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Dosing NSI-189: Why BID? Why sublingual?

nsi-189 dosing

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#1 Vaenom

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Posted 01 August 2014 - 11:52 PM


The high majority of NSI-189 user report taking it BID (twice a day) and I can't find the source for this indication. 

The Neuralstem papers, I've seen, talk about total dose for a day but doesn't specify if the total qty was administered in divided doses.

 

Also, I also failed to find the indication for taking it sublingually. Did I miss a paper? 

 

This seems to me as very important for the following reasons.

 

According to a Neuralstem paper, the 40mg/day and 80mg/day did not only better than the 120mg/day, but the 120mg/day didn't produced ANY reduction of cognitive impairment and depression. Now, if they didn't took it sublingually and we do, our sublingual 40mg/day or 80mg/day could amount to blood levels way higher; perhaps up with oral (not-sublingual) 120mg/day or possibly even higher. This could make us miss the good spots on the U-shaped curve. 

 

Now, about the daily dosage division, if Neuralstem didn't test NSI-189 BID or TID, we can't assume NSI-189 their results would have been positive if they divided the dosage. Some drugs mechanism of action could depend on a pulsating pattern that isn't satisfied by BID or TID dosing.

 

Having no idea of how this drug works, I'd rather take it exactly like those trials participant.

 

Any source for BID/TID and sublingual vs Oral?


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#2 medicineman

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Posted 01 August 2014 - 11:55 PM

I'm a biggish guy, 179cm, 90kg. I figure I needed the higher doses, and because I really can't be bothered to do it bd, I take a 100mg od.
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#3 drg

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Posted 02 August 2014 - 03:51 AM

I take 40mg once a day and swallow it. I think talk of sublingual is mostly because most drugs are better absorbed that way but from my own and others experience oral works well as well. Taking it twice a day allows for a more stable blood level but again not necessary if you find it inconvenience.
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#4 Vaenom

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Posted 02 August 2014 - 06:14 PM

I understood those rationals, but if NSI-189 MoA requires 24h pulsing rather than more stable blood level, we partially screw ourselves. If sublingual rise our blood levels equal or higher than the 120mg/day of Neuralstem trials, we absolutely screw ourselves. (120mg/day didn't get ANY lowering of cognitive impairement or depression. None)

 

So the questions that I think need to be answered clearly for our own good are:

Q1. Are we sure Neuralstem trials participants we're taking it BID or TID, rather that QD? Source?

Q2. Are we sure Neuralstem trials participants we're taking it sublingual, rather than oral? Source?

 


Edited by Vaenom, 02 August 2014 - 06:17 PM.

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#5 Nattzor

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Posted 02 August 2014 - 06:22 PM


Q1. Are we sure Neuralstem trials participants we're taking it BID or TID, rather that QD? Source?

 

 

Yes, check their latest trial (no study published, just some data). They compared dosing once, twice or thrice a day with 40 mg.

http://bionapcfa.blo...ed-to-know.html - There's the best summary you can get.

 


Q2. Are we sure Neuralstem trials participants we're taking it sublingual, rather than oral? Source?

 

No, they took it orally, in pills. No sane company would give the patients powder.

People take sublingual because they assume it has higher bioavailability (bypasses the first stage metabolism). Do "we" know if it's superior? Nope. For all we know it might have 100% bioavailability. People just want to maximise their dosage to get a better ROI.


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#6 Vaenom

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Posted 02 August 2014 - 06:51 PM

Thanks Nattzor!  I somehow missed that. 

 

The fact that the failed 120mg group was in fact taking 40mg TID (3x per day) gives a little more substance to my hypothesis that NSI-189 MoA has optimal pulsating dosing schedule. Though, I do think it's way more probably that the total higher dosage (independently or the dosing schedule) was what made the 120mg group failed.

Therefore, sublingual administration may - in theory - increase the odds we end up non-responsing like 120mg group and for the same reasons: too high NSI-189 blood level. 

 

As far as anyone knows, has anyone brought up that hypothesis in an NSI-189 thread? To me this seems an important issue for many reasons. 

 

Maybe my impression that most user take it sublingually is wrong and that'd explain why discussion of this hypothesis isn't likely?

 


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#7 FW900

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Posted 03 August 2014 - 05:56 AM

There is not a manual or a paper, the reason people dose sublingually is because it avoids first pass metabolism which has benefits versus oral administration. Avoiding first-pass metabolism for most drugs (aside from prodrugs), will translate as higher bioavailability. The drug is more quickly circulated, and will make it's way to the brain, quicker than taking it orally. The drug is directly absorbed by capillaries under the tongue and avoids the degrading environment of the stomach and GI track. That of the drug which does not get absorbed sublingually won't degrade in the mouth or anything and will eventually make it's way down to your stomach unless you decide to spit it out.

 

Additionally, there is unknown data to my understanding on the oral bioavailability on the freebase NSI-189, meaning it would be wasteful to take it orally. Phosphate has a decent oral bioavailability.

 

You won't find any sources, from NSI-189 or pubmed for sublingual use intended for humans; it's not beyond stage II trials at this point even. Not that you need sources, this is basic pharamcokinetics. There are several YouTube videos on first pass metabolism, I strongly suggest you watch those.

 

 

EDIT: I quickly skimmed through it but you are right on your line of thinking. There is a possibility that sublingual administration has a higher BA than the oral route, which could make it more effective, more potent. I thought you were just asking what the point of it was, not theorizing and building off your line of thinking. Sorry for my (slightly negative) tone.


Edited by FW900, 03 August 2014 - 06:01 AM.

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#8 medicineman

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Posted 03 August 2014 - 06:28 AM

I learn something new every day. I guess small and bd is the way to go.
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#9 Nattzor

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Posted 03 August 2014 - 09:39 AM

 

The fact that the failed 120mg group was in fact taking 40mg TID (3x per day) gives a little more substance to my hypothesis that NSI-189 MoA has optimal pulsating dosing schedule. Though, I do think it's way more probably that the total higher dosage (independently or the dosing schedule) was what made the 120mg group failed.

Therefore, sublingual administration may - in theory - increase the odds we end up non-responsing like 120mg group and for the same reasons: too high NSI-189 blood level. 

 

The problem is, I don't understand how they reached that conclusion. If you check all the graps, NSI-189 3x a day out-performed 1x and 2x a day. They MIGHT mean "Wasn't statistical significant compared to 2x a day", but they didn't actually say it.

 

 

As far as anyone knows, has anyone brought up that hypothesis in an NSI-189 thread? To me this seems an important issue for many reasons.

 

I did first when I heard about the "120 mg failed compared to 40 and 80 mg", but can't find any evidence for it now.
 


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#10 StevesPetRat

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Posted 03 August 2014 - 12:53 PM

My impression is that most people are trying a lot of different dosing schedules so they'll have a "personal plot" of the U curve anyway.
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#11 MizTen

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Posted 03 August 2014 - 06:59 PM

Thanks Nattzor! I somehow missed that.

The fact that the failed 120mg group was in fact taking 40mg TID (3x per day) gives a little more substance to my hypothesis that NSI-189 MoA has optimal pulsating dosing schedule. Though, I do think it's way more probably that the total higher dosage (independently or the dosing schedule) was what made the 120mg group failed.
Therefore, sublingual administration may - in theory - increase the odds we end up non-responsing like 120mg group and for the same reasons: too high NSI-189 blood level.

As far as anyone knows, has anyone brought up that hypothesis in an NSI-189 thread? To me this seems an important issue for many reasons.

Maybe my impression that most user take it sublingually is wrong and that'd explain why discussion of this hypothesis isn't likely?


In addition to my personal experience, reading through other user reports points to sublingual dosing being a large part of the problem with adverse side effects (especially increased anxiety). Switching to oral dosing with food ameliorated that for me.
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#12 Al Capacino

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Posted 04 August 2014 - 05:34 PM

I had very bad anxiety taking it sublingually. Now it's oral I'm better but increased oral dose to 2x 30mg today and anxiety has crept back in a little... not good. Has anyone else experienced initial anxiety? Does it fade away? I'm on day 3.
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#13 RTSW

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Posted 11 August 2014 - 10:46 PM

I had very bad anxiety taking it sublingually. Now it's oral I'm better but increased oral dose to 2x 30mg today and anxiety has crept back in a little... not good. Has anyone else experienced initial anxiety? Does it fade away? I'm on day 3.

 

Yes, terrible anxiety at the end of day 2.

I'm on day 3 as well, anxiety has been there throughout the entire day, but no spikes like on day 2. I did lower the dose from 40mg to 25mg, however, so it's not a sign of it subsiding.


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#14 Vaenom

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Posted 12 August 2014 - 01:44 AM

 

I had very bad anxiety taking it sublingually. Now it's oral I'm better but increased oral dose to 2x 30mg today and anxiety has crept back in a little... not good. Has anyone else experienced initial anxiety? Does it fade away? I'm on day 3.

 

Yes, terrible anxiety at the end of day 2.

I'm on day 3 as well, anxiety has been there throughout the entire day, but no spikes like on day 2. I did lower the dose from 40mg to 25mg, however, so it's not a sign of it subsiding.

 

 

Al Capacino and Mitzen, were you on the phosphate of the freebase NSI-189? Also, from which seller or buy group?

 

I'm sensible to drugs and prone to anxiety, so I'm surprised I didn't do any yet on NSI-189. I'm taking 40mg BID sublingual of the freebase.


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#15 RTSW

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Posted 12 August 2014 - 02:22 AM

 

 

I had very bad anxiety taking it sublingually. Now it's oral I'm better but increased oral dose to 2x 30mg today and anxiety has crept back in a little... not good. Has anyone else experienced initial anxiety? Does it fade away? I'm on day 3.

 

Yes, terrible anxiety at the end of day 2.

I'm on day 3 as well, anxiety has been there throughout the entire day, but no spikes like on day 2. I did lower the dose from 40mg to 25mg, however, so it's not a sign of it subsiding.

 

 

Al Capacino and Mitzen, were you on the phosphate of the freebase NSI-189? Also, from which seller or buy group?

 

I'm sensible to drugs and prone to anxiety, so I'm surprised I didn't do any yet on NSI-189. I'm taking 40mg BID sublingual of the freebase.

 

 

Interesting to see you not showing signs of anxiety on the freebase version. Up until the point where I am in the main thread (I'm still going through it all), I saw many anxiety cases in the phosphate and sublingual administration groups (although the latter is likely just a dose-dependent anxiety response, since more NSI is expected to be made available in the bloodstream through that method), and even a case of anxiety disappearing when switching from phosphate to freebase. Could the freebase be offering diminishing effects? Or would the anxiety be something inherent to the phosphate form?


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#16 Vaenom

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Posted 13 August 2014 - 07:05 PM

 

 

 

I had very bad anxiety taking it sublingually. Now it's oral I'm better but increased oral dose to 2x 30mg today and anxiety has crept back in a little... not good. Has anyone else experienced initial anxiety? Does it fade away? I'm on day 3.

 

Yes, terrible anxiety at the end of day 2.

I'm on day 3 as well, anxiety has been there throughout the entire day, but no spikes like on day 2. I did lower the dose from 40mg to 25mg, however, so it's not a sign of it subsiding.

 

 

Al Capacino and Mitzen, were you on the phosphate of the freebase NSI-189? Also, from which seller or buy group?

 

I'm sensible to drugs and prone to anxiety, so I'm surprised I didn't do any yet on NSI-189. I'm taking 40mg BID sublingual of the freebase.

 

 

Interesting to see you not showing signs of anxiety on the freebase version. Up until the point where I am in the main thread (I'm still going through it all), I saw many anxiety cases in the phosphate and sublingual administration groups (although the latter is likely just a dose-dependent anxiety response, since more NSI is expected to be made available in the bloodstream through that method), and even a case of anxiety disappearing when switching from phosphate to freebase. Could the freebase be offering diminishing effects? Or would the anxiety be something inherent to the phosphate form?

 

 

In the trials, they took the phosphate NSI-189 orally, not sublingually. There's very little doubt that sublingual NSI-189 raises blood level way higher than oral. Possibly multiple time. Since we don't know if freebase NSI-189 is well absorbed orally, it makes sense to take freebase sublingually, but sublingual of the phosphate form doesn't for the following reason: the neuralstem trial results suggest more  is not always better with NSI. The higher dosage group (120mg day, in three oral dose) actually failed to show results. 

 

The oral freebase probably offer diminishing effects. The sublingual freebase may or may not reach sufficient blood level. Oral phosphate is the way  to go since it's the way neuralstem got results in their trials. Sublingual phosphate is probably counterproductive in many ways. I'm confused as to why this isn't more known and understood. May we need ScienceGuy to caplocks the truth in red for all of us, in a new post. I'm thinking to confirm my rational with Neuralstem people since, apparently, they are willing to answer this kind of questions.


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