Opioid addiction and individual differences in onset.

[psynce of sound]

Hi N&PD I have for a long time pondered over how and why I seem to never suffer any sort of withdrawl.
This is most noticeable with opioids. To give a slight preface to this specific I have been prescribed dhc for a year now and I also enjoy oxy and a rare bit of diamorphine on the side. This has been on going for 2 maybe 3 years. Within that time I have been very silly in dosing for a niave individual to such drugs. I still do silly amounts on and off.
For example I had a 5/6 day run with diamorphine and stopped without issue, same with oxy.

This is a running theme for all my use of a wide variety of drugs. I do get rebound symptoms with certain substances I.e. benzos.

Now I have done a bit of reading into this aspect of addiction/drug use. My reading has brought me too G Protein Coupled Receptors (GCPR) and how these play a role in both addiction and tolerance.

Despite this I am still unsure how I seem to be less susceptible than the average person.
So I would simply like to ask if any of you good folk have any hypothesis on what mechanism(s) may be at play?

Thank you for any responses.

 

[polymath]

Hi N&PD I have for a long time pondered over how and why I seem to never suffer any sort of withdrawl.
This is most noticeable with opioids. To give a slight preface to this specific I have been prescribed dhc for a year now and I also enjoy oxy and a rare bit of diamorphine on the side. This has been on going for 2 maybe 3 years. Within that time I have been very silly in dosing for a niave individual to such drugs. I still do silly amounts on and off.
For example I had a 5/6 day run with diamorphine and stopped without issue, same with oxy.

This is a running theme for all my use of a wide variety of drugs. I do get rebound symptoms with certain substances I.e. benzos.

Now I have done a bit of reading into this aspect of addiction/drug use. My reading has brought me too G Protein Coupled Receptors (GCPR) and how these play a role in both addiction and tolerance.

Despite this I am still unsure how I seem to be less susceptible than the average person.
So I would simply like to ask if any of you good folk have any hypothesis on what mechanism(s) may be at play?

It's extremely likely that you will get physically dependent too if you push it too far. But there are several receptors in the human body that have to be functioning for opioid tolerance to develop (neuropeptide FF, cholecystokinin receptor and others) and mutations altering the genes that code those receptors could make the development of tolerance and dependence slower.

 

[psynce of sound]

It's extremely likely that you will get physically dependent too if you push it too far. But there are several receptors in the human body that have to be functioning for opioid tolerance to develop (neuropeptide FF, cholecystokinin receptor and others) and mutations altering the genes that code those receptors could make the development of tolerance and dependence slower.

Yes I couldn't agree more about continuing to push things further. As such I have been making strides to reduce my use a lot.
Anywho I must say I suspected gene mutations to be involved heavily. I haven't been introduced to some of the things ok have mentioned. You have my thanks for response, it has given me further avenues of thought.

 

[dopamimetic]

I've been on opioids (morphine/methadone, up to 420/60mg/d respectively) for most of the last 2 years and before that, maybe 6 months on buprenorphine 1-4mg/d without developing real physical tolerance or withdrawal, but very probably it's due to my penchant for dissociatives as NMDA antags are known for their tolerance inhibiting effects in regards to opioids. Nocebo certainly plays a role too, if one'd rushed into w/d repeatedly and builds up a fear against it, then this fear will worsen the withdrawals just by itself..

But as you say, the point is not to push things too far ... I did, on the disso lane, as I got away with so much I began to do more exotic combos and finally caught psychosis. I regret.

 

[whos there]

Hi N&PD I have for a long time pondered over how and why I seem to never suffer any sort of withdrawl.
This is most noticeable with opioids. To give a slight preface to this specific I have been prescribed dhc for a year now and I also enjoy oxy and a rare bit of diamorphine on the side. This has been on going for 2 maybe 3 years. Within that time I have been very silly in dosing for a niave individual to such drugs. I still do silly amounts on and off.
For example I had a 5/6 day run with diamorphine and stopped without issue, same with oxy.

This is a running theme for all my use of a wide variety of drugs. I do get rebound symptoms with certain substances I.e. benzos.

Now I have done a bit of reading into this aspect of addiction/drug use. My reading has brought me too G Protein Coupled Receptors (GCPR) and how these play a role in both addiction and tolerance.

Despite this I am still unsure how I seem to be less susceptible than the average person.
So I would simply like to ask if any of you good folk have any hypothesis on what mechanism(s) may be at play?

Thank you for any responses.

so the longest run on opiates was 6 days? i could see scraping by without withdrawal if thats the case, but maybe i read you wrong.

I've been on opioids (morphine/methadone, up to 420/60mg/d respectively) for most of the last 2 years and before that, maybe 6 months on buprenorphine 1-4mg/d without developing real physical tolerance or withdrawal, but very probably it's due to my penchant for dissociatives as NMDA antags are known for their tolerance inhibiting effects in regards to opioids. Nocebo certainly plays a role too, if one'd rushed into w/d repeatedly and builds up a fear against it, then this fear will worsen the withdrawals just by itself..

But as you say, the point is not to push things too far ... I did, on the disso lane, as I got away with so much I began to do more exotic combos and finally caught psychosis. I regret.

^that is fucking crazy, 2 yrs on methadone with no physical wd, even with everyday nmda antagonism thats some super neurochemistry you got there.
were you using dxm?

 

[dopamimetic]

I really don't know but I attribute most to the dissos cause I know how it feels to be on the beginning of an opioid withdrawal - when I took morphine alone for some weeks and then would miss a dose. Just never allowed opioid WD to fully manifestize, thus no kindling and yeah it's weird. In the end I also see that hi dose opioids don't give me anything. The magic lies in using them sparingly and at low dose (usually opioids are only fun when you've got severe tolerance), and combined with dissociatives. I also appear to tolerate just any amount of NMDA antagonism without any psychosis, in fact hi-dose morphine was pro-psychotic for me and when I then took some DXM it was like "finally the good stuff" and everything calmed down ...

 

[Neithman]

high dose morphine also produces some pro psychotic symptoms in me, but they are weak in intensity and only occur when i take double my usual dose. I often experience those symptoms short before sleeping and manifest in a second train of thought as dopamimetic described before.
I think this is due being in a half awake half nodding state where consciousness is in a state of being half automatical and this produces an uncontrollable state of not being able to control the train of thought.
Also this could be because kappa agonism of morphine which is more pronounced at high dose

 

[polymath]

Sometimes when I nod off on opiates, I kind of fall asleep and stay conscious at the same time, and can hear my own snoring like a 3rd person observer... But no actual hallucinations, ever. Elderly pain patients can react even to small morphine doses with delirium as far as I know, but that's just a result of their already poor physical condition.

 

[dopamimetic]

Hehe, that's called dissociation, probably and might be from kappa activity. Like this effect, but from opiates / morphine I get just weird things, like something with wake & sleep being inversed, can't explain it better... feeling soooo tired but can't sleep, yet awake but not here... yeah they have some weird stimulating side for sure. Benzos, for example, are more purely sedating for me. Dissos tend to be stimulating. Have to say that I never had a true nod off morphine, and never a true hole from ketamine, and went psychotic/delirant repeatedly from antipsychotics. I must have some truly weird piece of DNA.

 

[psynce of sound]

so the longest run on opiates was 6 days? i could see scraping by without withdrawal if thats the case, but maybe i read you wrong.

I take dhc daily and mess with oxy and h every other week. I do go for a few days without quite often. I get mad cravings (fro drugs in general but no issues that can be attributed to withdrawl.

 

[clubcard]

Those NMDA antagonists also have affinity for the mu receptors so they just substitute. MXE is the most potent mu ligand, well it's metabolite. Adder posted the story of 3-OH (the metabolite) and 4mg floored him. Adder is a man of few words but let me tell you - he's one of the 4 people here (I know of) who have made LOADS of stuff. I think I knew him in a previous iteration and we went through a synth problem. I say that because his solution struck me as a natural and Adder is very very similar. And lo, he posted BDPC report. First into man. Crazy guy but always worth asking. I respect him deeply.

 

[novaveritas]

Those NMDA antagonists also have affinity for the mu receptors so they just substitute. MXE is the most potent mu ligand, well it's metabolite. Adder posted the story of 3-OH (the metabolite) and 4mg floored him.

Wrong
MXE is not a potent mu ligand, none of the published assays show any interaction. The idea that somehow it is a mu agonist comes from poor quality thinking from years ago, where somebody decided that because meta methoxy is often on opioids like tramadol therefore meta methoxy stuck to anything makes opioids similar to the flawed thinking that methylenedioxy makes entactogens whatever it is stuck to.

There are two main MXE metabolites, O-desmethylmethoxetamine and normethoxetamine, but a lot of MXE is excreted unchanged.
O-desmethyl is the methoxy being metabolized to a OH. In rats this is the major metabolite but not in humans. The evidence shows in man this is a very minor metabolite
O-Desmethylmethoxetamine the 3-OH you call it might be a mu agonist but there is zero evidence

Normethoxetamine is the main human metabolite by CYP2B6 and CYP3A4 catalysed de-ethylation

Menzies et al. Drug Test Anal.6, 506?515. (2014)
Meyer et al. Anal. Bioanal. Chem. 405, 6307?6321 (2013)

The potency of MXE is due to the extreme lipophilicity leading to high brain concentrations combined with slow metabolism.

 

[clubcard]

I never said MXE was an opioid - I said the phenolic (3-OH) metabolite was. The metabolite found in human studies, to be exact. https://doi.org/10.1002/dta.1541 What's more, it's a very potent opioid (4mg floored Adder who had a habit at the time). The reports on the whole class (BDPC being one of the others) are on BL and are very detailed indeed. Go back and look at Lednicer's work Adder was working through. I didn't claim anything, I reported on others actual WORK. Upjohn patented 44 analogues & derivatives of 4-(4-bromophenyl)-4-(dimethylamino)cyclohexanone class with extensive QSAR data. He even had pictures of dreiding models published! You will note the m-OH on the aromatic, you will note the benzylamine & cyclohexane moieties. Upjohn spent a LOT of money on it and Adder put in a LOT of effort making & reporting.



Stop the arrogance and the aggression, this is a site for adults; or don't and get suspended, your choice.

 

[novaveritas]

I never said MXE was an opioid - I said the phenolic (3-OH) metabolite was. The metabolite found in human studies, to be exact. https://doi.org/10.1002/dta.1541 What's more, it's a very potent opioid (4mg floored Adder who had a habit at the time). The reports on the whole class (BDPC being one of the others) are on BL and are very detailed indeed. Go back and look at Lednicer's work Adder was working through. I didn't claim anything, I reported on others actual WORK. Upjohn patented 44 analogues & derivatives of 4-(4-bromophenyl)-4-(dimethylamino)cyclohexanone class with extensive QSAR data. He even had pictures of dreiding models published! You will note the m-OH on the aromatic, you will note the benzylamine & cyclohexane moieties. Upjohn spent a LOT of money on it and Adder put in a LOT of effort making & reporting.



Stop the arrogance and the aggression, this is a site for adults; or don't and get suspended, your choice.

are you a mod now?
not that it matters because you just keep twisting and editing your posts. This aint personal you are being called out on your science, and its errors. Errors in this field have consequences people can easily die believing what you write is true or factual.

It helps if your references actually support your point.
From your ref

of all of the metabolites observed in vitro and in vivo, normethoxetamine (2) predominated, based on its MS signal in-
tensity, indicating it is the main metabolite of methoxetamine. The only exception was in one of the three urine samples, where

dihydromethoxetamine (8) gave the highest signal abundance followed by normethoxetamine.

desmethylmethoxetamine is a minor metabolite in humans and you were suggesting that these NMDA antagonists substitute for opioids through mu agonism, specifically that MXE had direct or indirect mu agonism "Those NMDA antagonists also have affinity for the mu receptors so they just substitute."

please post a link to the BL thread with desmethylmethoxetamine as a mu agonist rather than a serious hard hitting NMDA antagonist. bioassay to identify receptor interactions is super shady and fraught with problems. I cant UTFSE.

 

[dopamimetic]

Yep, NMDA antagonists do stimulate the release of many brain chemicals, maybe including endorphins/enkephalins/dynorphins (?) - recently I read something about oxytocin, don't remember exactly where. And quite a few are actual opioids, DXM is one of them, MXE through its metabolite (there's some super-computerish metabolism calculator online which also confirms said metabolism) but this brings us to another thing, metabolites of opioids - I think to remember that morphine has some pro-inflammatory metabolite, which might be responsible for some of the less positive side effects?

Main human metabolite doesn't mean there aren't minor but very potent ones

But NMDA antags indeed cut opioid tolerance down, I've been able to go down so much faster repeatedly while using dissos concurrently than if I'd tapered alone (it's not exactly right that I never catched physical addiction. Just not withdrawal. And it's so much easier to build down on NMDA antags than on opioids (or, probably, benzos) - yet I can't let them be completely, temptation's always there and with the net also just one order away.. they are like a miracle cure for my Asperger-like introvertedness syndrome.. just fuck prohibition. It'd be so easy.

Stop the arrogance and the aggression

And this.

 

[novaveritas]

Yep, NMDA antagonists do stimulate the release of many brain chemicals, maybe including endorphins/enkephalins/dynorphins (?) - recently I read something about oxytocin, don't remember exactly where. And quite a few are actual opioids, DXM is one of them, MXE through its metabolite (there's some super-computerish metabolism calculator online which also confirms said metabolism) but this brings us to another thing, metabolites of opioids - I think to remember that morphine has some pro-inflammatory metabolite, which might be responsible for some of the less positive side effects?

Main human metabolite doesn't mean there aren't minor but very potent ones

But NMDA antags indeed cut opioid tolerance down, I've been able to go down so much faster repeatedly while using dissos concurrently than if I'd tapered alone (it's not exactly right that I never catched physical addiction. Just not withdrawal. And it's so much easier to build down on NMDA antags than on opioids (or, probably, benzos) - yet I can't let them be completely, temptation's always there and with the net also just one order away.. they are like a miracle cure for my Asperger-like introvertedness syndrome.. just fuck prohibition. It'd be so easy.

And this.

The human data from real humans and real analytical techniques shows that O-desmethylmethoxetamine is a minor metabolite period.The real experimental data trumps the computer model every time.

Approach it scientifically, real scientific data is that methoxetamine has a ki at MOR of >10000 nM greater than 10000 nM assay using radioligand displacement. the hypothesis is a 50mg methoxetamine dose is converted to the metabolite in sufficient quantities and this metabolite is not excreted as a glucuronide or similar adduct and that this metabolite is a super potent agonist at MOR and this metabolite has to be roughly 1000x the affinity of the parent, from which only differs from by a single methyl group similar to codeine-morphine or tramadol-O desmethyl tramadol, and ask Is that hypothesis likely. The idea tha MXE is an opioid either directly or thru its metabolite is a myth unsupported by the evidence but this myth doesn't want to die.
O desmethylMethoxetamine might possibly be a mu agonist but its far from proven and the whole spoeculation is pretty weak and all the evidence points to the null. The clubcardian position is MXE is a mu agonist through its metabolite without any real evidence based on entirely on speculation and weak conjecture.

 

[dopamimetic]

I'm right now on MXE and I'd bet it has opioid activity, much more so than ketamine. O-PCM I'm unsure about.

Don't want to argue, really, I'm just curious. Maybe it's even a distinct separate mechanism, like endorphin/enkephalin release, that MXE hasn't been screened for yet.

 

[clubcard]

The original patents for ketamine are worth looking at because of the citations the patents give and more importantly, the patents cite them. US Patent 3,254,124 is a good place to start. If you look at the series Adder posted, you can see how he began with the 1950s ring-substituted PCP studies, went through the ketamine modification (the ketone) and on to Upjohn's opioids. I was surprised to find that 2-(2-chloro-5-methoxyphenyl)-2-(methylamino)cyclohexanone i.e. 5-MeO ketamine got a patent to itself. I don't know if patents were relatively cheaper back then or if Parke Davis considered that 1 compound as their next product (the narrower the claims of a patent, the stronger the patent is). Today, that's quite a lot of time & money so for some reason, they had cause to nail their claim to it. Progress in Opioid Research - Proceedings of the 1986 International Narcotics Research Conference, 75 pages 173-176 (HIGH AND LOW AFFINITY PSYCHOTOMIMETIC OPIOID BINDING SITES:
CHARACTERIZATION BY A NOVEL 3 H-PCP-ANALOG) states that 3-OH PCP competes for DOP & KOP opioid sites. It IS pretty old with sigma receptors classed as opioid receptors and no NOP receptor studies. Of course, affinity ≠ efficacy.

The work of Schmidhammer et al seems to suggest that MOP/DOP interaction greatly increases analgesia and Gr?nenthal have taken off from where Upjohn ended and developed MOP/DOP/NOP ligands that also seem very potent. It's also interesting that DOP antagonists will precipitate abstinence syndrome in morphine-dependent animal models but none of these studies are in man. I suppose one think I would like to know is if diphenidine and 3-MeO diphenidine have any impact on prevention of withdrawal. It's just a shame that isophenidine never got rolled out. Out of that whole 1,2-diphenylethylamine class, the only one I actually though was comparable to MXE (the EPC group tested), never got a chance.


PS novaveritas no, but you were sent a warning from the mods, weren't you? You got a stack of posts pulled for being an arse.

 

[novaveritas]

The original patents for ketamine are worth looking at because of the citations the patents give and more importantly, the patents cite them. US Patent 3,254,124 is a good place to start. If you look at the series Adder posted, you can see how he began with the 1950s ring-substituted PCP studies, went through the ketamine modification (the ketone) and on to Upjohn's opioids. I was surprised to find that 2-(2-chloro-5-methoxyphenyl)-2-(methylamino)cyclohexanone i.e. 5-MeO ketamine got a patent to itself. I don't know if patents were relatively cheaper back then or if Parke Davis considered that 1 compound as their next product (the narrower the claims of a patent, the stronger the patent is). Today, that's quite a lot of time & money so for some reason, they had cause to nail their claim to it. Progress in Opioid Research - Proceedings of the 1986 International Narcotics Research Conference, 75 pages 173-176 (HIGH AND LOW AFFINITY PSYCHOTOMIMETIC OPIOID BINDING SITES:
CHARACTERIZATION BY A NOVEL 3 H-PCP-ANALOG) states that 3-OH PCP competes for DOP & KOP opioid sites. It IS pretty old with sigma receptors classed as opioid receptors and no NOP receptor studies. Of course, affinity ≠ efficacy.

The work of Schmidhammer et al seems to suggest that MOP/DOP interaction greatly increases analgesia and Gr?nenthal have taken off from where Upjohn ended and developed MOP/DOP/NOP ligands that also seem very potent. It's also interesting that DOP antagonists will precipitate abstinence syndrome in morphine-dependent animal models but none of these studies are in man. I suppose one think I would like to know is if diphenidine and 3-MeO diphenidine have any impact on prevention of withdrawal. It's just a shame that isophenidine never got rolled out. Out of that whole 1,2-diphenylethylamine class, the only one I actually though was comparable to MXE (the EPC group tested), never got a chance.


PS novaveritas no, but you were sent a warning from the mods, weren't you? You got a stack of posts pulled for being an arse.

is this a different series to http://www.bluelight.org/vb/threads/504286-PCP-analogs-(Cumulative)-Retrospective-Bioassays ???
because Adders series is 3-OH PCP not the desmethyl metabolite of methoxetamine. There is a huge difference desmethylmethoxetamine is a Phenyl cyclohexanone, with a secondary amine using Adders code desmethylmethoxetamine would be called 2-oxo-3' hydroxy PCE or soemthing like it
3-OH PCP is a phenylcyclohexane with a tertiary amine and is most certainly not a metabolite of methoxetamine. Basic error on your part.
Further questions arise, Hugo24 who is a sound researcher made 3-OH PCP and didn't report the same effects as Adder.

If you have real evidence that stands up that desmethylmethoxetamine is a mu ligand and a potent one post it.

 

[Limpet_Chicken]

Diphenidine does indeed reverse the effects of opioid withdrawal. When it was available, I used to buy the local head shop out of the stuff on a regular basis in fact, if ever I ran out of pain meds, I'm not claiming it to be an opioid (although in the case of diphenidine and analogs, given the structural similarity to lefetamine, I could see it being the case, potentially),what is certain though, is that I could take a dose of the stuff and the withdrawals would just disappear. Although strong NMDA antagonists in general are good at doing that in my experience.