Dissociative (PCP) Mania - Mechanism?

[dopamimetic]

When thinking about the dissociatives in general, but especially those that are more stimulating (and seem to induce psychosis in certain predisposed individuals, independently if they have had psychotic episodes before or not) like PCP, 3-MeO-PCP and possibly the diarylethylamines like ephenidine, a really remarkable feature is that they are capable of switching one to, or even inducing, a maniac state of mind. Unlike any other stimulants, this energy seems to come out of nowhere from times to times, one will not have to pay the bill afterwards in many cases, at least not as the amphetamines would make one to do. It's certainly nothing to rush into, and requires a great deal of self control and care, but at least for me as an usually chronically depressed / dysthymic individual this dissociative-induced hypomanic bliss is really estimable. Things like the enormously accelerated information processing ability (doesn't mean I make less mistakes at all, but not more either, just the overall efficacy is dramatically increased) that requires next to no mental effort sometimes and doesn't have this cold, mechanical hyper-focused feeling of e.g. Ritalin seem to confirm that it's not about delusional thinking, but really alternated brain activity.

I'm also needing much less sleep. Finally waking up fully refreshed, confident and motivationally awake again after 7-8 hours of sleep instead of being tired all day long after 10h or so.

Think this has sort of been overlooked because it isn't anything the 'average' human should do, but it's really and deeply relieving for some therapy resistant depressed ones.
Would be very interested too in what this means in regards to MRI activity and especially the speculated NMDA antagonist neurotoxicity etc. - I think prolonged mania can be neurotoxic on it's own, independent of being drug-induced or not. So maybe as long as one maintains a healthy, not-too-manic state, things would just normalise? (Hope dies last, as always )

The PCP Psychosis: Prolonged Intoxication or Drug-Precipitated Functional Illness?

The suggested mechanisms of toxicity from ketamine, which might apply here too - cholinergic overexcitaton and NADPH oxidase-originating reactive oxygen species as far as I know - are interesting for sure because this might implicate that one could avoid a great deal of it ... maybe while leaving the mood-brightening, energising properties of the NMDA antagonists intact?

Funny anecdote about PCP:

Because it made laboratory animals so "serene" that one could put one's hand in their mouths with impunity, the drug was named "Sernyl"®.

 

[cpuller]

Happens to me when taking small doses of MXE and I think it happens when the dissociative effects wear off. After that I have a dopaminergic push that makes it possible for me to read all night without problems (usually novels nothing dense)
It feels a lot more natural than a amphetamine rush more like what you do is really satisfying.

 

[dopamimetic]

This is exactly the phenomenon I mean! Used to think of it being dopaminergic in origin too, but as you say, it is very distinct overall and feels much more natural (also somewhat more creative or accompanied with cognitive flexibility vs. the rigidity and hyper-focus of straight stimulants and also somewhat 5-HT-ish if you ask me). All dissociatives seem to share that afterglow but everyone has some individual feelings to it. Ketamine is a bit numbing and straight stimulatory, MXE has this opioid (probably confirmed through the 3-HO-2'-OxO-PCE metabolite) and serotonergic thing to it, with some bits of being cozy lazy and DXM maybe has the most pronounced 'antidepressant-ish' feeling. 3-MeO-PCP is straight on mania-inducing, that one needs much more care than the others but it gives the strongest boost in energy also. Could be the most toxic / over-excitatory one too.

It requires sort of becoming used to the dissociative effects, at first the memory disturbances are too strong but interestingly this fades away somewhat quickly at least for me and isn't completely about tolerance as one would expect - then I'm readily able to study complex matter on this effect, and what I learn tends to last more or less. Nice side effect is that thinking about fascinating things on dissociatives tends to be euphoric and motivating... Think there are bits of memory impairment but on the other side overall accelerated speed of cognition and very pronounced increased flexibility, better visualisation of complex things and maybe a bit of 'imagined synesthesia' that is real and not just thinking of being smarter as it tends to happen on amphetamine-like substances.

Funny that I seem to be much better in foreign languages in this mode too. It's really good to learn creative things, more nootropic for me than any of the racetams I've tried

I'm always supplementing with N-acetylcysteine when using dissociatives for now as there seems to be evidence for increased oxidative stress being a key reason for neurotoxicity from them and the NAC doing a good job in avoiding that - can't say for sure yet, but think it has the tendency to smoothen things out a bit towards the end of the experiences.

 

[polymath]

I know a guy who's been diagnosed with bipolar and he got his first manic episode last christmas after abusing DXM heavily for a couple of months. I personally just feel depressed the day after robotripping.

 

[dopamimetic]

Have you ever tried low-dose DXM (100-250mg's perhaps)? There are multiple possibilities - maybe it just hits something that modifies mood and it can go the one or other way, but I think it's more dependent on the individual and probably on the dosage used. High dosages of dissociatives tend to have a dysphoric side to me too, this happened on DXM as well as on MXE and even made me to throw my stash away once because of overwhelming sadness that came straight out of nowhere after the all-surrounding euphoria subsided :/ so it's a hit-or-miss thing but for me it's really dosage dependent and the lower dosages have a true potential that nothing else is able to compete with.. from time to time I'm really amazed about how easily NMDA antagonism is able to unlock hidden cognitive abilities in me, that I really wouldn't be able to unleash without the aid of drugs. And while there's indeed something about memory disruption, sometimes I forget about the exact words I've read or written etc. but the comprehension of abstract concepts, the core of what I've learned, remains. This happens on a level below the conscious language-based thinking and it's really interesting in regards to foreign languages - when sober, I have this heavily word-/language based thinking that makes is complicated to dive deeply into another language or something. In the dissoverse, there's no more need for words ... things just flow freely ... it's not really explainable and might easily be frightening to people who are new to that experience, but it's real and truly estimable. More common but nice too, the concept of 'fear' is somewhat alien to the dissoverse. It's more about trust and positiveness.

The potential to induce mania seems to be very real. Was this full-blown mania that required medication or can it be controlled if one knows what to expect? I don't get (hypo)manic episodes without dissociatives (or maybe paroxetine once) but think it comes somewhat close. If someone's not expecting this effect, it can easily go out of control. But for those like me who use to be depressed all the time, it's really unique.

 

[sekio]

stimulatory action (Dopamine release) + dissociation + lack of paralysis = people act like morons and do dumb things with no memory of it.

this happened to me enough, I would know.

 

[dopamimetic]

It's definitely more than just that.

I've been down the depressive spiral again the last days because I ran out of expensive ketamine and MXE isn't available anymore (thanks, EU and roflcoptr media) with only realising half of it. Every day it got a bit worse. Now I took just 2-3mg of 3-MeO-PCP and ... voila. That energy, motivation, drive is there again. Dopaminergics don't do the trick.

Would be really interested about what's going on in my brain. It definitely is not just tolerance or withdrawal but real mood swings and the arylcyclohexylamines are able to hit the switch, over whatever magical mechanism.

PCP is somewhat cold pushy maniac while MXE had this cozy warmth. Maybe it's about PCP x PCE x PCM? Would make an interesting assay.

 

[Solipsis]

I've recently posted a thread here in NSP (dont have the link handy, am on mobile) questioning the "secondary" effects of potent NMDA antagonists.

The reason is/was that the dopaminergic action as primary pharmacology does not appear to be supported by data on compounds like PCP and 3-MeO-PCP.

Either I missed something and that is false, or I would suggest that we need alternative explanations for the mania and other "positive" (in schizo/ psychiatric terms) symptomatic effects.

If sekio is right perhaps much less dopaminergic activity is needed than under normal circumstances.. given the vacuum NMDAR mediated dissociation provides.
Should we look at the rather meager DRI action as relative instead of relative or qualitative? Meaning: maybe only a little DA push is needed to flip out when dissociated because controlling circuits are inhibited because of the dissociation?

Along similar lines: perhaps our natural primal urges and thoughts are enough to become manic when left unchecked... Compare it to strong GABAergics mediated blackouts where loss of control and inhibitions can be enough for worrisome behavior.

Loss of function/ hyperfunction are two sides of the same medal because of the role of inhibitionsn correct?

Is dopaminergic involvement proven and sound? Do antidopaminergics work to counter dissociative mania?

Is this kind of theory satisfactory pharmacologically/ neurologically?

 

[serotonin2A]

I've recently posted a thread here in NSP (dont have the link handy, am on mobile) questioning the "secondary" effects of potent NMDA antagonists.

The reason is/was that the dopaminergic action as primary pharmacology does not appear to be supported by data on compounds like PCP and 3-MeO-PCP.

Either I missed something and that is false, or I would suggest that we need alternative explanations for the mania and other "positive" (in schizo/ psychiatric terms) symptomatic effects.

If sekio is right perhaps much less dopaminergic activity is needed than under normal circumstances.. given the vacuum NMDAR mediated dissociation provides.
Should we look at the rather meager DRI action as relative instead of relative or qualitative? Meaning: maybe only a little DA push is needed to flip out when dissociated because controlling circuits are inhibited because of the dissociation?

Along similar lines: perhaps our natural primal urges and thoughts are enough to become manic when left unchecked... Compare it to strong GABAergics mediated blackouts where loss of control and inhibitions can be enough for worrisome behavior.

Loss of function/ hyperfunction are two sides of the same medal because of the role of inhibitionsn correct?

Is dopaminergic involvement proven and sound? Do antidopaminergics work to counter dissociative mania?

Is this kind of theory satisfactory pharmacologically/ neurologically?

What is the rationale for saying that PCP doesn't interact with DAT? The interaction is well characterized. The initial binding studies with PCP and analogs like TCP showed that they bound to two sites, referred to as PCP Site 1 and PCP Site 2. PCP Site 1 was eventually shown to be the classical PCP binding site in the NMDA receptor channel. Site 2 was shown to be DAT. That work is what led to the development of BTCP as a selective DAT inhibitor. If you don't believe that PCP binds to DAT, then how would you explain the existance of BTCP? Is it just a coincidence that BTCP has high affinity for DAT?

Is this based on Bryan Roth's report in PLOS One? Even they acknowledged that their data with regard to DAT was probably caused by their choice of radioligand. When study after study shows something, and then a single subsequent study finds something different, you shouldn't immediately discount all previous work.

 

[Solipsis]

Yes actually it was concluded from the PLOS One article, thanks for the elucidation.

I wish someone had clarified that sooner, unfortunately there was noone paying attention and contributing discussion like you are.

And apparently D2 antagonists do work for PCP psychosis, now that I am checking it from a regular desktop. Heh ok.

Sekio mentioned DA release though, that's not right is it?

 

[sekio]

It's probably some combination of NMDA-antagonist induced DA release, PCP-caused DA uptake inhibition (a la BTCP), and direct D2 agonism (a la ketamine)

I have, uh, first hand experience that the primary treatment of PCP mania is usually (but of course, dependent on your exact medical system in the locality you're recieving treatment) IV haloperidol and possibly lorazepam, and e.g. an anticholinergic like benztropine to help deal with the EPS. Also, four point restraints, activated charcoal per os, etc, the whole fucking sideshow.

The anticholinergic and benzodiazepine are strongly contraindicated in my mind though: the benzo increases disinhibited behaviour (anger, lashing out) and the anticholinergic is not only really unpleasant but doesn't do shit but make everything worse (lower gastric motility, haldol is already an anticholinergic?)

Also, re: why ketamine and MXE are different from PCP/MK801/diphenidine: I suspect ion channel involvement. (he says, waving his hands in the air.) Clearly they are more complex than just lower affinity NMDA antagonists.

 

[dopamimetic]

It is real. Finally catched a psychotic break. Fuck. I know, I did it to myself. Don't know what to do now, have destroyed my life. Funny that I'm still not suicidal or something like that, currently I'm pretty ok for all the shit that's going on, the antidepressant afterglow is real for sure. Much less social anxiety.

Well, have to stay away from drugs now. Fuck again. Don't want that depressed, negative, anxious old self back.. I really hope for riluzole but they won't prescribe it to me because it's too little known. Even memantine is not accepted, but it didn't work as expected anyways.. currently I get dosed up on valproate which interestingly I don't really notice anything from at 600mg/d but maybe it is anxiolytic. Maybe it does nothing.

Thing is - I still, or even more, think that the NADPH oxidase is the key. Things went bad quickly when I forgot to strictly take at least 3x 600mg of N-acetylcysteine per day, which probably alleviates the oxidative stress and neurotoxic / schizophrenia-like changes from dissociatives.

Problem - it also takes a good part of the dissociation away. This led to dosing higher (and to combinations) without achieving what I wanted, but getting into a rather fucked up state.
The upside is - the antidepressant, mood-elevating, stimulating and (unfortunately, only partially) anxiolytic components remain without the dissociative madness.

And probably the shit would not have happened with ketamine or MXE, I've used them enough to say that. 3-MeO-PCP is just too crazy. About DXM I'm really unsure now, all the papers make it look pretty safe and safer than e.g. ketamine because it inhibits NADPH oxidase and 3-hydroxymorphinan is anticonvulsive and limits glutamate release, but it has also a very dirty toxic side to it and especially dextrorphan is a bit too close to ephenidine by structure. Could be that this is genetically dependent and I have bad luck, or that they are unsafe in General. Don't know.

But there is a reason for the quinidine in the Nuedexta med for pseudobulbar affect... it not only potentiates the DXM but prevents too much DXO forming (or any at all?).

 

[Solipsis]

Very sorry to hear that such disaster has struck, dopamimetic - I read what happened in the 3meo PD thread..

Hope that you survive this well and are able to adapt, find a place of healing, rest and peace quickly. And I implore you to consider that while dissociatives may have positive applications it is often very risky as is repeatedly demonstrated and the cure must not be worse than the disease.

I really appreciate your contributions but would rather see you taking the best of care of yourself if the alternative is that you are thinking too feverishly about these pharma neuro theories. But who am I to tell you what to do, right? Just take care.

Also, re: sekio thanks a lot ^^

 

[dopamimetic]

Thanks for your reply.. yeah maybe I have been obsessed a bit by these dissociatives, they were just that magical cure but there was a catch. I made mistakes but all would not have to happen if we didn't have this illogical war on drugs, with access to prescription pure ketamine or mxe such disaster wouldn't occur. Fuck the ignorance. I don't even know what role the administration of chlorprothixene played as this drug made me go psychotic without and before any other serious drugs. Weird genetics.

I'm currently in an open social care facility of which I'm happy that such one exists thinking of the nightmare of psychiatric wards.. time will heal.

But well.. I still and nevertheless believe in the therapeutic potential of dissociatives but some are just too strong and..everything said..

 

[Bad Robot]

At least your not on antipyscotics dopamimetic, its hard when the drugs turn on you, I was a weed nerd and have had to try and turn my back after over indulging in my own supply, I was put on invega and sodium valporate when I had a funny turn, you can bouce back from this, the break might do you good and like you said, at least your not in a pysch ward, that is a tough place to come back from, take it easy.

 

[dopamimetic]

Yeah ... but I'm currently on sodium valproate too, and I'm very surprised by it's effects - at least for me it certainly is not anti-(hypo)manic. I'm currently sleeping a mere 6 hours per night despite taking 30mg of mirtazapine at bedtime! I can't say it for sure yet as this is just day 5 of 600mg's of valproate, but this stuff definitely seems to have some disinhibiting / stimulatory side to it. Well, not that I don't estimate this, it's just kinda surprising. If this was a double-blind trial, I'd easily think to be on >20mg's of methylphenidate. Weird. Nice.

And while I know that not everyone shares this opinion, I am really with you on that I think that antipsychotics are (or can be) bad. They are called major tranquilizers but this is just plainly wrong - benzos etc. are the real major tranquilizers, but dopamine antagonism doesn't tranquilize anything per se... as I've written in that other thread about them, I am convinced that dopamine has a modulatory role (there are publications about this too, dopamine is a protecting factor against glutamatergic over excitability for example) and while these neuroleptics seem to work for a good part of the people, there are also quite some who have nasty adverse effects and some doctors tend to blatantly ignore them / write the people off as schizophrenic when they really aren't. Somehow I think that dopamine antagonists are one of the drugs with the worst effects : side effects ratio.

--

I don't know really but in retrospective I can't avoid to feel that DXM has a very dark edge to it. The dextrorphan molecule is strikingly similar to ephenidine and all these after-MXE dissociatives (MXP, ephe-/diphenidine) seem to be a major step backwards, maybe not for everyone but for some ... I know of the horror stories about PCP and there will be some truth behind, but it seems to be generally accepted that these stories were exacerbated and with e.g. ketamine such things just don't happen (but ketamine is more of an anesthetic too).. it's interesting to read that some find ephenidine to be 'less dark' than arylcyclohexylamines - there's still so much to learn about genetics, the glutamate system etc.

Once again, fuck the war on drugs. It's a war on people, on your children, your fellows, and it can't be won. It's a disastrous money and people burning self-sustaining hell.

 

[Bad Robot]

The blocking of dopamine is just wrong, I'm still recovering from an antipychotic depo they gave me in hospital, its made me even iller than I was before I went in voluntary for smoking too much cannabis, can't say I could tell what the valporate did for me, I got a couple of injections of invega for my troubles. At least your able to keep peeps updated from the retreat, its going to be tough giving up your hobby I think, keep calm in there and don't be asking for your own drug cocktail of choice, you can bounce back from this.

 

[dopamimetic]

Have to take great care of course ... and I will do that, try to stay away from any drugs including alcohol and also (foremost) dopamine antagonists. Glad when things calm out.

But I'm still and nevertheless convinced that especially MXE has great therapeutic potential. Curiously the reactions seem to vary very much between individuals, some have glowing reactions to ketamine, others like DXM or even the ephenidine/diphenidines ... this is very probably genetically predisposed, maybe NMDA polymorphism? I'm not sure if the 3-MeO-PCP is to blame, or at least to blame alone, because I have been thinking that 'supplementing' with low (3x 22mg/d) dose DXM inhibits the NADPH oxidase and thus the neurotoxic potential and putative schizophrenia-like brain changes. This has definitely been wrong, at least for me. I've used MXE quite heavily without any other supplements or drugs and it never felt as toxic by far as DXM alone now.

I can't say whether just the metabolite dextrorphan built up too much and the NADPH theory was right or not, but it looks also like the supplementing with N-acetylcysteine did not help but might rather have contributed to the psychosis. I can't prove anything, this is just my gut feeling now, but there's a good chance that it tends in that direction.

What makes me just wondering - where was the flaw in all that? Is NAC maybe not for everyone? Is dextrorphan more toxic than I thought (have to say here that I 'ab'used DXM in my adolescence over extended periods of time without serious consequences besides some bad trips, but no psychosis... but I've been on venlafaxine then too, which is moderately-strong in inhibiting the CYP2D6 and thus leads to potentially greatly reduced levels of DXO.. not to speak of the risk of serotonin syndrome, of which I didn't know back then, of course). Other thing is that DXM, above a certain dosage threshold, maybe 350mg's or so, triggered severe panic attacks up to two days after the dosing, so this could support the theory that DXO is really nothing to mess with. There's also someone on erowid who synthesized pure DXO and has had very negative experiences with it, long lasting after effects and next to no dissociative-like effects.

I'm doing other things now, have to take care of myself of course, but want to share my thoughts and impressions with you ... maybe it's of help for the one or other who is interested in the same things and could avoid rushing into problems.. or just speculate about the origins.

Peace,
dopa

 

[Solipsis]

I hope this appropriate to ask here, but I wonder what NSPers would say is the predicted long term effect of taking low-moderate supplemental doses of 3-MeO-PCP and then discontinuing? Disregarding what we observe, so completely theoretical as if it were a novel drug...
Just break it down in the NMDA antagonism, DRI action and sigma action (the latter probably being hard to say much about)? So from these actions you get withdrawals from each? Not like the acute effects after a fully trippy dose... but therapeutic doses.

 

[dopamimetic]

Interesting question, yes ... theoretically, one would have to expect a dopaminergic / stimulant withdrawal - lethargy, some depression and maybe anxiety / insomnia or oversleeping, but the NMDA antagonism seems to compensate for that to some extent while causing a glutamatergic rebound on it's own (which is a bit curious thinking of that it - at least in the case of ketamine - is said to actually increase glutamate trafficking, so that a rebound shouldn't occur or consist more of hypo-glutamate). Sigma seems to be really unknown at least afaik.. agonism is linked to glutamate release and/or dopamine release if I'm right, but there seems to be something unique to sigma receptors ...

But thinking of the greatly varying experiences people have from the same dissociatives in the same dosages - it might depend on genetics. Others will probably be able to give better answers ... I really thought to be into something with the NADPH oxidase seeing all the papers about ketamine-induced oxidative stress, loss of GABAergic interneurons and such, and for me it has proven to be wrong. MXE alone was much, much less hard than the combo with N-acetylcysteine, which is opposite to all I've read.