Here are a few thoughts I have to address some common (and a couple specific) comments and so forth. I wanted to knock this out over lunch because otherwise it's never gonna get done, so I'm not going to go back and quote anyone in particular.
1) NSI-189's primary mechanism of action is hippocampal neurogenesis. Probably not. This phase 1B data (please read the poster if you haven't seen it already) indicates a dramatic reduction in cortisol in both rapid and chronic responders. No cortisol response is shown in partial or non-responders. I imagine the neurogenesis helps with the long-term effects, though.
2) NSI-189 takes X days to act; any response faster than that is placebo. Probably false. My personal experience, for what it's worth, was extreme fatigue for days 1-3 and unprecedented depression relief at day 4. But better than that, refer to that phase 1B data again. There is a subgroup which shows response in both decreased cortisol and depression symptoms within the first 10 days (this was the smallest time step they used for repeat measurements, so it may have even been faster).
3) NSI-189 has anxiogenic effects in the short term for some. Possibly due to the spike in initial cortisol observed in a subset of the test group.
4) NSI-189 has longer-term anxiogenic/adrenergic/noradrenergic effects. Possibly due to cortisol suppression. Although it is regarded as the "stress hormone", cortisol in is released in response to elevated adrenaline only after several minutes. Its initial purpose is to protect both body and brain from the effects of too much adrenaline for too long. It's only with chronic, daily exposure to elevated levels that cortisol becomes harmful. Thus, perhaps, the reduced cortisol response amplifies the effects of adrenaline. I don't know, I feel great, but I had my anxiety dispatched almost entirely before taking NSI-189.
5) NSI-189 has anxiogenic/gastrointestinal effects. Even more speculative than points 3-4. There are tons of neurons in the gut, and some receptors and neurotransmitters there have been strongly linked to anxiety. In particular, activation of serotonin type 4 receptors in the gut can cause anxious behavior. I would be shocked if NSI-189 somehow "knew" only to affect the neurons in the brain... Anyway, I find taking NSI-189 sublingually after food eliminates any GI symptoms. Here is another cheap, safe, and easy possibility. (Or just eat more meat/dairy/eggs/legumes with your NSI)
6) Can I take NSI-189 with corticosteroids? Based on the MoA mentioned in 1), my advice would be: no. However, to expand on that, it'd be no, ditch the steroids for long term use!! I bet NSI-189 will have a better effect, long term, than steroids on autoimmune disease management (not so much acute flares), than corticosteroids, because it helps improve stress resistance, which is a big factor in autoimmunity. If you want to hear more of my amateur speculations please ask.
7) Will NSI-189 make me smarter? Yes, if the origin of your cognitive issues is related to stress, I would say so. The prefrontal cortex is a total diva when it comes to functioning under pressure.
8) What about the sharp U shaped curve? Do I have to get the dosing perfect? I doubt it. The sample size, if you look at the Phase 1B above, simply isn't large enough to draw such conclusions. 6 people took 120 mg and they had on average slightly less benefit than the 6 people on 80 mg. Well, damn, color me skeptical at the statistical significance of that result. For me, relatively large doses have worked better. I'm tempted to try a rapidly escalating dosage protocol when I receive the next batch of SL's stuff, if I do, I'll let you all know how it goes. (I don't intend to megadose long term, just would be interested to see how it feels)
9) NSI-189 makes me crave carbs. This is certainly possible. Cortisol increases gluconeogenesis (the production of glucose from protein and/or fats), and low carb dieters have been shown to have elevated cortisol (40% higher than low fat dieters; even low GI dieters, however, had a 20% increase relative to low fat). Thus it's not entirely impossible that lowering cortisol will increase the body's need for glucose in more readily available forms.
10) What are good adjuncts for NSI-189? Your mileage may vary, but I'm taking/eating/doing alpha-GPC, TAU, NALT, shilajit, B-vitamins (allithiamine, riboflavin, niacinamide, P5P, pyridoxine, pyritinol, methylcobalamin), mixed tocopherols (alas, I wish a tocopherol-free mixed tocotrienol existed), taurine, citrulline, K2, magnesium malate, selenomethionine, potassium iodide, zinc picolinate, boron (as borax), blueberries, liver, cod liver oil, lots of seafood, leafy greens, yoga, weights, punching bag, an 11 pm bedtime, and plenty of socializing with good results.
Edit: I lied, here are 2 more thoughts
11) Is NSI-189 all good? Here is one subtle side effect that I've noticed after being on it a while. There's stuff that's sort of just... inaccessible. Stupid little facts mostly. I struggle to remember certain actors' names, for example, when I used to just rattle off "Oh, Janeane Garofalo was in 'Clay Pigeons' with Vince Vaughn in '98". But it's not gone either, it's just not there right away. Usually I sleep on it and it pops into my head the next day. So I did a little digging and this turned up (along with a number of other papers). Could it explain what's happening? I don't know. It doesn't bother me, unlike the memory problems I was having 2 years ago, so I don't really care, ultimately.
12) What's next for your pet rat? Well, there are 2 ways I want to go, in terms of experimentation. The first is neurofeedback, which seems like it has the potential to be really fascinating. The second is to combine TB4 and Dihexa, since they both act on the same receptor (hepatocyte growth factor), though TB4 is, I believe, a direct agonist whereas Dihexa is a positive allosteric modulator. I might throw in Cerebrolysin, because if you're injecting one thing, you might as well inject another. In my personal life, I'm working on starting a lifestyle-and-nutrition-centered health app and courses, while working as a postdoctoral researcher in quantum optomechanics and applying to finance jobs (might as well sell out big).
And now back to regularly scheduled life. If you'd like me to address something specific, or you have a comment, aside from posting it here please send me a PM so I know to come back and take a look (or you can find my email in my other super long post).
Edited by StevesPetRat, 02 February 2016 - 09:48 PM.
