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NSI-189 Mechanism Of Action

nsi-189 neurogenesis mechanism of action target prediction

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#31 hazy

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Posted 24 March 2017 - 02:55 AM

yeah ok, it might cause anxiety through its serotonin action, so its not really norepinephrine/dopamine type of a pro-sexual anxiety and its very unlikely this to occur you think? because, im not sure of experiences of serotonin overload anxiety and how they work, but overload of norepinephrine/dopamine anxieties are not that bad since they are also pro-sexual :o

 

though, i can imagine what serotonin overload pronounced anxiety might be like, zero sexual drive and lots of irritation and lack of motivation yikes


Edited by hazy, 24 March 2017 - 02:57 AM.


#32 UltraCitron

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Posted 26 March 2017 - 08:50 PM

I made a picture to highlight the structural similarities between BZP, Piberaline, Befuraline, and NSI-189:

nsi189bzp.png

 

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?

Wow interesting! So it seems to have a definite bi-phasic effect? This could indeed suggest some metabolism into something else. I don't have any experience with BZP, so I don't know if that sounds like a typical BZP experience - but it certainly sounds different. Venlafaxine and NSI-189 are both fairly potent NET inhibitors with serotonergic activity. And NSI-189 has a long half life, so perhaps it's just peaking 4 hours in? Or maybe it is metabolizing. We would need to test for BZP metabolites to know for sure. 
 

 

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

Well, Neuralstem's binding tests don't show any glucocorticoid activity, but did show very strong binding to 5HTand 5HT7. It wouldn't be surprising if it slightly activates other 5HT receptors. I think that the anxiety caused by NSI-189 can be explained by its strong nor-epinephrine reuptake inhibition. Taking venlafaxine gives me the same character of anxiety. Although, I think the 5HT3 activity changes the effects of norepinephrine and dopamine, as shown in the paper (The Role of 5-HT3 Receptors in Drug Abuse and as a Target for PharmacotherapyI linked about 5HTand in my last post. It seems like the 5HTreceptor could mediate the functioning of the 5HT system, and potentially normalize it for some people.

 

yeah ok, it might cause anxiety through its serotonin action, so its not really norepinephrine/dopamine type of a pro-sexual anxiety and its very unlikely this to occur you think? because, im not sure of experiences of serotonin overload anxiety and how they work, but overload of norepinephrine/dopamine anxieties are not that bad since they are also pro-sexual :o

 

though, i can imagine what serotonin overload pronounced anxiety might be like, zero sexual drive and lots of irritation and lack of motivation yikes

Again, I personally feel like the anxiety is caused by it's strong NRI properties. It feels similar to other NRI's, but I think the 5HT3 activity modulates the norepinephrine effects. 

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#33 Mind_Paralysis

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Posted 26 March 2017 - 11:18 PM

Hold up a minute... if that 5HT3-affinity is what we initially figured, ak a ANTagonistic - then NSI-189 could actually be a slightly potent antipsychotic! Which would mean, that yes, it would affect DA and NE even more, through this action - but presumably in an inhibiting way, yes?

 

On the other hand, the bouts of rage and irrationality which many of us have suffered, implies more like a psychotic action...

 

I can see those effects being caused by the NRI-effects, however, I don't think NRI-effects are enough to explain them - mainly because I'm on Atomoxetine at the moment, one of the purest and most potent NRI's out there - and it has never caused increased anxiety and mood-swings - on the contrary! Unlike NSI-189, it is actually slightly anxiolytic and seems more to... FLATline mood.

 

It also, causes fatigue - which admittedly, is something I have noticed on NSI-189 as well, just less so.

 

Curiously enough, an NDRI with other-modulating properties is the only drug which I can compare to NSI when it comes to the irrationality it induces: BUPROPION.

However, it does so while also making you less empathic - which is not a feature of NSI-189 - it seems to make me more empathic.

 

 

I suppose all three of these drugs are interesting examples, since they've got wildly differing effects, even though they've all got potent NRI-effects:
 

Bupropion

NSI-189

Atomoxetine

 

 

Hey, UltraCitron, could you have a look at Momelotinib as well, since the OP mentioned how there was structural similarities between that JAK-STAT modulator, and NSI-189? Would be interesting to see them side by side - along with the info on how that one metabolises.

 

 

BTW... can't we order drug-tests to check for this? If it metabolises into BZP or a similar metabolite, it would be possible to get a false positive at least, yes? Then we would know if that's an actual metabolite. Where does one find and order blood-tests for such a rare drug as BZP? (not exactly the go-to drug on the 12-panel tests, yes...?)

 

 

If it's of any use, I had a 12-panel drug test and it did not find jack sh*t - nothing, no compounds where in my blood-stream which would even give a false positive for any of the 12 most common drugs of abuse.

I believe I have read about other such reports on Reddit, where people taking NSI-189 had to undergo 12-panel tests. (mine was to prep me for treatment with Modafinil, it's considered a drug of abuse in my jurisdiction, so hence I needed to be checked for drugs)

 

 

Is BZP known to cause any false positives for amphetamines, MDMA, cocaine or anything like that?

Effects-wise it seems to be more like MDMA, so I imagine it could show up as MDMA, but perhaps not if there are too many structural differences.



#34 hazy

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Posted 27 March 2017 - 03:35 AM

stink, just quick question off topic. you said you are on atomexetine right now and you say its a very potent NRI? i have to ask, as a potent NRI inhibitor, does it cause vasoconstriction as a side effect, related to lets say some of the amphetamines used for ADHD?



#35 Florian Seichert

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Posted 09 April 2017 - 02:49 PM

Does anybody know what the (h) after the target means wenn it comes to the binding affinities?

 

post-40578-0-97262100-1489402096.jpg



#36 Finn

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Posted 09 April 2017 - 06:38 PM

Does anybody know what the (h) after the target means wenn it comes to the binding affinities?

 

My guess would be human. The other receptors could be mouse or rat or primate receptor results. In wikipedia, for some substances, when listing receptor affinities, some affinities are for human receptors and some for non-human. Maybe doing in vitro measurements for non-human equivalents of certain receptors is still much easier and cheaper.


Edited by Finn, 09 April 2017 - 06:41 PM.


#37 hazy

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Posted 10 April 2017 - 02:46 AM

so it has opioid activity, or am i misunderstanding this system since im not a specialist? i must say, opioid receptors will greatly improve mood and it will work for depression, but it will never help with nootropic activity for some reason which i cannot understand yet



#38 YoungSchizo

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Posted 11 April 2017 - 02:51 PM

So, is NSI-189 worth a shot for a schizophrenic? I'm diagnosed schizo-affective, even though I have almost no psychotic symptoms on the current regimen I'm on, I struggle really hard with my negative symptoms/depressive mood and impulsive behavior.



#39 Mind_Paralysis

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Posted 11 April 2017 - 03:26 PM

So, is NSI-189 worth a shot for a schizophrenic? I'm diagnosed schizo-affective, even though I have almost no psychotic symptoms on the current regimen I'm on, I struggle really hard with my negative symptoms/depressive mood and impulsive behavior.

 

Too early to say - if that 5HT3-affinity is of the agonistic form, then it's a psychotic - then it would be enormously bad for you.

 

Now, if it turns out to be ANTagonistic, then I say, go right ahead! = )

 

But we don't know... : O

 

 

Side-note, can we actually e-mail some of the people from Neuralstem and ask them whether or not the affinities are agonistic or antagonistic? That would seem to be the simplest way of knowing.



#40 UltraCitron

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Posted 14 April 2017 - 01:14 AM

I have a strong feeling NSI-189 is a 5HTantagonist. I think this because it actually seems to help with nausea. I haven't experienced any nausea from things that might normally make me nauseous, like a high dose of bacopa or some hard-to-digest food. It also seems to affect my heart beat in a similar way to escitalopram, which increases QT interval, and which 5HT3 antagonists such as ondansetron (Zofran) are supposed to do.

I looked into Momelotinib, and it looks structurally similar at first glance. It wouldn't surprise me if NSI-189 does indeed work its neurogenic magic through JAK STAT inhibition.



#41 Mind_Paralysis

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Posted 14 April 2017 - 08:18 AM

stink, just quick question off topic. you said you are on atomexetine right now and you say its a very potent NRI? i have to ask, as a potent NRI inhibitor, does it cause vasoconstriction as a side effect, related to lets say some of the amphetamines used for ADHD?

 

Quick reply:

 

Not to any greater extent, it would seem. I've got slightly colder hands and feet, I think, but I've got naturally cold hands and feet, so it's hard to tell.

 

My blood-pressure and heart rate are all normal - VERY good even, can't recall my last readout, but it was something like 88 for the heart rate at least.
 

 

No difference from when I used Amphetamine or Methylphenidate, which also did not appear to effect my heart to any greater extent.

 

That doesn't mean people don't get vasoconstriction from Atomoxetine though... BUT - it does appear to be a fairly RARE side-effect, judging from this data-set on eHealthMe.

 

 

http://www.ehealthme...soconstriction/

 

 

Still, there's of course this proof-of-concept study on actual human beings which shows that it seems to be a viable treatment for orthostatic hypotension.

 

EFFICACY OF ATOMOXETINE VERSUS MIDODRINE FOR THE TREATMENT OF ORTHOSTATIC HYPOTENSION IN AUTONOMIC FAILURE

https://www.ncbi.nlm...les/PMC4231172/

 

 

Although few people report vasoconstriction as a side-effect, there seems to be a greater number of people reporting colder hands and feet, which are signs of vasoconstriction, from decreased blood-flow.



#42 Florian Seichert

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Posted 14 April 2017 - 10:46 AM

 

 

So, is NSI-189 worth a shot for a schizophrenic? I'm diagnosed schizo-affective, even though I have almost no psychotic symptoms on the current regimen I'm on, I struggle really hard with my negative symptoms/depressive mood and impulsive behavior.

 

When it comes to psychotic symptoms, I would say it worsens my symptoms. I am currently on 10 mg aripiprazole ( abilify). When on 20-40 mg nsi it feels like to high dopaminergic transmission with sympthoms like paranoia, feeling of strength, tunnel vision and this sort of dopamine-like hallucinations (seeing somebody standing there for a moment, seeing faces where no faces are). 

In terms of negative symptoms (depressive mood and impulsive behavior) you mentioned nsi had a positive effect on me. 

 

No clue if it has something to do with the 5-ht3 receptor. But I have to note my physiology is generally different from those of most other people (also suffering from ASD). 


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#43 YoungSchizo

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Posted 14 April 2017 - 01:57 PM

 

 

 

So, is NSI-189 worth a shot for a schizophrenic? I'm diagnosed schizo-affective, even though I have almost no psychotic symptoms on the current regimen I'm on, I struggle really hard with my negative symptoms/depressive mood and impulsive behavior.

 

When it comes to psychotic symptoms, I would say it worsens my symptoms. I am currently on 10 mg aripiprazole ( abilify). When on 20-40 mg nsi it feels like to high dopaminergic transmission with sympthoms like paranoia, feeling of strength, tunnel vision and this sort of dopamine-like hallucinations (seeing somebody standing there for a moment, seeing faces where no faces are). 

In terms of negative symptoms (depressive mood and impulsive behavior) you mentioned nsi had a positive effect on me. 

 

No clue if it has something to do with the 5-ht3 receptor. But I have to note my physiology is generally different from those of most other people (also suffering from ASD). 

 

 

Scary shit dude, I'd better stay away from NSI then.


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#44 PeaceAndProsperity

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Posted 14 April 2017 - 05:38 PM


When it comes to psychotic symptoms, I would say it worsens my symptoms. I am currently on 10 mg aripiprazole ( abilify). When on 20-40 mg nsi it feels like to high dopaminergic transmission with sympthoms like paranoia, feeling of strength, tunnel vision and this sort of dopamine-like hallucinations (seeing somebody standing there for a moment, seeing faces where no faces are). 

In terms of negative symptoms (depressive mood and impulsive behavior) you mentioned nsi had a positive effect on me. 

 

No clue if it has something to do with the 5-ht3 receptor. But I have to note my physiology is generally different from those of most other people (also suffering from ASD). 

 

Very interesting. Do you think NSI-189 activates 5ht3 receptors? Could be a bad batch but nsi-189 did not seem to worsen my schizotypal symptoms at all, but I am not sensitive to dopamine (it seems), but glutamate and serotonin.

 



#45 PeaceAndProsperity

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Posted 14 April 2017 - 05:44 PM


My blood-pressure and heart rate are all normal - VERY good even, can't recall my last readout, but it was something like 88 for the heart rate at least.

 

88 heart rate is not good, that's borderline too high. Should be 60-70 when resting, max 70. I'm a big guy, 130kg and very tall and my heart rate stays at those 60 70 when I don't take the wrong stuff.

 



#46 UltraCitron

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Posted 14 April 2017 - 09:03 PM

 


When it comes to psychotic symptoms, I would say it worsens my symptoms. I am currently on 10 mg aripiprazole ( abilify). When on 20-40 mg nsi it feels like to high dopaminergic transmission with sympthoms like paranoia, feeling of strength, tunnel vision and this sort of dopamine-like hallucinations (seeing somebody standing there for a moment, seeing faces where no faces are). 

In terms of negative symptoms (depressive mood and impulsive behavior) you mentioned nsi had a positive effect on me. 

 

No clue if it has something to do with the 5-ht3 receptor. But I have to note my physiology is generally different from those of most other people (also suffering from ASD). 

 

Very interesting. Do you think NSI-189 activates 5ht3 receptors? Could be a bad batch but nsi-189 did not seem to worsen my schizotypal symptoms at all, but I am not sensitive to dopamine (it seems), but glutamate and serotonin.

 

Well, NSI-189 is a dopamine reuptake inhibitor, and we certainly know a lot more about DRIs than ligands of 5HT3 and 5HT7 receptors. And these symptoms sound very much like DRI effects, do they not? The weird thing is people have said that NSI negates the effects of other drugs. It seems extremely likely that this is caused by 5HT3 antagonism. One profound effect I've noticed from NSI is a complete removal of any desire to drink alcohol - and when I do, it does hardly anything. It feels like I'm just drinking some chamomile tea or something, I don't get drunk in the normal way. Check out the findings of The Role of 5-HT3 Receptors in Drug Abuse and as a Target for Pharmacotherapy (all of you should be reading this study!):  "Preclinical findings indicate that antagonism of the 5-HT3 receptor in the ventral tegmental area, nucleus accumbens or amygdala reduces alcohol self-administration and/or alcohol-associated effects. " This corresponds strongly with my own experience.

 
Stinkorninjor, you brought up an interesting point about atomexetine not causing anxiety. What puzzles me is that something like racemic amphetamine (e.g. Adderall) causes great anxiety because of the selectivity of the levo enantiomers for NET reversal and thereby increasing synaptic nor-epinephrine. And strong NDRIs like MDPV certainly cause anxiety. So, maybe norepinephrine requires dopamine to be anxiogenic. Or perhaps atomexetine has selectivity for transporters in different areas of the brain from, say amphetamine. Or perhaps atomexetine somehow causes preferential activation of norepinephrine autoreceptors - which is a negative feedback loop for norepinephrine. My point is the NET inhibition could still be part of the anxiety, but there's a lot of uncertainty. We should also be looking at the other targets - there are 7 listed targets in that NS slide, so we should be asking how binding to this combination of receptors creates the specific effects of NSI.


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#47 hazy

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Posted 15 April 2017 - 02:57 AM

not sure why people concentrate so much on antagonism on 5th3 receptors when this stuff might actually have opioid activity and if thats not more important, than i guess i dunno shit



#48 aperson444

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Posted 15 April 2017 - 04:59 AM

It should be noted that IC50 values above 10 uM are relatively high, especially for something with an active dose of ~40 mg. Now, it is possible that plasma concentrations reach 1 uM (brain concentration is typically higher if a compound is efficiently absorbed into the brain), but it is unlikely. We'd need to see further in vivo pharmacokinetic data to be sure. Knowing the Ki or the EC50 of the compound would help give a clearer picture of activity at the receptors.


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#49 UltraCitron

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Posted 15 April 2017 - 08:09 PM

It should be noted that IC50 values above 10 uM are relatively high, especially for something with an active dose of ~40 mg. Now, it is possible that plasma concentrations reach 1 uM (brain concentration is typically higher if a compound is efficiently absorbed into the brain), but it is unlikely. We'd need to see further in vivo pharmacokinetic data to be sure. Knowing the Ki or the EC50 of the compound would help give a clearer picture of activity at the receptors.

This was also in the back of my mind! Those are indeed high concentrations and may not be relevant in normal dosages. We need more studies. 



#50 Mind_Paralysis

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Posted 16 April 2017 - 06:15 PM

 

It should be noted that IC50 values above 10 uM are relatively high, especially for something with an active dose of ~40 mg. Now, it is possible that plasma concentrations reach 1 uM (brain concentration is typically higher if a compound is efficiently absorbed into the brain), but it is unlikely. We'd need to see further in vivo pharmacokinetic data to be sure. Knowing the Ki or the EC50 of the compound would help give a clearer picture of activity at the receptors.

This was also in the back of my mind! Those are indeed high concentrations and may not be relevant in normal dosages. We need more studies. 

 

 

Indeed - I think we've delved enough into these affinities for the time being - Neuralstem has after all come to the conclusion that none of these affinities are actually relevant to its main, unrelated, mechanism of action!

 

Now then - what do we make of JAK-STAT modulation? Would inhibition enhancement of the JAK-STAT pathway cause neurogenesis? I suppose it's inhibition, since I believe Momelotinib was mentioned as being an inhibitor.

 

But what does JAK-STAT actually do? I'm reading up on it now, and it seems as if this pathway is a part of a process which governs immune cell, cell-division, and cell-death? Certainly interesting! Could the method through which NSI-189 works, then be through EPIGENETICS??

 

I.e, NSI-189 causes upregulation of naturally occuring transcription-factors, which orders the hippocampus to produce more stem-cells? Would this then imply that neurogenesis can occur without increased BDNF-signalling? (obviously it must, since I believe neuralstem has claimed that NSI-189 does not increase BDNF production, yes?)

 

 

Hmm... perhaps it does something different from what we thought... perhaps it's not that it increases neurogenesis to any unknown degree, but it alters the immune-system, or cell-resilience - we know that Depression is a neuro-degenerative disease - perhaps it merely makes it so that the neurodegeneration STOPS, and the brains normal, low-level neurogenesis can then more easily repair the damage?

 

Hmm -- JAK - Janus Kinase, governs response to Interferon Gamma, which suppresses the activity of VIRUSES and other pathogens... Could it be... that depression is in fact a form of INFECTION? Which then causes problems with neural plasticity.

 

 

What DO we know about the immune system and depression? Are people with immune suppression more easily depressed than others? Has any connections been made? Do people with auto-immune disease get more easily depressed?



#51 Finn

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Posted 17 April 2017 - 04:27 PM


I looked into Momelotinib, and it looks structurally similar at first glance. It wouldn't surprise me if NSI-189 does indeed work its neurogenic magic through JAK STAT inhibition.

 

 

Neuralstem claimed in their presentation "No binding or functioanal activities against 900 other kinases (DISCOVERX KinomeScan)"

 

The assay list contains JAK1, JAK2 and JAK3.

 

https://www.discover...ling/kinomescan


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#52 Mind_Paralysis

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Posted 17 April 2017 - 09:56 PM

 

I looked into Momelotinib, and it looks structurally similar at first glance. It wouldn't surprise me if NSI-189 does indeed work its neurogenic magic through JAK STAT inhibition.

 

 

Neuralstem claimed in their presentation "No binding or functioanal activities against 900 other kinases (DISCOVERX KinomeScan)"

 

The assay list contains JAK1, JAK2 and JAK3.

 

https://www.discover...ling/kinomescan

 

 

...

 

...If I could give you "informative" one more time for a single post, this one would be the one to warrant it!

 

Ok - that pretty much changes everything in this thread. JAK-STAT, at least the JAK part, is now off the table.

 

Wow! Ok... any other ideas? I suppose some of the other affinities listed in the simulation might be of interest, hmm... I suggest we have a look at all of the simulated affinities and the actual released, tested ones, and make sure that nothing else is a dead end.

 

 

Anyone with Autism interested in having a look? The list is too much for my SCT-brain to do any more than just quickly glance at it.

*looks beggingly and expectantly at Florian Seichert*
 


Edited by Stinkorninjor, 17 April 2017 - 10:00 PM.


#53 Shai Hulud

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Posted 09 January 2018 - 12:34 PM

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.

attachicon.gifmoa – kopio.jpg

 

I'm not 100% sure I am able to read this right, but I do think these are all in vitro measurements with at a pretty high concentration used and all the affinities are in the µmol range, i.e. all pretty weak. And I think that's the point of the paper: To show that it's not working in a similar way to other drugs (therefore making the company more interesting for investors).

 

I'm very much interested in the potential multidrug resistance protein 1 mechanism. Maybe NSI-189 helps the brain (or whole body) in cellular detoxification processes, therefore lowering inflammation. The protein also helps to protect stem cells from toxins, which could play a role in enhanced neurogenesis.



#54 world33

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Posted 03 March 2018 - 12:39 PM

Hi guys I found this interesting thread while searching for NSI-189 that I took again tonight after a long time. I suffer from Generalized Anxiety Disorder since my early 30s, in particular morning anxiety, that in my opinion is related to chronic stress and high cortisol levels (upper limit of the range in the morning) and/or compromised glucocorticoid sensitivity. The fact that adaptogens, like rodhiola rosea and ashwagandha, high dosage phosphatidylserine and EGCG (a potent 11β-hydroxysteroid dehydrogenase type 1 inhibitor) have the most positive effect on me to control my GAD, in addition to escitalopram SSRI, proves my theory. The effect NSI-189 has had on me tonight is also very profound especially in terms of focus, concentration, vision etc (can it be increased BDNF in such a short time?). I tried NSI-189 before and I experienced the same positive effects in the first few days but after a while I would experience a strong anxiety rebound effect. I wonder whether this rebound effect could be due to increased cortisol, norepinephrine or an inflammatory response to the compound (I have a sensitive bowel and often feel bloated when taking several supplements at the same time).
 
Under a genetic point of view the following Genes are currently associated with Generalized Anxiety Disorder according to Malacards.org; for each gene I provide a potential drug/supplement to treat the mutations:
1) HTR1A
Try HTR1A Agonists
Buspirone, Tandospirone
 
2) SLC6A4
Try SSRI
In particular Escitalopram
 
3) TSPO
Try TSPO agonists
Etifoxine
 
4) HTR2A
Try HTR2A Antagonists
?
 
5) SLC6A2
Try SSRI
In particular Escitalopram
 
6) MAOA
?
 
7) PSMD9
?
 
8) HTR3A
Try 5-HT3 receptor antagonists
List at https://en.wikipedia...tor#Antagonists
 
9) TPH1
Try anything that increase serotonin (watch out for serotonin syndrome and do not mix them)
L-Tryptophan
5-HTP
SSRI 
 
10) CRHR1
Try CRHR1 antagonists
Antalarmin, Quercetin
 
11) RGS2
Not sure what could help for this gene
 
12) BDNF
Try BDNF enhancers
Excercise, SSRI, Lion's mane, NSI-189 (still under clinical investigation and potentially risky)
Others
 
13) DRD2
DRD2 agonists 
Cabergoline (not for long term due to potential receptors down-regulation)
 
 
What in your opinion NSI-189 could positively affect my anxiety in the first few days, acting on the above genes, and what could cause this rebound effect?
Has NSI-189 any effect on glucocorticoid levels and/or sensitivity in your opinion?
 
I wish I could give more insights on the mutations I have but the 23andme raw data is quite limited in order to analyze all the above genes and associated SNPs.
I plan to do a Whole Exome test with Genos and investigate more as soon as I can afford the 499$ test.
 
If anyone is interested I wrote a short Guide to find Genetic Causes of Mental Illness in this Longecity post
For example the genes associated with Asperger Syndrome are the ones listed here by Malacards (no elite genes)
 
Lastly, if anyone is interested in knowing the Alibaba supplier where I sourced NSI-189 please send me a private message.

Edited by world33, 03 March 2018 - 12:51 PM.


#55 dramachiavellian

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Posted 03 March 2018 - 08:08 PM

Hi guys I found this interesting thread while searching for NSI-189 that I took again tonight after a long time. I suffer from Generalized Anxiety Disorder since my early 30s, in particular morning anxiety, that in my opinion is related to chronic stress and high cortisol levels (upper limit of the range in the morning) and/or compromised glucocorticoid sensitivity. The fact that adaptogens, like rodhiola rosea and ashwagandha, high dosage phosphatidylserine and EGCG (a potent 11β-hydroxysteroid dehydrogenase type 1 inhibitor) have the most positive effect on me to control my GAD, in addition to escitalopram SSRI, proves my theory. The effect NSI-189 has had on me tonight is also very profound especially in terms of focus, concentration, vision etc (can it be increased BDNF in such a short time?). I tried NSI-189 before and I experienced the same positive effects in the first few days but after a while I would experience a strong anxiety rebound effect. I wonder whether this rebound effect could be due to increased cortisol, norepinephrine or an inflammatory response to the compound (I have a sensitive bowel and often feel bloated when taking several supplements at the same time).
 
Under a genetic point of view the following Genes are currently associated with Generalized Anxiety Disorder according to Malacards.org; for each gene I provide a potential drug/supplement to treat the mutations:
1) HTR1A
Try HTR1A Agonists
Buspirone, Tandospirone
 
2) SLC6A4
Try SSRI
In particular Escitalopram
 
3) TSPO
Try TSPO agonists
Etifoxine
 
4) HTR2A
Try HTR2A Antagonists
?
 
5) SLC6A2
Try SSRI
In particular Escitalopram
 
6) MAOA
?
 
7) PSMD9
?
 
8) HTR3A
Try 5-HT3 receptor antagonists
List at https://en.wikipedia...tor#Antagonists
 
9) TPH1
Try anything that increase serotonin (watch out for serotonin syndrome and do not mix them)
L-Tryptophan
5-HTP
SSRI 
 
10) CRHR1
Try CRHR1 antagonists
Antalarmin, Quercetin
 
11) RGS2
Not sure what could help for this gene
 
12) BDNF
Try BDNF enhancers
Excercise, SSRI, Lion's mane, NSI-189 (still under clinical investigation and potentially risky)
Others
 
13) DRD2
DRD2 agonists 
Cabergoline (not for long term due to potential receptors down-regulation)
 
 
What in your opinion NSI-189 could positively affect my anxiety in the first few days, acting on the above genes, and what could cause this rebound effect?
Has NSI-189 any effect on glucocorticoid levels and/or sensitivity in your opinion?
 
I wish I could give more insights on the mutations I have but the 23andme raw data is quite limited in order to analyze all the above genes and associated SNPs.
I plan to do a Whole Exome test with Genos and investigate more as soon as I can afford the 499$ test.
 
If anyone is interested I wrote a short Guide to find Genetic Causes of Mental Illness in this Longecity post
For example the genes associated with Asperger Syndrome are the ones listed here by Malacards (no elite genes)
 
Lastly, if anyone is interested in knowing the Alibaba supplier where I sourced NSI-189 please send me a private message.

 

i know there's a relatively new antidepressant, vilazodone, that hits almost all of those receptors as well as being an SSRI. as far as NSI-189 goes, i personally think the visual acuity comes from 5ht1/2 agonism. it's similar to party drugs/psychedelics in this regard but much milder. this mild psychedelia combined with norepinephrine modulation is a likely culprit for the anxiety side effect, as well as the beneficial effects seen on attention and executive function in the phase ii clinical study. there might be something more to NSI-189 than its affinity for monoamines (it certainly felt that way for me personally). i don't know for sure


 


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#56 world33

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Posted 04 March 2018 - 01:49 AM

i know there's a relatively new antidepressant, vilazodone, that hits almost all of those receptors as well as being an SSRI. as far as NSI-189 goes, i personally think the visual acuity comes from 5ht1/2 agonism. it's similar to party drugs/psychedelics in this regard but much milder. this mild psychedelia combined with norepinephrine modulation is a likely culprit for the anxiety side effect, as well as the beneficial effects seen on attention and executive function in the phase ii clinical study. there might be something more to NSI-189 than its affinity for monoamines (it certainly felt that way for me personally). i don't know for sure


Interesting, thank you for the feedback

#57 dramachiavellian

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Posted 04 March 2018 - 11:42 AM

 

i know there's a relatively new antidepressant, vilazodone, that hits almost all of those receptors as well as being an SSRI. as far as NSI-189 goes, i personally think the visual acuity comes from 5ht1/2 agonism. it's similar to party drugs/psychedelics in this regard but much milder. this mild psychedelia combined with norepinephrine modulation is a likely culprit for the anxiety side effect, as well as the beneficial effects seen on attention and executive function in the phase ii clinical study. there might be something more to NSI-189 than its affinity for monoamines (it certainly felt that way for me personally). i don't know for sure


Interesting, thank you for the feedback

 

agh sorry i meant vortioxetine, not vilazodone!


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#58 world33

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Posted 05 March 2018 - 12:52 PM

i know there's a relatively new antidepressant, vilazodone, that hits almost all of those receptors as well as being an SSRI. as far as NSI-189 goes, i personally think the visual acuity comes from 5ht1/2 agonism. it's similar to party drugs/psychedelics in this regard but much milder. this mild psychedelia combined with norepinephrine modulation is a likely culprit for the anxiety side effect, as well as the beneficial effects seen on attention and executive function in the phase ii clinical study. there might be something more to NSI-189 than its affinity for monoamines (it certainly felt that way for me personally). i don't know for sure


Interesting, thank you for the feedback

agh sorry i meant vortioxetine, not vilazodone!


Unfortunately it does not seem to be working for GAD according to this paper:

The efficacy and safety of multiple doses of vortioxetine for generalized anxiety disorder: a meta-analysis
https://www.ncbi.nlm...les/PMC4844447/

:-(





Also tagged with one or more of these keywords: nsi-189, neurogenesis, mechanism of action, target prediction

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