Pharmacology Kappa opioid agonist hallucinogens that are not salvinorin derivatives

[LucidSDreamr]

Are there compounds that are non salvinorin analogues that are kappa opioid agonists that are hallucinogenic?

Is the psychedelic effect of salvia solely kappa agonism caused?

 

[Neuroprotection]

Are there compounds that are non salvinorin analogues that are kappa opioid agonists that are hallucinogenic?

Yes there are. I’m no expert in chemistry, but I think some members of the benzomorphan class of synthetic opioids like cyclazocine and pentazocine are very potent kappa agonists. For a short time after their discovery, it was thought they were a breakthrough non-addictive opioid for pain treatment. however, their strong action at the kappa Opioid receptor made them powerful hallucinogens with extremely dysphoric and paranoid components. there are more selective kappa Opioid agonists, most have research codenames so I can’t remember them off by heart and as I am blind, it’s hard for me to copy them. However, just go to the Wikipedia article on kappa opioid receptor and there should be a long list of ligands there. I would personally warn against kappa agonists, The Kappa receptor is designed to oppose reward and induce aversion in the brain. I assume you’re looking for such drugs as a synthetic, perhaps longer lasting alternative to salvia? whilst I’ll never recommend salvia to anyone and never try it myself, if you like its effects then stick to it. at least SalvinorinA is very short acting so less chance of suffering if your trip screws up.


Is the psychedelic effect of salvia solely kappa agonism caused?






Yes, all scientific evidence so far has overwhelmingly, if not exclusively pointed to Kappa opioid agonism as being solely responsible for the psychoactive/Behavioural effects of SalvinorinA

 

[Skorpio]

Kappa agonism is necessary for the psychadelic effects of salvia, but it isn't sufficient for psychadelic effects.

Like many GPCRs kappa opioid receptors can signal through G-proteins (gi/o) or beta arrestin can scaffold mapk proteins. The beta arrestin pathway seems the most important when it comes to hallucinatory effects, though based on studies on the 5ht2a receptor, likely both pathways need some activation for this to occur.

 

[Neuroprotection]

Kappa agonism is necessary for the psychadelic effects of salvia, but it isn't sufficient for psychadelic effects.

Like many GPCRs kappa opioid receptors can signal through G-proteins (gi/o) or beta arrestin can scaffold mapk proteins. The beta arrestin pathway seems the most important when it comes to hallucinatory effects, though based on studies on the 5ht2a receptor, likely both pathways need some activation for this to occur.

I wonder why research on kappa opioid antagonists is so scarce and scattered. i’ve heard Kappa blockade shows promise in treating depression, reward deficiency as well as chronic stress and trauma. rather unusually, kappa opioid antagonism has shown antipsychotic potential which is paradoxical given that it can considerably enhance dopamine signalling. personally, I think research slowed down and many potential benefits went unnoticed after scientist switch from the ultra long acting/irreversible Kappa antagonists to Very weak ultra short acting often partial antagonists. this was done after one particular antagonist caused cardiac arrhythmia in a medical trial many years ago, but it is unfortunate, because it may be that long term Kappa opioid antagonism is needed for the full benefits to be realised.

 

[Skorpio]

I wonder why research on kappa opioid antagonists is so scarce and scattered. i’ve heard Kappa blockade shows promise in treating depression, reward deficiency as well as chronic stress and trauma. rather unusually, kappa opioid antagonism has shown antipsychotic potential which is paradoxical given that it can considerably enhance dopamine signalling. personally, I think research slowed down and many potential benefits went unnoticed after scientist switch from the ultra long acting/irreversible Kappa antagonists to Very weak ultra short acting often partial antagonists. this was done after one particular antagonist caused cardiac arrhythmia in a medical trial many years ago, but it is unfortunate, because it may be that long term Kappa opioid antagonism is needed for the full benefits to be realised.

I have to run so this post will be short, but I know of one pretty historic lab that still uses Jdtic and norbni for looking into kappa antagonism.

Thing is jdtic (the one which caused ventricular tachycardia), has a pretty weird mechanism of action where it engages p38 to modify serotonin receptors downstream. Other antagonists don't seem to have this sustained effect

 

[LucidSDreamr]

benzomorphan class of synthetic opioids like cyclazocine and pentazocine are very potent kappa agonists. For a short time after their discovery, it was thought they were a breakthrough non-addictive opioid for pain treatment. however, their strong action at the kappa Opioid receptor made them powerful hallucinogens with extremely dysphoric and paranoid components.

great post and I’m going to look more into it but I have to add a joke on this.

Legoland creates a whole new world of pain so bad you’ll forget your physical pain

 

[Neuroprotection]

great post and I’m going to look more into it but I have to add a joke on this.

Legoland creates a whole new world of pain so bad you’ll forget your physical pain

I like that joke, but ironically, it’s probably true. just out of curiosity, what is The reason for your interest in Kappa agonists?

 

[LucidSDreamr]

I like that joke, but ironically, it’s probably true. just out of curiosity, what is The reason for your interest in Kappa agonists?

I guess I just find it facinating how salvia is has this such anamolous mechanism of psychedelia and it’s a very unique character to it and I had never heard of other kappas being hallucinogenic but have heard of other kappa agonists in pain medicine research. It also has no nitrogen which is unusual for any psychedelic drug or opioid be it dissociatives or 5HT agonists. Salvinorin is one of a kind. I don’t particularly like it but I like all my memories of the experiences after they were finished If that makes sense. I don’t think I would ever try it again and it’s been like 20 years since I did it a bunch of times.

In have a chronic pain condition and was a heroin addict long ago for recreational reasons so I am interested in opioids in general.

I didn’t read the kappa wiki yet but I did read the delta wiki and there are some interesting things there re potentiation with mu agonists and reversal of respiratory depression from mus but causing respiratory depression at high doses.

I’ve even found mu agonists to be psychedelic in ways. #1 a strong hit of dilauded while dope sick or clean will give me CEVs akin to a first time weed smoker. Just for a few minutes. But never with oral or slower realsing ROAs, just IV. Also there are the nod out dreams common with mu agonists that are more like delusions or dreams than actual psychedelic experiences.

I wouldn’t mind trying a powerful mu agonist that also has strong kappa agonism and is a combined analgesic/euphoric drug + psychedelic….is the SAR toward mu and kappa have much overlap? Or are they basically such differently shaped binding pockets that this isn’t a possibility?

 

[G_Chem]

I wonder why research on kappa opioid antagonists is so scarce and scattered. i’ve heard Kappa blockade shows promise in treating depression, reward deficiency as well as chronic stress and trauma. rather unusually, kappa opioid antagonism has shown antipsychotic potential which is paradoxical given that it can considerably enhance dopamine signalling. personally, I think research slowed down and many potential benefits went unnoticed after scientist switch from the ultra long acting/irreversible Kappa antagonists to Very weak ultra short acting often partial antagonists. this was done after one particular antagonist caused cardiac arrhythmia in a medical trial many years ago, but it is unfortunate, because it may be that long term Kappa opioid antagonism is needed for the full benefits to be realised.

Pretty sure buprenorphine is a kappa opioid antagonist.

-GC

 

[Neuroprotection]

I guess I just find it facinating how salvia is has this such anamolous mechanism of psychedelia and it’s a very unique character to it and I had never heard of other kappas being hallucinogenic but have heard of other kappa agonists in pain medicine research. It also has no nitrogen which is unusual for any psychedelic drug or opioid be it dissociatives or 5HT agonists. Salvinorin is one of a kind. I don’t particularly like it but I like all my memories of the experiences after they were finished If that makes sense.

Yes, though I’ve not tried psychedelics, I guess I can imagine/understand how even quite dark/dysphoric experiences, So long as they are not terrifying, can open the door to a sense of spirituality and self reflection. maybe it’s analogous to how occasionally feeling sad or even crying can be a therapeutic experience by facilitating self reflection flushing out negativity.

I don’t think I would ever try it again and it’s been like 20 years since I did it a bunch of times.

In have a chronic pain condition and was a heroin addict long ago for recreational reasons so I am interested in opioids in general.

I didn’t read the kappa wiki yet but I did read the delta wiki and there are some interesting things there re potentiation with mu agonists and reversal of respiratory depression from mus but causing respiratory depression at high doses.

I’ve even found mu agonists to be psychedelic in ways. #1 a strong hit of dilauded while dope sick or clean will give me CEVs akin to a first time weed smoker. Just for a few minutes. But never with oral or slower realsing ROAs, just IV. Also there are the nod out dreams common with mu agonists that are more like delusions or dreams than actual psychedelic experiences.

Mu and possibly Delta agonists aren’t considered hallucinogens in the traditional sense, but interestingly Mu receptors and their endogenous ligand endorphin are involved in the derealisation of some mental health conditions. rather than promoting enhanced connectivity with the outside world and the inner mind like classical 5HT2A psychedelics, or producing sensory deprivation like the NMDA antagonists, I believe Mu agonists generally slow down almost all arousal related brain activity. people describe Mu opioids as producing a sort of blanket effect around their consciousness and suppressing emotional pain/anxiety, whilst not interfering with normal reasoning skills. interestingly, Mu agonists have been shown to suppress classical psychedelic affects in animals, with researchers attributing these effects to opposing downstream effects of these receptors. actually, the opioid antagonist naloxone can apparently worsen ketamine induced psychosis and cognitive impairment where as morphine or L-type calcium channel blockers decrease psychotic symptoms. I guess this makes sense, since 2 key downstream effects of Mu activation are T and L type calcium channel inhibition as well as decreased nor adrenaline and glutamate levels in many areas of the brain. these distinct effects are highly complimentary and result in overall decrease of neuronal excitability. this could actually stabilise brain networks against psychotic activation, but paradoxically could facilitate an emotionally numbing dream like state which can be problematic for those suffering from derealisation.

I wouldn’t mind trying a powerful mu agonist that also has strong kappa agonism and is a combined analgesic/euphoric drug + psychedelic….is the SAR toward mu and kappa have much overlap? Or are they basically such differently shaped binding pockets that this isn’t a possibility?

There are many drugs with mixed Kappa/Mu agonism but generally, they would still be a very unpleasant experience. The drugs I mentioned previously have Mu agonism, but the kappa opioid activation suppressed any positive effects and the drugs were too aversive for human use. Kappa opioid receptors seem to have the ability to oppose both dopaminergic and non-dopaminergic reward

 

[Neuroprotection]

Pretty sure buprenorphine is a kappa opioid antagonist.

-GC

Yes, it is but I think it’s rather weak and non-selective. Nevertheless, there are some clinical trials using buprenorphine combined with naltrexone to block Mu activity and this Kappa antagonist combination showed rather positive results. I think what makes Kappa opioid antagonism unique as a depression treatment is that it blocks the so-called negative valence system responsible for encoding negative experiences and generating despair like behaviours. in the long-term, it could also boost reward sensitivity. combined, this tackles an aspect of depression (Anhedonia), which most currently available medications either fail to address or make the condition worse. it should be noted that kappa opioid receptors negatively modulate the dopaminergic system so antagonising them could be the first step towards the recognition and hopefully implementation of dopaminergic strategies in depression treatment.

 

[LucidSDreamr]

Yes, though I’ve not tried psychedelics, I guess I can imagine/understand how even quite dark/dysphoric experiences, So long as they are not terrifying, can open the door to a sense of spirituality and self reflection. maybe it’s analogous to how occasionally feeling sad or even crying can be a therapeutic experience by facilitating self reflection flushing out negativity.





Mu agonists have been shown to suppress classical psychedelic affects in animals, with researchers attributing these effects to opposing downstream effects of these receptors.

There are many drugs with mixed Kappa/Mu agonism but generally, they would still be a very unpleasant experience.

Salvia is in. No way pleasant or spiritual self reflective like psilocybin and lsd are often labeled to be. Ime.

It is just so surreal and wild that it is fascinating. But no benefits of integration into one’s real life.

I guess mixed kappu mu would not be fun. Mu agonists are beautiful because they are both a "smart drug" with in addersll like effect plus pain releif when not abused.

Re mus dampening psychs in animals…not in this animal. The psychedelics are so overpowering tan opioid can not cut through it. Doesn’t synergize either. Benzos can quite well though but not reverse it or anything.

But I haven’t done any psychedelic in like a decade at this point and never will again most likely. They are too serious on the mind more than recreational and were repetitive to me eventually. No real utility once you see what they are…you can carry those lessons with you without having to repeat them

 

[Neuroprotection]

Salvia is in. No way pleasant or spiritual self reflective like psilocybin and lsd are often labeled to be. Ime.

It is just so surreal and wild that it is fascinating. But no benefits of integration into one’s real life.

I guess mixed kappu mu would not be fun. Mu agonists are beautiful because they are both a "smart drug" with in addersll like effect plus pain releif when not abused.

Re mus dampening psychs in animals…not in this animal. The psychedelics are so overpowering tan opioid can not cut through it. Doesn’t synergize either. Benzos can quite well though but not reverse it or anything.

But I haven’t done any psychedelic in like a decade at this point and never will again most likely. They are too serious on the mind more than recreational and were repetitive to me eventually. No real utility once you see what they are…you can carry those lessons with you without having to repeat them

Interesting thanks for sharing your experiences. i’m surprised you describe Mu agonists as “smart drugs“, though maybe I shouldn’t be too surprised that positive mood states and suppression of some neuronal excitability could lead to better focus and work performance.

 

[LucidSDreamr]

Interesting thanks for sharing your experiences. i’m surprised you describe Mu agonists as “smart drugs“, though maybe I shouldn’t be too surprised that positive mood states and suppression of some neuronal excitability could lead to better focus and work performance.

Yes. It could be a function of just being dependent and being useless when not "well"…but even when I’ve been totally clean and non dependent a low dose work wonders for sitting down to get lots of work done with motivation and focus