What determines how euphoric an opioid is?

[TheJuner]

Sorry if this is a silly question, but I would really like to know. From my understanding there's a variety of factors, such as how fast the onset is, how long the high lasts, the MOR affinity/whether or not the substance is a full or partial agonist, potency, and whether or not the opioid is naturally occurring (morphine, codeine, thebaine, etc.), semi-synthetic (heroin, oxycodone, hydrocodone, hydromorphone, oxymorphone, etc.), and fully synthetic (pentazocine, fentanyl, meperidine, tramadol, tapentadol, etc.). There's also other properties opioids can have which can enhance the euphoria and analgesia of said substance, such as ketobemidone (fully synthetic, strong opioid that also binds to the NMDA receptor) and Levorphanol (fully synthetic opioid that acts as both an NMDA antagonist, SNRI, and is 6-8x the potency of morphine, as well as is a KOR agonist which I find interesting). However, there's examples which contradict what I'm saying. Potency=/=euphoria. If potency translated to more euphoria, fentanyl analogues and nitazenes would be the most sought after, despite their potency, neither of them are as euphoric as morphine, heroin, oxy, etc.. Mu affinity doesn't necessarily equal euphoria either, sure the affinity an opioid has for the mu opioid receptor certainly does play a role in its euphoria (partial agonists are nowhere nearly as euphoric as full agonists like morphine, take buprenorphine as an example), but again, fentanyl is an incredibly strong MOR agonist and isn't as euphoric as pure heroin. For the whether or not the opioid is natural, synthetic, or semi-synthetic, many opioid users prefer morphine and its esters to other opioids (hydromorphone, oxycodone, fentanyl, etc.) as shown in studies which have been published on this topic. Outside of this, many opioid users prefer semi-synthetic opioids to synthetic opioids and report semi-synthetic opioids to generally produce the most desirable effects. However, there is once again counter examples to both of these. Take ketobemidone for example, in an old study (when ketobemidone was still undergoing trials iirc), it was administered to a group of morphine addicts and was found to be more addictive than morphine, and produced euphoric effects superior to heroin. Furthermore, take dextromoramide (Palfium); Palfium has been described by old opioid users as being the most euphoric opioid, with an incredibly fast/intense onset even when administered orally. Finally (and this one is kind of cheating since this is a combination drug), dipipanone/cyclizine (Diconal). When administered intravenously, this combination is said to have produced an incredibly intense and long lasting rush. The interesting thing about these three substances is that: 1. They're all fully synthetic opioids. 2. Neither of them are that potent. Dextromoramide is three times the potency of morphine, Ketobemidone is roughly 2.4x the potency of morphine, and Dipipanone is 0.4x the potency of morphine (25mg dipipanone=10mg morphine).

 

[AlsoTapered]

No, it's a very good question and possibly the hardest of all to explain. There are at least 3 different types of opiate receptor (MOR, DOR, KOR, NOR) and the relative activity at each site will alter the subjective effects. Then, as you allude to, euphoria is often increased by the subjective effects being dynamic and so generally shorter acting opioids are generally considered to be more euphoric.

Then you have to consider what other affinity an opioid agonist has. NMDA, as well as monoamine transport all appear to alter the subjective effects and increase euphoria.

ROA will affect the dynamic nature of the subjective effects so that will also colour the experience.

But it's VERY hard to predict the euphoria of an opioid. Generally it would seem less potent opioids are more euphoric possibly because lower affinity means they will bind, be released and bind again.

 

[AlsoTapered]

FYI of those known to possess euphoria due to multiple actions we have:

Dipipanone - mu agonist/NMDA antagonist
Ketobemidone - mu agonist/NMDA antagonist
Levodromoran - mu agonist/NMDA antagonist
dextronortilidine - mu agonist/DRI
notrildine/norisotilidine - mu agonist/DRI/NMDA antagonist

So in the case of nortilidine, one enantiomer of the trans pair possesses the opioid and dopaminergic effects while the other is the NMDA antagonist effects. I cannot get the reference to the levo enantiomer as it's in a large reference book that doesn't appear to be in the digital domain and isn't worth buying for 1 reference.

 

[TheJuner]

Dipipanone - mu agonist/NMDA antagonist

I can't find anything about dipipanone and it's supposed NMDA antagonism, do you have any sources on this?

 

[TheJuner]

Also another thing, nortildine is the active metabolite of tildin, right? So, and this relates to another post I made on here, wouldn't a CYP2D6 enzyme inducer like glutethimide enable your body to convert more of the tildin into nortildine?

 

[Rectify]

The most euphoric ones tend to have a dopamine pharmacophore and are lipophilic.

 

[TheJuner]

The most euphoric ones tend to have a dopamine pharmacophore and are lipophilic.

Interesting. I can only think of one example of this though (nortildine which acts as a DRI), do you have any resources on this?

 

[AlsoTapered]

The most euphoric ones tend to have a dopamine pharmacophore and are lipophilic.

ALL opioids are lipophilic - it's part of the definition of the term 'opioid'. 'moderately lipophilic' may reduce onset slightly but that may not be true (it's a guess on the part of some theorists) and more practically, it precludes those which are TOO lipophilic to cross the BBB.

 

[Abitofeverything]

I think an often under evaluated part of this is individual genetics, while it doesn’t apply to these drugs I found I have a the following:

CYP2C19 mutation - rapid metabolizer and a SLCO1B1 mutation causing slow transport to/from liver​

Which may not matter as far as initial reaction, but maybe sustained or length of euphoria felt.

I’ve found NOR inhibitors potentiate most, but maybe that’s true for everyone ?

 

[DeathIndustrial88]

There are 3 main opioid receptors... mu, kappa, delta.

These receptors also have sub-receptors, such as mu1, mu2, mu3.
Most opioids bind to mu, but they don't all bind to the sub receptors.

I believe it's mu2 that is responsible for the warm euphoria people are generally after.
Although agonizing mu in general is going to give some effect.

Fentanyl for example, is 50x "stronger" than morphine & heroin, but it doesn't actually feel better because it probably doesn't bind to mu2 or have a binding profile that is favorable for euphoria at all.

 

[AlsoTapered]

There are 3 main opioid receptors... mu, kappa, delta.

These receptors also have sub-receptors, such as mu1, mu2, mu3.
Most opioids bind to mu, but they don't all bind to the sub receptors.

I believe it's mu2 that is responsible for the warm euphoria people are generally after.
Although agonizing mu in general is going to give some effect.

Fentanyl for example, is 50x "stronger" than morphine & heroin, but it doesn't actually feel better because it probably doesn't bind to mu2 or have a binding profile that is favorable for euphoria at all.

No, their are 4. MOP, NOP, DOP & KOP. Some highly potent 'opiates' actually hit the NOP quite selectively so they are MUCH safer BUT I don't know if they support someone dependent on an old-school opioid that only hits MOP, DOP & KOP.

Sufentanil and 14-ethoxymetopon have a lot of NOP activity which is why their TIs are measured in the 10000+ range.

 

[DeathIndustrial88]

No, their are 4. MOP, NOP, DOP & KOP. Some highly potent 'opiates' actually hit the NOP quite selectively so they are MUCH safer BUT I don't know if they support someone dependent on an old-school opioid that only hits MOP, DOP & KOP.

Sufentanil and 14-ethoxymetopon have a lot of NOP activity which is why their TIs are measured in the 10000+ range.

Yeah,
I'm well aware there's more than 3, there's even more than 4. The sigma receptor also use to be considered an "opioid receptor" too. But none of them have anything to do with question at hand. Most of the common opioids used by people most likely bind to mu2, causing the euphoria we all know & love.


Also it's "there", not "their" lol

 

[AlsoTapered]

No - sigma receptors have been found all through the body so they haven't been classified as opioid receptors since the 70s.

Sorry about the error in my response. But I hope you overcame it.

 

[AlsoTapered]

Also another thing, nortildine is the active metabolite of tildin, right? So, and this relates to another post I made on here, wouldn't a CYP2D6 enzyme inducer like glutethimide enable your body to convert more of the tildin into nortildine?

I think nortilidine and bisnortilidine are both considered to be opioids BUT I believe nortilidine is ALWAYS used as the reference and for various reasons (Like LogP) I think it's by far the more potent of the two.

Certainly a German RC company offered nortilidine and when it was banned, they didn't offer bisnortilidine as an alternative.

I'm not sure if CYP2D6 would yield nortilidine or just keep on trucking and convert to bisnortilidine.

BTW If you look at the Wiki page on Tilidine their is a reference to the 'reversed ester' which is equipotent.

But both tilidine and isotilidine (if I may be permitted to name it) are a total pain to produce. Both are VERY costly. I know Germans who ONLY use tilidine. No M, H,F, Oxy or anything else. They only like tilidine. One guy said the stimulant properties meant he took it before exams - certainly not the usual opioid (ab)user groups.

 

[DeathIndustrial88]

No - sigma receptors have been found all through the body so they haven't been classified as opioid receptors since the 70s.

Sorry about the error in my response. But I hope you overcame it.

Exactly what I said.... they use to be classified as opioid receptors.


Sounds like your just like trying to sound like a smart ass by being condescending.
This coming from some one who claimed clonazepam causes liver damage the other day on another thread. Lol Which is not true at all.

I encourage people to learn pharmacology & teach themselves shit. You should spend more time studying than spreading misinformation & trying to "correct" people on BL who aren't even incorrect to begin with.

Me : Sigma receptors use to be classified as opioid receptors
You : No you're wrong, they haven't been classified since the 70's..


Get over yourself bro.

 

[AlsoTapered]

Exactly what I said.... they use to be classified as opioid receptors.


Sounds like your just like trying to sound like a smart ass by being condescending.
This coming from some one who claimed clonazepam causes liver damage the other day on another thread. Lol Which is not true at all.

I encourage people to learn pharmacology & teach themselves shit. You should spend more time studying than spreading misinformation & trying to "correct" people on BL who aren't even incorrect to begin with.

Me : Sigma receptors use to be classified as opioid receptors
You : No you're wrong, they haven't been classified since the 70's..


Get over yourself bro.

Re-read what you wrote. 'use to be' - so forgive me not correctly divining your poor attempt at posting.

I didn't make some big deal about NOP, I simply corrected you. People correct me all the time and I don't presume that their is some strange competition going on. We are only interested in getting the facts right.

 

[DeathIndustrial88]

Re-read what you wrote. 'use to be' - so forgive me not correctly divining your poor attempt at posting.

I didn't make some big deal about NOP, I simply corrected you. People correct me all the time and I don't presume that their is some strange competition going on. We are only interested in getting the facts right.

How did you "correct" me about NOP?
I'm aware of NOP, but did not mention it in that comment because it was irrelevant to the question asked by OP.
If the mu-sub receptors are responsible for the euphoria, then who cares about NOP?

Not to mention I said "there are 3 main opioid receptors".... meaning there's more than 3 but I'm about the list the main three relevant ones.
You simply added more information to what I already said, which is great & I appreciate, but you did it in a condescending manner, as if I was just spewing nonsense that needed to be fixed or something. When nothing I said was even nonfactual. Not listing NOP doesn't make what I said "incorrect".

 

[sekio]

I can't find anything about dipipanone and it's supposed NMDA antagonism, do you have any sources on this?

It's a close analogue of methadone, so it follows that it likely has NMDA antagonist properties.

but you did it in a condescending manner, as if I was just spewing nonsense that needed to be fixed or something.

All he said was "No, their(sic) are 4. MOP, NOP, DOP & KOP." Nothing else. No insults, no attacks. It was a simple correction.
He then went on to provide examples. I know it can be hard to discern intention from someone's text posts online, but it doesn't hurt to assume good faith unless clearly shown otherwise.

If the mu-sub receptors are responsible for the euphoria, then who cares about NOP?

Wiki: Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP (nociceptin receptor) agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.
Opioids can have other targets than the mu opioid receptor.
In fact buprenorphine, norbuprenorphine, etorphine, and thienorphine all interact with NOP, making it relevant to their pharmacology,

 

[DeathIndustrial88]

It's a close analogue of methadone, so it follows that it likely has NMDA antagonist properties.


All he said was "No, their(sic) are 4. MOP, NOP, DOP & KOP." Nothing else. No insults, no attacks. It was a simple correction.
He then went on to provide examples. I know it can be hard to discern intention from someone's text posts online, but it doesn't hurt to assume good faith unless clearly shown otherwise.


Wiki: Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP (nociceptin receptor) agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.
Opioids can have other targets than the mu opioid receptor.
In fact buprenorphine, norbuprenorphine, etorphine, and thienorphine all interact with NOP, making it relevant to their pharmacology,

Oh so now you're both attacking me. lol

For the 100th billionth time, THE NOP RECEPTOR HAS NOTHING TO DO WITH THE ORIGINAL QUESTION ASKED BY OP.
Are you guys fucking blind/deaf?

IT was NOT a "CORRECTION" either, because nothing I said was INCORRECT.
MU, KAPPA and DELTA ARE the MAIN three receptors. Adding NOP doesn't make anything I said "INCORRECT".

Yeah exactly. NOP agonists are usually non-addictive.... WHICH MEANS THEY HAVE JACK SHIT TO DO WITH EUPHORIA LIKE OP ASKED.

Not to mention I doubt OP is sitting there using etorphine, norbuprenorphine (which almost nobody on earth has ever probably actually used) or thienorphine. So who gives a shit about their pharmacology? OP came in here & asked what makes an opioid euphoric. Bringing up NOP & etorphine in your answer is absolutely pointless, since OP didn't ask for a pharmacology lesson.

Not to mention also that buprenorphine & norbuprenorphine aren't even very euphoric & that has nothing to do with their interaction at NOP. Buprenorphine generally doesn't effect NOP until higher doses.

Doesn't look like OP gives two shits about NOP or etorphine or any of the answers in general, so who gives a shit?


AlsoTapered was telling another person to quit their medicines the other day because they cause liver damage. Which was absolutely untrue, but did I see you jump in when I tried to correct him? Of course not sekio, cause you obviously play favorites with people around here. Telling people to stop their medicines over bogus liver damage claims deserves more of a "correction", than me not mentioning "NOP" on this thread.

He also tried to "correct" me again when I said sigma receptors use to be classified as opioid receptors. And then he proceeded to state the very same fact I had just stated. And now your ass is gonna sit there & tell me I should "assume good faith" toward somebody who's just trying to sound smarter than me & take a shit on everything I say? Fuck that. You clearly didn't actually read this thread & merely jumped in to defend AlsoTapered.



Seriously, both of ya'll should get a life. Nothing I said was "Incorrect" and I have every right to take it as insult when some one sits there trying to 'correct' me. OP doesn't need to know jack shit about NOP or etorphine to have his fucking question answered. You guys are just obsessed with trying to sound "smarter" than everybody. To the point where you're both delusional in thinking you "corrected" me. lol Pathetic.

As for @TheJuner , what I said about mu2 being responsible for euphoria from COMMONLY USED opioids is still true & a fact. Sorry these egotistical nerds had to hijack the thread into talking about NOP & etorphine & other bullshit.

 

[Mjäll]

Dude has a point there