D-Methadone

[dopamimetic]

Have been curious about this compound for some time now ever since I've read that it is a NMDA antagonist - one which appears to have individually different effects as some people on opioid maintenance get adverse effects from using the racemate, like WD symptoms setting in much earlier than with just levomethadone while for other like me the racemate is at least more euphoric if not of overall slightly higher potency. The latter makes sense, but never heard of other NMDA antagonism triggering withdrawal.. d-methadone will have to be much weaker at NMDA than l-metha is as an opioid as ppl use over 100mg without dissociation and otherwise there would be a slower tolerance development..

But now seen that d-metha completed clinical phase II trial for major depressive disorder which sounds pretty promising. Source (anybody able to fetch the full paper?)
Also it is a SNRI and possible opioid agonist. Source, again somebody able to fetch it? Scihub unfortunately isn't.

Does anybody have experiences with pure d-methadone or similar compounds? Am interested in other dextro isomers of opioids too but guess they are hard to isolate ... also, was Morphanol (levorphanol & DXM) ever sold or tried clinically?

 

[polymath]

As discussed in some other thread a few months ago (I think), d-methadone can potentially cause same kind of cardiac arrhythmias as large doses of loperamide.

Edit: it was in this thread: https://www.bluelight.org/xf/threads/embutramide-and-related-cmpds.884732/#post-14755782

 

[dopamimetic]

Ok wasn't that the reason they withdrew levactylmethadol from market? Think I've heard before about methadone but thought it wasn't that much of a concern if you stay low, once I knew a woman taking over 200mg/d and to me 60mg felt pretty good, much lighter physically than an equipotent dose of morphine, also had ECG done on it so think it's safe for me but again probably you won't feel things like arrythmia until it's too late.

Too sad it will render the compound worthless as a dissociative but hope they will complete the trials.. it can't be much worse than DXM+bupropion which is approved afaik.

Just checked here: http://swisstargetprediction.ch/result.php?job=565196096&organism=Homo_sapiens which tells that methadone is mostly selective to mu, delta and kappa but thought it was mu only?
One of the few things found by googleing for morphine delta opioid:

In contrast, morphine did not cause a substantial desensitization of the delta-opioid receptor. These results indicate that methadone is different from morphine in its regulation of the delta-opioid receptor. In addition, these results also indicate that the mechanisms of delta-opioid receptor desensitization induced by acute and chronic methadone treatment are different. Source

 

[polymath]

This article is readable via Sci-Hub and contains the mu, delta and kappa affinities of methadone isomers:

The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine

The finding affinities of racemic methadone and its optical isomers R-methadone and S-methadone were evaluated for the opioid receptors mu1, mu2, delt…

www.sciencedirect.com

Methadone is also a serotonin reuptake inhibitor, as said in this poster presentation

https://www.ecnp.eu/presentationpdfs/70/P.1.g.077.pdf

As far as I know, SSRI treatment elevates your pain treshold by affecting delta receptors indirectly, and that effect can be blocked with a delta receptor antagonist.

 

[paracelsius]

Methadone has a pretty "dirty" pharmacology. In addition to opioid, nmda, monoamines.. its major metabolite (2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline, EMDP)
is actually a potent nicotinic cholinergic antagonist (more potent than the gold standard mecamylamine. That's why smokers on methadone double their cigarette smoking to counteract nicotinic antagonism of methadone metabolite EMDP (there were a study I couldnt find but google scholar "nicotine methadone cholinergic). I believe that metabolite is also an NMDA antagonist (as most nicotinic channel blockers are)..Interesting though it is also an anxiolytic and antidepressant.. oh here the paper: Anxiolytic- and Antidepressant-like Effects of the Methadone Metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681651/

 

[Skorpio]

I believe that metabolite is also an NMDA antagonist (as most nicotinic channel blockers are)..

Do you have a source for this? Even a wiki page with affinities would suffice.

 

[polymath]

Methadone has a pretty "dirty" pharmacology. In addition to opioid, nmda, monoamines.. its major metabolite (2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline, EMDP)
is actually a potent nicotinic cholinergic antagonist (more potent than the gold standard mecamylamine. That's why smokers on methadone double their cigarette smoking to counteract nicotinic antagonism of methadone metabolite EMDP (there were a study I couldnt find but google scholar "nicotine methadone cholinergic).

That's a quite bad thing, as it makes aging methadone patients lose their health more quickly and that can be explained by anti-drug warriors by saying it's "deterioration caused by the methadone".

 

[dopamimetic]

Does prolonged nicotinergic antagonism produce changes which irreversibly accumulate over time or is it reversible upon cessation of the agent? Would nicotine offer a certain degree of protection (from a health point of view of course not administered by smoking but let's put that beside for now)?

I thought of the main issue about methadone being hormone suppression as quite a few long term, higher dose substituted individuals indeed don't make an overly healthy impression. And/or of being from circumstances of street drug addiction, IV use, malnourishment, maybe hepatitis in some etc but this is just based off impressions from the local addiction clinic. As thanks god they are pretty relaxed and give me the pills for 1-4 weeks I don't spend much time there and the ppl usually arent too pleased if some stranger asks intimate details about addiction.
But if course I might be wrong or it's both.

I remember a thread here that muscarinic anticholinerges are bad in the long run and increase the risk for dementia too. Guess this is relevant when thinking about the use of paroxetine or tricyclics for longer time.

But also that nAchR upregulate readily and quickly, e.g. memantine has some initial brain fog from alpha7 antagonism which lifts after few days.
These alpha7 antags do make nicotine less effective for me but don't remember to notice any difference here when I was on methadone.

And it's somehow stupid that substitution is limited to methadone, buprenorphine and in a few countries morphine. They should be able to prescribe anything which improves the life of an individual.

 

[polymath]

Nicotine receptors are a bit unusual in that both an antagonist and prolonged activation are able to block them. That's why both nicotine agonists and tubocurarin-like compounds cause muscle weakness, both effects block the neuromuscular junction after a while. It's also why the first cigarette in the morning makes a smoker feel dizzy but those later during the day have a different kind of effect. I think some publication ages ago claimed that the nicotine receptor blocker biperiden actually relieves tobacco withdrawal symptoms instead of precipitating them. That must have something to do with the same effect.

 

[paracelsius]

Do you have a source for this? Even a wiki page with affinities would suffice.

No I dont think this has been done (testing NMDAr antagonism of methadone metabolites EDMP and/or EDDP). The reason I said I believe EDMP is also an NMDA antagonist is that most nicotinic cholinergic channel blockers (especially alfa3beta4 selective) are also NMDA channel blockers (dextromethorphan, bupropion, ibogaine, mecamylamine, memantine, amantadine...etc). Not the other way around tho! Very different molecules but they all share this in common (nicotinic + NMDA channel blockers). So being one of the most potent a3b4-nAChR channel blocker reported, I'd expect it to also be a potent NMDAr antagonist.. but no I dont a have reference.. just a theory (would be nice to test that with pure EDMP)

Nicotine receptors are a bit unusual in that both an antagonist and prolonged activation are able to block them. That's why both nicotine agonists and tubocurarin-like compounds cause muscle weakness, both effects block the neuromuscular junction after a while. It's also why the first cigarette in the morning makes a smoker feel dizzy but those later during the day have a different kind of effect. I think some publication ages ago claimed that the nicotine receptor blocker biperiden actually relieves tobacco withdrawal symptoms instead of precipitating them. That must have something to do with the same effect.

The reason nicotinic agonists behave as "antagonist" is that activation of nicotinic cholinergic receptors leads very quickly to desensitation (downregulation). The more you activate them, the less receptor the brain/body makes availaible so as to keep cholinergic signalling balanced. The end result of activation is less receptor available -> less cholinergic signalling sometimes lower to baseline. So the overall effect over time is the same as that of an antagonist (I guess you can say agonists are also indirect antagonists!!) that's why it is pretty hard to develop pure nicotinic agonists as drugs : they may work in the beginning but you quickly end up with the exact opposite of what you are trying to do in the first place: antagonism instead of activation!.. weird how the brain works

 

[dopamimetic]

that most nicotinic cholinergic channel blockers (especially alfa3beta4 selective) are also NMDA channel blockers (dextromethorphan, bupropion

Sorry to keep asking, but do you know for sure about bupropion? I was searching about it but only found some vague info about bupropion reducing glutamatergic activity but nothing about the how or how much.
Bupropion for sure interacts with DXM, yet unpredictably so and has been attributed to enzyme inhibition but it doesnt explain enough. Once when using an acute dose of maybe 300mg DXM while on bupro 150mg XR + venlafaxine 150mg, nothing of the usual dissociation but got a strange but probably serotonin mediated, slightly psychedelic experience (like only DXM but nothing converted to DXO - repeatedly combined with venla and it alone doesn't change much at all).
Much later, my second try of bupro but w/o venla (think again 150mg but might have been 300), catched a cold and took 50mg DXM HBr retard in morning and evening - this time much the opposite, like it made DXO to build up. Slowly increasing, heavy 'stoned' type of dissociation, usually I wouldn't get dissociated from just 100mg HBr, let alone as retard. Remember that more than once I kind of felt to 'nod' not completely unlike opioids but instead of tiredness it was a feeling of dissociation, as if I was near an anesthetic dose but usually memory is inhibited at such levels.
With time this faded away, the strong combined NRI became more and more intense (heavily speedy yet no insomnia), worringly increased tinnitus and restlessness made me stop the DXM. Besides this, it was a nice experience and despite my usual sensibility to NE, no anxiety at all. Might make an interesting combo with memantine.

 

[paracelsius]

Sorry to keep asking, but do you know for sure about bupropion? I was searching about it but only found some vague info about bupropion reducing glutamatergic activity but nothing about the how or how much..

BP is a nicotinic cholinergic antagonist selective for a3b4-nAChR subtypes. The same receptor subtype involved in Ibogaine's "psychedelic" effect..not really "psychedelic" in the classical sense but "oneiorogenic" with dreamlike visuals mediated (mostly) by antagonism of a3b4 in the pineal gland but not by 5-HT2a activation of classical pyschedelics..

...the interaction of bupropion with (−)-ibogaine sites on hα3β4 AChRs is tested by [3H]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized hα3β4 AChRs with 2-fold higher affinity than at resting receptors, suggesting that these compounds share the same binding sites..ref: "Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903430/

...There is emerging evidence that BP inhibits, in the low to intermediate micromolar range, various nicotinic acetylcholine receptors (AChRs) expressed in different neuronal pathways. The BP selectivity for different AChRs follows the sequence: α3- > α4- ~ α1- > α7-containing AChRs. This receptor blockade may contribute to its dual therapeutic activity as either an antidepressant or anti-nicotinic drug..ref: "Interaction of nicotinic receptors with bupropion: "Structural, functional, and pre-clinical perspectives"..ref

Now, Ibogaine and its O-demethylated metabolite noribogaine are NMDA antagonists in addition to a3b4 antagonism..what I am saying is most a3b4 antagonists like Ibogaine, Methadone, EDDP, EMDP, DXM..etc are also NMDA antagonists (the two channels seem to be homologous)..The question is their relative affinity. Do BP doses that are nicotinic and/or monoaminergic are also glutamatergic? I don't know. For Ibogaine, doses that activate simultaneously both nicotinic, monoaminergic, neurotrophic and glutamergic are within the same range so it is hard to pinpoint the specific mechanism responsible for its effects in this case. DXM affinity for nicotinic receptors is lower than its NMDA antagonism so much of its effect is glutamatergic and not cholinergic. and so is (S)-methadone..etc "The Effect is in the dose"

..Might make an interesting combo with memantine..

... the combination BP/DXM is being developed as a fast-acting AD alternative to esktamine:

Dextromethorphan/Bupropion: A Novel Oral NMDA (N-methyl-d-aspartate) Receptor Antagonist with Multimodal Activity..ref

My guess memantine/BP would probably be better as the dissociative dose needed might be lower than either drug alone..If I was them, I would go with DXO/BP instead! something like 100mg 1:1 w/w DXO-HBr/BP.

But I don't get why the combination DXM/BP may be superior to esketamine, DXO or to BP alone tho!. For one, I dont think it has anything to do with drug-drug interactions : DXM metabolism is mostly via O-demethylation to DXO while BP is C-hydroxylation to hydroxy-PB metabolites.. totally different enzymes system!!).but I guess they have a patent on that combo so they can charge lots of $$$$$$