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ALKS 5461/CERC-501 kappa antagonists

alks 5461 cerc-501 kappa antagonists

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#151 Laurus

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Posted 15 June 2017 - 11:14 AM

Hi guys, I believe that someone know the answer. I have a question:

How is it possible that mianserin which is kappa receptor AGONIST can be a working proven antidepressant if its mechanism of action is opposite to cerc501 ?

Hi!

 

The (potential) clinical profiles as well as primary mechanisms of action vary significantly. Mianserin's antidepressant effects seem to be primarily related to its antagonism of adrenergic receptors while it has only minor effects on KORs.

 

Furthermore, Mianserin is a PARTIAL agonist which means that its effects resemble the ones of FULL agonists but to a lesser extent. Since partial agonists can occupy receptors which would be otherwise occupied by full agonists they can be also considered "partial antagonists", inhibiting the work of full agonists, in our case dynorphines.



#152 brighterpath

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Posted 21 June 2017 - 04:45 AM

Anyone have any updates? I am beginning to combine cerc 501 with low dose NSI 189. Let it be known to the archive of the internet that I am the first member of my species to combine these two compounds together! 



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#153 Stinkorninjor

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Posted 21 June 2017 - 03:24 PM

Right, so I just opened my test-tube, because I just failed to retrieve my ordered caps, since my identification-papers have expired - hence I experience near-suicidal feelings of failure and worthlessness - basically, an intense form of existential anxiety, caused by punishment-sensitivity - mine is obviously through the f***ing roof!

 

Hence, it's a good day to try CERC-501.

 

But JESUS! This stuff absolutely REEKS of petrol! The impurity is definitively MTBE, because this stuff smells exactly like diesel or some other form of synthetic fuel! Very reminiscent of various forms of fuel I've smelled through the years.

 

This is good though! Because we know MTBE is flammable and volatile as no tomorrow, and it's also highly water-soluble. The compound itself does indeed not appear to be so though, as I just added water, and even with vigorous stirring, it's not solving very well, mostly just floating on the surface. It should hence be fairly easy to separate MTBE from CERC-501. I've heated my oven to ca 45 degrees celsius, and will soon put the solution of water + cerc + MTBE in there, to have it vaporize the h20 and MTBE away from the CERC-501.

 

I honestly don't have time nor the money to get DMSO though, so I'll just use it sublingually, once the drying is complete - if this is at all absorbable from tissue, which it should be, because the bloody studies mention 25% bioavailability, they don't mention any use of any special solvents, then sublingual should be enough to get some action out of this.



#154 Stinkorninjor

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Posted 22 June 2017 - 07:38 AM

I've had it drying in the oven for about 8 hours now... the water still hasn't evaporated! And it still smells like petrol (although slightly less)... Damn, dudes, this is going to take forever!

 

Annoying as all h*ll.

 

 

EDIT:

Just read up on water-evaporation - seems as if the reason it keeps humid for so long is the very, very small surface-area of the water - almost the same as the depth - I might need to pour the solution FROM the test-tube into one with a bigger surface area. However, I am somewhat concerned by this... because the CERC-501 seems a bit doughier than yesterday, might actually be slightly dissolved, and I don't want to lose any cerc-501 from the central mass, into the water! : ( The only way to not lose any CERC-501, is to dry it within the same container, until no liquid remains.

 

#hatesmylife

 

EDIT2:

 

Right, I finally got tired of waiting, so I just scooped out some of the semi-hard sticky goo out of the tube and took it sublingual. I feel a slight tingly feeling on mucuous membranes. It's hard to say how much I got, maybe 3-7 mg's, less than a tenth of the total I believe, at least - the total would be 100 mg worth of CERC-501.

 

SO! Let's see if there is any effect.

 

I too plan on combining it with NSI-189, but I want to test it on its own merits first - I won't report on any effects or side-effects until about day 3 of dosing, so as to not affect any of you guys either, but a report will be coming soon. (in three days)

 

This stuff is so sticky that some of it seems to have gotten stuck in my teeth...

 

It tastes about the same as it smells - slightly like gasoline. My breath is probably ever so slightly like gasoline now... something to take into account.


Edited by Stinkorninjor, 22 June 2017 - 08:16 AM.


#155 Stefan Scicluna

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Posted 27 June 2017 - 03:02 PM

any updates on this i'm interested - I'm also testing NSI-189 at the moment



#156 vere

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Posted 27 June 2017 - 04:32 PM

Hi everyone,
 
I haven't posted here yet but I also participated in the group buy and have been trying CERC-501 consistently for about the past month now since receiving it and I wanted to post how I am doing on it so far.
 
I am trying CERC-501 for my emotional flatness and anhedonia. I have had severe depression for 4 years that has worsened despite (and also because of) the many treatments I've tried. The only thing that has ever returned my feelings and ability to care was ketamine. I had complete emotional recovery, but only right after ketamine infusions as I was coming off it, and then I would be nearly back to normal soon after. I felt the same kind of relief (though not as strong as ketamine) when I started trying dextromethorphan to get the feeling of ketamine at home between travelling out to get infusions. In the long run though, it made me worse.
 
At first I thought it was purely NMDA antagonism that may have been helping me, but when I tried memantine I didn't get the same kind of emotional recovery (though it has been one of the more consistently, mildly helpful medicines I have tried in its own right, just not in the same way). I know there are some differences in the NMDA blocking of memantine vs. something like ketamine/dextromethorphan, and I think that has a lot to do with it. But I started to think maybe the differences were also in part because ketamine and dextromethorphan are both kappa agonists and memantine is not. 
 
There are probably a lot of different potential explanations for kappa agonism being helpful, but in my case I personally wondered if the antidepressant effects I felt from ketamine/DXM were some sort of rebound from their kappa agonism - especially because I felt nothing emotionally from ketamine (other than the disassociative trip) during the infusion, but had an extremely emotional experience coming off ketamine. Dextromethorphan has a pretty short half-life too, so maybe what I felt was actually some sort of kappa agonism afterglow. It's a total guess, but it led me to wanting to try CERC-501, since I believe kappa antagonism would be a better way to do this in the long term, as opposed to kappa agonists in the long term which feel detrimental. Also, kappa antagonism itself as a mechanism just sounded like one of the more promising ideas I'd heard in a while.
 
I tried CERC-501 starting at 10mg a day. I experimented with some different doses (5-10mg, 10-20mg, 20-25mg.) I definitely felt slightly worse at higher doses (though not worse than baseline). I wondered if that was because at a certain dose, with the half life being kind of long, the cumulative concentration of CERC-501 was enough to cause it to antagonize mu, which I guess it is known to do at about 25mg. About 10mg daily has been the best for me.
 
I've tried it with and without DMSO and I felt the effects were about the same for me. It seems to be absorbed just as well regardless of using DMSO, or at least to the extent of my ability to notice it. DMSO also made me smell like a little like creamed corn, so I kind of felt like it wasn't worth it for the similar results I was getting.
 
I definitely notice the smell and the sort of aftertaste that must be coming from the MTBE, as people have been talking about here. I think over the course of me taking it, I've noticed some gastrointestinal upset either coming from that or the CERC-501 itself. But otherwise, no side effects at all from the medication.
 
Though I'm not really bothered by it, I've tried heating CERC-501 to try to get rid of the MTBE  in my toaster oven on warm, around 100-120 degrees fahrenheit for around 10 minutes. I did manage to get rid of the taste of it a little by heating it, but I stopped doing it because it seemed like I wasn't doing as well on days that I was heating it (could have also been coincidence). I don't know if it could compromise CERC at all, but if it does, I don't want to risk wasting the medication. Also, to get it to where I didn't taste the MTBE anymore completely, sometimes the CERC itself would melt a little/get sticky like Stinkorninjor mentioned - I have had it stick to my teeth before as well. 
 
As far as the actual effects of the medication go, I do like taking it. It hasn't been the end all be all cure for my problems, but I didn't expect that or think it was possible. I am going to continue using it for as long as there is a supply for it, because I do feel some benefits from it and it makes day to day more manageable. CERC-501 is one of the few things I've even wanted to bother giving a chance to work in the long term and see where it goes. It feels safe and clean to take.
 
It helps my ability to tolerate things that would normally just frustrate me and ruin my entire day. It also helps me to take an interest in small ways in working again, which I used to love doing. It has helped me to enjoy some music again, or to actually want to sit down and listen to music. This is something that went away completely when I took Nuedexta (dextromethorphan/quinidine) for a couple months straight. 
 
Sometimes, though still rare, I have quick moments where I look at something more like I used to before depression. I still wish I could hold onto those moments longer though. I feel more often now that I can see what is wrong with how I am and have been, and it makes me see the point more in wanting to get better and change that. This is something I'm not capable of understanding or acknowledging in my normal state, like my brain just completely shuts it out and numbs me to it beyond my control.
 
CERC-501/kappa antagonism really does feel more like it is disinhibiting something, rather than actively doing something. This isn't bad though, it feels more natural, like I'm not completely shut off and numb all the time, so it makes it actually possible for me to do or at least acknowledge things that would make me feel better. I think the only downside to it feeling so normal is that I might forget what I am actually normally like off the medicine. I would like to try tapering off it at some point to see how I feel, but I haven't done that yet.
 
Now that I've felt what CERC does on its own, like others, I'll be trying some other things with it. Memantine and NSI-189 have both helped me slightly in the past, so I'll be trying it with those. I think depression is a multi-faceted issue that can't necessarily only be addressed by one mechanism or one thing alone. For me, I think it was several of the mechanisms of ketamine happening at the same time that gave me such instant recovery. I think long term recovery is a different story and CERC-501 is something I can see helping in that.
 
But I also will keep looking for something else new to use with CERC-501, probably something glutamatergic, because I do feel like I am still missing something. I still lack the attachment and emotions/feelings tied to what I used to care about deeply. I still don't feel like myself and how I used to be as a person. I'm still just distracting myself a lot of the time. That's something it is hard to see myself ever getting back sometimes, but I'll keep trying and I'm glad to be taking something that can break me out of my normal patterns even a little, and hopefully help me at least get back up a bit from the low point I have gotten to.
 
Hope that helps anyone who was interested in hearing a personal experience on what CERC-501 feels like so far, and looking forward to hearing how others are doing on it.
 

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#157 Stinkorninjor

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Posted 27 June 2017 - 09:59 PM

Uaaaghh!!

 

I want to contribute my 3-day experience with the drug as well, but SCT and anhedonia or whatever, is making it difficult.

 

I experienced similar things on the first day of using the drug - a very discrete effect - slightly STIMULATORY actually - which makes sense, since apparently kappa-antagonism causes the release of dopamine and norepinephrine - but I also experienced something unexpected... namely, a slight, sort of... ANALGESIC effect! I noticed that all of a sudden, exercising was not as grueling mentally, OR physically - it was as if it hurt less, and I actually made both more repetitions and more sets of exercises that day.

 

This, however, was only on day one - the day when the CERC-501 was the MOST soluble - still soft from heating it and from having soak in water for, like, more than 24 hours.

 

It still tasted and smelled of MTBE, but somewhat less so, at that moment. I took the compound sublingually that day.

 

Ever since, I also left it to evaporate the last bit of liquid, and it no longer smells of MTBE, but it does still taste a bit of it.

However... I have not noticed any effect what so ever since that day, when it was gooey and semi-dissolved - nothing whatsoever. In fact, after more than, like 20 minutes worth of dissolving under my tongue, the compound still does not dissolve...

 

The colour is, still, btw, a yellowish tone - but now it's harded into a crystalline resin, and not a yellow powder.


I'm not entirely sure if I can judge the effects correctly, since I did heat it to at least 45 degrees for, what, 12 hours? Minimum. And I then let it soak in liquid as well - this may well have destroyed the compound, for all that we know.

 

However... the fact that it's still so undissolvable, does imply, to me, that it's probably still CERC-501 - just that, alas, apparently I have weak saliva, and the compound is indeed JUST AS hard to dissolve as our friend Brighterpath claimed.

 

Hey, btw - Brighterpath and Tolerant - what are you guys experience with this drug? Did you experience a slight stimulatory effect? Slight analgesic effect? (higher pain tolerance is perhaps a more apt description)  Very subtle antidepressant effects? Subtle anxiolytic effects?

 

 

Btw, I ordered 100 mg, so I simply took my resin apart into 10 pieces, which should amount to 10 doses at 10 mg each. The dosing is of course not entirely accurate though, since I haven't weighed any of it...


Edited by Stinkorninjor, 27 June 2017 - 10:00 PM.


#158 Stefan Scicluna

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Posted 27 June 2017 - 11:13 PM

where can i buy this looks interesting to try? does it work immediately or needs to build in the bloodstream like SSRIs? which I tried all of them including SNRI and all TCAs to no avail. My anhedonia is killing me 



#159 Stinkorninjor

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Posted 28 June 2017 - 09:33 AM

where can i buy this looks interesting to try? does it work immediately or needs to build in the bloodstream like SSRIs? which I tried all of them including SNRI and all TCAs to no avail. My anhedonia is killing me 

 

I wouldn't buy this yet, because there is too little feedback on the drug yet - and as far as I can tell, many of us are having mixed results.

 

You have to remember, this drug hasn't had as many trials and as much rigorous testing as something like NSI-189.

 

With that said, the side-effects profile is outstanding, and the fact that it doesn't have any discontinuation-symptoms and a quick onset, are of course good things.

 

Just hold off on this until more of us Group buy-ers have written some statements about it.
 



#160 brighterpath

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Posted 28 June 2017 - 09:01 PM

My experience is strikingly similar to that of Vere's. I use it after heating it up to get rid of the MTBE, which definitely seems to work because it takes away the gasoline like taste and smell. I take it with pharma grade DMSO mixed with juice, since I believe the water solubility to be strikingly low in it's current form. Then again, I haven't been taking it without it, so it's hard to compare. I have not found that heating takes away any efficacy. 

 

I went down on the dose to under 10mg when using with DMSO, because using higher doses for several days seemed to blunt my emotions a little bit, which may be due to the mu antagonism. 

 

I find that it keeps certain negative thoughts away, but you wouldn't notice it. I keep a journal, and I notice it afterward that I didn't have a lot of negative or catastrophic thoughts while I was on the compound, or I will start to have negative thoughts and realize that I hadn't dosed in about two days. It really does feel like a "lack of" something rather than the drug putting something extra in there. 

 

I also find that I get more done without realizing when I am using the compound. I often have hard time focusing and organizing stuff, but when I am consistently dosing, my environment is generally cleaner and more stuff gets done without me really realizing it, like I would with stimulants. 

 

If I go off of the drug for a few days, I find that I get into a state of mild confusion where things aren't quite clear and I'm not quite as awake. Nothing detrimental, just something I notice. This might be a withdrawal effect. I am still experimenting on this end. 

 

But for me, derealization has been the biggest issue, and this has finally confirmed that kappa opioid antagonism is not the only source of the problem, at least for me. I remember the naloxone study only helping about 30% of the patients, and it seems like the kappa opioid, dopamine, and glutaminergic systems are linked in incredibly complicated ways. I am now looking into glutaminergic drugs as well, as I think underactivation of the NDMA receptors could be a part of the problem (ex. NDMA antagonists cause dissociation). 


Edited by brighterpath, 28 June 2017 - 09:03 PM.

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#161 Stinkorninjor

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Posted 29 June 2017 - 08:33 PM

My experience is strikingly similar to that of Vere's. I use it after heating it up to get rid of the MTBE, which definitely seems to work because it takes away the gasoline like taste and smell. I take it with pharma grade DMSO mixed with juice, since I believe the water solubility to be strikingly low in it's current form. Then again, I haven't been taking it without it, so it's hard to compare. I have not found that heating takes away any efficacy. 

 

I went down on the dose to under 10mg when using with DMSO, because using higher doses for several days seemed to blunt my emotions a little bit, which may be due to the mu antagonism. 

 

I find that it keeps certain negative thoughts away, but you wouldn't notice it. I keep a journal, and I notice it afterward that I didn't have a lot of negative or catastrophic thoughts while I was on the compound, or I will start to have negative thoughts and realize that I hadn't dosed in about two days. It really does feel like a "lack of" something rather than the drug putting something extra in there. 

 

I also find that I get more done without realizing when I am using the compound. I often have hard time focusing and organizing stuff, but when I am consistently dosing, my environment is generally cleaner and more stuff gets done without me really realizing it, like I would with stimulants. 

 

If I go off of the drug for a few days, I find that I get into a state of mild confusion where things aren't quite clear and I'm not quite as awake. Nothing detrimental, just something I notice. This might be a withdrawal effect. I am still experimenting on this end. 

 

But for me, derealization has been the biggest issue, and this has finally confirmed that kappa opioid antagonism is not the only source of the problem, at least for me. I remember the naloxone study only helping about 30% of the patients, and it seems like the kappa opioid, dopamine, and glutaminergic systems are linked in incredibly complicated ways. I am now looking into glutaminergic drugs as well, as I think underactivation of the NDMA receptors could be a part of the problem (ex. NDMA antagonists cause dissociation). 

 

I'll suggest the same thing I suggest to everyone else with Depersonalisation - LAMOTRIGINE - it's the antidepressant drug with the most evidence of efficacy for Depersonalisation, working as a modulator of glutamate activity - it's worth a check - might even be an interesting idea to COMBINE it with CERC-501! = ) Perhaps you should make sure to stash away a small amount of CERC-501 until you can combine it with Lamotrigine?

 

Awesome to hear your experiences btw! = ) Interesting that you as well seems to have experienced some of that... pseudo-stimulatory effect? Even if it doesn't feel the same, the effects seem similar.

 

What do you make of my experiences btw? That I don't get much effect, because the drug never dissolves in my mouth? Could my entire first day have been PLACEBO? It's possible... except I did not foresee any sort of analgesic effect - I didn't think I'd get less physical pains when doing my exercises.

 

For those not in the know - increased susceptibility to pain have been noted in certain atypical forms of depression - and I actually think I might have a bit of this - as well as a bit of exercise-intolerance (which could be of the auto-immune variety - I think I've always had that - I seem to get more easily inflammated and recover slower than my friends - burnout just made it more obvious) - but CERC actually seemed to take those problems away - haven't trained that hard or that well, ever since!


Edited by Stinkorninjor, 29 June 2017 - 08:35 PM.


#162 keystroke

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Posted 29 June 2017 - 10:11 PM

Sorry for the cross-post but: Is it still possible to buy some CERC-501 from the group buy? I would like to get some. Have been following this thread but didn't realize my old ImmInst account worked. Thanks! :)



#163 keystroke

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Posted 09 July 2017 - 08:19 AM

Any updates on effects? Should be receiving some soon. :)



#164 Stinkorninjor

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Posted 09 July 2017 - 11:56 AM

Having trouble sourcing whatchamacallit DMSO, so I've got no updates - it's damn tricky to get imported into the Nordic countries! Which, I suppose, is understandable - it's some real-deal chemicals.



#165 brighterpath

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Posted 14 July 2017 - 10:18 PM

Since I now know that my particular condition is more about the glutaminergic system than the opioid system, I am happy to sell the rest of my CERC-501 stash. I do not plan to order more in the future, for the time being. If anyone would like the rest of this substance please let me know. 

 


Edited by brighterpath, 14 July 2017 - 10:38 PM.


#166 samson75

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Posted 15 July 2017 - 08:21 AM

Hello, so, from reading reviews on the two CERC-501 threads; it seems that it's a failure and does not help for depression....

Has someone from the groupbuy had a positive outcome or is that product definitly useless ?

Does someone have news from other promising future AD like rapastinel for exemple?



#167 Stinkorninjor

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Posted 15 July 2017 - 02:02 PM

YO! Wasup' bitches! :D

 

I'm currently reporting in with some new data - this is the first day I'm using the drug and getting a response once more! Solubility is definitively an issue with this drug, but you need not

rely on DMSO to get the benefits! I tried a new form of dissolvent today - VINEGAR! Of the apple-cider variety - and lo and behold, it works! It dissolves the drug after about 20 minutes, depending on your mixture of vinegar to water, and then allows the drug to work its magic!

 

I am now once more experiencing what I experienced on the first day of trial, which was with an actually dissolved Cerc-501 solution (heat + water as solvent) - a subtle antidepressant, subtle anxiolytic, subtle stimulant and even subtle analgesic effect! : D

 

My mood is noticeably up from yesterday - my will to exercise and exercise-performance is also VERY noticeably up! Yesterday I could barely do 5 push-ups, today I did 16! More than three times as many.

 

I'm also the SECOND member of my species to combine it with NSI-189, and so far, so good! Seems to be synergistic, much like I hypothesized.

 

I was prior to this once more seeing diminishing returns from NSI-189 - it goes in cycles, the benefits, but with CERC-501 added, I once more feel positive and energized! = )

 

 

A small note - this may not entirely be a positive thing, since Kappa-AGONISTS have been shown as proof-of-concept to work as a mood-stabilizer - effectively cutting Bipolar MANIA down to size within the hour of ingestion. As such, it doesn't stand too hard to reason that kappa-ANTagonism will have the opposite effect on bipolars... effectively sending them into mania.

 

As some of you may know, I have been evaluated for Bipolar NOS - "Not Otherwise Specified" - a rare, atypical form of Bipolar Disorder, which displays somewhat different symptoms than regular type 1 or type 2 bipolars - making it harder to diagnose. The results on my mood can then be seen from this critical lense as well... a sign of Bipolar Disorder.

Something to keep in mind, friends.

 

However... the kappa-agonist Atomoxetine caused the OPPOSITE reaction in me (at high doses), which was depression - so no mood-stabilizing there.

 

Anyways, I'm enjoying this day, and the beautiful sunshine outside, and I do believe I shall attempt some art as we speak - just something simple - perhaps some music to go with it. = )

 

 

Full diagnosis:

ADHD-PI with comorbid DCD, Dyscalculia, Dysthymia, Anxiety and Occupational Burnout.

 

 

Full stack for transparency:

Guanfacine 1 mg

NSI-189 20 mg

Melatonin 0.5 mg

Gabapentin 300 mg

Zink Citrate 35 mg

Magnesium Citrate 700 mg

 

 

Hello, so, from reading reviews on the two CERC-501 threads; it seems that it's a failure and does not help for depression....

Has someone from the groupbuy had a positive outcome or is that product definitly useless ?

Does someone have news from other promising future AD like rapastinel for exemple?

 

No, no, no... you are drawing too many conclusions here! If you look closer, you will find that the reports are MIXED - that it's a 50/50 sort of success-rate. As such, it's more or less like any other antidepressant - but with a SUPERIOR side-effects-profile! : )

 

Remember, depression has many causes, this is but yet another NEW way of dealing with depression and anxiety - now, I will admit, I myself expected a more universal powerful response, but that's just regular wishful thinking from someone in a bad spot - alas, my science was bad.

 

This doesn't mean the drug is bad, or ineffective - just that it doesn't help everyone.



#168 samson75

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Posted 15 July 2017 - 03:49 PM

Thanks for the answer, i'm curious to hear more experiences.



#169 vere

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Posted 15 July 2017 - 03:59 PM

Yeah, as much as I would like to hear an awesome resounding positive response to CERC-501, I don't think we can call it a failure for depression necessarily since we have a pretty small sample size. Also, the few people who have tried and reported their results here all have varying diagnoses so it's hard to come to a consensus.

 

I have depression but probably a more atypical one that is mostly anhedonia and lack of emotions. Barely anything has ever even touched my depression so trying CERC has been worthwhile for me, even if it only has a sort of partial effect. I'm used to taking a medicine and either having it do absolutely nothing or feeling worse from it. This did something and made me feel slightly better (with also no side effects), so I would find that pretty significant. Doesn't return my ability to care about anything but definitely helped me with day to day frustration/negative thoughts and improved my ability to work.

 

But, after taking it now for going on two months straight at 10mg a day, I feel like I am having trouble noticing what it is doing anymore. I did also do some mixing with NSI-189 and Memantine to little additional benefit. I don't work like I did a couple weeks ago and I find I'm more easily angered again recently. Nothing worse than what I was like before, but today I think it's about time that I start tapering off to see how I am without it. This is one of the few medicines I wanted to take this long and this consistently. 

 

Now I am really curious to try out what Stinkorninjor mentioned about dissolving it in vinegar though. Sounds interesting, that's great that you are getting effects from it again!

 

I think if I stop it for a while and maybe start it up again at another time, I might get better results again. I also feel that my problem is mainly with the glutamatergic system, and have felt that way since trying ketamine. But, I do see CERC-501 as being potentially helpful in adjunct to something affecting glutamate. So I'm desperately searching for the next thing I haven't tried, but most of the glutamatergic medicines that would be helpful are still in development. I think a lot of people are probably in that place right now.

 

But overall, yeah, if you're looking at CERC-501 and wondering if it might help you, it might be worth a shot. Though it's a subtle medicine, I think you'd be able to tell from the first day to the first week what it is going to do for you. I didn't get any increasing benefits beyond that. And it seems like there will be a decent amount of this compound available for more people to try just from this group buy. I think it would be great to see across a larger amount of people and different conditions, how this medicine affects them, so we can learn a little more about the role kappa antagonism plays in varying mental health conditions.

 


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#170 Finn

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Posted 17 July 2017 - 03:54 AM

 

 

However... the kappa-agonist Atomoxetine caused the OPPOSITE reaction in me (at high doses), which was depression - so no mood-stabilizing there.

 

 

 

Kappa agonist metabolite, 4-hydroxyatomoxetine (4-OH ATX) gets rapidly glucuronidated to the inactive 4-hydroxyatomoxetine glucuronide.

 

In extensive metabolizers, 4-OH ATX peak plasma levels are just 1.27% of the ATX peak plasma levels, in poor metabolizers it was too low to even measure, AUC exposure too low to measure in both EMs and PMs

 

Disposition and Metabolic Fate of Atomoxetine Hydrochloride: The Role of CYP2D6 in Human Disposition and Metabolism

http://dmd.aspetjour...content/31/1/98

https://www.pharmgkb...way/PA166160830

 

I don't think strong kappa agonist effect is needed to explain suicidal ideation side effect of ATX, which isn't statistically significantly higher than methylphenidate's according to meta reviews. 

 

For SSRIs, suicidal ideation doubles for under 18 year olds, goes up by 50% for 18-24 year olds, and is still somewhat increased for males up to 30. 

 

For ATX suicidal ideation also seems to be much more increased in pediatric patients compared to adults, for whom there was no increase in this meta analysis, children are probably more sensitive to suicidal ideation side effect overall. 

 

Frequency of suicidal ideation with atomoxetine treatment was 0.37% in pediatric patients (vs. 0.07% with placebo) and 0.11% in adults (vs. 0.12% with placebo)

 

https://www.ncbi.nlm...les/PMC4202998/

 

Meta-Analysis of Suicide-Related Behavior or Ideation in Child, Adolescent, and Adult Patients Treated with Atomoxetine

 

 

Suicide related events and attention deficit hyperactivity disorder treatments in children and adolescents: a meta-analysis of atomoxetine and methylphenidate comparator clinical trials

 

https://www.ncbi.nlm...les/PMC3691607/

 

Results

 

In total there were 5 suicide-related events, atomoxetine (ATX) 3/559 and methylphenidate (MPH) 2/465. There were no suicide attempts nor completed suicides. Meta-analysis finds no difference of a difference in risk between ATX and MPH with a Mantel-Haenszel risk ratio of 0.52 (95% CI; 0.06, 4.54).

 


Edited by Finn, 17 July 2017 - 04:23 AM.

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#171 Stinkorninjor

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Posted 17 July 2017 - 04:25 PM

 

 

 

However... the kappa-agonist Atomoxetine caused the OPPOSITE reaction in me (at high doses), which was depression - so no mood-stabilizing there.

 

 

 

Kappa agonist metabolite, 4-hydroxyatomoxetine (4-OH ATX) gets rapidly glucuronidated to the inactive 4-hydroxyatomoxetine glucuronide.

 

In extensive metabolizers, 4-OH ATX peak plasma levels are just 1.27% of the ATX peak plasma levels, in poor metabolizers it was too low to even measure, AUC exposure too low to measure in both EMs and PMs

 

Disposition and Metabolic Fate of Atomoxetine Hydrochloride: The Role of CYP2D6 in Human Disposition and Metabolism

http://dmd.aspetjour...content/31/1/98

https://www.pharmgkb...way/PA166160830

 

I don't think strong kappa agonist effect is needed to explain suicidal ideation side effect of ATX, which isn't statistically significantly higher than methylphenidate's according to meta reviews. 

 

For SSRIs, suicidal ideation doubles for under 18 year olds, goes up by 50% for 18-24 year olds, and is still somewhat increased for males up to 30. 

 

For ATX suicidal ideation also seems to be much more increased in pediatric patients compared to adults, for whom there was no increase in this meta analysis, children are probably more sensitive to suicidal ideation side effect overall. 

 

Frequency of suicidal ideation with atomoxetine treatment was 0.37% in pediatric patients (vs. 0.07% with placebo) and 0.11% in adults (vs. 0.12% with placebo)

 

https://www.ncbi.nlm...les/PMC4202998/

 

Meta-Analysis of Suicide-Related Behavior or Ideation in Child, Adolescent, and Adult Patients Treated with Atomoxetine

 

 

Suicide related events and attention deficit hyperactivity disorder treatments in children and adolescents: a meta-analysis of atomoxetine and methylphenidate comparator clinical trials

 

https://www.ncbi.nlm...les/PMC3691607/

 

Results

 

In total there were 5 suicide-related events, atomoxetine (ATX) 3/559 and methylphenidate (MPH) 2/465. There were no suicide attempts nor completed suicides. Meta-analysis finds no difference of a difference in risk between ATX and MPH with a Mantel-Haenszel risk ratio of 0.52 (95% CI; 0.06, 4.54).

 

 

Very interesting information!

 

I actually recall now how I first assumed that, since I'm a slow metaboliser, my CYP2D6-mutation would prevent the metabolite from forming to any greater extent - hence how I overcame my fear of ATX and gave it a try.

 

I assumed that my SI was caused by the kappa-agonism anyway, but that may well have been an erroneous assumption. I did experience some SI from higher dosages of Methylphenidate as well, so that certainly fits the pattern.

 

Would you happen to know if there is comparable data on Reboxetine, regarding Suicidal Ideation and other problematic neuropsychiatric side-effects? Because the "conventional wisdom", from users and Dr's online, seems to be that RBX causes less SI, and actually has some antidepressant effects - meanwhile, ATX, which on paper, has almost the same MOA, seems to cause far more problematic neuropsychiatric effects. (this could of course only be a mirage, since it was revealed that RBX is probably ineffective as an antidepressant, for a majority of patients)

Of course, a 1:1 comparison isn't possible, since RBX is far more selective towards pure NRI action, while ATX has these miniscule effects on Serotonin, NMDA and Kappa-networks. I personally am sceptical that it's the SRI-effects which cause these problems, since SNRI's are not in general considered to have this bad reputation - I will admit that there is probably some bias again, from me here - because I did not experience any of the problematic side-effects from Duloxetine, which is an SNRI. Neither did I experience SI while taking Sertraline, an SSRI, so the S-component does not seem to affect me in an SI-manor.

An interesting note here... do we know if the NMDA-antagonistic properties of ATX are tied to the parent-compound, or to any of the metabolites? Reading up on it, I can't seem to find any info on it being tied to the metabolite...

 

This is intersting, if this property is a part of ATX proper, because this doesn't seem like a plausible MOA to cause SI either! Selective NMDA-antagonists do not have the side-effect of depression and SI to my knowledge - in fact, another NMDA-antagonist, Magnesium-L-Threonate, was not pro-depressive for me - quite the opposite! As some of you may recall, I was also using a rather high dosage - about double the recommended dosage.

 

Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations.

https://www.ncbi.nlm...pubmed/20423340

 

Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain--an in vivo study.

https://www.ncbi.nlm...pubmed/24348020

 

Atomoxetine Protects Against NMDA Receptor-mediated Hippocampal Neuronal Death Following Transient Global Cerebral Ischemia.

https://www.ncbi.nlm...pubmed/28356001

 

 

Small side-note: While ATX caused SI, it was actually slightly anxiolytic - while MPH was less depressive, but far more anxiogenic.
 

MagLT was also slightly anxiolytic, so that's at least one property shared between two NMDA-antagonists, when using myself as the test-subject.

 

 

*throws hands up in the air*

 

Well, f*** if I can explain it! I would like to thank you for keeping me on my toes however, Finn, you have a more natural scientific mind than me, less prone to impulsive, premature conclusions - you're always keeping that enquiring mind open.



#172 Finn

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Posted 17 July 2017 - 05:12 PM

Norway nice medication statistics site http://www.norpd.no/ , you can do searches by age category etc. Of those 6 reboxetine users in bracket 15-19 , they all are probably 18 or 19. So out of 286 Norwegian reboxetine users in 2016, not a single one of them was under 18. 

 

N06AX18 2016 All ages     286

0 - 4     0

5 - 9     0

10 - 14     0

15 - 19     6

20 - 24     14

25 - 29     25

 

 

 

There are lots of people younger than 25 years on atomoxetine, but relatively few in reboxetine, so you would expect that there are a lot more people commenting of atomoxetine suicidal ideation side effect online. 

 

 

https://www.ncbi.nlm...pubmed/10901157

 

Reboxetine: tolerability and safety profile in patients with major depression.

 

Data from patients treated with reboxetine (n = 1503) or placebo/comparator drugs (n = 1027)    ____  no increase in suicidal ideation

 

If you could somehow get thousands of children on reboxetine, that should give interesting results to compare to ATX. But reboxetine isn't probably going to become pediatric drug at any point.


Edited by Finn, 17 July 2017 - 05:17 PM.

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#173 keystroke

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Posted 21 July 2017 - 09:55 PM

Received it today, thanks brighterpath!



#174 keystroke

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Posted 24 July 2017 - 10:49 PM

Any advice on how to physically manipulate the yellow resin which sticks to the inside of the vial? Thanks!



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#175 brighterpath

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Posted Yesterday, 02:01 AM

I use this: https://www.amazon.c...0?ie=UTF8&psc=1







Also tagged with one or more of these keywords: alks 5461, cerc-501, kappa antagonists

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