Long-term use of dissociatives

[dopamimetic]

I've read somewhere that with ketamine addicts, there are visible changes / vacuoles on the MRI after using 500mg/d for 6 months or more. Does this generalize to all the NMDA antagonists or might it be special to K? Subjectively the effects of K vs MXE / DXM / O-PCM are remarkably different, with K feeling more ... narcotic and kinda more toxic to me, and afaik it's anaesthetic activity has been found to being not even related to NMDA antagonism.

I'm not looking for a way to judge my use. I'm curious, and of course like to use the safest ones...

 

[clubcard]

Can you empty your message space please?

S

 

[AlphaMethylPhenyl]

Ketamine can ruin your bladder. It's also unhealthy in chronic use brain-wise.

All recreational NMDA antagonists (with the main action being such) are hard on the brain in chronic use.

 

[Vastness]

This question is an interesting one to me also - I don't think there is enough research to answer your question as specifically as you would probably like. But probably the brain-damaging effects (to put it bluntly, no assessment implied as to the permanence of this damage) are probably almost universal to NMDA antagonists, while ketamine itself and arylcyclohexylamines have additional physiological bad stuff going on - specifically bladder and kidney stuff.

You've probably seen this study about Brain damages in ketamine addicts as revealed by magnetic resonance imaging, given it's one of the only ones out there, to my knowledge, but it's an interesting read so I'll link it anyway.

 

[RandomClean3]

I've read somewhere that with ketamine addicts, there are visible changes / vacuoles on the MRI after using 500mg/d for 6 months or more. Does this generalize to all the NMDA antagonists or might it be special to K? Subjectively the effects of K vs MXE / DXM / O-PCM are remarkably different, with K feeling more ... narcotic and kinda more toxic to me, and afaik it's anaesthetic activity has been found to being not even related to NMDA antagonism.

I'm not looking for a way to judge my use. I'm curious, and of course like to use the safest ones...

Applies to all of them, PCP, ketamine, tiletamine, DXM, nitrous, MXE, etc. However, chronic usage is key. Olney's lessions are a result of drug induced vacuolation, however, vacuolation is reversible, and it takes VERY heavy usage for it to cause neurotoxicity. The original study was done on mice and extrapolated to humans. That was a mistake since rats have a much faster brain metabolism, which makes them vulnerable, but experiments on primates failed to cause lesions at equivalent dosages. So my answer is yes, it can happen, and yes, it applies to all NMDA antagonists, however, it's the product of very heavy usage. Remember that ketamine and nitrous oxide are both used in general anesthesia, usually with a benzodiazepine or anticholinergic to prevent possible damage. DXM is given to children. Memantine and amantadine are used for neurodegenerative diseases. A lot of people would be brain damaged if they were immediately neurotoxic, but that's not the case, it requires prolonged blockade of the NMDA receptor, so if you're going to use, do it sparingly. Because of their nature they still can have very bad effects long term, the NMDA receptor needs to be activated for LTP, aka, memories and learning. An ocassional trip won't ruin you, although I would avoid the -phenidines, too potent, too new, too risky. Structurally, ketamine and MXE are VERY similar, though with a much cleaner pharmacology. The one thing I would recomend is not try a PCP/K analogue you don't know, a small change can turn them into amphetamine-like stimulants to powerful opioids, always do the research, always have someone who has tried it before you.

This question is an interesting one to me also - I don't think there is enough research to answer your question as specifically as you would probably like. But probably the brain-damaging effects (to put it bluntly, no assessment implied as to the permanence of this damage) are probably almost universal to NMDA antagonists, while ketamine itself and arylcyclohexylamines have additional physiological bad stuff going on - specifically bladder and kidney stuff.

You've probably seen this study about Brain damages in ketamine addicts as revealed by magnetic resonance imaging, given it's one of the only ones out there, to my knowledge, but it's an interesting read so I'll link it anyway.

The bladder stuff is specific to ketamine, PCP, MXE, TCP, DXM, etc don't have that issue.

 

[Thomas29]

I Am very interested in this as well since I Am coming across my first ever Sealed Bottle of Veterinary Grade Liquid Ketamine, The problem is I have never used the stuff before so I got a lot of research to do on Ketamine before I take the plunge And try out A small dosage. Specifically how frequently could A User take Ketamine without noticing any Bladder issues Like I have Read even using Dextromethorphan every 2 Months has screwed up the magic and they lost it without even abusing it. I don't how it works with Ketamine are the Bladder Damaging Effects A cumulative thing similar to smoking and it causing cancer.


How New is the knowledge of Ketamine causing Bladder problems in Users anyway? I don't mean to hi-jack your Thread OP I thought these are some questions you might be wondering yourself about Ketamine but the Research might not be available.

 

[Vastness]

vacuolation is reversible

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?

Remember that ketamine and nitrous oxide are both used in general anesthesia, usually with a benzodiazepine or anticholinergic to prevent possible damage.

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.

The bladder stuff is specific to ketamine, PCP, MXE, TCP, DXM, etc don't have that issue.

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

 

[RandomClean3]

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

 

[Vastness]

Thank you for taking the time to write such a detailed response!

I wonder if theanine has any effects on the subjective psychedelia, I will give this a try next time I indulge. Obviously all we are really hoping for is to be able to have our cake and eat it too, reducing any potential neurotoxicity without reducing the fun effects.

I guess this goes without saying, but given what you mentioned about the duration required to induce vacuoles in rats, as well as the "K-hole" being the neurological danger zone, so to speak, I guess it stands to reason that shorter, lighter sessions would be a lot safer than heavier "binges" involving multiple hole or close-to-hole doses. Subjectively and anecdotally the latter type of session does feel a lot more damaging, or stupefying at least.

I have used racetams before to quickly re-associate myself if my plans have changed while under the influence of a dissociative, or to kill a lingering unpleasant comedown. I've always wondered if they did indeed reduce dissociative tolerance too, since they seem to have opposite mechanisms of action, but I'm not sure if this has ever been researched either way even though it makes logical sense... are you aware of any research done in this specific area? (The effects of racetams or similar nootropics on dissociative tolerance.)

Unfortunately, just for me personally short acting benzos seem to make me too impulsive, at least xanax (and zolpidem - I know this is technically not a benzo but it is short acting and definitely similar). If I tried taking 2mg alprazolam to round off a K session it's probably a 50/50 chance if I'd actually go to bed or decide to stay up and continue binging, either on K or whatever other drugs I happened to have around... 8) Diazepam at least I seem to be able to get on with fairly well and do use usually to kill the lingering overstimulation that I always get from K after the desirable effects have worn off. It's a shame that I don't seem to be able to be sensible with the shorter acting benzos because on the whole I feel these substances are a lot more "convenient" in some ways, but I just don't seem to be able to trust myself when I'm on them.

 

[RandomClean3]

Racetams as a whole vary somewhat in how they act, and it's not completely understood. Broadly speaking, the are agonists of glutamate receptors. Some are positive allosteric modulators of AMPA, there's also some evidence they act on the NMDAR and they're known for increasing cation intake, all of these effects would counter the effects of NMDA antagonists.
For what I've researched, damage is completely dose dependent, so moderation is key. And moderation being not taking enough to knock out a hippo. As for benzos, diazepam is actually faster acting than alprazolam, it just has a longer half life, but the effects themselves last maybe 8 hours. And in fact I would prefer it since the active metabolites would continue to antagonize the effect of ketamine without being sedated or high. Anticholinergics have the same effect, and benadryl is OTC, so that could be a solution, although I would test it with a small dose before trying anything. I personally like noopept, you can snort a small dose and it hits very quickly in case you need to kill the high.
While xanax and zolpidem probably end the trip as well, you have to consider ketamine is also a stimulant, so while the NMDA aspect may be down, you still have a reuptake inhibitor in your system and if the benzos already make you impulsive, there may be some potentiation of that effect. My benzo tolerance is through the roof so I can't speak of dosages, but maybe trying something more sedative or less euphoric, like flurazepam or oxazepam.

 

[Thomas29]

^ I conquer about the advice of using Valium since after the Effects themselves wear off you still have long acting part of it not effecting you per say but still providing some protection And I also have A wicked High Benzo tolerance so I have no idea either what Dose would be A good idea.

 

[RandomClean3]

^ I conquer about the advice of using Valium since after the Effects themselves wear off you still have long acting part of it not effecting you per say but still providing some protection And I also have A wicked High Benzo tolerance so I have no idea either what Dose would be A good idea.

Same here, after taking 40 mg and not feeling it, like what do you do.... lol