Diacetyldihydromorphine (Improved Diamorphine/Heroin analog)

[Skorpio]

My answer to this is always the same: so what? Everyone is addicted to something. Some people are useless do-nothings who binge-watch netflix all day long, others are addicted to playing video games, sex, smartphones, gambling, drinking alcohol (oh now THAT is the right type of drug, right?), etc.
So why is it such a huge issue when euphoria causes me to be addicted to a substance that does absolutely no harm to my body or even my mind, much less to other people?


I don't believe that to be the case honestly. I think this whole aversion towards opioids and really drugs in general is a rather modern phenomenon that was kickstarted by the puritan movement in the early 20th century and finally got hold of society when the Anti-Opium law was passed in 1930, but prior to that Opium was part of so many medicines and has always been used recreationally since thousands of years, even though it never replaced alcohol in the west unfortunately. So I don't see this animosity towards opioids as something that has a deep, underlying root cause, but instead it is entirely driven by propagandistic indoctrination that is barely a century old. The fact that people don't even really know why they are against it, except repeating like programmed bots anti-drug talking points, proves that this has no deeper cause and is a superficial, albeit tenacious aversion.

This anti-opioid sentiment is more of a western thing anyway. The west is pathologically obsessed with being in control at all times and being productive and disciplined (with the exception of Japan where these qualities are taken to an extreme, which explains why drug use is frowned upon even more in Japan than in the west), which to a certain extent aren't bad qualities, but since an opioid high embodies the exact opposite of these qualities, it is only logical that a culture which is primed to embrace such attitudes comes to hate such a substance class. Society should allow periodical relaxations of such attitudes and learn to be more tolerant.
The middle east for example is very different in this regard. They have a history of Opium use. Just as much as alcohol is (unfortunately) part of western culture, Opium has always been part of middle eastern culture and that is simply because these people have a completely different mentality than we have. Even though Opium is illegal on paper in Iran, nobody really gives a shit when you start smoking Opium in public. It's an unenforceable law to prohibit Opium use.
The west should learn to be more like the east, even if it is only for the sake of our organ health. Seriously, what the fuck is it with the western mind and its degenerate thirst for an utterly toxic substance that harms nerves, cells and even the DNA? Alcohol wasn't even originally made to be drunk, but for conservation, and yet we somehow ended up integrating this crappy substance into our culture.


...and nobody seems to care about the societal harm caused by alcohol. And mind you, we aren't talking about the harm caused by alcohol addicts, but mere "social" drinking.


Yes, yes and yes. The problem is we don't know how to do that with the proteins/neurons/switches/pathways/receptors that are ultimately responsible for opioid-induced euphoria because we haven't been able to even agree on what the cause of that phenomenon is. If we can figure out the basics, then we can go deeper into the specifics and maybe find out how to develop a drug that prevents euphoria. I do NOT know how to do that. I just said it COULD be possible because we have been able to do similar things with other drug-induced side effects, that's all.

When compared to a plain stimulant (a dopamine releaser or reuptake inhibitor), opioids are pretty darn close to selectively activating the reward center.

Neuroprotection alluded to GABAergic spiny msn neurons leading into the nucleus accumbens. These neurons act as an inhibitory "brake" on dopamine release from (Edit) the vta (and subsequent reward/euphoria). Opioids prevent these neurons from firing, relieving the inhibition of dopamine release.

The issue that Someguyontheinternet was getting at with opioids, is that the same opioid receptors in those regions also exert inhibitory control of other regions of the brain, causing side effects like respiratory depression. The receptors involved in these different circuits are the same, which makes finding a region-selective agonist akin to searching for the holy grail.

Rresearch animals are often bred with this bacterial protein called cre recombinase expressed in certain cell types. Cell type specificity is achieved by wiring the expression of cre to proteins expressed in specific cells (which allows for targeting of functionally similar populations). This protein recognizes recombination sites on DNA called LoxP sites, and can flip the DNA between two of these sites backwards. When scientists inject a virus containing backwards DNA flanked by loxP sites into a precise anatomical region, only cells expressing cre will orient the DNA correctly. This allows for targeting of both specific cell types and specific regions, which allows for probing of circuits.

Now the payload of these viruses activated by cre can be anything from proteins which indicate neuron firing, to customized receptors called DREADDs that bind to a drug (clozapine-N-oxide) that lacks affinity at any normal receptor.

Putting an inhibitory DREADD in GABAergic medium spiny neurons would turn clozapine-N-oxide into the closest thing to an opioid devoid of off target effects. Of course that would require breeding cre into people for many generations and be tremendously unethical, and will hopefully not occur (imagine the horrible social control that would be exerted if an entity did this at a population level).

 

[Neuroprotection]

When compared to a plain stimulant (a dopamine releaser or reuptake inhibitor), opioids are pretty darn close to selectively activating the reward center.

Neuroprotection alluded to GABAergic spiny msn neurons leading into the nucleus accumbens. These neurons act as an inhibitory "brake" on dopamine release in the vta (and subsequent reward/euphoria). Opioids prevent these neurons from firing, relieving the inhibition of dopamine release.

The issue that Someguyontheinternet was getting at with opioids, is that the same opioid receptors in those regions also exert inhibitory control of other regions of the brain, causing side effects like respiratory depression. The receptors involved in these different circuits are the same, which makes finding a region-selective agonist akin to searching for the holy grail.

Rresearch animals are often bred with this bacterial protein called cre recombinase expressed in certain cell types. Cell type specificity is achieved by wiring the expression of cre to proteins expressed in specific cells (which allows for targeting of functionally similar populations). This protein recognizes recombination sites on DNA called LoxP sites, and can flip the DNA between two of these sites backwards. When scientists inject a virus containing backwards DNA flanked by loxP sites into a precise anatomical region, only cells expressing cre will orient the DNA correctly. This allows for targeting of both specific cell types and specific regions, which allows for probing of circuits.

Now the payload of these viruses activated by cre can be anything from proteins which indicate neuron firing, to customized receptors called DREADDs that bind to a drug (clozapine-N-oxide) that lacks affinity at any normal receptor.

Putting an inhibitory DREADD in GABAergic medium spiny neurons would turn clozapine-N-oxide into the closest thing to an opioid devoid of off target effects. Of course that would require breeding cre into people for many generations and be tremendously unethical, and will hopefully not occur (imagine the horrible social control that would be exerted if an entity did this at a population level).

Thank you for that well thought out response. you likely know much more than me about neuroscience, especially neural circuitry. however, in regards to MSNs, I was actually alluding to those containing D1 dopamine receptors that reside inside the nucleus accumbens. these are the Neurons that dopamine acts upon to generate rewards. if I’m not mistaken, the VTA is the brain site responsible for releasing dopamine into the nucleus accumbens.
In regards to targeting specific brain circuits, I’m fully aware this wouldn’t be possible at the moment. However, I do feel that combining knowledge from various fields, like Epigenetics, neuropharmacology etc could help us discover more efficacious and safer drugs. of course, due to the reasons you mentioned, these won’t be free of side-effects. however, imagine that we could learn to bypass dopaminergic tolerance as well as modulate the Brain E/I balance, we could have a non-psychotomimetic amphetamine which could produce extreme euphoria reward without tolerance ever building up. i’m also wondering if things like magnetic brain stimulation could be used to shutdown brain regions responsible for suppressing reward.

 

[someguyontheinternet]

A colleague mentioned this paper to me the other day, it seems relevant to the discussion of preventing addiction to opioids.

Angiotensin-converting enzyme gates brain circuit-specific plasticity via an endogenous opioid

Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We find ...

www.ncbi.nlm.nih.gov

 

[Neuroprotection]

A colleague mentioned this paper to me the other day, it seems relevant to the discussion of preventing addiction to opioids.

Angiotensin-converting enzyme gates brain circuit-specific plasticity via an endogenous opioid

Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We find ...

www.ncbi.nlm.nih.gov

Very interesting paper. Thanks for posting it. I think pharmacological treatments like these are best for those wanting to quit opioids, where interventions that Address negative mood states are most affective in supporting abstinence. unfortunately, the problem with many promising pharmacological interventions for The addiction process, whether they target tolerance or reward, is that they will Blunt the experience of reward or being high. Active drug users may then avoid these interventions in order to get their reward. One thing I’ve learnt about addiction since coming on this site a few years ago is that neurobiological changes are only one part of the equation with psychological factors and human consciousness playing a major role, perhaps larger than previously thought. I also learned this through my own mild addiction/obsession with nicotine as an opportunistic smoker. living with my parents, I rarely get the opportunity to smoke/vape. When I did, it was biologically pleasurable for sure and the craving certainly had a biological aspect as well. however, there was also some strangely appealing ritualistic context around it. The cycle of cravings followed by relief as well as the anticipation of sneaking and getting ready to light a cigarette were all positive. of course, the extensive planning and fear of getting court made the process exhausting over time. therefore when I ran out of cigarettes or didn’t have the opportunity to smoke, I would feel somewhat relieved. I only started getting agitated A few weeks after quitting when boredom and stress would cause me to miss smoking.

 

[someguyontheinternet]

Wouldn't it be useful in opioid naive patients who are starting an opioid pain treatment?

 

[Hexenstahl]

unfortunately, the problem with many promising pharmacological interventions for the addiction process, whether they target tolerance or reward, is that they will Blunt the experience of reward or being high.

I disagree. I take ultra low dose naltrexone since almost two years now to keep my tolerance at a stable level and it doesn't blunt the experience of reward or being high at all. In fact it is actually known to potentiate and prolong the high and analgesia on top of reducing tolerance. When I was still on heroin between january 2022 and august 2023 I hadn't had to increase my dose even once (I scored from a dealer during that period who had a stable quality throughout) and since I'm on Levomethadone since september 2023 I have been able to keep my dose at a nice 4ml/40mg and get high every single day.

Perhaps what you say is true regarding other methods/substances but not with what I'm taking. In fact I have posted a textbook reference today in my ULDN thread where this is confirmed by science along with the studies I have posted there over time.

 

[Neuroprotection]

Wouldn't it be useful in opioid naive patients who are starting an opioid pain treatment?

Oh yes, of course it would. sorry I wasn’t that clear, I was talking about those who were psychologically dependent and for whom drugs offer a form of comfort.

 

[Neuroprotection]

I disagree. I take ultra low dose naltrexone since almost two years now to keep my tolerance at a stable level and it doesn't blunt the experience of reward or being high at all. In fact it is actually known to potentiate and prolong the high and analgesia on top of reducing tolerance. When I was still on heroin between january 2022 and august 2023 I hadn't had to increase my dose even once (I scored from a dealer during that period who had a stable quality throughout) and since I'm on Levomethadone since september 2023 I have been able to keep my dose at a nice 4ml/40mg and get high every single day.

Perhaps what you say is true regarding other methods/substances but not with what I'm taking. In fact I have posted a textbook reference today in my ULDN thread where this is confirmed by science along with the studies I have posted there over time.

Sorry about that, I’d forgotten about ULDN which is probably an exception to the rule. on a sidenote, do you have any opinion about selective Kappa opioid antagonists? apparently, they don’t do much for physical opioid withdrawal but reverse depressive behaviours including Anhadonia during and after the withdrawal syndrome.

 

[AlsoTapered]

The simplest modifications to the prototype phenanthracine opiate, morphine, is modification of the N-substituent and/or modification of the C-ring. Both have been widely explored and it's interesting to note that by modification of the N-substituent (replace N-methyl with a 2-(2-furanyl)ethyl) moiety, potency can be increased by a factor of 60. Replacing the cyclohex-7-en-6-ol with a 6-methylidenecyclohexane increases potency by a factor of 60.

I don't think anyone has ever tried both modifications at the same time and it's quite unlikely that the product is 1800 times more potent BUT the N-substitution was tested on levorphanol and the product proved to be some 480 times more potent than morphine.

Anyone with access to noroxymorphone COULD test out the predicted QSAR although the chemistry is quite involved. Well, INTERESTING as I see it.

 

[Neuroprotection]

The simplest modifications to the prototype phenanthracine opiate, morphine, is modification of the N-substituent and/or modification of the C-ring. Both have been widely explored and it's interesting to note that by modification of the N-substituent (replace N-methyl with a 2-(2-furanyl)ethyl) moiety, potency can be increased by a factor of 60. Replacing the cyclohex-7-en-6-ol with a 6-methylidenecyclohexane increases potency by a factor of 60.

I don't think anyone has ever tried both modifications at the same time and it's quite unlikely that the product is 1800 times more potent BUT the N-substitution was tested on levorphanol and the product proved to be some 480 times more potent than morphine.

Anyone with access to noroxymorphone COULD test out the predicted QSAR although the chemistry is quite involved. Well, INTERESTING as I see it.

I wonder how one would go about using an opioid that potent safely. I guess it could be done if you dilute appropriately into a solution of known concentration.

 

[jasperkent]

Puritanism: The haunting fear that someone, somewhere, may be happy. -- H.L. Mencken

 

[Hexenstahl]

Puritanism: The haunting fear that someone, somewhere, may be happy. -- H.L. Mencken

I NEED to tattoo this somewhere visible lol!

I wonder how one would go about using an opioid that potent safely. I guess it could be done if you dilute appropriately into a solution of known concentration.

That is exactly what I asked AlsoTapered recently in a PM when discussing this topic. I guess with volumetric dosing it could be done safely.

on a sidenote, do you have any opinion about selective Kappa opioid antagonists? apparently, they don’t do much for physical opioid withdrawal but reverse depressive behaviours including Anhadonia during and after the withdrawal syndrome.

Interesting, that is the first time I'm reading about this. I remember reading somewhere recently that a synthetic opioid was designed that specifically agonized the kappa receptors, more so than the µOR and it somehow lead to dysphoria. Damn, I wish I had the link to that study!

 

[Skorpio]

Thank you for that well thought out response. you likely know much more than me about neuroscience, especially neural circuitry. however, in regards to MSNs, I was actually alluding to those containing D1 dopamine receptors that reside inside the nucleus accumbens. these are the Neurons that dopamine acts upon to generate rewards. if I’m not mistaken, the VTA is the brain site responsible for releasing dopamine into the nucleus accumbens.
In regards to targeting specific brain circuits, I’m fully aware this wouldn’t be possible at the moment. However, I do feel that combining knowledge from various fields, like Epigenetics, neuropharmacology etc could help us discover more efficacious and safer drugs. of course, due to the reasons you mentioned, these won’t be free of side-effects. however, imagine that we could learn to bypass dopaminergic tolerance as well as modulate the Brain E/I balance, we could have a non-psychotomimetic amphetamine which could produce extreme euphoria reward without tolerance ever building up. i’m also wondering if things like magnetic brain stimulation could be used to shutdown brain regions responsible for suppressing reward.

Good catch, I tend to often mix up the vta and nucleus accunbens. I'll edit for clarity. The neurons start in the vta and project into the nucleus accumbens.

Magnetic brain stimulation is interesting, but falls into the opposite trap of small molecules, where it can be targeted to a region of the brain, but is cell type agnostic, activating all circuits in that region. In circuits with multiple layers of inhibition this will lose a lot of nuance regarding the signal path.

This recent review in Science, does a good job at laying out a lot of the circuits involved in reward, and is written by a scientist, Garret Stuber, who does great work.

Mega link cuz fuck paywalls

 

[someguyontheinternet]

Sorry about that, I’d forgotten about ULDN which is probably an exception to the rule. on a sidenote, do you have any opinion about selective Kappa opioid antagonists? apparently, they don’t do much for physical opioid withdrawal but reverse depressive behaviours including Anhadonia during and after the withdrawal syndrome.

Kappa antagonists are definitely interesting. I think it's a major player in kratom. I don't know about pure kappa antagonists though, I'd love to try one

I NEED to tattoo this somewhere visible lol!


That is exactly what I asked AlsoTapered recently in a PM when discussing this topic. I guess with volumetric dosing it could be done safely.


Interesting, that is the first time I'm reading about this. I remember reading somewhere recently that a synthetic opioid was designed that specifically agonized the kappa receptors, more so than the µOR and it somehow lead to dysphoria. Damn, I wish I had the link to that study!

Salvinorin A is a kappa agonist. Activating kappa has been shown to increase anhedonia and induce dysphoria

Major Depressive Disorder and Kappa Opioid Receptor Antagonists

Major depressive disorder (MDD) is a common psychiatric disease worldwide. The clinical use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs)/serotonin–norepinephrine ...

www.ncbi.nlm.nih.gov

 

[Skorpio]

Kappa antagonists are definitely interesting. I think it's a major player in kratom. I don't know about pure kappa antagonists though, I'd love to try one

Salvinorin A is a kappa agonist. Activating kappa has been shown to increase anhedonia and induce dysphoria

Major Depressive Disorder and Kappa Opioid Receptor Antagonists

Major depressive disorder (MDD) is a common psychiatric disease worldwide. The clinical use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs)/serotonin–norepinephrine ...

www.ncbi.nlm.nih.gov

Kappa antagonists have rather differing effects based on their preference for beta arrrestin or g-protein pathways (and the biased signaling for kappa receptors gets weird).

NorBNI tends to be a really popular antagonist (wild structure, a dimer of morphinans) that seems to block one arm of signaling. JDTiC is a different antagonist that gets called irreversible, but rather than alkylating the receptors, it fucks with c-jun kinase and has effects that way that last in the timescale of weeks.

These antagonists have pretty different effects on stress and DA signaling and generally complicate reading research about the kappa receptor (and of course performing that research).

 

[someguyontheinternet]

What are the differences between stress and dopamine kappa signaling physiologically?

 

[Neuroprotection]

What are the differences between stress and dopamine kappa signaling physiologically?

I don’t think there’s much of a difference. Both excessive stress via ACTH or recreational drug use via dopamine overflow can trigger upregulation of dynnorphin production. This is the endogenous agonist of Kappa Opioid receptors and through this mechanism, works to suppress dopamine release. I think the Dynnorphin/Kappa receptor system can also suppress norepinephrine and possibly serotonin signalling in certain brain regions as well as decreasing presynaptic glutamate and GABA release in the nucleus accumbens. collectively, these affects constitute a powerful negative feedback system that suppresses reward and contributes to prolonged Anhadonia.

 

[Neuroprotection]

can anyone help me understand why the hell we have so many mechanisms including brain circuits and endogenous substances to suppress reward and my God do they do a good job of hanging around! i’m going to go to bed now, but I’ll be happy to post links to support my opinion tomorrow. my basic opinion is that several identifiable mechanisms exist in the brain whose sole purpose is to negatively regulate reward activity and they do an extremely good job of it.

 

[someguyontheinternet]

I don’t think there’s much of a difference. Both excessive stress via ACTH or recreational drug use via dopamine overflow can trigger upregulation of dynnorphin production. This is the endogenous agonist of Kappa Opioid receptors and through this mechanism, works to suppress dopamine release. I think the Dynnorphin/Kappa receptor system can also suppress norepinephrine and possibly serotonin signalling in certain brain regions as well as decreasing presynaptic glutamate and GABA release in the nucleus accumbens. collectively, these affects constitute a powerful negative feedback system that suppresses reward and contributes to prolonged Anhadonia.

I was thinking more along the lines of where the kappa receptors are, what neurons in which circuits have kappa inputs rather than dynorphin signaling outputs. I think most (or all?) kappa receptors are presynaptic and modulate vesicle release through GIRK mediated hyperpolarization so they could be on a variety of types of neurons that release different transmitters but where they are in which circuits is the important part for determining the impact on behavior

There are negative feedback systems all throughout biology at what seems to me to be every level of intracellular cell signaling and throughout the brain and other organs. Feedback systems to maintain homeostasis are some of the biggest drivers of signaling and change

 

[Skorpio]

What are the differences between stress and dopamine kappa signaling physiologically?

Here is a review that kind of gets into it. It's far enough from my specialty that I don't want to misstate something. I always hear about medial prefrontal cortex projections onto the basolateral amygdala being important, but idk if that's just my proximity to labs looking into that pathway.

Also here's a review about the different second messengers of the kappa opioid receptor, which tackles some of its complexity.