The new "abuse free opoid analgesic" BU08028

[aced126]

What do you make of sex? AFAIK there are very few people who get addicted to sex. I mean truly addicted! to the point of being unable to function 24/7. But an earth-shaking orgasm can be as "wildy euphoric" as far as the brain is concerned. So it should in theory be reinforcing since the brain uses the same mesolimbic reward system activated by opiates and stims. So is sugar and other palatable food. Now, why is the urge to repeat more and more the experience of sex (or food) is somewhat less than say meth? is it because it is less euphoric? Not really. IMO the brain has evolved a feedback mechanism to prevent imprinting that (highly) euphoric memory of sex or food experience in a endless loop of: Experience this Brain state-Feel-Good-Experience the state again-Feel Good..etc. One can think of kappa opioids receptors KOR activation. kappa activation is DYSPHORIC the exact polar opposite of EUPHORIA. KOR agonists induces aversion (the mental equivalent of the "yuck-est" vomit!) Why would the brain evolve a pathway for aversion? It could simply use the absence of euphoria. Could it be that KOR are activated along with euphoria-mediating mesolembic dopaminergic armada in the presence of natural stimulus such as sex or food so as to provide a balanced euphoric-dysphoric experience to be shelved in memory for reuse later. The pathway mediating LPT triggered by sex probably diverge from the one triggered by exogenous drugs. I mean they both generate euphoria via the same mechanism but one is reinforcing the other not so much..

I can think of a few answers to this question. One is obviously that we have evolved such that we don't compulsively seek these actions. When we eat, for example, ghrelin secretion drops and we get less hungry.

Another answer is the fact that drugs like methamphetamine are capable of releasing immense amounts of dopamine from VTA neurons projecting onto the NAc (I think one study measured a 1200% increase) and natural rewards are simply not able to do this to this sort of degree.

 

[Cotcha Yankinov]

I think that a fair number of young people (especially guys, sorry) do compulsively seek sex and masturbate a couple times a day, just saying. So I don't know if there is some anti-addiction mechanism naturally built in other than receptor homeostasis type stuff. It could be something as simple as the refractory period that limits sex addiction. Or oxytocin mediating satisfaction or something could be the anti-addiction mechanism as far as having AFTER achieved orgasm, but compulsively seeking sex before orgasm seems to be the proclivity of most young guys.

But anyways, the important thing to consider is the environment/mood of the human WHILE they are contemplating using this theoretical substance/machine.

If you just had something very tragic happen and you're in extreme emotional distress and/or horrible physical pain, and you knew that you could just escape into pure bliss for 12 hours, I think you would be a lot more likely to ingest that substance and start thinking with your "short term" brain. And if we are talking about this substance becoming readily available to everybody in say, the united states, I would venture a guess that quite a few people would start using it regularly, just to escape their pain at present. So part of what I was getting at earlier is that some things that people are addicted to may not be as much about positive reward, but avoiding negative feelings.

I don't know how much of this applies to the specific dorsal striatum mediated action sequences that Serotonin2A spoke of, but I do imagine that if someone repeats an action that helps them avoid suffering enough, that they will become quite accustomed to repeating that action sequence, possibly habitually.

So another thought experiment, we'll use your machine idea: There is a subject who has gone through a great deal of trauma and has at present great emotional and physical distress. There is a machine that can alleviate all emotional and physical distress for 12 hours, so no euphoria, just decreasing negative symptoms. There is a motor sequence involved in activating the machine, pulling a handle and getting in or something. Now we could have variant 1, where the subject has no recollection of the relief, and variant 2, where memory of the relief remains intact. So we may ponder questions for both variants. For example:

Under variant 1, with no recollection of the relief, how much would the subject push commitments and life aside in order to attain this temporary relief?

Under variant 2, with recollection of the relief and with the subject (most likely) using the machine extremely often, would we see similar addiction related neural changes like we see with the addicting drugs? (except I wouldn't expect the same changes in reward associated areas, maybe just the more habit/motor related areas)

I just thought really hard about this and I genuinely think that if I were in that position I would definitely not take the drug. It's quite hard to explain why, but I guess the simplest way to explain it is that there is no point of undergoing an experience if you cannot have any recollection of it, in my opinion. If you can't remember any of it, can it even be called an experience?

So not that I don't agree with your decision to not take the substance but I'll pick on you big time devils advocate and point out that life is an experience that you (probably) won't have any recollection of after you die, so what's the point of undergoing it? So I'll extend my acute euphoria machine type idea to instead a machine that you enter, and it keeps you alive in absolute pure euphoria for (random number) 10 years and THEN you die. The issue of not recalling the experience becomes less of a thing as the experience extends to however long you would've lived. I mean for example, lets say you knew you were only going to live 50 more years. You could either go about your present life, OR choose to spend 50 years in this extreme euphoria machine that also keeps you alive, and then you die at the end of it. Go or no go? Immediate commitments to loved ones aside maybe though.

I understand it might be hard to find words for this stuff lol, but I hope this provokes some thoughts.

 

[DotChem]

And then you have Medidation and the medidative States of the mind (brain) .. mind is probably more descriptive. I so happen to regularly practice buddhist meditation (mahayana school) for some years now. Pretty much all the euphoric states induced by psychoactives can be achieved through meditation and more. I do not know if any study has been done on that but if there is anything that should get the brain addicted is the intense euphoric Bliss that meditator often experience. I so happen to have experience such states: blissful, for lack of words to describe it!..So if anything should get the brain hooked THAT IS IT but it doesn't. Once you train the mind to watch the mind (so to speak) experiencing bliss or any other states like dissociative states (like NMDA K-hole), then the reinforcing, the need to repeat the experience is no longer there. Why? I don't know. The mind experience the same euphoric state just like sex (just incredibly more intense) Is it because the mind is seeing the experience "as it is" just that: a State of mind.. not so different from any other state of mind unless you make it so. YOU! who are You? I mean what is the "YOU" watching the experience?well..there is no "You"! It is only a construct of your own mind. there is neither pleasure, nor pain only States of Mind.. "YOU" make it so: pleasurable, painful, neither pleasure nor pain ... then the mind label and register the experience therefore the reinforcing or not.
Now who are "YOU"? or rather what are "YOU"?.. I mean the part of you watching your thoughts, feeling and emotions coming and going and labeling them. If you're not already practicing meditation, take a few minute and watch your thoughts coming to your awareness and your mind labeling them: good, bad, avoid, go for it, got to do this, got to that, scary, friendly...etc
I so happen to believe that the part of brain that is watching, the part that is aware (like when "YOU" see a window "YOU" know you see a window and not a banana) is that deep brain structure called the Claustrum. Salvinorin A the Salvia divinorum compound a selective kappa agonist binds and activate KOR at the claustrum .. The key to consciousness.. Incidently kappa agonists "cure" addiction...
I also happen to believe that Ibogaine another kappa agonist that seems to reset your entire store of conscioussness including the consciousness you have of drug-induced euphoria experience act via activation of Claustrum KOR receptors. Ibogaine (like Salivia) experience is basically to bring you back to BEFORE reinforcing started. (that is to rewire the brain and re-register the experience of euphoria correctly (so to speak). Label it correctly ..for what it is as just another State of Mind ... for a hardcore with a 30 years heroin addict to no longer make the sight of needles such a big deal after just a single dose! It is quite remarkable!

 

[serotonin2A]

The general assumption here seems to be that reinforcement is generally bad, and all things that are reinforcing have the ability to potentially trigger addiction. However, reinforcement is a natural process and the brain evolved to be exposed to reinforcing stimuli.

The problem with drugs like cocaine and heroin is not that they are reinforcing per se but rather that they reliably trigger a level of reinforcement that is pathologically strong. Heroin quickly becomes the only reinforcement that matters. Sex is reinforcing but is not such a strong or reliable reinforcer that it can trigger pathological behavior in most people.

 

[aced126]

I think that a fair number of young people (especially guys, sorry) do compulsively seek sex and masturbate a couple times a day, just saying. So I don't know if there is some anti-addiction mechanism naturally built in other than receptor homeostasis type stuff. It could be something as simple as the refractory period that limits sex addiction. Or oxytocin mediating satisfaction or something could be the anti-addiction mechanism as far as having AFTER achieved orgasm, but compulsively seeking sex before orgasm seems to be the proclivity of most young guys.

But anyways, the important thing to consider is the environment/mood of the human WHILE they are contemplating using this theoretical substance/machine.

If you just had something very tragic happen and you're in extreme emotional distress and/or horrible physical pain, and you knew that you could just escape into pure bliss for 12 hours, I think you would be a lot more likely to ingest that substance and start thinking with your "short term" brain. And if we are talking about this substance becoming readily available to everybody in say, the united states, I would venture a guess that quite a few people would start using it regularly, just to escape their pain at present. So part of what I was getting at earlier is that some things that people are addicted to may not be as much about positive reward, but avoiding negative feelings.

I don't know how much of this applies to the specific dorsal striatum mediated action sequences that Serotonin2A spoke of, but I do imagine that if someone repeats an action that helps them avoid suffering enough, that they will become quite accustomed to repeating that action sequence, possibly habitually.

So another thought experiment, we'll use your machine idea: There is a subject who has gone through a great deal of trauma and has at present great emotional and physical distress. There is a machine that can alleviate all emotional and physical distress for 12 hours, so no euphoria, just decreasing negative symptoms. There is a motor sequence involved in activating the machine, pulling a handle and getting in or something. Now we could have variant 1, where the subject has no recollection of the relief, and variant 2, where memory of the relief remains intact. So we may ponder questions for both variants. For example:

Under variant 1, with no recollection of the relief, how much would the subject push commitments and life aside in order to attain this temporary relief?

Under variant 2, with recollection of the relief and with the subject (most likely) using the machine extremely often, would we see similar addiction related neural changes like we see with the addicting drugs? (except I wouldn't expect the same changes in reward associated areas, maybe just the more habit/motor related areas)



So not that I don't agree with your decision to not take the substance but I'll pick on you big time devils advocate and point out that life is an experience that you (probably) won't have any recollection of after you die, so what's the point of undergoing it? So I'll extend my acute euphoria machine type idea to instead a machine that you enter, and it keeps you alive in absolute pure euphoria for (random number) 10 years and THEN you die. The issue of not recalling the experience becomes less of a thing as the experience extends to however long you would've lived. I mean for example, lets say you knew you were only going to live 50 more years. You could either go about your present life, OR choose to spend 50 years in this extreme euphoria machine that also keeps you alive, and then you die at the end of it. Go or no go? Immediate commitments to loved ones aside maybe though.

I understand it might be hard to find words for this stuff lol, but I hope this provokes some thoughts.

In the situation you proposed, the person is a in a state of trauma which is improving. Therefore it's only a matter of time until he is back to a stable state. So he would want to minimise the time spent in a sub-stable traumatic state. Under variant one, the subject would probably try to attain this temporary relief (I would) but only because it decrease the time spent in the traumatic state. If we altered the machine such that it put us in complete amnestic euphoria for 24 hours and then time travelled us back to the same point in time, I would not want to do it nor see the point even if I were in a traumatic state.

If I was in a constantly depressed state, and I was able to enter this machine, would I? Well it depends how depressed I was, but if I constantly entered that machine, wouldn't that be a bit like suicide? But when I was out of the machine, I would not remember at all how well it cured the depression. Then, the drive to re-enter the machine would be PURELY from the fact that I'm feeling truly terrible in my current state. I wouldn't really ever know how I felt in the machine. For all I know I literally could be feeling much worse, but it would all be wiped by amnesia. Actually this brings me to another point. If I were to enter 2 machines, one providing complete amnestic euphoria and the other providing complete amnestic dysphoria for 24 hours, it would genuinely not matter to me which one I go in (if the experience is truly amnestic). For all you know the labels could be switched around and I would never even know. The slightest reward (e.g I get 1 dollar if I go into the dysphoric one) would push me over to the dysphoric one.

So I come to my next point. If one is in a stable (not changing at all) state where they enjoy life, they would not enter the euphoric or dysphoric machine. If one is in a stable state where they truly hated life, and they entered the machine all the time, JUST to get away from life, then this is equivalent from suicide. If we compare this to say, heroin, at first the user might do it to escape life. But later on, heroin use IS driven by the euphoric memories and also by the reinforcing changes occurring at the cellular level.

 

[Cotcha Yankinov]

Thanks for the thoughts everybody

So if the main issue is that drug use becomes compulsive and habitual with addiction related neuroplasticity, are there scenarios where people might compulsively use substances that are not classically euphoric in the opiate euphoria sense? Seems to be a resounding "no" in the case of LSD except for a possible exception of people using it to escape their miserable lives rather than chase euphoria, which I'm curious if we would still see some of the same neuroplastic changes in severe escapism scenarios that we have associated with regular addictions.