The dissociative are maybe the most obscure drug class out there (I may be wrong though) - they directly interfere with the deep circuits of our consciousness. I have spent much time in trying to find what's currently known about them and to understand it as far as I could. It's just so infinitely complex. I definitely agree to that they don't follow any "classical" known scheme of tolerance development, but whatever (if I put besides for a moment that I just accepted to be unable to comprehend all the stuff) my conclusion was that it's two mechanisms: 1) the immune system responding to xenobiotic influences, a complex cascade involving things like NADPH oxidase, reactive superoxides, and whatnot and 2) direct learning process. This is true for every drug but maybe much more for such ones that directly alternate the ways we perceive and form memories. Maybe it's just impossible to reset the brain to a dissociative naive state (is this even possible for any drug? For some more than others, perhaps?)
Said that, things are still obscure and interesting.
Dissociatives appear to affect every individual very differently, maybe more so than any other drug class.
For me, they exhibit only incomplete cross tolerance. And the actual tolerance threshold is very dependent on the current state of mind, on a random day a given dose can have next to no effect but on the next day be nearly overwhelming.
Then, different ones behave differently. Ketamine for example has a nearly infinite but predictable tolerance curve for me. Also it is the cleanest one, by far. When tolerance goes up, you begin to feel the secondary effects much more (obviously). DXM for example has strong weird inhibitory effects on the muscles and leaves me nearly unable to walk straight or to speak simple sentences at 350mg or so and above, with the mind being completely clear due to NMDA tolerance. Ketamine interestingly has little (negative) secondary effects for me, it isn't immobilizing at all but behaves like a short-lived stimulant. You could say it behaves somewhat like cocaine below the tolerance threshold (probably it has some DAT inhibiting effects, but this is speculative). MXE becomes a serotonergic with a hint of unpredictable NMDA antagonist buildup, but is nowhere near that nasty O-PCE with its nearly never ending after effects- Would say it is on par with memantine with the duration, maybe even longer. Oh, and ketamine isn't equal to ketamine. One batch gave me these infamous K stomach cramps, all the others not. One batch had slight physical, but strictly physically only, withdrawal after a week-long binge - mainly tremor. All the others not. And so on.
Now thinking of memantine, which also is a NMDA antagonist, things become even more difficult. Wouldn't I know the technical details, I'd say it acts on completely different receptors, yet it becomes clearly dissociative when dosed high enough (but lacks any psychedelic effects, which ketamine lacks for me too, but I can get a deeply relaxing dream-like near-hole on it, just that it isn't psychedelic at all). Pregabalin has acute dissociative-like effects too though, and it doesn't act on NMDA receptors at all. It's even much worse in terms of tolerance.
Back to the disso's. Sorry that I couldn't contribute anything usual, all my loved theses proved to be more or less wrong. There is a load of interesting stuff on PubMed, especially on this "ketamine / PCP model of schizophrenia" about changes resulting from dissociative abuse. Still the question though if this happens to anyone, just a part of the population, of even just a fraction and they just picked those who complained / got negative effects?
I'm very interested on the topic.
