6219 replies to this topic

[Hungry Hippo]

 

 I'd have to disagree. If what you're saying is the case and neurotransmitters are not at all involved in depression then why is a drug like Wellbutrin that increases dopamine effective in treating depression? Personally, I suffer from depression and anhedonia and I find drugs that increase dopamine like wellbutrin, modafinil, or adderall alleviate some if not all my depressive symptoms. My brain fog goes away, anhedonia, and of course I experience a significant boost in energy.  

 

 

What I'm saying is that the main theories, although they are shifting in other directions lately, say that neurotransmitters are the cause, are the biological expression of depression. These theories are based on that there is an effect when you influence neurotransmitters. But getting an effect is not the same as 'it is the cause'. That's a fallacy. With this I don't say that wellbutrin, modafinil or adderall do not work, but that the mechanism that's causing depression can be something totally different. 

 

One of the upcomming theories is that depression is the effect of an inflammation. Brains of depressed people were examined after they died and they had one thing in common: neuroinflammation. Now it's studied on the living. I volunteert and took part in it.

 

There is a form of depression that is caused by a virus.

 

GLYX13 is known to free people from depression for twee weeks after 1 injection. Works by a different mechanism.

 

That's what I tried to say.

[Hungry Hippo]

Has anyone experienced any joint pain on NSI-189?  I find it to be great, except for this issue, and I have read about several similar experiences before I began taking it as well.  

 

All the joints that I use frequently in sports are quite sore - wrists and elbows in particular.  My muscles are also considerably stiffer than usual, even after minimal exertion.  This happened to a minor extent a year ago when I tried NSI-189, but is much more pronounced this time, presumably because I am more active now.

 

I had this too. After a while I got a kind of verve pain with it, a very sharp pain.

[Hungry Hippo]

Ill back up what you said

 

 

 

The Role of Dopamine in the Pathophysiology of Depression

• 
  Boadie Dunlop
• 
  Charles B Nemeroff

 

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia, United States

Archives of General Psychiatry (Impact Factor: 14.48). 04/2007; 64(3):327-37. DOI: 10.1001/archpsyc.64.3.327

Source: PubMed

ABSTRACT

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in major depression. The physiological alterations underlying reduced dopamine (DA) signaling could result from either diminished DA release from presynaptic neurons or impaired signal transduction, either due to changes in receptor number or function and/or altered intracellular signal processing. There are data supporting each of these mechanisms, although interpretation of previous research is confounded by issues around study population, medication status, and technological limitations. In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably by acting on serotonergic or nor-adrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure. Animal models of major depression show considerable responsiveness to manipulations of DA neurotransmission. Several studies, including postmortem investigations, particularly of subjects with severe depression, have demonstrated reduced concentrations of DA metabolites both in the cerebrospinal fluid and in brain regions that mediate mood and motivation. Although the neuroimaging findings are not unequivocal, several studies support the hypothesis that major depression is associated with a state of reduced DA transmission, possibly reflected by a compensatory up-regulation of D(2) receptors. These alterations in DA signaling may underlie the findings of increased "liking" or "high" feelings reported by severely depressed subjects treated with d-amphetamine compared with the response of less severely ill and normal control subjects. The efficacy of medications that directly act on DA neurons or receptors, such as monoamine oxidase inhibitors and pramipexole, suggests that subtypes of depression stemming from a primary DA dysfunction exist. Further research on the contribution of DA to the pathophysiology of depression is justified to improve outcomes for patients with treatment-resistant and nonremitting depression.

and much more with this google search

 

https://www.google.c... depression pdf

Thats a reply for the hungry hippo

 

Thank you! I think it's quite interesting research.

 

Yes, when you press the dopamine button, there's an effect. But the cause can be something different. There's a lot of 'may' in the text. I'm just saying that there's a possibility that the cause of depression can be something totally different - a cause that can lead to an inbalance of the DA. (And fifteen years ago 'we' were so sure that serotonine was the cause of depression. All that research that pointed out that serotonine...)

 

And when something works it works. I'm not arguing that.

 

And be aware of that last sentence: treatment-resistent is a moral concept, we should get rid of that.

 

I'm not treatment-resistant, the treatment is just not right.

 

 

 

 

[Hungry Hippo]

 

  Cortisol suppression. This is a documented effect in humans, unlike hippocampal volume increase, which is speculative (I mean, it's probable, sure, since it does so in the animal model, but still).

I had the opposite effect -- much improved athletic endurance, less soreness, etc. -- but I believe my cortisol was way too high to begin with (I don't know this for a fact, because the doctor laughed in my face when I suggested that testing it might be informative).

 

 

I've read your posts about this. Very interesting...

[Autonomous]

I'm going to take a shot in the dark since I can't comment on effects from a first person perspective. However, what I have noticed, and what has been striking about a lot of the comments and experience reports has been that the implied "effect" threshold profile of NSI-189 may simply be misunderstood.

 

The way I've been hypothesizing is that NSI-189 may in fact be something you use a treatment or dosage pattern similar to chemicals like d-amphetamine (in the case of ADD/ADHD). There's a critical dopamine transport signalling pathway that is reversed, in essence, in some subtypes. In these subtypes the responders will have a spiked dosage cause excessive fatigue, yawning, etc. But it happens in a certain range. Whereby doses under cause headaches. Dosages at cause fatigue and sleepiness with an anxiolytic response. Whereas doses slightly above come the anxiolytic and alterness enhancement together mildly. Anything above is either excessive stimulation, or a plateau effect.

 

This also would imply 4-6 days consecutive with 1-1.5/2 days in between as the optimal weekly scheduling. No more than 2 dosings in a day as a third just leads to oxidative stress, insomnia, and disrhythm over the following 2 days. In general a practice of lowest effective dose is followed. Which to many people's shock and horror, in the case of d-amphetamine, can be as low as 2.5-5mg/day for some people up to 5mg x2 (of course prorated or adjusted up based upon bmi and metabolic rates). Whereas the typical individual usually was either overprescribed or illicitly dosing around 20-40mg or more.

 

I think the big challenge is the perception issue around this. For one, people want to always feel or see or experience something. But that implication is dangerous and very biased when determining optimal response.

 

Lets take a moment, take a step back, and ask the question for once. Do the response patterns for NSI-189 mimic the same response patterns (ie: sleepiness, lead feeling, drowsiness, threshold responses, headaches, overstimulation, etc) that may occur in subtypes of responders and non-responders of equivalent psychostimulants.

 

That seems to be the trend that is missing in detail from the discussions on here and reddit. I think everyone is reaching at what it may trend as in terms of antidepressants, ssris, maois, etc. However, there are very few bringing up the psychostimulants (except as mentions of synergy or contraindication of quality pairing), specifically how the NSI-189's response profiles in terms of side effects and responder vs non-responder is almost identical if not very similar to those of d-amphetamine response profiles in ADD/ADHD individuals.

 

Sort of keeps open this black box idea of whether this dopamine transport pathway, which seems to be where a potential majority of the effects of NSI-189 are contained, is at all this relevant focus area going forward as the root. Whether this is either simply addressing axonal damage, whether the influence on BDNF expression in general that is related to dopamine-affecting psychostimulants is the central modulator, or whether we're all here simply looking at what is in responders vs non-responders fundamentally a phenotypic difference in some part of the pathway the NSI-189 is simply modulating and thus leading to a cascade of BDNF expression and thus this plasticity and down-the-line neurogenesis / hippocampal volume changes.

[playground]

 

One of the upcomming theories is that depression is the effect of an inflammation. Brains of depressed people were examined after they died and they had one thing in common: neuroinflammation. Now it's studied on the living. I volunteert and took part in it.

 

There is a form of depression that is caused by a virus.

 

 

 

+1 Hungry Hippo.

 

Pathogens cause dementias and other neurological conditions too (depression, MS, chronic fatigue syndrome, parkinson's, etc)

 

This whole "amyloid plaques" routine is a scam, amyloid is an immune response to pathogen attack.

 

There are super-potent anti-bacterial, anti-fungal, anti-viral agents in carrots !  (and other veggies)

Drinking a glass of carrot juice on a daily basis will put these super potent chemicals to work

destroying the pathogens in your body... and there's zero toxicity in drinking carrot juice (or veggie juice).

 

That might be the best, and the most widely ignored, advice on this thread.

 

Edited by playground, 02 March 2016 - 03:14 PM.

[playground]

 

 

  Cortisol suppression. This is a documented effect in humans, unlike hippocampal volume increase, which is speculative (I mean, it's probable, sure, since it does so in the animal model, but still).

 

 

I smell a rat here (no pun intended, nor disrespect to Steve)

 

Let's the consider evidence:

 

1. =>   The pharma industry is full of the most abject, scamming liars around

who will give the sick and elderly the most heinous of poisons so long as their company is turning a profit.

eg: Cancer medicines that are so toxic they they actually decrease a patient's chance of recovery....etc..etc.

 

2. =>   NeuralStem refuse to reveal how NSI-189 works.

 

3. =>  There's no evidence of NSI-189's neurotrophic effect in humans.

 

Question:  If a detailed exposition of how NSI-189 worked ... would help garner interest, investment and sales

interest in NeuralStem or NSI-189... would a detailed exposition be released ?  

Answer:   Does a bear shit in the woods ?

 

Question:  There are 'rumors' flying around that NSI-189 works via it's neurtrophic action.  And there's

some details about mice hippocampal volume growing by 20%..  So why isn't there a detailed exposition

by NeuralStem elucidating how NSI-189 achieves this hippocampal growth ?

Answer:  Because they don't have a detailed understanding of any NSI-189 effect on hippocampal growth.

And there's been no independent confirmation of this 20% increase in hippocampal volume finding.  It is even true ?

 

Question:  Why hasn't NeuralStem shown that subjects given NSI-189 over a period of N months

have improved working memory, or improved short term memory, or improved long term memory

or increased powers of concentration .. or at least... better able to piss into the toilet without missing ?

Answer:  Could it be this whole 'neurogenic' aspect of NSI-189 is a load of ... smoke and mirrors ?

 

There's money involved, remember, not everything they say can be taken as gospel (or even 'any' of what they say).

 

I suspect that Steve'sPetRat is correct in focusing on the anti-cortisol aspects of NSI-189.

 

PS...

 

Do you think the shills and vendors will try to persuade you that my argument is wrong ?

Edited by playground, 02 March 2016 - 03:54 PM.

[Autonomous]

 

 

  Cortisol suppression. This is a documented effect in humans, unlike hippocampal volume increase, which is speculative (I mean, it's probable, sure, since it does so in the animal model, but still).

 

 

 

Question:  Why hasn't NeuralStem shown that subjects given NSI-189 over a period of N months

have improved working memory, or improved short term memory, or improved long term memory

or increased powers of concentration .. or at least... better able to piss into the toilet without missing ?

Answer:  Could it be this whole 'neurogenic' aspect of NSI-189 is a load of ... smoke and mirrors ?

 

 

I think a good point to bring up here is that the time scales for activity in animal models can often not accurately reflect those in humans. In the case of neurogenesis involved with other psychostimulants (getting back to my prior post) that affect BDNF levels, the initial results demonstrated simply that there was greater persistence rates of neurons with higher levels of differentiation. Rather than increased numbers of progenitor cells. Furthermore, the effects took sometimes months to years and required that the stimulant be introduced during a period of elevated neurogenesis (such as adolescence) for the long-term neurogenesis effects to be fully evident through the persistence model.

[Omega 3 Snake Oil]

anti cortisol effects of NSI189? I've had issues with my HPA axis for several years, I believe related to Lyme disease. For a while I had low cortisol with poor sleep, then I had fairly high cortisol with REALLY poor sleep. I wonder if NSI will help with this... the only sleep remedy that's really worked for me is high dose melatonin, which to me suggests it's an issue with the hypothalamus-pituitary region.

[thedarkbobo]

anti cortisol effects of NSI189? I've had issues with my HPA axis for several years, I believe related to Lyme disease. For a while I had low cortisol with poor sleep, then I had fairly high cortisol with REALLY poor sleep. I wonder if NSI will help with this... the only sleep remedy that's really worked for me is high dose melatonin, which to me suggests it's an issue with the hypothalamus-pituitary region.

 

Well I think it doesn't, maybe just slightly.

 

Personally this week was stresfull for me (it's when I can feel heart fatigue or something like this) so I've taken β-Androstenetriol...only thing I've got to lower cortisol so far.

[playground]

anti cortisol effects of NSI189? I've had issues with my HPA axis for several years, I believe related to Lyme disease. For a while I had low cortisol with poor sleep, then I had fairly high cortisol with REALLY poor sleep. I wonder if NSI will help with this... the only sleep remedy that's really worked for me is high dose melatonin, which to me suggests it's an issue with the hypothalamus-pituitary region.

 

I'm not suggesting your Lyme disease isn't a factor.... and i'm not ruling out a problem with your HPA axis.

 

I just want to mention to you that:

 

=> Too much salt in your diet is a primary cause for sleeping problems.

     (most people, over 50%, sleep better when they go for a 'no salt' dietary intervention).

     *** this works very well ***.  Try it for 1 week.

 

=> Watching TV, or Computer use, late into the evening disturbs your sleeping pattern.

     (you could impose a 9pm or 10pm cut off time and go and read a book, or magazine, in bed, instead)

     ** this works too **

 

=> Could you switch from coffee to tea, or only drink coffee in the  mornings,  and/or only drink herbal tea

     after 4pm.  (or some other rules that result in a halving of your caffeine intake)

 

If you're not entirely happy with this advice,

return it within 28 days, for a full refund (no quibbling).

[Autonomous]

 

anti cortisol effects of NSI189? I've had issues with my HPA axis for several years, I believe related to Lyme disease. For a while I had low cortisol with poor sleep, then I had fairly high cortisol with REALLY poor sleep. I wonder if NSI will help with this... the only sleep remedy that's really worked for me is high dose melatonin, which to me suggests it's an issue with the hypothalamus-pituitary region.

 

I'm not suggesting your Lyme disease isn't a factor.... and i'm not ruling out a problem with your HPA axis.

 

I just want to mention to you that:

 

=> Too much salt in your diet is a primary cause for sleeping problems.

     (most people, over 50%, sleep better when they go for a 'no salt' dietary intervention).

     *** this works very well ***.  Try it for 1 week.

 

=> Watching TV, or Computer use, late into the evening disturbs your sleeping pattern.

     (you could impose a 9pm or 10pm cut off time and go and read a book, or magazine, in bed, instead)

     ** this works too **

 

=> Could you switch from coffee to tea, or only drink coffee in the  mornings,  and/or only drink herbal tea

     after 4pm.  (or some other rules that result in a halving of your caffeine intake)

 

If you're not entirely happy with this advice,

return it within 28 days, for a full refund (no quibbling).

 

 

I'd add that the issue is not so much salt as it is the amount of water people are drinking, and how much potassium they are getting from their diet. If you're taking in everything in proper proportions, it is not a significant issue. The kidney's are very effective at eliminating salt from the body.

[Omega 3 Snake Oil]

I've heard that adding a bit of Himalayan salt is good for the adrenals? How does salt affect sleep?  And I've been off of caffeine altogether for two months. And yes to screen time, I wear blue blocking sunglasses if using a screen after 10PM

[Blackkzeus]

 

 

 I'd have to disagree. If what you're saying is the case and neurotransmitters are not at all involved in depression then why is a drug like Wellbutrin that increases dopamine effective in treating depression? Personally, I suffer from depression and anhedonia and I find drugs that increase dopamine like wellbutrin, modafinil, or adderall alleviate some if not all my depressive symptoms. My brain fog goes away, anhedonia, and of course I experience a significant boost in energy.  

 

 

What I'm saying is that the main theories, although they are shifting in other directions lately, say that neurotransmitters are the cause, are the biological expression of depression. These theories are based on that there is an effect when you influence neurotransmitters. But getting an effect is not the same as 'it is the cause'. That's a fallacy. With this I don't say that wellbutrin, modafinil or adderall do not work, but that the mechanism that's causing depression can be something totally different. 

 

One of the upcomming theories is that depression is the effect of an inflammation. Brains of depressed people were examined after they died and they had one thing in common: neuroinflammation. Now it's studied on the living. I volunteert and took part in it.

 

There is a form of depression that is caused by a virus.

 

GLYX13 is known to free people from depression for twee weeks after 1 injection. Works by a different mechanism.

 

That's what I tried to say.

 

 

I see what you're saying. You could very much be right. Do you think your depression might be caused by a virus? 

[Blackkzeus]

By the way what are the symptoms experience from depression? 

[pheanix997]

I've been thinking it may be false to attrobite my enhanced vision to depression-induced brain impairment. I thought that if NSI is so drastically improving my vision, then my lifelong low level depression must have caused cognitive damage which was now being repaied.

However, I've been on an SSRI for 5 years and my vision has deteriorated with it. Things like severely diminished vision when viewing objects in front of a bright background like windows or doors. For example a person's face would be blackened and impossible for me to see if they were standing in front of a window. I'm now linking these and other vision problems to the SSRI.

So maybe the avg. person taking NSI wont notice vision enhancement because the impairment is not caused by depression.

***Forgive my typing errors I only have internet access with my phone atm.

Edited by pheanix997, 05 March 2016 - 06:26 AM.

[Hungry Hippo]

 

Let's the consider evidence:

 

You're absolutely right. The choice to develop a drug is made not by looking at it's effectiveness, but motivated by profit, e.g. because it does not work, makes you sick or when you're taking that one you need another drug too. Sometimes you hear someone complain about that he had made a good medicine but it was wiped off the table because it was too promissing.

 

I have a little hope about Neuralstem. It seems they want to make good drugs. But it's for sure that when a lot of money is invested and the drug is not working, they make it work on paper.

 

Of course, I could be totally wrong about them.

[Hungry Hippo]

 

 

 

I see what you're saying. You could very much be right. Do you think your depression might be caused by a virus? 

 

 

I don't know. It's not what I suspect. 

[drg]

There is a big shift in the general attitude towards this drug from the initial group members. Someone would have to go through the thread to prove me right but it seems like more people are speaking negatively of NSI189 in the past 6 months than compared to the first year of people trialling it. There could be a million reasons but probably people just aren't bothering reporting positive reactions.

[Junk Master]

IMO there's just a weeding out of the placebo effect.  Also, as has been mentioned before, those who have the most positive responses to NSI-189 no longer bother to post their positive experiences because they aren't depressed anymore.

 

If I were to quantify my own experiences I'd say it has been the most powerful nootropic/anti-depressant I've used but not the sort of magic bullet cure people were hoping for.  I think it works best for those suffering from PTSD or PTSD like symptoms.  I'm also extremely dubious of any claims of hippocampal growth.

 

I do think it has great potential for improving brain function in former binge drinkers as well.

[pheanix997]

Even if NSI doesnt beat out placebo in trials and fails to get approved, it's inevitable future drugs similar to it will serve a big need. I can see future doctors, when faced with depressed patients, prescribing both a more potent mood booster along with a cognitive repairitive agent. The former more specialized to lift mood in the present, the latter to repair cognitive damage from untreated depression.

With that said, I think these companies need to specialize their developments more: highly specialized agents, rather than trying to make the next one size-fits-all cure for depression. It's all about the money though and making big sensational claims to garner attention.

NSI may pair well with one or two other drugs, e.g. a serotonin enhancer to facilitate balance and good cheer + a dopaminergic to combat body fatigue, then the NSI-like drug working less acutely behind the scenes, undoing years of damage.

[chemicalambrosia]

Neuralstem has added what I believe is new information to their investor presentation.

 

http://investor.neur...esentation+.pdf

 

Interesting information I think, especially for some of those who think they can "feel" the MOA. (edited to add snarky emoticon).

 

 

"> No appreciable binding activity against 52 neurotransmitter
related receptors/ion channels/enzymes
– Novoscreen: Adenosine, GABA, Glutamate, Histamine, Muscarinic, Nicotinic,
norepinephrine, opioid, or and serotonin receptors, Ca++, Cl-, K+ channels, PKA,
PKC, CRF, MAO-A/B, or CREB and ERK pathways (related to BDNF release)

 

Edited by chemicalambrosia, 05 March 2016 - 04:43 PM.

[Forty Six & 2]

Is there any indication what the MOA is?
Pretty sure I know, but didn't bother doing the in vitro assay as unimpressed overall with NSI-189. May get to it just to satisfy curiosity and conform a theory. Anyway, I won't speculate here, but if they gave any indication as to what IS the MOA certainly would be good to know, other than that we now know much of what it does not have affinity for.

[Flex]

Your saying it would work for ppl suffering from just anhedonia and not depression? i dont see how, anhedonia is mostly dysregulation of the reward system and nsi induces braingrowth and recovery and brainareas associated with depression such as the hipocampus, i dont see how that can help anhedonia unless depression is the cause of the anhedonia

 

look into the pathways of the Hippocampus (You know like e.g. thalamo cortical axis). IIRC the Hippocampus deactivates the Pallidum which in turn deactivates either the VTA, Striatum or something like that.

So this should disinhibit the latter area(s) to a certain extend.
 

Edited by Flex, 05 March 2016 - 08:52 PM.

[Autonomous]

 

 

Let's the consider evidence:

 

You're absolutely right. The choice to develop a drug is made not by looking at it's effectiveness, but motivated by profit, e.g. because it does not work, makes you sick or when you're taking that one you need another drug too. Sometimes you hear someone complain about that he had made a good medicine but it was wiped off the table because it was too promissing.

 

I have a little hope about Neuralstem. It seems they want to make good drugs. But it's for sure that when a lot of money is invested and the drug is not working, they make it work on paper.

 

Of course, I could be totally wrong about them.

 

 

They are motivated by profit and the contract they have with DARPA.
 

Edited by Autonomous, 06 March 2016 - 04:32 PM.

[drg]

I would consider the darpa contract a good sign

[Hungry Hippo]

Even if NSI doesnt beat out placebo in trials and fails to get approved, it's inevitable future drugs similar to it will serve a big need. I can see future doctors, when faced with depressed patients, prescribing both a more potent mood booster along with a cognitive repairitive agent. The former more specialized to lift mood in the present, the latter to repair cognitive damage from untreated depression.

With that said, I think these companies need to specialize their developments more: highly specialized agents, rather than trying to make the next one size-fits-all cure for depression. It's all about the money though and making big sensational claims to garner attention.

NSI may pair well with one or two other drugs, e.g. a serotonin enhancer to facilitate balance and good cheer + a dopaminergic to combat body fatigue, then the NSI-like drug working less acutely behind the scenes, undoing years of damage.

 

Ladostigil is certainly one of the upcoming meds I want to try. Unfortunately the testing takes absurdly long. I believe it's almost six years now. While the shady BRINTELLIX was rushed in little time on the market, Ladostigil has a hard time of getting approved.  
 

I would consider the darpa contract a good sign

 

That's what I thought.
 

[Omega 3 Snake Oil]

I'm about to try NSI189 for the first time. Before I do, I want to make sure nothing I take is contraindicated.

selegiline - 1.25 mg every morning
l-theanine - 50 mg every morning
ALCAR - 200 mg most mornings
melatonin - 16 mg every night
zopiclone - 3.75 mg every night
low dose naltrexone - 4.5 mg every night - stopped taking four nights ago, I think it was causing problems for me re: ACTH and adrenal function
various antibiotics for Lyme disease
various herbs for Lyme


Any potential issues?

[dwaaam]

I'm about to try NSI189 for the first time. Before I do, I want to make sure nothing I take is contraindicated.

selegiline - 1.25 mg every morning
l-theanine - 50 mg every morning
ALCAR - 200 mg most mornings
melatonin - 16 mg every night
zopiclone - 3.75 mg every night
low dose naltrexone - 4.5 mg every night - stopped taking four nights ago, I think it was causing problems for me re: ACTH and adrenal function
various antibiotics for Lyme disease
various herbs for Lyme


Any potential issues?

 

Shouldn't be any issues, but keep in mind that it is still a research chemical, even though it has gone through Phase Ib trials on healthy humans.

 

Why are you taking a low dose naltrexone? Is it for the Lyme or some other condition?

Edited by dwaaam, 16 March 2016 - 07:51 PM.

[Omega 3 Snake Oil]

Yeah, taking LDN for Lyme related chronic fatigue. I felt it helped for a bit but then I developed adrenal issues, I think the increased ACTH from LDN may have been part of the cause.