33 replies to this topic

[VICREP]

I'm starting this thread in hope of generating enough interest to potentially start a group, which may be partially funded by a reliable member of this board, who I have been in regular correspondence with through email.

 

For those of you that don't know KOR antagonism has shown substantial promise in a range of psycho-pathologies, including:

 

Depression

 

Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats

http://www.sciencedi...028390811002589

 

"These data suggest that blockade of KORs before exposure to a stressor (in this case, cocaine withdrawal or forced swimming) can attenuate the development of stress-induced behavioral adaptations."

 

Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats.

http://www.ncbi.nlm....pubmed/19924112

 

"These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants."

 

ANXIETY

 

Antidepressant and anxiolytic-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats

http://www.researchg...star_Kyoto_rats

 

"the KOR antagonist DIPPA produced clear anxiolytic-like effects in WKY rats, and partial anxiolytic-like effects in SD rat."

 

STRESS

 

Role of kappa-opioid receptors in stress and anxiety-related behavior.

http://www.ncbi.nlm....pubmed/23836029

 

"Collectively, available data suggest that KOR disruption produces anti-stress effects and under some conditions can prevent the development of stress-induced adaptations. As such, KOR antagonists may have unique potential as therapeutic agents for the treatment and even prevention of stress-related psychiatric illness, a therapeutic niche that is currently unfilled."

 

 

etc..

 

Along with a great body of literature supporting KOR blockade for addiction, and anhedonia. The potential for it treating anhedonia really interests me as it such a tough symptom to treat, anyone who has struggled through it knows.

 

 

There is a lot more available evidence, which I will leave up to anyone that wants to do some background research. Feel free to add in articles.

 

So where are the we with currently tested KOR antagonists?

 

JDtic is a selective, long acting Kappa antagonists that halted in trials due to the appearance of ventricular tachychardia in some subjects. It was subject of a group buy on these forums, most users IIRC didn't notice much, had troubles with dosing, and were scared away by the potential development of VT.

 

ALKS-5461 which is a combination drug of buprenorphine and samidorphan, which gives selective kappa antagonism, designed by Alkermes. This one looks very promising, granted fast track designation by the FDA for treatment resistant depression, as an add on to SSRI's (would also be effective as a monotherapy). Problem obviously is the scheduling of the 2 drugs that are combined to make it. Not ideal for custom synthesis and distribution.

 

Then we have CERC-501 (formerly known as LY-2456302).

A thread was made about this drug last year (http://www.longecity...o-jdtic/page-2)

  LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders

 

Abstract

Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long-lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivopharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (t_max: 1–2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED₅₀ = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders.

 

Anyone that would like to participate in a group buy for LY2456302 please state your interest in this thread.

 

[nicklesprout]

has anyone tried it yet? any experience reports? i'd be interested potentially...

[nicklesprout]

Ibogaine is a KOR agonist and it has antidepressant effects, i've tried it, i wonder what an antagonist would do.

[VICREP]

has anyone tried it yet? any experience reports? i'd be interested potentially...

 

It's hard to find any reports of KOR antagonists online that have the selectivity, affinitiy, MOA like CERC-501 since this is a novel mechanism in the psychiatric world. 

 

Ibogaine is a KOR agonist and it has antidepressant effects, i've tried it, i wonder what an antagonist would do.

 

Yeah Iboga is a KOR agonist, which probably accounts for a lot of the unpleasant effects during the peak (dissociation, fear, anxiety, nausea, etc), and the resulting downregulation of KOR is theorized to be one of the benefits of ibogaine treatment and contributes to the after glow. Ibog is also an NMDA antagonist etc

[Bukujutsu]

I'd definitely be interested in a good KOR antagonist that has effects similar to this: http://en.wikipedia.org/wiki/ALKS-5461

 

Some interesting options are listed under Potentially Investigational Substances: http://mentalhealthd...for-depression/

 

I'd highly recommend reading that and researching whether any of those mentioned is a feasible, effective, and safe candidate.

[Strangelove]

I am definitely in, but I am afraid would be hard to generate interest as not many are informed of potential benefits of Kor antagonism.

 

A more "catchy" title of potential benefits in depression, anxiety and sense of well being can generate more interest?

[KieranA001]

What about TeamTLR KOR-antagonist extract. I have been using if for some time now and it's really good. Now, it doesn't give me razor sharp vision like JDTic did when I took that, but it seems to get rid of my social phobia and helps with my mood. I found with JDTic it gave me VT so I stopped taking it. I wanna feel something similar to what you get from a mix of alcohol and Phenibut. I find my mood to be uplifted in a specific way in which I don't just feel good it's like the mood increase has meaning to it like a dopamine agonist does when you take one of them. Kinda like that. 

 

So yeah, something like I described plus razor sharp vision like when you smoke your first cigarette or like when you take a cholinergic type drug. 

[Strangelove]

What about a small group buy (to save money) from the herbal extract from TLR, just to see what a pharmaceutical KOR-antagonist might feel like?

 

14 x 200mg is $90 we can split the $90? Who is interested and in how much?

 

[jefferson]

Count me in for a group buy for a promising kappa antagonist. I believe this pharmacological pathway might be among the most promising to treat my depression.

 

I haven't done much research, but it seems like a group buy of ALKS-5461 has too many practical, legal, and possibly addictive problems. First of all, someone would be ordering a schedule III drug (buprenorphine), and then an experimental proprietary (Samidorphan), and then need to find out how to combine them most effectively in the most exact doses. If you get it wrong and the bupe mu agonism isn't completely cancelled out, you're risking opiate addiction, which would not be fun. Google suboxone addiction and withdrawal to see what that's like.

 

I really hope I'm wrong, but Team TLR and their custom-made products sound too good to be true. I am very uncomfortable buying something from an online vendor claiming it is the result of some super secret in-house research. We don't even know the molecular structure. Just because their "kappa antagonist" makes you feel good means nothing except that it makes you feel good. It could just be a low dose mu agonist or something similar. Maybe even buprenorphine...

 

In my opinion, Cerc-501 is a much simpler, safer buy. It is not scheduled, and is a pure kappa antagonist with no effects on the mu receptor, which makes me more comfortable taking it. http://www.ncbi.nlm....pubmed/24071566 is an introduction to the molecule. It is in phase II trials starting now, so it has already passed preliminary safety studies in humans, another advantage over more suspect candidates like JDtic. 

 

So I vote for Cerc-501. Let's generate some interesting in this group buy! Looks promising.

 

 

[KieranA001]

I have already tried LY2456302, I took a bit of it under the tongue and it gives me some form of stimulating effect. To me it just acted as a good stimulant, and maybe made my mood a bit better. KORX-OX from TeamTLR is good, and it isn't like a mu-agonist at all. I have tried Kratom before, and it feels completely different to KORX-OX. With KORX-OX, I get a nice mood / good social effects from it. I really wish other people at least tried it, as it does have some potential even if you are skeptical of using it it's no different to taking a research chemical! And at least as a company they have to secure their products safety in order to stay a company.

 

I know some of you don't like TeamTLR but still not all of their stuff is useless. But, by all means try what you want. I'd like to try other kappa antagonists, but at the moment it's KORX-OX for me. JDTic was by far the best the only thing with that if the VT in the chest, which really messes it up. 

[VICREP]

I have already tried LY2456302, I took a bit of it under the tongue and it gives me some form of stimulating effect. To me it just acted as a good stimulant, and maybe made my mood a bit better. KORX-OX from TeamTLR is good, and it isn't like a mu-agonist at all. I have tried Kratom before, and it feels completely different to KORX-OX. With KORX-OX, I get a nice mood / good social effects from it. I really wish other people at least tried it, as it does have some potential even if you are skeptical of using it it's no different to taking a research chemical! And at least as a company they have to secure their products safety in order to stay a company.

I know some of you don't like TeamTLR but still not all of their stuff is useless. But, by all means try what you want. I'd like to try other kappa antagonists, but at the moment it's KORX-OX for me. JDTic was by far the best the only thing with that if the VT in the chest, which really messes it up.

How did you get onto trying ly2456302? How long? What doses?

[KieranA001]

 

I have already tried LY2456302, I took a bit of it under the tongue and it gives me some form of stimulating effect. To me it just acted as a good stimulant, and maybe made my mood a bit better. KORX-OX from TeamTLR is good, and it isn't like a mu-agonist at all. I have tried Kratom before, and it feels completely different to KORX-OX. With KORX-OX, I get a nice mood / good social effects from it. I really wish other people at least tried it, as it does have some potential even if you are skeptical of using it it's no different to taking a research chemical! And at least as a company they have to secure their products safety in order to stay a company.

I know some of you don't like TeamTLR but still not all of their stuff is useless. But, by all means try what you want. I'd like to try other kappa antagonists, but at the moment it's KORX-OX for me. JDTic was by far the best the only thing with that if the VT in the chest, which really messes it up.

How did you get onto trying ly2456302? How long? What doses?

 

 

After I tried JDTic from the first group buy, I brought some from a guy who brought it from a chemical research company. Forgot the name of the company, the website looked a bit like international peptide website. It will come back to me.. As for dose, I brought I 5ml vial, and took a bit on the end of a toothpick, and got a strong coffee effect, felt very alert. Only took it twice and then ditched the rest because it wasn't what I wanted. It did make me clear minded though, it kinda feels like Ethylphenidate

[VICREP]

I have already tried LY2456302, I took a bit of it under the tongue and it gives me some form of stimulating effect. To me it just acted as a good stimulant, and maybe made my mood a bit better. KORX-OX from TeamTLR is good, and it isn't like a mu-agonist at all. I have tried Kratom before, and it feels completely different to KORX-OX. With KORX-OX, I get a nice mood / good social effects from it. I really wish other people at least tried it, as it does have some potential even if you are skeptical of using it it's no different to taking a research chemical! And at least as a company they have to secure their products safety in order to stay a company.

I know some of you don't like TeamTLR but still not all of their stuff is useless. But, by all means try what you want. I'd like to try other kappa antagonists, but at the moment it's KORX-OX for me. JDTic was by far the best the only thing with that if the VT in the chest, which really messes it up.

How did you get onto trying ly2456302? How long? What doses?

After I tried JDTic from the first group buy, I brought some from a guy who brought it from a chemical research company. Forgot the name of the company, the website looked a bit like international peptide website. It will come back to me.. As for dose, I brought I 5ml vial, and took a bit on the end of a toothpick, and got a strong coffee effect, felt very alert. Only took it twice and then ditched the rest because it wasn't what I wanted. It did make me clear minded though, it kinda feels like Ethylphenidate

Did you find it anxiolytic at all?

Any comedown?

[jefferson]

I am conflicted on Team TLR. At least with Cerc-501 (LY2456302), we know it has passed rudimentary safety studies in humans. No telling about the TLR product! It's much more of a gamble. I've been burned once by a RC, so I'm very sensitive to risk here. I guess it depends how desperate you are which determines how much risk you're willing to accept. I'd rather spend a few more hundred to make sure I'm getting a safer product that we can be fairly certain is a real kappa antagonist (though independent testing from any Chinese lab synth should be required).

Edited by jefferson, 27 June 2015 - 04:37 AM.

[KieranA001]

 

 

 

I have already tried LY2456302, I took a bit of it under the tongue and it gives me some form of stimulating effect. To me it just acted as a good stimulant, and maybe made my mood a bit better. KORX-OX from TeamTLR is good, and it isn't like a mu-agonist at all. I have tried Kratom before, and it feels completely different to KORX-OX. With KORX-OX, I get a nice mood / good social effects from it. I really wish other people at least tried it, as it does have some potential even if you are skeptical of using it it's no different to taking a research chemical! And at least as a company they have to secure their products safety in order to stay a company.

I know some of you don't like TeamTLR but still not all of their stuff is useless. But, by all means try what you want. I'd like to try other kappa antagonists, but at the moment it's KORX-OX for me. JDTic was by far the best the only thing with that if the VT in the chest, which really messes it up.

How did you get onto trying ly2456302? How long? What doses?

After I tried JDTic from the first group buy, I brought some from a guy who brought it from a chemical research company. Forgot the name of the company, the website looked a bit like international peptide website. It will come back to me.. As for dose, I brought I 5ml vial, and took a bit on the end of a toothpick, and got a strong coffee effect, felt very alert. Only took it twice and then ditched the rest because it wasn't what I wanted. It did make me clear minded though, it kinda feels like Ethylphenidate

Did you find it anxiolytic at all?

Any comedown?

 

Nope. I actually felt in increased anxiety. KOR-antagonism is a hard one to explain as it depends on the drug you use. With JDTic I felt it acted more as an anti-depressant. Like, it felt clean and it was really nice getting that warm glow. I kinda felt more emotional on it, but more aware of everything that was going on. I felt like I could actually feel my mood more in-depth, but it helped the depression a bit. It kinda felt like a dopamine agonist. Like, not just a mood uplift it felt natural, and kinda like having a really good day out. You can actually feel confidence in yourself and find it hard to find anything to worry about.

 

No comedown from ly2456302, the stimulation just wears of after awhile. At higher doses, I did feel a bit of a mood uplift but the stimulating effects were too overwhelming. 

[jefferson]

A very interesting paper was published a month ago, C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors, detailing recent efforts to make analogues of Buprenorphine with less mu agonism and more kappa antagonism.

Buprenorphine is a successful analgesic and treatment for opioid abuse, with both activities relying on its partial agonist activity at mu opioid receptors. However, there is substantial interest in its activities at the kappa opioid and nociceptin/orphanin FQ peptide receptors. This has led to an interest in developing compounds with a buprenorphine-like pharmacological profile but with lower efficacy at mu opioid receptors.

→ source (external link)

 It seems that someone has created a handful of buprenorphine analogues with these desired characteristics, purportedly. The paper even goes into the synthesis of them.

 

Buprenorphine with little or no mu agonism and even greater kappa antagonism would be very promising. You're also avoiding the problem of ordering a scheduled drug, as well as minimizing the chance for addiction. Obviously this has undergone no human testing, not even rudimentary testing in rats, so it's higher risk. I have no idea how much harder or more expensive it'd be to get a synthesis of one of the more promising analogues like 15a or 8a-d, but does anyone want to consider it?

 

The chemistry in the paper is way beyond me, so someone else needs to have a look. The paper is free.

[Joe Monroe]

is there still a possible group buy for this?

[VICREP]

Not much interest, so unlikely. Maybe another thread structured/titled differently would pull in some members.

[VICREP]

Bump.

I really think for anyone dealing with depression, anxiety, anhedonia, etc, a KOR antagonist would be well worth chasing up

[nicklesprout]

did you find a source and a price? more specifics may generate more interest. i'm interested but can't do much about it until we have something concrete.

[chasefooo]

Long time lurker. Group buy probably already lost steam. But i am very interested. If anyone found a source for cerc-501 or similar kappa antagonist, please let me know or post.

[satsumass]

Thread looks dead. But I'd also be interested in a group buy of the CERC.

[Viridarius]

I'd be interested as well. I've been looking into novel depression treatments.

[Ondomondo]

Same here, if there's any life left in this. I seem to have missed the boat on JDTic, but I'd be very interested in trying CERC or possibly one of the other alternatives.

[tolerant]

I recently started a similar thread, but maybe it's time to resurrect this thread. I would definitely be interested, obviously.

[Mister_x]

I am interested!

[John Felipe]

I would give my left pinky for the ability to receive a K-opioid antagonist. I have debilitating anhedonia and can hardly take living this way anymore

[sativa]

I would give my left pinky for the ability to receive a K-opioid antagonist. I have debilitating anhedonia and can hardly take living this way anymore

Re anhedonia, have you focused on strengthening your adrenal glands, and eliminating stress in your daily life?

Also, dietary changes such as reducing (ideally, temporarily eliminating!) grains (rice is OK) and dairy might be advisable as these contain substances that act as opioid agonists.

Here are foods with morphine like characteristics:

> Casomorphin (from casein found in milk of mammals, including cows)
> Gluten exorphin (from gluten found in wheat, rye, barley)
> Gliadorphin/gluteomorphin (from gluten found in wheat, rye, barley)
> Soymorphin-5 (from soybean)
> Rubiscolin (from spinach)
> Menthol – Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound menthol activates the kappa opioid receptor

(Source: https://selfhacked.c...Characteristics )


I would advise against SSRIs as these can lower testosterone and dopamine which seems highly undesirable.

Please have a read of these links, I think they might be helpful and insightful for you:

30 Ways To Naturally Improve Mood and Motivation By Increasing Orexin/Hypocretin - https://selfhacked.c...igue-naturally/

It would be highly insightful to your current state (and how to move forward) to know what condition your immune system is in, and take appropriate remedial measures.

Immune system status - th1 or th2 dominance
- https://selfhacked.c...-th2-dominance/

Finally, dietary lectins can cause anhedonia and a lack of motivation for some. It would be advisable to temporarily eliminate the main lectin containing foods and see what improvements this brings. Here is a comoaxt list.

Food Groups Excluded on the Lectin Avoidance Diet
- https://selfhacked.c...ingoidance_Diet

Edited by sativa, 21 August 2016 - 08:50 AM.

[amu621]

Feel free to PM for the group buy for CERC-501, for the time being, I'll be spearheading it and gathering a list of interested parties.

[Mind_Paralysis]

 

I would give my left pinky for the ability to receive a K-opioid antagonist. I have debilitating anhedonia and can hardly take living this way anymore

Re anhedonia, have you focused on strengthening your adrenal glands, and eliminating stress in your daily life?

Also, dietary changes such as reducing (ideally, temporarily eliminating!) grains (rice is OK) and dairy might be advisable as these contain substances that act as opioid agonists.

Here are foods with morphine like characteristics:

> Casomorphin (from casein found in milk of mammals, including cows)
> Gluten exorphin (from gluten found in wheat, rye, barley)
> Gliadorphin/gluteomorphin (from gluten found in wheat, rye, barley)
> Soymorphin-5 (from soybean)
> Rubiscolin (from spinach)
> Menthol – Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound menthol activates the kappa opioid receptor

(Source: https://selfhacked.c...Characteristics )


I would advise against SSRIs as these can lower testosterone and dopamine which seems highly undesirable.

Please have a read of these links, I think they might be helpful and insightful for you:

30 Ways To Naturally Improve Mood and Motivation By Increasing Orexin/Hypocretin - https://selfhacked.c...igue-naturally/

It would be highly insightful to your current state (and how to move forward) to know what condition your immune system is in, and take appropriate remedial measures.

Immune system status - th1 or th2 dominance
- https://selfhacked.c...-th2-dominance/

Finally, dietary lectins can cause anhedonia and a lack of motivation for some. It would be advisable to temporarily eliminate the main lectin containing foods and see what improvements this brings. Here is a comoaxt list.

Food Groups Excluded on the Lectin Avoidance Diet
- https://selfhacked.c...ingoidance_Diet

 

 

Two words: too weak.

 

Pretty much all of the substances listed either show NO affinity for KOR, Menthol being the one exception to my knowledge, or have FAR GREATER affinity for the DOR or MOR -receptors - in essence cancelling the KOR-effects OUT.

 

I'm guessing you haven't researched the data and side-effects of the compound known as Atomoxetine, right? Well, the primary metabolite of Atomoxetine, is THE MOST POTENT KOR AGONIST EVER FOUND...! : O

 

This is suspected to be the source of the suicidal thoughts which characterize Atomoxetine, which sorts it out from other sNri's and NRI's. Some have then found that Tianeptine, a potent DOR and mild MOR -agonist, actually immediately counteracts suicidality - in minutes, the DOR and MOR-receptors override the world-crushing weight around ones neck which is KOR-agonism.

 

So... not gonna' help, dude. There's a reason why people keep eating those foods you listed - if they ONLY made you feel like sh*t, then no-one would - but they don't.

 

For the few who have these chronic issues, they are either born with Kappa-receptor hypersensitivity - which means a naturally, extreme response to any sort of punishment or setback, or, they have been molded by life-long (like myself), environmental circumstances caused by neuropsychiatric disease, has caused so much upregulation of Kappa-receptors, because of so much punishment, that the behaviours of anhedonia and avoidance have become highly entrenched within their persona - Pavlov's dogs, and all that.

 

 

For us, your suggestions are pointless and time-wasting - they won't help.

 

 

Now, with all that whining of mine put aside, I would like to thank you for trying - for giving a shot at giving advice to those that are in need. = ) I'd love to see you delve further into the subject - regarding learned helplessness, punishment-sensitivity and long-term changes to the brain as a result of environmental stressors.

 

You have talent and a good mind, and I think you do contribute to this forum.