This is interesting and good to know if true, I must confess I don't really understand what "vacuolation" is however, would you happen to have any references explaining this in more detail, specifically instances where they are shown to be induced and then reversed with time and presumably abstinence?
Also interesting - same question, would you happen to have some references that go into more detail about why the latter classes of substances would prevent damage? Any references to medical sources or studies suggesting that this is indeed the case would also be especially appreciated. Subjectively, co-administration of benzodiazepines with dissociatives in my experience blunts some of the psychedelic effects, although I know this might have zero relevance to how protective they are against dissociative-induced neurological changes.
I'm not sure this is correct, I have seen a few studies suggesting that this is quite possibly an arylcyclohexylamine-specific issue rather than a ketamine specific one... Not sure about PCP or TCP (if that is indeed an ACH) but MXE has been studied, although granted, mostly in rodents - but surely still a reason to be wary given it's similarity to ketamine and corresponding similarity of the effects on the bladder and kidneys:
Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice.
Ketamine Analog Methoxetamine Induced Inflammation and Dysfunction of Bladder in Rats
First, I was too broad regarding bladder and kidney damage. What I meant was arylcyclohexylamines are a very broad group of drugs. In the case of MXE, it has similar toxicity, but it's considerably more potent, so in practice it's treated as a less toxic version of ketamine. The toxicity is by direct contact, it's not systemic, so it's completely dose dependant, and ketamine is relatively a low potency drug when compared to other members of the class. The commonality I see with bladder toxicity is the ketone group, it's right next to an amine and it's metabolized to an alpha-hydroxy ketone and an unsaturated ketone, taking all of them into account there is broad range of reactivity that may be responsable.
Vacuoles are an organelle that consists in a membrane filled with fluid. Most cells can produce them, but you shouldn't see them in neurons. It's reversible because the cell can expell the fluid though exocitosis, but in the case of Olney's lessions, they can be as big as the nucleus, in that case they eventually break, releasing extracellular fluid into the cell, usually resulting in cell death. It's not clear why this happens, but given the NMDAR functions, it makes sense. Stimulating the NMDA receptor results in axonal elongation, so antagonizing it could result in a reversal, which would result in vacuoles. Vacuoles are common in a variety of neurodegenerative disorders, and they can be induced in mice by administration of an NMDA antagonist within 4-8 hours.
I don't think the fact benzodiazepines ruin the trip is not related to their neuroprotective capabilites. In fact benzodiazepines, barbiturates and anticholinergics are known to supress the psychotomimetic (Psychosis-like) effects of ketamine, which likely include visuals, distortions, etc. Simply put, the long-term damage and the desired effects are caused by the same mechanism, so if something prevents the damage, it will likely reduce the desired effects as well.
Even though we're still figuring out how these drugs prevent NMDA antagonist induced neurotoxicity, they have been used together for a while now. Tiletamine is only available with zolazepam. Ketamine is usually used with thiopental, midazolam or propofol. Inhalational anaesthetics like sevoflurane, desflurane, haloethane, etc have also been shown to act as GABA positive allosteric modulators, and since ketamine rarely is enough to maintain anaesthesia, it has always been administered with a neuroprotectant. Glutamate and GABA are the most abundant neurotransmitters, and when you fuck with them there is a much more complex response than just the initial neurotransmitters. If you antagonize the NMDA receptor, calcium can't go through the ion channel, so more glutamate is released by the pre-synaptic neurons to try to remedy this, but the channel will remain closed, while the excess glutamate activates AMPA and Kainate receptors. You can balance the excess glutamate by activating GABA receptors, hence why they stop the neurotoxicity. The alpha-2 adregenic agonists reduce presynaptic release of glutamate. The other two neuroprotectors are different, and not as well understood. The NMDA receptor regulates the M3 receptor (muscarinic), so when NMDAR is antagonized, M3 gets overstimulated. The other 2 glutamate receptors, Kainate and AMPA, are also overstimulated because of excess glutamate. It's believed these effects combined are responsable for the lessions and the psychotomimetic effects. This has been somewhat proven by protection against the neurotoxic effects using antimuscarinics (scopolamine, trihexyphenidyl) as well as AMPA/Kainate antagonists (Theanine, the others are only experimental).
If I used NMDA antagonists, and this is just my opinion, I would take theanine suplements daily, it's cheap, it won't do any bad. I would also have take non-racetam nootropics to fight the oxidative stress (Sulbutiamine is BAE, watch out for libido changes though, specially if you're a man, let's just say your little guy will get happier more often and longer than usual) and I think I would take a racetam, phenylpiracetam and noopept being my favorites, avoiding it before a trip. A racetam can kill a ketamine trip, but I believe they lower each other's tolerance, just don't take them together. And remember to take a choline suplement while on racetams, alpha-GPC is my go to. All of this would be to fight any potential damage and oxidative stress. The final thing I would have, a fast acting benzo and an antimuscarinic (diphenhydramine is easy to get OTC, if you have something else, that's fine) I would keep these to kill any bad trip. When you fall in the K-hole or completely lose it, that's an overdose as far as your brain is concerned, that's the moment you risk neurological damage, so if a trip goes bad, have something to end it. 100 mg Benadryl, 2 mg alprazolam and off to bed.
Some sources, a lot of what I wrote I learned because of my field, so I'll probably miss some, feel free to ask.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1471-4159.2004.02458.x
https://www.neurotransmitter.net/nan.html
https://www.ncbi.nlm.nih.gov/pubmed/26781158
https://www.ncbi.nlm.nih.gov/pubmed/11803444
https://www.grc.com/health/research...eventive effects on cognitive dysfunction.pdf
I think I lost a couple, but I am a nice person, so why would I lie