• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

MXE μ opioid binding affinity (or MXE on Methadone)

skabbo

skabbo

Bluelighter
Joined
Nov 17, 2003
Messages
75
As the title implies, I'm wondering how much is known, if indeed anything, about the exact affinity Methoxetamine has for the μ opioid receptor. I've been taking 70mg of Methadone a day for about 5 years, and have the accompanying tolerance. Theoretically, would MXE feel qualitatively "different" than to someone with those receptors.. Receptive?

Since, because of the nature of the substance, much of the info I've read on this subject has been speculative, I guess I'm looking for someone with an opioid tolerance who's tried it. Even more specifically, someone who has tried it both with and without an opioid tolerance (I know, getting rather specific!)

Thanks in advance
 
Last edited:
MXE is primarily a NMDA antagonist and serotonin reuptake inhibitor, it's not an opioid at all.
 
sekio said:
MXE is primarily a NMDA antagonist and serotonin reuptake inhibitor, it's not an opioid at all.
Click to expand...

I realize that it isn't an opioid, but there is lots of speculation about its similarity to 3-OH-PCP, and whether this results in opioid-like effects. Here's a thread that began to touch on it: http://www.bluelight.org/vb/threads/594568-MXE-and-opiate-receptor-affinity

Unfortunately it didn't get as far as to speculate on the effects of tolerance.

Thanks for the reply.

Edit: As I've been searching around more, the main concern seems to be the potentiating effect that NMDA antagonists have on opioids, which I know well from my pre-methadone days mixing Ketamine and Oxycodone. Methadone is of particular concern due to its long half-life. Dose needs to be adjusted accordingly, but I don't see anyone complaining of lessened effects due to opioid tolerance - if anything, the opposite; people who have massive opioid tolerances and wouldn't feel a large shot of H, but experience what they swear feels like about 30mg of tolerance-free Oxycodone when combining MXE with a maintenance opioid.
If anyone else has any experience with the combo, any and all anecdotes are appreciated.
 
Last edited:
While MXE has been screened for and does not bind to opioid receptors at least in vitro, I would swear that NMDA antagonists taken the first times at all have some heavy opioid like feeling to them (DXM as well as MXE, even Memantine had this). Maybe some kind of downstream endorphine activity, or "simulating" that feeling by adjusting dopamine and glutamate and countering norepinephrine and so on, I don't know.

But what really wonders me is that dissociatives are able to, like skabbo said, potentiate opioids as well as to some degree substitute for them - maybe individual or genetically dependent from partial to nearly completely. There are many anecdotal reports of people who got around withdrawal with NMDA antagonists. This worked for me too more than once with AH-7921 as well as with dopaminergic stimulant tolerance, almost magically.

Now with the fact that the racetams and Sunifiram can stop them from being dissociative while keeping their "brain restart" antidepressant effect, could it be that at least for some, a combined NMDA antagonist and Piracetam treatment for some weeks would make a revolutionary treatment for opioid dependence?
 
dopamimetic said:
While MXE has been screened for and does not bind to opioid receptors at least in vitro, I would swear that NMDA antagonists taken the first times at all have some heavy opioid like feeling to them (DXM as well as MXE, even Memantine had this). Maybe some kind of downstream endorphine activity, or "simulating" that feeling by adjusting dopamine and glutamate and countering norepinephrine and so on, I don't know.

But what really wonders me is that dissociatives are able to, like skabbo said, potentiate opioids as well as to some degree substitute for them - maybe individual or genetically dependent from partial to nearly completely. There are many anecdotal reports of people who got around withdrawal with NMDA antagonists. This worked for me too more than once with AH-7921 as well as with dopaminergic stimulant tolerance, almost magically.

Now with the fact that the racetams and Sunifiram can stop them from being dissociative while keeping their "brain restart" antidepressant effect, could it be that at least for some, a combined NMDA antagonist and Piracetam treatment for some weeks would make a revolutionary treatment for opioid dependence?
Click to expand...

Isn't it remarkable that NMDA antagonists completely clear opiate withdrawl?

I would not reccomend combining MXE and any racetams . It can get messy and cause glutamate toxicity, I feel. If you really want to combine the two, noopept + MXE is safer, but does not make any sense. It will completely stop MXE in its tracks. I have used it many , many times to pull people out of dangerous manic NMDA holes from 3-meo-pcp, MXE, etc.
 
lenses said:
Isn't it remarkable that NMDA antagonists completely clear opiate withdrawl?

I would not reccomend combining MXE and any racetams . It can get messy and cause glutamate toxicity, I feel. If you really want to combine the two, noopept + MXE is safer, but does not make any sense. It will completely stop MXE in its tracks. I have used it many , many times to pull people out of dangerous manic NMDA holes from 3-meo-pcp, MXE, etc.
Click to expand...

Why would racetams and NMDA antagonists cause glutamate toxicity? If anything NMDA antagonists should be able to prevent glutaminergic excitotoxicy caused by over stimulation of AMPA receptors. This may not be as much of a problem with noopept but I've heard of many people using small doses of NMDA antagonists in conjunction with sunifiram and other potent nootropics for this very reason.
 
^ When you take an NMDA antagonist, then the rebound reaction of your body is upregulation of NMDA receptors, which glutamate binds to. In short glutamatergic neurotransmission is increased. Racetams are NMDA agonists, so the effect is multiplied.
 
adder said:
^ When you take an NMDA antagonist, then the rebound reaction of your body is upregulation of NMDA receptors, which glutamate binds to. In short glutamatergic neurotransmission is increased. Racetams are NMDA agonists, so the effect is multiplied.
Click to expand...

Right but surely there are some issues with timing. NMDA antagonists with long half-lives (memantine for example) should be going long after the nootropics have worn off.
 
I wasn't really thinking of memantine posting that. It's different from arylcyclohexanamines in that it's an uncompetitive antagonist while arylcyclohexanamines are non-competitive antagonists. For uncompetitive antagonists to bind it's necessary that agonists are bound.

NMDA channels are different from metabotropic receptors like G protein receptors, the upregulation taking place after a (non-competitive) antagonist is in effect is like immediate. Anyway, the main thing here is that the warning was mainly for those using methoxetamine regularly, I guess, because I think it's rather impossible to cause neurotoxicity with a single dose of this drug when you have little or no tolerance. I also suspect that lower doses taken frequently on a regular basis could be more dangerous than a single "high" dose.
 
Last edited:
What is the mechanism for up/downregulation of these receptors? If one is on both an AMPA modulator and an NMDA antagonist at the same time the overall effect on glutamatergic transmission by one should be somewhat balanced out by the other. Simply looking at up/downregulation as a homeostatic mechanism we would expect little to no change in receptor density as a result no? I could see it being an issue if you take a racetam at the tail end of a dissociative high during the rebound phase where the active chemical is being removed from your body but the receptor density is still increased, in this situation I could see the racetam exacerbating any excitotoxicity. I also don't see how a direct NMDA agonist would have much of an effect as I don't see the concentration of the agonist to be the rate limiting step in the triggering of NMDA receptors but rather the receptor density.
 
adder said:
I wasn't really thinking of memantine posting that. It's different from arylcyclohexanamines in that it's an uncompetitive antagonist while arylcyclohexanamines are non-competitive antagonists. For uncompetitive antagonists to bind it's necessary that agonists are bound.
Click to expand...

Arylcyclohexylamines are uncompetitive NMDA antagonists. The binding site for PCP and other arylcyclohexylamines is located within the NMDA channel pore. The binding site is inaccessible unless the channel is opened by glutamate or another orthosteric agonist.
 
It should also be noted that methadone is itself an NMDA antagonist.

NMDA antagonists work wonders for tolerance and dependence, and as was said earlier in the thread, seem to completely cancel out acute opioid withdrawal. Whilst I still require continual pain medication for my knee/hip problems, after a while taking diphenidine, at up to 1-1.5g/day whilst subject to an opioid tolerance sufficient to make required several shots of at least 120mg morphine sulfate (IV) per day, with between 20-30 and 70mg or so of oxy added to said shots, between 3-4xdaily, I was able to quite literally jump straight off the opioids, to 0mg daily, taking just the diphenidine and continue this for a week or so, and then find myself totally free of opioid withdrawal.

Most impressed. Now, my opiate tolerance has crashed through the floor, the doses of morphine/oxy I was formerly taking, if I take the same amount now, its enough with the reduced tolerance courtesy of the NMDA antagonist diphenidine to hit me like a runaway freight train and have me nodding harder than ever. If I combine the two, opiates AND diphenidine, then I actually feel I need to be somewhat careful in my dosing, so as to stay safe.

I'd rate it a life-changing wonder drug in fact, and not feel like that description was approaching being hyperbole, or overselling it in any way.
 
serotonin2A said:
Arylcyclohexylamines are uncompetitive NMDA antagonists. The binding site for PCP and other arylcyclohexylamines is located within the NMDA channel pore. The binding site is inaccessible unless the channel is opened by glutamate or another orthosteric agonist.
Click to expand...

When you look at it that way, then they are. This uncompetitive/non-competitive division needs a major clarification because right now people are using this division for two different things.

Honestly, I'm still not convinced that arylcyclohexanamines effects are solely mediated through NMDA antagonism. Their structure seems so versatile that they could bind to many different sites. Call me a heretic, but that's what I believe.
 
Last edited:
adder said:
Honestly, I'm still not convinced that arylcyclohexanamines effects are solely mediated through NMDA antagonism. Their structure seems so versatile that they could bind to many different sites. Call me a heretic, but that's what I believe.
Click to expand...
I don't think many people would disagree that arylcyclohexylamines can hit other targets besides NMDA. It is very ligand- and dose-dependent. MK-801 is fairly selective for NMDA, whereas PCP can also interact with DAT, SERT, sigma sites, nicotinic channels, etc. However, not all of those interactions happen at concentrations that are physiologically relevant. But it is pretty clear that DAT probably plays a role in the response of humans to PCP.
 
serotonin2A said:
I don't think many people would disagree that arylcyclohexylamines can hit other targets besides NMDA. It is very ligand- and dose-dependent. MK-801 is fairly selective for NMDA, whereas PCP can also interact with DAT, SERT, sigma sites, nicotinic channels, etc. However, not all of those interactions happen at concentrations that are physiologically relevant. But it is pretty clear that DAT probably plays a role in the response of humans to PCP.
Click to expand...

I think DAT affinity is what seperates PCP from something like MXE. PCP has shown that it is much more likely to induce violent psychoses then other NMDA antagonists (granted, pretty much all NMDA dissociatives have a discernable risk of psychotic episodes.)

I think something that is interesting is that, on DXM, and even to an extent memantine, I felt a very strong opioidy like feeling, and Dextromethorphan's affinity for mu-opioid is like 1000x lower than morphine. I don't know about dextrorphan, but i'd expect it to be negligible as well (unlike levorphanol). With memantine this feeling was brief and relatively forgettable once the dissociation kicked in.
 
You must log in or register to reply here.
Top