6219 replies to this topic

[researchist]

I have read a couple about PTSD and depression. A lot about never felt like this before or for a long time. Maybe those are mild depression. Growing neurons in the hippocampus you would think would enhance memory and effect cognition in some ways. I read one where his cognitive tasks during his day had never been so easy. I thought I was looking at progressively brighter cognitive reports along with improvements in PTSD, depression and OCD. This is why I wish there were one place. Since everyone is talking about it rather than waiting until they finish their trial and not discussing it with anyone till it is done. (The subjective experiences would at least not be influenced by peer effects which are very strong) It seems like it would be very informative to everyone to be able to everyone who is interesting to see in one place what the results are. It could be changed as the subjects perceptions of it change up until he or she make their final edits and the list is sealed. I see sometimes the first few days are lackluster and then it gets better and better. I have not started my trials of it yet but I'm looking forward to it. I was expecting positive nootropic effects though.

[MizTen]

It's great to read your reviews guys. I'll postpone my final review until the end and oh boy it'll be interesting to see the MRI comparison
I'll post all my results here, but fellows! How about gathering the results in one place? I've prepared a form with a bunch of questions so we can have the results of our little trial in a bit better form. Go on and write down your observations:

https://docs.google....6ypUAM/viewform

Remarks very welcome

So I did this. Hope it's anonymous!! Yes, the MRIs will be interesting. Though I think that maybe more than a month would show more results. Where is the results page for your poll above?

[MizTen]

I have read a couple about PTSD and depression. A lot about never felt like this before or for a long time. Maybe those are mild depression. Growing neurons in the hippocampus you would think would enhance memory and effect cognition in some ways. I read one where his cognitive tasks during his day had never been so easy. I thought I was looking at progressively brighter cognitive reports along with improvements in PTSD, depression and OCD. This is why I wish there were one place. Since everyone is talking about it rather than waiting until they finish their trial and not discussing it with anyone till it is done. (The subjective experiences would at least not be influenced by peer effects which are very strong) It seems like it would be very informative to everyone to be able to everyone who is interesting to see in one place what the results are. It could be changed as the subjects perceptions of it change up until he or she make their final edits and the list is sealed. I see sometimes the first few days are lackluster and then it gets better and better. I have not started my trials of it yet but I'm looking forward to it. I was expecting positive nootropic effects though.

I agree peer effects can be strong. But they are also pretty easily distinguishable from new effects that are probably caused by the drug. Peer influence is much easier to spot in oneself after taking NSI-189.

I hope my comments don't influence your experience, but...

There were significant nootropic effects for me. My memory was definitely enhanced within about 6-8 days after starting the trial. I increased scores on a cognitive tests-game by about 15-22%. But it is just very hard to articulate the biggest effects because they were so global for me. It is impossible for me to completely separate the emotional and spiritual components from the other effects. Which is perhaps how things should be anyway.

It wasn't really clear what the effects were until a few days after starting. Two weeks after starting the effects were significant and obvious for me.

I think it is best used maybe once or twice after an initial trial, with mental, emotional, and physical learning strategies to support the neuronal growth. Old habits of thought, feeling, and behavior can still come back to haunt you a bit and then be relearned all over again while your brain is growing. So it might be optimal to have something positive to replace some of those old and less helpful habits while your brain is in this receptive open state.

I hope it works for you. Everyone is different, don't we see that all the time here!

[researchist]

I have read a couple about PTSD and depression. A lot about never felt like this before or for a long time. Maybe those are mild depression. Growing neurons in the hippocampus you would think would enhance memory and effect cognition in some ways. I read one where his cognitive tasks during his day had never been so easy. I thought I was looking at progressively brighter cognitive reports along with improvements in PTSD, depression and OCD. This is why I wish there were one place. Since everyone is talking about it rather than waiting until they finish their trial and not discussing it with anyone till it is done. (The subjective experiences would at least not be influenced by peer effects which are very strong) It seems like it would be very informative to everyone to be able to everyone who is interesting to see in one place what the results are. It could be changed as the subjects perceptions of it change up until he or she make their final edits and the list is sealed. I see sometimes the first few days are lackluster and then it gets better and better. I have not started my trials of it yet but I'm looking forward to it. I was expecting positive nootropic effects though.

I agree peer effects can be strong. But they are also pretty easily distinguishable from new effects that are probably caused by the drug. Peer influence is much easier to spot in oneself after taking NSI-189.

I hope my comments don't influence your experience, but...

There were significant nootropic effects for me. My memory was definitely enhanced within about 6-8 days after starting the trial. I increased scores on a cognitive tests-game by about 15-22%. But it is just very hard to articulate the biggest effects because they were so global for me. It is impossible for me to completely separate the emotional and spiritual components from the other effects. Which is perhaps how things should be anyway.

It wasn't really clear what the effects were until a few days after starting. Two weeks after starting the effects were significant and obvious for me.

I think it is best used maybe once or twice after an initial trial, with mental, emotional, and physical learning strategies to support the neuronal growth. Old habits of thought, feeling, and behavior can still come back to haunt you a bit and then be relearned all over again while your brain is growing. So it might be optimal to have something positive to replace some of those old and less helpful habits while your brain is in this receptive open state.

I hope it works for you. Everyone is different, don't we see that all the time here!

I have read some of your reports. You seem about as meticulous in your reporting as someone can be. They have been very interesting. Umm, Mizten, it would seem the results of your cognitive test improvements is well, into the range of statistical significance. I can't say that as no statistics have been done but gee, how did that feel? That's great.

[blood]

Perhaps those reporting their experiences with NSI-189 might also disclose their ownership status wrt Neuralstem stock?

[Major Legend]

Perhaps those reporting their experiences with NSI-189 might also disclose their ownership status wrt Neuralstem stock?

I don't see how this has anything to do with experiences. First people here won't report differently if they did have ownership of the stock, nobody here is likely to be able to afford owning price moving amounts.

Stock prices are hugely speculative in the short term, and some would even argue since 2000 in the long term due to increased leveraging, derivitave and high frequency trading automated by computers. Short term price movement of neural stem are likely to be speculative and a small stock like that can be moved by a huge array of factors.

[3AlarmLampscooter]

Finally gave NSI-189 a wikipedia article today: https://en.wikipedia.org/wiki/NSI-189

[MizTen]

Finally gave NSI-189 a wikipedia article today: https://en.wikipedia.org/wiki/NSI-189

That's pretty cool. But, I'm a bit horrified to see the Longecity group buy factoid in the article. Trying to keep a lowish profile here on this, I'm pretty sure I'm not alone in that.

[Nattzor]

Finally gave NSI-189 a wikipedia article today: https://en.wikipedia.org/wiki/NSI-189

Uhm, the group buy should not be in the article for legal reasons and because it's not wiki-material.

[researchist]

The article seems to be accurate. Lets see how it holds up to peer review. I had not seen a diagram of the structure before. It is a very sexy molecule.

Edited by researchist, 15 September 2013 - 11:15 PM.

[CatChelator]

We have to be aware of how this ad hoc and mostly out of control experiment might affect this drugs progress to public availability. If anything were to go wrong ie a death or injury due to misadministration of the drug or an unknown allergic reaction, then the proper trials and monitored research into NSI could very easily become untenable. Just thinking in terms of the need for this drug (if it works) to be accepted by mainstream medicine and not locked away in EU states like Cerebrolysin.

Edited by jonsnow, 15 September 2013 - 11:24 PM.

[researchist]

In the Wikipedia article it mentions that Darpa funded the research into NSI-189. I think that Darpa is interested in the neural stem technology. to rapidly regrow spinal cords and probably brain damage after field injuries. All the research Darpa does, as cool as some of it is all is somehow related to combat, "In addition to ALS, the company is also targeting major central nervous system conditions with its NSI-566 cell therapy platform, including spinal cord injury, ischemic stroke and glioblastoma (brain cancer)." Also the company received FDA approval to commence a Phase I safety trial in chronic spinal cord injury. http://www.prnewswir...-222498941.html, By the way I noticed this article last night http://www.neuralste...-cell-treatment. This technology is amazing.

[Hebbeh]

In the Wikipedia article it mentions that Darpa funded the research into NSI-189. I think that Darpa is interested in the neural stem technology. to rapidly regrow spinal cords and probably brain damage after field injuries

No. Darpa invested in the development of NSI-189 as a treatment to combat stress and PTSD....the #1 combat injury by far and hardest for the military to treat and deal with.

Courtesy of hadora...

Bump !
A very interesting reading

How Neuralstem Discovered This New Neurogenic Drug
About 10 years ago, the Army gave Neuralstem $2.5 million to develop a drug that would prevent hippocampal shrinkage and improve cognitive ability in soldiers who were experiencing severe stress due to extreme battle conditions. It turns out that when soldiers are stressed, particularly due to lack of sleep, they experience hippocampal atrophy (their hippocampus shrinks). The Army wanted a way to deal with this condition because the soldiers did not perform well when afflicted with hippocampal atrophy.
Neuralstem was hired because it was the only company that had proven it was able to grow hippocampal stem cells. In order to develop and test this new neurogenic drug for the Army, an unlimited supply of hippocampal stem cells were needed.
Neuralstem began the development process by testing 700,000 different drug compounds via computer models. From there, Neuralstem scientists selected the best 10,000 compounds and began testing them in the laboratory. Each compound was tested with different dosages, so this was quite a lengthy process. It was all possible because Neuralstem had access to an unlimited number of hippocampal stem cells.
Finally, Neuralstem narrowed the field down to one very potent neurogenic drug. This particular drug achieved what Neuralstem scientists were aiming for, hippocampal growth.
About the same time, the medical community started to become aware of the fact that the hippocampus was shrinking in depressed patients. Scientists began to think that perhaps the reason Prozac and other antidepressant drugs really work is because they are actually regenerating cells in the hippocampus. Animal studies were conducted and this was determined to be the case. MRI scans showed that antidepressant drugs increased hippocampal volume on a percentage basis, low to mid-single digits.
So everybody in Big Pharma started chasing neurogenic drugs as a means of beating depression and other cognitive diseases. Of course Neuralstem had a tremendous advantage here, because it was the only company that had access to an unlimited supply of hippocampal stem cells.
Neuralstem wanted to test its new drug for depression, so the company obtained about $500,000 from NIH, which it invested in animal studies to see the effect of its neurogenic drug on depression and hippocampal volume.
The company discovered that its drug was as good if not better than allthe antidepressive drugs on the market. The commercial antidepressants were showing hippocampal volume increases of about 5% or below, whereas Neuralstem's new drug was able to increase hippocampal volume up to 20%. By most other measures, Neuralstem's drugexcelled in decreasing depression symptoms.
Neuralstem was encouraged by these results so it decided to do a human study. This was the first human study with this class of drugs, so the FDA needed a strong safety trial first. Neuralstem conducted a placebo-controlled Phase Ia trial with 41 healthy volunteers to prove to the FDA that its small molecule drug was safe.
After that trial, the data was so good in terms of safety that the FDA gave Neuralstem the go-ahead for a Phase Ib trial so it could start dosing actual major-depressive disorder patients.
No Side Effects
Perhaps the most important information that came from that Phase Ia trial was the fact that there were absolutely no side effects. For example, one of the most popular antidepressants, Prozac lists common side effects which include nausea, insomnia, sexual dysfunction, and anxiety. Some of these side effects are worse than the actual depression, so many patients just quit using the drugs.
The company should soon be finished dosing the first cohort of major depressive disorder patients in the Phase Ib trial. These patients took the pill once a day for 28 days in a randomized placebo-controlled trial. The second and third cohorts will take the pill twice a day and three times a day respectively.
In addition to measuring all the kinds of things you measure for depression, Neuralstem is also taking MRI scans to see if it can detect an increase in hippocampal volume. All of these patients will receive MRI scans before, during, and after the trial. Even though this is primarily a safety trial, given the new nature of the drug, Neuralstem will be looking for increases in hippocampal volume as well as improvement in depression measurements.
This human trial will be finished in December 2012, and we will see results soon thereafter. Positive results could have a major effect on the share price.

Neuralstem's goal is to partner with one or more major pharmaceutical companies that will not only address the depression market, but will also address all the other neurogenic drug markets where hippocampal atrophy is an issue, including Alzheimer's, stroke, traumatic brain injury, antiaging, and post traumatic stress.

Neuralstem's New Drug Could Treat Alzheimer's
I believe the next major indication for Neuralstem's neurogenic drug will be Alzheimer's. Preliminary studies have indicated that cognitive diseases like Alzheimer's and dementia are directly linked to hippocampal atrophy. Remember, Neuralstem developed this product for the Army to prevent hippocampal shrinkage and to improve cognitive ability. We know that, at least in animal studies, that Neuralstem's drug increases hippocampal volume by up to 20%. Such a large increase in hippocampal volume implies considerable cognitive improvement. If a drug was able to increase cognitive ability in Alzheimer's and dementia patients, that would be a tremendous medical breakthrough.

http://seekingalpha...._readmore&ifp=0

[researchist]

In the Wikipedia article it mentions that Darpa funded the research into NSI-189. I think that Darpa is interested in the neural stem technology. to rapidly regrow spinal cords and probably brain damage after field injuries

No. Darpa invested in the development of NSI-189 as a treatment to combat stress and PTSD....the #1 combat injury by far and hardest for the military to treat and deal with.

Courtesy of hadora...

Bump !
A very interesting reading

How Neuralstem Discovered This New Neurogenic Drug
About 10 years ago, the Army gave Neuralstem $2.5 million to develop a drug that would prevent hippocampal shrinkage and improve cognitive ability in soldiers who were experiencing severe stress due to extreme battle conditions. It turns out that when soldiers are stressed, particularly due to lack of sleep, they experience hippocampal atrophy (their hippocampus shrinks). The Army wanted a way to deal with this condition because the soldiers did not perform well when afflicted with hippocampal atrophy.
Neuralstem was hired because it was the only company that had proven it was able to grow hippocampal stem cells. In order to develop and test this new neurogenic drug for the Army, an unlimited supply of hippocampal stem cells were needed.
Neuralstem began the development process by testing 700,000 different drug compounds via computer models. From there, Neuralstem scientists selected the best 10,000 compounds and began testing them in the laboratory. Each compound was tested with different dosages, so this was quite a lengthy process. It was all possible because Neuralstem had access to an unlimited number of hippocampal stem cells.
Finally, Neuralstem narrowed the field down to one very potent neurogenic drug. This particular drug achieved what Neuralstem scientists were aiming for, hippocampal growth.
About the same time, the medical community started to become aware of the fact that the hippocampus was shrinking in depressed patients. Scientists began to think that perhaps the reason Prozac and other antidepressant drugs really work is because they are actually regenerating cells in the hippocampus. Animal studies were conducted and this was determined to be the case. MRI scans showed that antidepressant drugs increased hippocampal volume on a percentage basis, low to mid-single digits.
So everybody in Big Pharma started chasing neurogenic drugs as a means of beating depression and other cognitive diseases. Of course Neuralstem had a tremendous advantage here, because it was the only company that had access to an unlimited supply of hippocampal stem cells.
Neuralstem wanted to test its new drug for depression, so the company obtained about $500,000 from NIH, which it invested in animal studies to see the effect of its neurogenic drug on depression and hippocampal volume.
The company discovered that its drug was as good if not better than allthe antidepressive drugs on the market. The commercial antidepressants were showing hippocampal volume increases of about 5% or below, whereas Neuralstem's new drug was able to increase hippocampal volume up to 20%. By most other measures, Neuralstem's drugexcelled in decreasing depression symptoms.
Neuralstem was encouraged by these results so it decided to do a human study. This was the first human study with this class of drugs, so the FDA needed a strong safety trial first. Neuralstem conducted a placebo-controlled Phase Ia trial with 41 healthy volunteers to prove to the FDA that its small molecule drug was safe.
After that trial, the data was so good in terms of safety that the FDA gave Neuralstem the go-ahead for a Phase Ib trial so it could start dosing actual major-depressive disorder patients.
No Side Effects
Perhaps the most important information that came from that Phase Ia trial was the fact that there were absolutely no side effects. For example, one of the most popular antidepressants, Prozac lists common side effects which include nausea, insomnia, sexual dysfunction, and anxiety. Some of these side effects are worse than the actual depression, so many patients just quit using the drugs.
The company should soon be finished dosing the first cohort of major depressive disorder patients in the Phase Ib trial. These patients took the pill once a day for 28 days in a randomized placebo-controlled trial. The second and third cohorts will take the pill twice a day and three times a day respectively.
In addition to measuring all the kinds of things you measure for depression, Neuralstem is also taking MRI scans to see if it can detect an increase in hippocampal volume. All of these patients will receive MRI scans before, during, and after the trial. Even though this is primarily a safety trial, given the new nature of the drug, Neuralstem will be looking for increases in hippocampal volume as well as improvement in depression measurements.
This human trial will be finished in December 2012, and we will see results soon thereafter. Positive results could have a major effect on the share price.

Neuralstem's goal is to partner with one or more major pharmaceutical companies that will not only address the depression market, but will also address all the other neurogenic drug markets where hippocampal atrophy is an issue, including Alzheimer's, stroke, traumatic brain injury, antiaging, and post traumatic stress.

Neuralstem's New Drug Could Treat Alzheimer's
I believe the next major indication for Neuralstem's neurogenic drug will be Alzheimer's. Preliminary studies have indicated that cognitive diseases like Alzheimer's and dementia are directly linked to hippocampal atrophy. Remember, Neuralstem developed this product for the Army to prevent hippocampal shrinkage and to improve cognitive ability. We know that, at least in animal studies, that Neuralstem's drug increases hippocampal volume by up to 20%. Such a large increase in hippocampal volume implies considerable cognitive improvement. If a drug was able to increase cognitive ability in Alzheimer's and dementia patients, that would be a tremendous medical breakthrough.

http://seekingalpha...._readmore&ifp=0

That is a great article. Thanks to both Hathor and Hebbah

[Hebbeh]

I didn't realize that NSI-189 was derived from nicotinamide. That explains a lot. Turnbuckle has posted and presented research that high dose nicotinamide has been researched with good results as an alzheimer's treatment. And every time I tried high dose nicotinamide, I was unable to continue due to insatiable hunger. I get the increased appetite with NSI-189, just not as severe. But then I'm dosing less than 20mg of NSI-189 vs 500+mg of nicotinamide. If I increased my dose of NSI-189 high enough, very possibly the ravenous hunger might be comparable.

I wonder how the nootropic effect of high dose nicotinamide stacks up against NSI-189.

If Turnbuckle doesn't weigh in, I will try to dig up his posts on the research.

[Turnbuckle]

I didn't realize that NSI-189 was derived from nicotinamide. That explains a lot. Turnbuckle has posted and presented research that high dose nicotinamide has been researched with good results as an alzheimer's treatment. And every time I tried high dose nicotinamide, I was unable to continue due to insatiable hunger. I get the increased appetite with NSI-189, just not as severe. But then I'm dosing less than 20mg of NSI-189 vs 500+mg of nicotinamide. If I increased my dose of NSI-189 high enough, very possibly the ravenous hunger might be comparable.

I wonder how the nootropic effect of high dose nicotinamide stacks up against NSI-189.

If Turnbuckle doesn't weigh in, I will try to dig up his posts on the research.

I prefer niacin because it also has a positive effect on HDL cholesterol. I don't have any trouble with the flush taking 2g every morning (though not everyone would agree). After my wife began having memory trouble, I gave her a bottle of niacinamide and she began 2g daily, and almost immediately noticed a normalization of both mood and memory. The value of niacinamide (and niacin) in reversing hyper-phosphorylation of tau protein can be found on pubmed--

These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.
...
Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated-α-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability.

http://www.ncbi.nlm....les/PMC2617713/

I've also noticed that MB and niacin can be used together. I've posted my experience with the combination on my profile page, section 13.

I've personally found no effect of niacin or niacinamide on appetite.

Edited by Turnbuckle, 16 September 2013 - 12:53 AM.

[Turnbuckle]

And every time I tried high dose nicotinamide, I was unable to continue due to insatiable hunger.

This is interesting--

Chronic niacin overload may be involved in the increased prevalence of obesity in US children

CONCLUSION: The appetite-stimulating effect of nicotinamide appears to involve oxidative stress. Excess niacin consumption may be a major factor in the increased obesity prevalence in US children.


http://www.ncbi.nlm....les/PMC2874142/

[Hebbeh]

And every time I tried high dose nicotinamide, I was unable to continue due to insatiable hunger.

This is interesting--

Chronic niacin overload may be involved in the increased prevalence of obesity in US children

CONCLUSION: The appetite-stimulating effect of nicotinamide appears to involve oxidative stress. Excess niacin consumption may be a major factor in the increased obesity prevalence in US children.


http://www.ncbi.nlm....les/PMC2874142/

Damn....I just took a 1500mg time release tablet from a bottle I still had....and am preparing to eat supper...

Thanks Turnbuckle....It's starting to make sense.

Edit...I've never tried the high dose nicotinamide while on C60/EVOO....so this will be interesting.

Edited by Hebbeh, 16 September 2013 - 01:58 AM.

[researchist]

I didn't realize that NSI-189 was derived from nicotinamide. That explains a lot. Turnbuckle has posted and presented research that high dose nicotinamide has been researched with good results as an alzheimer's treatment. And every time I tried high dose nicotinamide, I was unable to continue due to insatiable hunger. I get the increased appetite with NSI-189, just not as severe. But then I'm dosing less than 20mg of NSI-189 vs 500+mg of nicotinamide. If I increased my dose of NSI-189 high enough, very possibly the ravenous hunger might be comparable.

I wonder how the nootropic effect of high dose nicotinamide stacks up against NSI-189.

If Turnbuckle doesn't weigh in, I will try to dig up his posts on the research.

This might explain it that nicotinaimide increases dopamine directly and sometimes it doesn't, but nicotinimide is a precursor to NAD which is a precursor to NADH which increases dopamine, dopamine increases ghrelin, ghrelin increases hunger, and grows neurons in the hippocampus. Headaches are a side effect of hunger though I have no suggestions the mechanism.

This is from back in April. I had not seen it before. It seems to me that the statements made
here and in the article indicate that maybe NeuralStem thinks that NSI-189 will grow neurons in other areas of the brain than the hippocampus. I seem to have missed that in other reading.

Neuralstem, Inc. also announced "that it is working with the National Football League Alumni Association (NFLAA), based in Newark, NJ, to develop a trial for treating NFL alumni members suffering from traumatic brain injuries (TBI), with NSI-189, the lead compound in the company's neurogenic drug platform. NSI-189, currently in a Phase Ib clinical trial to treat major depressive disorder (MDD), appears to work by stimulating neurons in the hippocampus, a region of the brain that atrophies in depression and which could also be implicated in brain injury. Neuralstem believes that pre-clinical work, in which NSI-189 stimulated new neuron formation in multiple animal models, as well as data from the current trial in humans, will be applicable to a potential study of NSI-189 in the treatment of TBI symptoms."

http://blog.cottonwo...trial-test.html

Nicotinimide has complicated relationship with dopamine.
(1a) Nicotinimide enhances dopamine
Niacinamide helps maintain brain ATP/ADP ratios and thereby maintains brain energy and amine levels. Amphetamine-induced depletion of dopamine and energy stores can often be alleviated by niacinamide (Wan, et.al. 1999). Niacinamide, at the very least, would appear to be an inexpensive primary intervention tool due to its benefit of significantly reducing the aggression threshold. Niacinamide has yet another benefit for students. It was shown to have nootropic effects greater than piracetam! Niacinamide also beat piracetam as an antihypoxic, antiamnestic, and anxiolytic (Akhundov, et. al., 1990). Perhaps administrators and psychologists should be dispensing niacinamide rather than amphetamines and mood altering xenobiotics in our schools.
http://www.naturalhe...namide-b-3.html
(1b) Nicotinimide effects on dopamine paradoxical
Dopamine is an important neurotransmitter in the human central nervous system and also plays a key role in the development of postnatal brains. We previously reported that nicotinamide, a SIRT1 inhibitor, regulates tyrosine hydroxylase (TH) expression in vitro. To investigate the effect of nicotinamide-mediated TH regulation in vivo, nicotinamide was chronically injected into neonatal mice. Interestingly, nicotinamide-treated mice were smaller in size, and their locomotor activity was reduced. L-DOPA treatment caused hypersensitive locomotor activity that indicates a dopamine-depleted state. These changes seemed to be associated with dopamine metabolism in hypothalamus, since dopamine in hypothalamus was reduced but not in striatum. The present study suggests that the regulation of dopamine metabolism during the postnatal development is important and the underlying molecular mechanisms may be associated with SIRT1 signaling.

(2) Nad is produced from nicotinamide

Arch Biochem Biophys. 1990 Nov 15;283(1):40-5.
Importance of nicotinamide as an NAD precursor in the human erythrocyte.
Micheli V, Simmonds HA, Sestini S, Ricci C.

Source
Istituto di Chimica Biologica dell'Università di Siena, Italy.

Abstract

The effect of variation in the concentration of inorganic phosphate and of the pyridine precursors nicotinamide (NAm) and nicotinic acid (NA) on pyridine nucleotide synthesis was studied using intact human erythrocytes. A wide range of incubation times was employed. The results showed that under physiological conditions the rate of synthesis of NAD from NAm exceeded that from NA twofold, while the reverse situation pertained at higher and unphysiological substrate levels. The two pathways had different regulation points. For NAm the rate-limiting factor was the initial step, namely its conversion into the mononucleotide, while for NA it lay at the second step, conversion of NA mononucleotide (NAMN) to its adenine dinucleotide. At physiological substrate levels the uptake of NA and conversion to NAMN were rapid, while the uptake and conversion of NAm were time dependent. This process was stimulated significantly by inorganic phosphate only for NAm. These results indicate that while NA is the predominant precursor of human erythrocyte NAD at high (unphysiological) substrate and phosphate levels, NAm is more efficient as an NAD precursor under physiological conditions, suggesting an important and hitherto unrecognized role for nicotinamide in NAD synthesis in vivo.
http://www.ncbi.nlm..../pubmed/2146924
-----------------------------------------------------
(3) NAD ---> NADH
In metabolism, NAD+ is involved in redox reactions, carrying electrons from one reaction to another. The coenzyme is, therefore, found in two forms in cells: NAD+ is an oxidizing agent – it accepts electrons from other molecules and becomes reduced. This reaction forms NADH
http://en.wikipedia....ne_dinucleotide

(4) NADH raises dopamine levels

Low levels of dopamine are influenced by this B3 derivative by allowing it to actively raise the concentration of dopamine in the body.
Read more: http://www.livestron.../#ixzz2fDDZD1P3
------------------------------------------------------
(2a) Dopamine increases Ghrelin through complex signaling
Ghrelin is an appetite-stimulating hormone produced by the stomach. Although the ghrelin receptor (GHSR1a) is broadly distributed in the brain, ghrelin itself is nearly undetectable there. This intriguing paradox was investigated by Dr. Roy G. Smith, Dr. Andras Kern, and colleagues from The Scripps Research Institute in Florida. "We identified subsets of neurons in the brain that express both GHSR1a and the dopamine receptor subtype-2 (DRD2)," explains Dr. Smith. "Dopamine signaling in the hypothalamus is linked with feeding behavior, and mutations in DRD2 that attenuate dopamine signaling are associated with obesity in humans. We speculated that expression of both receptors in the same neurons might lead to interactions between GHSR1a and DRD2 that modify dopamine signaling."
http://www.scienceda...20125132608.htm
----------------------------------------------------------------------------------
(2b) More evidence of dopamine attenuating production of GHrelin

We also discovered that dopamine stimulates ghrelin secretion from MGN3-1 cells in a similar manner to the previously known ghrelin stimulators, epinephrine and norepinephrine. MGN3-1 cells expressed mRNA encoding dopamine receptors D1a and D2. The dopamine receptor D1 agonist fenoldopam stimulated ghrelin secretion, whereas the D2, D3 agonist bromocriptine did not. Furthermore, the D1 receptor antagonist SKF83566 attenuated the stimulatory effect of dopamine. These results indicate that the stimulatory effect of dopamine on ghrelin secretion is mediated by the D1a receptor.
http://www.ncbi.nlm....pubmed/21521750

(3) Growing Neurons
The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.
http://www.ncbi.nlm....pubmed/16491079
(4) Hunger
Our bodies secrete a hormone called ghrelin, which controls our hunger and drives our appetite. If we do not understand, monitor, and control our ghrelin, we can forget about losing weight.
Here's what we know about ghrelin today. It's a hormone secreted in the stomach when we are hungry. It is also known to increase appetite, so while the body is asking for food (and we are often denying it), ghrelin strategically triggers appetite in the brain. Why? Because we've trained ourselves to ignore a rumbling tummy, but once our brains get into the act, with our powerful imaginations fueling our appetite, it's far harder to resist food. We're dreaming of bagels, cheeseburgers, ice cream, and pizza. Never underestimate the power of the appetite to tempt us. It's an incredibly formidable foe.
http://www.sharecare...C36775E922F3EEC

(5) Headaches

Here we are, hungry, stomach growling, headache setting in, and our mood deteriorating by the minute. Our ghrelin is working hard, simultaneously increasing our appetite since we choose to ignore our physical hunger.
http://www.sharecare...C36775E922F3EEC
I dont know the exact headache connection but some of this stuff might eplain how some of the effects of NSI-189 and perhaps why it was derived from nicotinimide. A long involved route it may be correct or in may not. Ghrelin has been studied for its nootropic effects.

[Major Legend]

Can't edit from my phone but should also add I am doing my doses sublingual. I spoon 20-25mg on the scale and then flip it under my tongue. I haven't been experiencing any excess salivation or noticeable negative effects from sublingual and prefer feeling the quick onset of effects. I also take 100 mg UMP sublingual at the same time as have been using uridine this way for several years.

Hebbeh, How long have you been dosing it now? When did the initial side effects wear off. Basically I am on day 6 now and I feel strongly about quiting. It's nowhere near as bad as an SSRI though.

I am experiencing consistent lethargy, always stressed in a weird "in the brain way" I don't remember the last time I felt relaxed. The only time I feel really "game on" is when I use nicotine with this. Paths are okay, but cigarettes work even better, too bad we don't have e cigarettes here because I hate smoking tobacco.

On another note, I can't help but notice small bouts of improvements, such as noticing certain things that have previously completely escaped me, or having a snap memory in remembering a list I always forget. Perhaps i'm one of those daydreaming types whose daydreaming is actually my advantage and this kinda takes it away...I'm not sure, these things are very little placebo plausible.

Trying a few cambridge science tests - my improvements are negligible even I am trying to focus hard on them.

Some brain supplements may help, but I am not 100% sure if they do help mitagate symptoms or improve NSI's effects. I am thinking trying the sublingual route, or pairing it with noopept.

My experiences (my libido is fine, and I seem always hungry) are close to those described by you and psychopath :

Psychopath Early Response:

I have too headache next day after first dose (only 5mg). Third day headache subsided and i dose 3x20mg and have not any headache after that.
Anyway last week i dose 3x40mg every day for 5 days but i dont notice anything from nsi. I have burnout or depression. I was without energy, no libido, absolutely unhappy without reason but i think it was not cause of nsi. I just have it sometimes.

My gf is taking nsi with me, she has started having her typical bipolar episode now (actually maybe its not bipolar, just depression buts its rapidly cycling). But i dont see that she is any better than in episodes before.
She dont take any other meds. Probably one week is just too short to have any effect from nsi.

Hebbeh Early Response:
My first day was very positive....felt in the groove and interactions with others seemed more positive then usual all day...felt very upbeat and it wasn't placebo. Since then, not so much. I've been getting the headaches also. And I feel a little dizzy for about 3 hours after dosing then the dizziness changes to spaceness. And if I go too long without redosing, I crash like coming down off a strong stimulant. This pattern has been consistent with a variety of doses and never more than 80 mg/day and I've more settled on 2x20mg. Not sure I can keep on top of work feeling like this.....seems to be getting worse than better.

Edited by Major Legend, 18 September 2013 - 04:57 AM.

[Hebbeh]

I'm 33 days into it and still dosing. Mine is lasting longer as I'm dosing on average 25mg/day in 2 divided doses sublingual. The only headache I've had since the initial few days at the beginning, was just a few days ago on the day following the experiment with the 1500mg time release nicotinamide. Suffice it to say, I won't be repeating that experiment.

My experience overall has been a mixed bag. I feel changes have occurred in subtle ways. But I agree, I have experienced some degree of lethargy due mainly, I believe, to disturbed sleep patterns.

I'm at a point of considering a break to reestablish a new baseline.

Edited by Hebbeh, 18 September 2013 - 12:02 PM.

[MizTen]

My thoughts from 2+ weeks after finishing first round of NSI-189:

Some of the brain changes have remained, though I still see this drug as something that should be cycled and also supported by other modalities.
About 2-3 days after I stopped, I experienced an abnormally large surge of motivational drive which lasted for about 6 days. Because my trial was affected by some unusually stressful events, there is not a whole lot that I can be sure of in terms of what it was really doing, at least in the long term.

But I am pretty sure these (slightly negative effects) came from NSI-189, because they stopped when the drug trial ended:

• Very mild occasional headaches
• Occasional very mild sense of pressure or "whooshing" sensation in my head, possibly from increased vascular and electrical activity in the brain
• Increased hunger
• Some periods of feeling kind of "languid" not really fatigued or lethargic, but a bit demotivated (similar to what Major Legend and Hebbeh reported)

These positive effects I am pretty sure came from the drug, as they were reduced after stopping

• Improved memory and cognitive processing, some of them directly affecting how I was handling stressful situations
• Significantly increased libido
• Deepened and more restorative sleep
• Big picture perspective greatly enhanced
• My future planning became much more emotionally detached, but also more detailed and global
• Reflexes and proprioception noticeably enhanced
• Hypervigilance disappeared
• Very rapid recovery from extreme PTSD triggering stress events
• Distractability of ADD disappeared

There did not seem to be any effect on my exercise capacity, strength or endurance during the trial. But I didn't have time to really challenge myself in that area, nor was I particularly inclined to do so.

As far as cycling, I am not really sure how that will work, and of course everyone is different. For myself, it seems like 6 weeks on and 2 weeks off (or very low dose) might be right, possibly titrating up and then down, and limit total cycles in one year to maybe 3 on-off cycles. The issue of supportive modalities I haven't fully worked out, some of those will probably more effective if incorporated into a program of cycling.

But I am thinking that supplements like DHA, uridine, PQQ, idebenone, St. John's Wort, lithium orotate, lion's mane, and magnesium would be especially helpful. Some of them may be best in smaller than normal dosages, whatever that means around here!

It's possible that for me, rhodiola, ginseng, red tea, and white tea would help with the occasional feelings of languidness and demotivation while taking it.

But I will for sure be doing supportive modalities for my next trial, barring any unforseen events as there were for this one. I am already using them more than before, partly because they seem more effective than they were in the past.

• Brain entrainment and self-hypnosis tapes might be incredibly helpful in supporting what NSI-189 does, especially if you already have specific goals.
• Brain training games may have a much stronger and longer lasting effect.
• I think learning new physical activities and having fun adventures would enhance the effects and support neurogenesis. Those do already, but with the chemical boost of NSI-189, the reward effect of learning and doing new stuff (self-chosen) causes mild and beneficial stress that might really change your game, so to speak.

[Strangelove]

My thoughts from 2+ weeks after finishing first round of NSI-189:

Some of the brain changes have remained, though I still see this drug as something that should be cycled and also supported by other modalities.
About 2-3 days after I stopped, I experienced an abnormally large surge of motivational drive which lasted for about 6 days. Because my trial was affected by some unusually stressful events, there is not a whole lot that I can be sure of in terms of what it was really doing, at least in the long term.

But I am pretty sure these (slightly negative effects) came from NSI-189, because they stopped when the drug trial ended:

• Very mild occasional headaches
• Occasional very mild sense of pressure or "whooshing" sensation in my head, possibly from increased vascular and electrical activity in the brain
• Increased hunger
• Some periods of feeling kind of "languid" not really fatigued or lethargic, but a bit demotivated (similar to what Major Legend and Hebbeh reported)

These positive effects I am pretty sure came from the drug, as they were reduced after stopping

• Improved memory and cognitive processing, some of them directly affecting how I was handling stressful situations
• Significantly increased libido
• Deepened and more restorative sleep
• Big picture perspective greatly enhanced
• My future planning became much more emotionally detached, but also more detailed and global
• Reflexes and proprioception noticeably enhanced
• Hypervigilance disappeared
• Very rapid recovery from extreme PTSD triggering stress events
• Distractability of ADD disappeared

There did not seem to be any effect on my exercise capacity, strength or endurance during the trial. But I didn't have time to really challenge myself in that area, nor was I particularly inclined to do so.

As far as cycling, I am not really sure how that will work, and of course everyone is different. For myself, it seems like 6 weeks on and 2 weeks off (or very low dose) might be right, possibly titrating up and then down, and limit total cycles in one year to maybe 3 on-off cycles. The issue of supportive modalities I haven't fully worked out, some of those will probably more effective if incorporated into a program of cycling.

But I am thinking that supplements like DHA, uridine, PQQ, idebenone, St. John's Wort, lithium orotate, lion's mane, and magnesium would be especially helpful. Some of them may be best in smaller than normal dosages, whatever that means around here!

It's possible that for me, rhodiola, ginseng, red tea, and white tea would help with the occasional feelings of languidness and demotivation while taking it.

But I will for sure be doing supportive modalities for my next trial, barring any unforseen events as there were for this one. I am already using them more than before, partly because they seem more effective than they were in the past.

• Brain entrainment and self-hypnosis tapes might be incredibly helpful in supporting what NSI-189 does, especially if you already have specific goals.
• Brain training games may have a much stronger and longer lasting effect.
• I think learning new physical activities and having fun adventures would enhance the effects and support neurogenesis. Those do already, but with the chemical boost of NSI-189, the reward effect of learning and doing new stuff (self-chosen) causes mild and beneficial stress that might really change your game, so to speak.

Very nice report!

Wow, some great positive results here! The way I read this your positive results totally outweigh the side effects you experienced...?

I am not sure if you have posted this already, but what dosage you were taking?

[MizTen]

Thanks!

Yes, the positive results definitely did outweigh the very mild sides. I would add though, that if the occasional demotivation was a side effect, and I suspect it may very well be, based on other reports, that would be something to prepare for, and-or work with or around.

I started at 40 mg x3 per day, then went down to 30 mg 2-3 x per day.

[bocor]

i was wandering as i seem to be having early parkinson like symptoms i think due to exposure to solvents would nsi 189 potentially help in cases of parkinsons?

[Colli]

I'm experiencing increased stress, like I always feel constantly stressed that won't go away with alchohol or even xanax, for whatever reason I don't smoke, but cigarettes seems to be an effective counter. My recall has improved slightly (in the context of just remembering lists though), but my intellectual and emotional insight has somewhat decreased, hard to pinpoint but it feels like I am generally more anxious and stimulated. I no longer fall asleep on bus rides, and I feel way more introspective which is counter to my learned extroversion methods. I've had to take lots of stimulants (caffeine, nicotine, sugar) and relaxants to stay in a workable condition in the past two days, my work (creative based) has fallen behind (though I am working on something markedly more ambitious than my usual projects). I feel this general stress all around. The only thing that stands out as enhancing is my sense of smell has improved.

I am feeling really "odd" there is no mediation on my emotions, but I feel a slight change in my perception and way of thinking, I feel a little more disinterested towards life, but not in an unemotional way. I feel depressed, but its not dread nor the kind of dark foreboding that accompanies with being negative. I just don't feel good.

That is very close to my experience so far. I have experienced a noticeable increase in both general and social anxiety. I have become even more withdrawn than usual and go out of my way to avoid being around others.

I do have depression - I'm currently on Sertraline - and can actually state that my depression has worsened since starting NSI-189. In fact, I have had several episodes where people have had to talk me out of taking my own life.

I haven't gotten any cognitive gains, either - my Cambridge and Dual N Back scores attest to that.

These issues surfaced after I'd been taking NSI-189 for about three weeks; I have been taking it longer than that, though.

I have now stopped taking it, and I'm starting to feel a little better with every passing day. I wish I had received better results from this - it's so frustrating to see others reporting positive effects.

Edited by Colli, 20 September 2013 - 01:08 AM.

[h2o]

Today is my 30^th day on NSI-189 and this is my first real update since starting my trial. I originally was *very* interested in NSI because I have chronic treatment resistant depression. I pretty much have had dysthymia with some occurrences of major depression all of my adult life. But why I really wanted to try NSI is because of the worsening memory/concentration that occurs with long term depression and so the mechanism of action of NSI seemed spot on. Actually, I can relate to a lot of what OpaqueMind has experienced (which he describes wonderfully) about how early onset, long term depression destroys autobiographical memories.

I am female and in my mid 20s. I remember MizTen saying that she was surprised that people half her age are experiencing positive effects, but I don’t think it has anything to do with age but more to do with onset and duration of symptoms (among other issues). In fact researchers have found hippocampal shrinkage in depressed kids as young as five.

For the first week on NSI, I noticed a clear reaction right away. I started being aware of small environmental details that I usually would not notice. I especially was keen on noticing nuanced facial expressions. Some of my experiences were similar to taking Noopept at least at first. NSI also gave me a mild stimulating effect that was not quite like a stimulant. I also have ADD so that effect was welcome. In general I was just more focused and felt some sort of inner peace.

Overall, I would say that the strongest effects for me were the first week and then the effects tapered a bit and then strengthened after the third week. For the first week, I was taking 40mg once a day and that was more than enough, but I did notice an obvious come down effect about 12 hours later. The second week I dosed 30 mg 2 x a day but strangely I felt less of an effect even though I was dosing more overall. The following weeks I have been doing 40mg x twice a day which is the standard middle range dose.

As my trial went on, my emotions became reminiscent of how I felt like when I was younger so it felt like I was going back in time a bit. Also I am a very withdrawn person and keep to myself almost to the extreme and I found myself having small talk with store clerk which was interesting. I also wasn’t as self-conscious. I noticed that some people here have had opposite effects though and started becoming more withdrawn. Perhaps NSI is turning on a switch of some sort with regards to social interactions.

One remarkable feat of NSI is that it comes with little to no side effects, at least for me. I experienced no headaches which seem to be the number one common side effect. Occasionally, I experienced a mild, transient head pressure or tingling but it was not really bothersome to me and I have a low tolerance for pain and discomfort. People take anti-depressants to feel better not worse, right? On a scale from 0 (none) to 5 (severe) I would rate the side effect profile of NSI of being a 1 for being mild and infrequent.

Thirty days into I would say that NSI is promising and can help many people, especially those who do not respond to other treatments like SSRIs. Having said that, I still have a long way to go before I can be completely relieved of depression. No, I am not “cured” just yet of depression despite the hype that NSI can “cure” depression. No matter how good a drug is, one still needs to develop good habits over the long term. That is why I think at least 3 – 6 months of NSI is needed before real life changes happen instead of just subjective feelings of well-being.

Also, I want to add that I really appreciate everything ScienceGuy has done and am thankful that he gave me the opportunity to try NSI as well as setting the precedent for future group buys. I would also like to acknowledge VLK for his generosity in setting up the second group buy so many will actually be able to try NSI for longer periods of time. Last but definitely not least, let’s not forget NeuralStem (and Darpa) who funded and developed the compound.

Edited by h2o, 20 September 2013 - 02:00 AM.

[Hebbeh]

I'm experiencing increased stress, like I always feel constantly stressed that won't go away with alchohol or even xanax, for whatever reason I don't smoke, but cigarettes seems to be an effective counter. My recall has improved slightly (in the context of just remembering lists though), but my intellectual and emotional insight has somewhat decreased, hard to pinpoint but it feels like I am generally more anxious and stimulated. I no longer fall asleep on bus rides, and I feel way more introspective which is counter to my learned extroversion methods. I've had to take lots of stimulants (caffeine, nicotine, sugar) and relaxants to stay in a workable condition in the past two days, my work (creative based) has fallen behind (though I am working on something markedly more ambitious than my usual projects). I feel this general stress all around. The only thing that stands out as enhancing is my sense of smell has improved.

I am feeling really "odd" there is no mediation on my emotions, but I feel a slight change in my perception and way of thinking, I feel a little more disinterested towards life, but not in an unemotional way. I feel depressed, but its not dread nor the kind of dark foreboding that accompanies with being negative. I just don't feel good.

That is very close to my experience so far. I have experienced a noticeable increase in both general and social anxiety. I have become even more withdrawn than usual and go out of my way to avoid being around others.

I do have depression - I'm currently on Sertraline - and can actually state that my depression has worsened since starting NSI-189. In fact, I have had several episodes where people have had to talk me out of taking my own life.

I haven't gotten any cognitive gains, either - my Cambridge and Dual N Back scores attest to that.

These issues surfaced after I'd been taking NSI-189 for about three weeks; I have been taking it longer than that, though.

I have now stopped taking it, and I'm starting to feel a little better with every passing day. I wish I had received better results from this - it's so frustrating to see others reporting positive effects.

I'd be interested to know after you have normalized back to baseline in a few weeks or a month whether you experience any long term changes either positive or negative. If NSI-189 does deliver on the promise of regrowing lost neurons, I would expect the real benefit would become apparent not during the course of the drug and possible hippocampus growth, but to surface later down the road.

I can relate to many of the anecdotal accounts others have posted (positive and negative) which indicates to me that something is occurring and my motivating force at this time is to finish allowing any changes that may be materializing to consolidate. If NSI-189 does deliver, it isn't surprising that a drug this potent has potential negative side effects surfacing during the course of the trail. Hopefully, the real payoff will become apparent after the trial, once potential growth is complete and neurological changes have solidified.

[ScienceGuy]

Hi Everyone,

My two cents... It is clear that NSI-189 has quite a strong PHARMACOLOGICAL EFFECT; wherein, it is not unsurprising to read of individuals experiencing incidence of POSITIVE and/or ADVERSE EFFECTS. Personally I am of the view that manifestation of HEADACHE is indicative of too high a dose and that reducing dosage accordingly would perhaps be a sensible course of action... I myself have found my ideal dosage to be substantially lower than the dosage being used in the clinical trials, wherein specifically a dosage of just 5MG taken ONCE DAILY is the sweet spot for me

Consequently, I find myself to be in the extraordinary situation of having 50 GRAMS of NSI-189 spare... Wherein, I am going to offer to sell this at zero profit, firstly ONLY being offered to the same individuals who partook in the first group buy (for a variety of reasons); wherein, I am making 10 x 5 GRAM quantities available for sale with pricing as follows:

5 GRAMS NSI-189, my cost = your price = $54.50 / GRAM + 23% EU VAT + 4% PAYPAL FEE + $14.50 SHIPPING COST = $272.50 (5 GRAMS) + 23% EU VAT + 4% PAYPAL FEE + $14.50 SHIPPING COST = $363.08

PM me if you are interested; and I reiterate this is ONLY being offered to individuals whom I have mailed NSI-189 to previously

[Godof Smallthings]

Anyone who would be willing to sell me 1 gram, please PM me?