23 March 2017 - 11:53 AM.

[gamesguru]

If anything, 2A agonists are going to aggravate anxiety.  Some cases respond very badly to NSI.  PTSD and trait anxiety are pretty sure bets, but generalized cases are more of a shot in the dark.  NSI is thought to be a predominately glucocoriticoidal drug paired off with a minor serotonergic component.  The serotonergic activity could explain why some people are responding worse than others.  Just consider how not all anxiety genotypes have a SERT polymorphism, and how not all anxiety patients respond to buspirone, abilify, or even celexa.  the so-called treatment-resistants.  serotonin just makes panic attacks worse.  see this case study of a 61 year old woman