Some news on the NMDA front - snorted memantine is different, but why?

[AlphaMethylPhenyl]

This isn't true, a good friend of mine was a long time IV fentanyl/heroin user, when I introduced him to PCP and analogues he needed very little - 10mg of 3-MeO-PCE was more than enough to produce an effect.

I was the opposite, I'd do huge doses of 3-MeO-PCE but could be satisfied with very small fractions of what my friend would use as a recreational dose.

IMHO dissociatives are everything that opioids should have been. Better euphoriant, safer in OD, withdrawal is much easier, way better painkiller etc.

And several days to a week of effective treatment of depression in select populations.

 

[Skorpio]

Have you plugged meantime? If so how does it compare to oral and nasal?

A question of opinion:

Memantine is described as binding both orthosteric and pore sites on the NMDA receptors (1). The pore site is described as voltage dependant (Mg2+ needs to leave to open the site up, and this only occurs with voltage). This is touted as a big difference between it and pcp site binders. The pcp site also needs the mg2 gone, and seems to exhibit voltage dependency (2).

Do you guys think memantine has a lower affinity/efficacy than classic arylcyclohexylamines, or that the orthosteric sites contribute or that some pharmacokinetic reason causes the difference in subjective effects.

Also if anybody knows more about memantine binding please add.


Sources:

1. Caught in the act: multiple binding sites for memantine pless 2014 structure

2. Interaction of mg2 and phencyclidine in use dependant block of nmda channels 1991 Lerma et al. neuroscience letters

 

[sekio]

And several days to a week of effective treatment of depression in select populations.

That's the cherry on top. Opioids don't improve lives like K does.

 

[dopamimetic]

Memantine is called a low-trapping NMDA antagonist while most recreational ones are high-trapping. While I think to get the picture, maybe somebody more knowledged is able to explain this better. As for affinity, plain dose-effect comparison, I'd think memantine is maybe 1/2 ketamine - given that it accumulates quite a bit in the body and acute dosage of 160mg was pretty dissociative, enough to drift somewhat with eyes closed (nowadays the most easy marker for dissociation to me) yet nowhere a full dissociation - something I never ever reached before anesthetic/toxic levels, in opposition to many. So dunno how in/accurate.

I thought that memantine kinda replaces the Mg though/binds more strongly to the same site than Mg, read that somewhere but might be wrong. That high-trapping ones need the Mg gone is kinda strange as the opposite would make more sense in regard to psychotomimesis/disconnecting from reality? But well then, mem in lower dosages leaves the normal function of the receptors mostly intact while e.g. arylcyclohexylamines are complete blockers.

I'm confused about the tolerancy thing though. Yeah, for sure dissociatives potentiate opioids and to some degree the opposite too. Opioid withdrawal is a short period of increased disso tolerance, also to some degree toe other way round to me. But now, opioids are said to increase NMDA receptor density. Dissociatives too, otherwise they would exhibit negative tolerance(?) like e.g. antidopaminergics. Think in the DXM FAQ they said that NMDA was "too complex" to simply upregulate, somewhere else that it upregulates both with ant/agonism which would make sense in regard to e.g. sarcosine or other weak partial agonists but still, is this true? There a known mechanism behind disso tolerance and re-regulation?

Today impressed again by memantine's ability to deal with withdrawal, especially PAWS which is pretty underrated among docs imho. Which makes another question arise, fuck am I on protracted NMDA antagonist withdrawal all the time with the opioids just worsen it with some symptoms on top? Data suggests not but who really knows? For some certain individuals dissociatives are the very only drugs that create huge craving..

 

[sekio]

For some certain individuals dissociatives are the very only drugs that create huge craving..

Cravings yes, in that I find the experience curiously repeatable, but physical withdrawals, not in my experience.

 

[dopamimetic]

It's not physical as in opioids, but maybe comparable to BZDs/ethanol+stim in that especially high dosages cause a rebound of an inbalance of excitation/inhibition and kinda depressive hangover also from low-ish doses, I know it's probably strange that I even with high tolerance continue to feel very little doses like maybe 10mg DCK but for me it's that way. Note there is probably some interference with opioids, these things were much less pronounced before I made the mistake to try to settle on them cause of legal issues, thought it was tolerance and might indeed be part but guess its more the opioids. Might be that I hit the neurotoxic range, never did crazy high doses but certainly was for months over the equivalent to the 0.5g ket/day that caused visible changes in one paper.

Still feels strange that all most of the problems began with the opioids. Wonder if they will go with them too. Anything more specific known about the interactions of opioids with dissociatives - not the usual other way round? Certainly the tolerance pattern changed but I can't decouple things from each other.

For sure they, and I mean all of those I have tried incl memantine, so it's not the K effect but specific to NMDA, change my personality. It's more than just mania, might be a relevant part of the experience but what really matters to me is probably about tension, stress, whatever. They turn my sober state of introverted apathic tension into positive usable energy, really it's not magic but the most impressive effect any medicine ever had to me and remains to be. So part of withdrawal is me not supporting my sober natural state

 

[Drag2019]

I'm trying to say that there is a lot more to learn about this subject than we think we know about this. Things about NMDA that is. One can only make an educated guess about things like this right now. I think it's possible that there is something to what you're saying and a connection between the 2 in some way for lack of a better way to say it.

Edit: Forgot to add Quote Reply

 

[dopamimetic]

Have you plugged meantime? If so how does it compare to oral and nasal?

Only thing I ever plugged was morphine (not worth it imho even tho it's more potent than nasally but comes on more slowly) and some K variant that I shouldnt have as it was impure and caused much more strong irritation than to the nasal tissue which made me stop using this route).

As the memantine was pure and still a minor-medium irritant you'd need to try a small qty first. Guess it makes no big difference as I need to relativate my initial postings, the noted differencies are more a matter of dosage and my chronic bad habit of eyeballing substances and underestimating amounts (police sees the posession of a mg scale as evidence, after loosing my 3rd scale I didnt yet buy another one). Maybe its a tad more potent through non-oral routes but you get the same effects orally when taking >60mg/d. People with history of mania probably shouldn't as it's a whole different thing than with 20mg..

Edit:

The persistent activation of NMDARs is also responsible for the neural changes accompanying different variants of neuropathic pain, including nerve injury-induced neuropathy, diabetic neuropathy, chronic inflammatory pain, cancer pain, and post-herpetic pain. In these conditions of persistent pain, mu-opioid receptor (MOR)-activating opioids do not provide efficacious relief (Chapman et al, 1994; Sigtermans et al, 2009). Thus, to treat neuropathic pain in the clinic, opioid doses must be substantially increased beyond those effective against nociceptive pain, and the relief is, in most cases, only partial. Neuropathic pain is characterized by tactile allodynia and hyperalgesia, which remit with drug treatments that block NMDAR function, for example, ketamine, methadone, and memantine (Mizoguchi et al, 2009).

This sounds somehow a lot like part of my problems. Could excessive use of NMDA antagonists lead to re-regulations that (when off them) mimic neuropathic pain? Or is that very unlikely?

 

[dopamimetic]

And so on..

The observation that MOR-acting opioids are of limited efficacy in neuropathic pain is supported by pharmacological and molecular studies indicating that morphine analgesia is under negative functional regulation by the NMDAR–neural nitric oxide synthase (nNOS) cascade (Inoue et al, 2003; Rodríguez-Muñoz et al, 2008). However, the relationship between MORs and NMDARs is bidirectional, and tolerance to morphine develops as a consequence of MOR-induced potentiation of NMDAR–calcium and calmodulin-dependent kinase-II (CaMKII) activity (Trujillo, 2002; Garzón et al, 2008). Indeed, MOR-acting opioids regulate glutamate-activated NMDAR currents in different areas of the nervous system, including the thalamus (Narita et al, 2008), nucleus coeruleus (Koyama and Akaike, 2008), brainstem medulla (Chen and Huang, 1991; Kow et al, 2002), and spinal dorsal horn neurons (Rusin and Randic, 1991). Most relevantly, acute opioid administration increases NMDAR function in neurons with opioid receptors (Martin et al, 1997; Przewlocki et al, 1999).

Source.

 

[copium7777]

nicotinic AcH receptor antagonism

I was told that this wasn't significant,, or at least not enough to make it a negative interaction with stuff like benadryl. Doc knew of the antihistamines I'm on when prescribing.

 

[copium7777]

nicotinic AcH receptor antagonism

I was told that this wasn't significant,, or at least not enough to make it a negative interaction with stuff like benadryl. Doc knew of the antihistamines I'm on when prescribing.

 

[Nagelfar]

…Opioids don't improve lives like K does.

My only times using DXM recreationally in any large amount doesn't even include memories: just assault charges against multiple hospital security at once, where I got away, that show up in warrants months later. I was taken-in due to odd behavior against my will, got out on my own single-minded approach to carrying out the will to get away? Apparently.

I'll take addictive experiences I can actually remember rather than public spectacles I have to pay for with memories being locked up to reflect on something I have no recollection of.

I can say because of it that I possess some vague first-hand understanding of the PCP Hulk stereotype, but it wasn't anything I could direct or enjoy during the unfolding of the whole scenario. Would rather have fond memories of living on the streets in the winter without a jacket and feeling warm & fine, than a single foggy frame of me fighting off three uniformed guys trying to restrain me to a room (probably the only moment saved in recall due to the peaking of adrenaline), don't remember how I navigated my way out or away from the building, don't remember my *reason* for wanting to get out or if I even knew why I was there. Just a total lack of individual free agency; taking that stuff was like seeing Artemis naked in the woods and her turning me into a stag, and having my own dogs set upon me. No; would rather spend time with Morpheus.