Racetam - NMDA interactions

[dopamimetic]

So it looks like racetams are kinda of an antagonist to nmda antagonism, they tend to reverse their effects completely which an agonist probably wouldn't do(?) but to be toxic(?).

Just found this:

Subchronic treatment of aged mice with piracetam (500 mg/kg p.o. for 14 days) elevates N-methyl-D-aspartate (NMDA) receptor density by about 20% and normalizes the enhanced affinity of L-glutamate for the NMDA receptor. Since deficits at the level of the NMDA receptor might be one of the mechanisms underlying age-associated cognitive impairment, the effects reported for piracetam may be relevant for the cognition-enhancing properties of this drug.

I never used racetams since they have strong adverse effects to me, it's long since but what I remember is pretty much of what I use NMDA antagonists against, which kinda makes sense. Heavy dysphoric inner tension, "over-association" (thinking about the past, about others, etc) and stuff alike. I used to think that I just don't react good to increased cholinergic transmission as racetams usually are described as cholinergics, some as AMPAkines but never really read about NMDA. Thought too that NMDA antagonism increases the ratio of AMPA to NMDA activity so AMPAkines shouldn't really have bad effects at low dosages (??)

The point about normalizing enhanced affinity (in aged mice) is interesting. If this is true too in some psychiatric conditions, then this would fit with both my good experiences w/dissos and the theory about NMDA subfunction = psychosis ... Are there other substances with this effect?

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Sorry, other thing for which I didn't want to open yet another thread. D-cycloserine, a weak partial NMDA agonist with supposedly anxiolytic effects. The agonist part was enough to scare me away but might this be something like the ultra low dose naltrexone of dissociatives, actively lowering tolerance and increasing effects?? The anxiolytic thing sounds quite plausible.

Ok, this doesn't sound too good:

The effects of pharmacologically manipulating N-methyl-D-aspartate(NMDA)-receptor activity were examined during extinction of an appetitive instrumental response in rats. After reaching acquisition criterion, subjects were treated with the antagonist dizocilpine maleate (MK801; 0.1 mg/kg), the agonist D-cycloserine (3 mg/kg), or vehicle-alone (control) and tested during a non-reinforced (extinction) session. The antagonist decreased the average number of responses occurring during the test session whereas the agonist increased the average number in contrast to controls. The effect on retention performance may be mediated by differential influence on the N-methyl-D-aspartate-dependent synaptic plasticity that occurs during associative learning. In conjunction with other studies, these data suggest that N-methyl-D-aspartate agonism may be an effective intervention for memory dysfunction.

Just that for me I would've thought otherwise. With less NMDA activity I'd press that lever many times more often but guess the rat's situation is a bit different and it tries to escape the heavy stress by getting some reward stimuli and the disso just let 'em drift away ...

 

[Vastness]

There is at least one other substance with this effect, as far as I understand what you are asking - I just found out about this recently myself, honestly because I was (also?) looking into possible ways to reduce tolerance to dissociatives.

Sarcosine is an "NMDAR enhancing agent", apparently also an indirect one rather than a direct agonist, which "increases glycine concentrations in the brain, thus causing increased NMDA receptor activation".

It is being investigated for both schizophrenia and depression, apparently with some promising results.

I just checked the wiki linked there, and it somewhat implies that there could be toxicity issues at a level of around 10mg/kg, which was demonstrated in rats. But most of what I've seen elsewhere recommends taking between 1-2 grams per day (although I admit I haven't myself checked a primary source to verify this). I literally just started taking it today, I took 1 gram a few hours ago - I seem to be fine so far - although it's too early I think for me to conclude if it has any significant effects on my mood or anything, I wouldn't say I've felt anything as such, although I expect it is likely "subtle" like many of the racetams, and benefits are supposed to be more of a long term thing. Again though, honestly, my primary goal is to potentially reverse long term permatolerance to NMDA-antagonist dissociatives, or potentially shorter term undesirable neurological changes.

It's interesting that you react badly to racetams, myself I do take racetams on and off, have done for a while and I actually find most of them quite anxiolytic. I also find dissociatives to be anxiolytic. I'm not sure what to make of this really except that perhaps NMDA dysregulation is not the biggest factor in my own anxiety, and that therefore both classes of substance are effective for different reasons. I haven't taken racetams consistently for quite a while, originally I was very regimented, taking a stack at regular intervals, and I feel I got a lot of benefit from them doing this. Any time since, the effect has never been quite as pronounced, but then I've also never quite replicated the frequency and duration of my earlier experiments... I have also wondered if they could reverse dissociative tolerance, although again I don't feel I've been disciplined enough in my use of them to be confident drawing any conclusions either way, maybe they do somewhat, or maybe they would if I took every day for while... actually I just remembered typing this that the main reason I haven't taken them consistently for a long time is that they all really fuck with my sleep which quickly starts to outweigh any other benefits. Interestingly (perhaps) dissociatives also fuck with my sleep. Some people claim to be able to sleep right after coming down from a dissociative, but I pretty much always get some kind of rebound uncomfortable stimulation which inhibits sleep, I presume this to be NMDA rebound, although it might not be... I think, thinking about it, that the effects of both dissociatives and racetams on my sleep has worsened the more often I've taken them... again though, no clue what conclusions to draw from that.

Anyway, I do plan to be disciplined taking sarcosine, I'll take at least a gram a day for a couple of months and then see where I'm at with dissociative permatolerance and report back.

 

[dopamimetic]

Interesting. Oh yeah for sure dissociatives fuck heavily with sleep, I tend to find most of them to be stimulants on par with amphetamine but qualitatively very different. The effect is relaxed, euphoric - anxiolytic which is a very very rare combination. The rebound from higher dosages (w/ tolerance, e.g. 1g K in 12h), something Ive asked about before here and apparently nobody else gets, is mentally horrible sometimes and really feels toxic w/o some GABAergic including heavy noise on all senses especially visual, auditoral and scattered thoughts.

Racetams Ive only tried briefly, so maybe this needs further investigation - i'd absolutely love it to have them work your way, sth else than nmdais that is anxiolytic without being a sedative. Think I tried aniracetam primarily and sunifiram, aniracetam (or oxi) is indeed an effective antagonist to dissos as Ive thought maybe this makes it more smooth and found them to cancel each other.

Possible that I react badly to low dosages where the anxiolysis doesnt yet set in and higher ones wouldn't be worse in terms of tension.. Know about at least one person with similar experiences, in that racetams are associating.

 

[Vastness]

The rebound from higher dosages (w/ tolerance, e.g. 1g K in 12h), something Ive asked about before here and apparently nobody else gets, is mentally horrible sometimes and really feels toxic w/o some GABAergic including heavy noise on all senses especially visual, auditoral and scattered thoughts.

I get this, definitely. Horrific, I agree. Not all dissos are equivalent though, I'll say - ketamine seems to be particularly bad, for some reason... although there could be some bias here just coz ketamine is the dissociative I have most experience with, so have experienced the widest range of aftereffect severity.

i'd absolutely love it to have them work your way, sth else than nmdais that is anxiolytic without being a sedative. Think I tried aniracetam primarily and sunifiram, aniracetam (or oxi) is indeed an effective antagonist to dissos

I probably should add a caveat - when I found them most effective for anxiety, I had no experience with "real" anxiolytics, ie, benzos, z-drugs, gabapentinoids. No racetam really comes close to a solid dose of any of these. I also do not find all of them anxiolytic. Aniracetam is one of the most anxiolytic racetams, as I recall, closely followed by oxiracetam. Pramiracetam I found highly anxiogenic on the few occasions I tried it. Phenylpiracetam varies, it can be anxiogenic or just somewhat neutral, but I've also found it to be quite anxiolytic, I think purely by virtue of it's (IMO, obvious) dopaminergic effects.

Noopept and phenylpiracetam was my beginner anxiolytic and stimulant combo, back when I was younger and my brain was fresher, whereas now my go-to will be phenibut and armodafinil.

Noopept megadoses I still find to be quite anxiolytic, not in the in your face way of a hard GABA drug like one of the aforementioned but enough to counter bad feelings - such as those induced by dissociatives the day after a heavy session. I also used to find it to have a cumulative effect in lower doses after a few days, I don't know if I still would, I suspect maybe not, but this was more repeatable than megadoses which may be inadvisable to take often for other reasons.

Finally - as far as "disso antagonism", piracetam for me is effectively a dissociative antidote, capable of rapidly bringing me down from close to K-hole to something close to full sobriety - if probably somewhat off still, in actuality.

I haven't experimented with all disso/racetam combos of course (lol, I mean, why would I? Would surely be interesting if someone had though! ) but I have found that not all racetams work for this purpose with all dissos - I attempted to use a large dose of noopept (~50mg) to abort a post-peak uncomfortably weird medium size dose of of 3-HO-PCP (maybe 20-25mg...? Can't remember exactly) and found it did not work really at all, but gave me an uncomfortable feeling of pressure in my head and like my brain was being pulled in different directions... which obviously it was, in a sense, even if pharmacologically, rather than physically... so, caution is advised, I guess.

 

[dopamimetic]

Well yeah now when reading I remember - my worst experience which scared me off the whole group was in fact pramiracetam!! I don't remember what but I read good things about it and it was the one of which I took the most. Noopept had little effects yet as said I didn't try other ones than sunifiram (either 2,5 or full 5mg and it wasn't too bad but pretty speedy, kinda like a robust dose of caffeine).

Interesting to read they have such big differencies. I was most interested in the AMPAkines as I thought that the cognitive benefits I get when catching the exact right dose of the right disso, like almost 1:1 memory of things I just read once or very impressive visualization abilities which greatly helped me with understanding e.g. chemical structures (granted, as I didn't use that knowledge over time it got lost again, as usual but some of the marks I got with stuff learnt on low-dose disso were nice) might be due to increased AMPA activity from the additionally released glutamate (?)

Oh yeah, K and for me O-PCE are among the worst dissos when it comes to rebound. DCK had almost none, followed by 2F-DCK. DXM is absolutely terrible in higher dosages but different, here it's norepinephrine I guess. I suspected the dissos to suppress or mess with sympathic/parasympathic tonus yet I can't really describe why. I really dunno if it was an anticholinergic impurity in certain Chinese batches (light yellow ones, especially bad with slight oily ones) because at some point of my most reckless time I got absolutely weird physical symptoms, tremor, impaired speech etc. while remaining lucid mentally. Was scary for sure if the chemical wouldn't have been so stunningly anxiolytic. This never happened again so I guess it in fact was an impurity. Once I collapsed in a public bathroom after redosing, remember little of it and was able to get up again and arrived home by myself but then I thought I really fucked up my health. Was the same batches. Fuck war on drugs.

Dissociatives remain to be the single most impressive anxiolytics to me, of course GABAergics and certainly opioids are of similar efficacy but they are anti-manic and sedative. Only NMDA antagonism gets you anxiolytic hypomania with full-on energy. I love it though I suspect it fucks me up long-term not unlike amphetamine addiction maybe, loosing interest in healthy things and such, focusing on the positive feelings and such instead of the things giving you them (besides drugs) and am really unsure if I should and can avoid it..

A friend once was prescribed piracetam for post-addiction concentration issues but that was conservative Germany which only give 600mg or something alike which had no effect in her and none in me.

3-HO-PCx are strange. They were the only ones where I really disliked the high, they are said to be opioids but were completely unlike mu opioids to me, similarly unlike mu opioid + DCK. Might well be thus that this influenced your experience, or do you get similar results from them like from other ones?

Definitely interested in your results from sarcosine. I acquired some but never used it (long ago, some nice caring individual since flushed all of my lil pharmacy. I understand its difficualt to explain to non-druggies why you like to do 'dangerous' things like barely known research chemicals and dissociative holes, even if I avoid doing them in tha bathtub - and that its NOT suicidal intent).

 

[Vastness]

Piracetam may even have kidney health benefits, I've kept it in my post-binge recovery stack and it does seem to help noticeably with kidney weirdness.

This is interesting, I didn't know this but I'll have to read up on it. Piracetam does feel fairly healthy in some vague way, I must say, even despite the sleep issues, I would like to be more consistent with taking it but... those damn sleep issues also. I do worry about my kidney health from time to time given the quantities of different substances I do from day to day. I've had kidney function tests from time to time but most of them top out at >90 eGFR, IIRC, which is above the range of any actual diagnosable pathology, but there's still a wide range of variation in actual kidney function above this and I'd like to see where I am compared to my age and weight demographic. IIRC, again, kidney dysfunction in otherwise healthy people can be symptomless until pretty close to actual kidney failure, if it's a gradual thing, or simply reduce the useful longevity of the organ, even without any critical medical incidents... so gradual kidney damage might just manifest as a fairly quick onset of kidney disease in later life, at an earlier age than this would otherwise occur... but anyway that's just irrelevant health anxiety at this point I guess, nothing else to do except try to make good health decisions going forward... and take piracetam, maybe.

I was most interested in the AMPAkines as I thought that the cognitive benefits I get when catching the exact right dose of the right disso, like almost 1:1 memory of things I just read once or very impressive visualization abilities which greatly helped me with understanding e.g. chemical structures (granted, as I didn't use that knowledge over time it got lost again, as usual but some of the marks I got with stuff learnt on low-dose disso were nice) might be due to increased AMPA activity from the additionally released glutamate (?)

This reminded me of something I did notice with pramiracetam, despite the anxiety inducing effect I stubbornly persisted with it for a while, and I think I was able to overcome the anxiety with the right combo of other racetams (probably aniracetam and noopept definitely, maybe something else, can't remember if I was onto anything harder by then, I think not though) - and I did notice the memory enhancing effects more than any other racetam. To the point that I would hear a phone number once, and be able to recall it perfectly a few hours later, and other things like that. Again I'm not really sure if I put this to any good use - I suspect probably not, as my main interest with the racetams was to combat long standing general social anxiety issues which were really hindering my life - and they were very effective for this at the time, giving me the boost I needed to really make lasting improvements in my life - so this recall enhancement remained largely an academic curiousity. Honestly I'm not sure I've ever noticed a definite memory or visualisation enhancement effect on a dissociative but that might be more to do with my tendency to redose until either heavy dissociation, or uncomfortable weirdness, depending on the flavour of dissociative I'm using, rather than stick to lower "functional" doses...

Dissociatives remain to be the single most impressive anxiolytics to me, of course GABAergics and certainly opioids are of similar efficacy but they are anti-manic and sedative. Only NMDA antagonism gets you anxiolytic hypomania with full-on energy. I love it though I suspect it fucks me up long-term not unlike amphetamine addiction maybe, loosing interest in healthy things and such, focusing on the positive feelings and such instead of the things giving you them (besides drugs)

Definitely identify with the struggle of knowing that one needs to keep an interest in healthy things, not just drug induced feelings, while equally feeling that the drug induced feelings of positivity are something of a necessity to continue having an interest in non-drug related things in everyday life. That's a clumsy sentence I just wrote but you get the sentiment hopefully, am just echoing your own really. That said - while dissociatives are definitely anxiolytic, I have very rarely used them for this explicit purpose - primarily because I am very wary of the line between functional anxiolysis and dysfunctional mania or incapacitation - again depending on the flavour - so for safety I tend not to do these out in the world or when I'm interacting with others from day to day (except on the rare occasion in a social disso-friendly party type setting, again such events unfortunately for me are rare, my social circle does not include too many disso fans in real life). I manage to induce functional light anxiolytic manias with fluctuating doses of phenibut, tianeptine, and armodafinil primarily, although I'll substitute in phenylpiracetam, kratom, and others now and then, currently a little deeper into a kratom phase than I am really comfortable with - but the former 3 I've found to be seemingly most sustainable long term, with the smallest penalties for overindulgence with any one of them. Amphetamine I love too and is obviously very functional but this feels a lot less sustainable and tends to lead to me overusing benzos and generally far larger swings up and down in mood and productivity.

3-HO-PCx are strange. They were the only ones where I really disliked the high, they are said to be opioids but were completely unlike mu opioids to me, similarly unlike mu opioid + DCK. Might well be thus that this influenced your experience, or do you get similar results from them like from other ones?

3-HO-PCP I believe I did feel some mu agonism, at least with my first, fairly low dose experiment, of 10mg, from which I had a definite afterglow for a few hours which may well have persisted for longer if I hadn't ruined it by following up this nice, pleasant, light experience with a ketamine binge. My next experience was the 20mg dose I mentioned which started nice but quickly proceeded into uncomfortable weirdness. That said I think I still prefer 3-HO-PCx to 3-MeO-PCx, even though I don't think I like any kind of 3-x-PCx that much at all really, but there's just something so enticingly bizarre about them that I keep trying to get something enjoyable out of them. And again, very low doses, I think - can be good. But I have a tendency to redose until it's uncomfortable.

Just for the record and so you have an idea of the kind of dissociative fan you're talking to, in case I haven't mentioned it - DCK is probably my favourite dissociative right now, closely followed by good old ketamine, but unfortunately the effects of the latter have been somewhat spoiled by permatolerance recently. 2F-DCK I would probably rate except that I don't like how weak it is, especially given the toxicities of the arylcyclohexylamine class and therefore doses needed. MXE it took me a long time to get, I think I do like it now after really disliking it for a long time but I still have a kind of lukewarm attitude towards it and admit I still don't fully appreciate it the way so many people do. I think it is a very deep and complex drug though for sure, and an appreciation for this as well as a desire to understand what other people see in it lead me to persist with it even while I was somewhat doubtful about it. Heh, it strikes me typing that that it's probably also a hard thing for a non-druggie to understand why someone would keep trying a substance that is not explicitly, obviously enjoyable, out of a desire to "get it"... but quite a few dissociatives have been like that for me. Probably quite a few psychedelics too, saying that, maybe that's part of the nature of these 2 classes.

 

[dopamimetic]

Oh for sure DCK is my favourite too out of all of the dissos I know and that's most of these ever sold as RCs. It is potent, yet not insanely so like the 3-MeOs, has a longer but manageable half life, next to no glutamatergic rebound, isn't anesthetic, euphoric but one of the least manic ones, psychedelic yet remarkably clear and makes life overall magic (that's sth all the clear dissos share). I dislike the weirdness too and MXE definitely has something very weird to it. It is metabolized extensively and I guess it is one of the metabolites being pretty toxic as to me it had more phases with the weirdness setting in late. This chemical is more for moderate doses I'd say, with like 15mg (w/ less tolerance) sublingual I had absolutely magic experiences with it. 50mg intranasal were a psychotic mess at the same time. MXPr isn't the same, it has a similar signature but somehow I didn't like it but nowadays I have acquired permatolerance too and longer ago when I acquired some MXE again it lost all the specific magic and I liked DCK much more. Possibly it was degraded though, certainly less potent than it should have been - thought it was tolerance but since DCK was and is still active at even just 10-15mg intranasal - no dissociation but anxiolysis, mood list and stimulation.. I'm really curious about the binding profile of it but guess we will need longer until they assay the individual subunits of the NMDA complex ...

These dissos are so much individually different like maybe only tryptamines/psychedelics are, have few experiences with them though as they all became heavy anxiogenics to me since I got hooked on that shitty venlafaxine. Has worse w/d than 200mg morphine since there's nothing that helps with it while you can literally skip the feared opioid w/d with dissociatives. Actually when replacing the morphine with DCK I felt great the first times when the mood limiting effect of the morphine started to lift and all the comfortably cuddly warmth of the DCK began to unfold.. know I am pretty alone with that, even when I know at least three other people, all opioid users with tolerance, who felt great on dissos again. Two of them overdid it and experienced brief psychosis though.

The combo of opioid and dissociative can be great, would even say it's not physically dangerous as long as you don't compulsively do more opioids under the influence as the potentiation appears to be mostly mental acutely and not to increase respiratory depression, I am not completely sure as I blacked out probably quite a few times but yeah, always woke up again w/o ill effects which you can't say about opioids alone.
They definitely take the edge off, before I didn't enjoy high dosages of dissociatives nearly as much, but they also have a pro-psychotic effect together. I have experienced this, nowadays I can't do the combo anymore without hearing voices, sth I don't get from dissos alone even over extended amounts of time and in excessive dosages. In my reckless times I hit anesthetic dosages many times w/o side effects other than some physical discomfort sometimes from bad positions etc.
Oh and opioids indeed limit dissociative tolerance. In the times w/o morphine I had much higher complete tolerance (in that I didn't feel anything from low doses) than while on it. In acute withdrawal the tolerance to dissociatives is increased but while on opioids the development is limited. Weird.

2F-DCK is the one I like second, to me it was about half as potent as DCK, similar but different ... one of the less manic ones too, certainly less toxic than K but it, umm, lacks some part of the psychedelis of DCK. Might be that it shares an additional mechanism with K which DCK doesn't have. This could be a plus for these people experiencing psychotomimetic effects but to me, and from some ones like DXM I get the very strong, DCK is still one of the best in this regard.

3-MeO-PCE is great too, it has an absolutely unique feeling which tolerance doesn't stop but ... it is weird too, in a different way. In late stages I get an uncomfortable physical feeling of like my skin was made out of pergament paper, think it has a strong affinity to peripheral NMDAr's. And I got two completely different batches of it, both from reputable vendors. One was almost frightingly warm, almost like DXM w/o tolerance but very different. I had no experience with opioids back then and thought it would be one but the warmth was certainly dissociative nature and is very different from opioids. This batch had a strong uncomfortable rebound from very little while the second batch was equally strong even with tolerance, much less warm, much more magic and clear and lacked the rebound. Weird again. Unfortunately I didn't do any analysis and the first one was seized as people noticed my weirdness so couldn't do any more experiments.

I completely agree to you that dissociatives have the strange tendency to like them even after mixed/bad experiences. In early times I'd be scared of them a day or a few and then desire to visit dissoverse again would slowly grow ... but what absolutely hooked me were the anxiolytic, antidepressive/pro-hypomanic, extrovertive effects. Remember the very first time of DXM, standing outside while in afterglow and being absolutely overwhelmed by pure joy of life, noticing all the little details and emotions in a never known clarity, all the fear, tension, depression, anxiety just gone ... when you've lived with sucicidal tendencies for as long as you can remember, this is pure magic. I've done the major part of commercially available psychopharms and none had only remotely similar effects.

Oh, I was out many many times on low doses of dissociatives especially 2F-/DCK and people tend not to notice it unless they know. Tend to think that hypomania is attractive to the exact same people which would call the use of drugs irresponsible and avoid you for that fact etc. People with inhibitions, maybe. They like the dissociated me as long as they didn't know me sober before and don't know that I'm on drugs. People who know always tell me I have a drug problem and put out the effects I have while not on dissociatives. They associate the sober me, my inhibitions etc. with drugs. This confirmed that dissociatives are somewhat special drugs, at least for certain invidiuals, less of an illusion and more really attacking the core of uncomfortable introvertedness and mental problems. For sure the mania is a problem tho, I learned to control it to a certain degree but it's not possible to do that completely. The more time passed in mania, the less controllable it becomes.. Think I never did things I really couldn't explain to myself, unlike in psychotic moments, but it's socially awkward and potentially criminally relevent. BZDs, alcohol, amphetamines etc. tend to be similar though with less benefits. Mostly it is from compulsive re-dose. Would say it'd be possible to do a XR low dose 2F-DCK pill with little side effects.

But yeah, they are physically toxic I got some seemingly permanent issues like frequent urge to pee, thankfully no pain, through acutely there was sometimes like bladder infection ... as dissos are effective anesthetics, you don't feel these effects on binges, and I am reluctant about abusing them in a heavily suicidal time when my first gf put me out on street, to escape from reality. This was when my tolerance was the highest and I of course didn't care to watch healthy water intake and such. Might have been avoidable, I am not sure about future use and consequences, certainly I don't want to have to pee into a bag but life w/o dissociatives is no choice on the long run so I have a problem for sure.

Do you know whether the diphenidines share this toxicity? I am aware it is just speculative at this time but I heavily suspect it's about the structure and not a direct result of NMDA antagonism as we have drugs like DXM and memantine which aren't urotoxic. Memantine has cystitis listed though I don't experience any discomfort besides insomnia (heavy, and limits its use unfortunately). DXM is no choice as it became a strong psychotomimetic agent.
Oh and do you know anything about peripheral NMDA receptors? Got curious about them the past days when I read they exist and we have purposed antagonists yet of course no RC. They even are effective in blocking morphine tolerance which is pretty remarkable and I wonder what else they do, maybe a similar inhibition of physical response to emotions like you get on dissociatives - at least for me the response to negative, yet not to positive(!) emotions is completly blocked in a dose-dependent manner.

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Did you ever get a depressive rebound from dissociatives? This I am really unsure about. DCK certainly gives this to me, 2F less but too. Overall I lost a good part of my energy while sober and acquired increased feelings of tension, hopelessness etc and subjective inflammation (headache, muscle ache etc) when discontinuing NMDAi's which seems to be upregulated receptors - they do upregulate, which I mentioned in another thread that it confuses me with the theory of model psychosis and downregulated NMDAr's being propsychotic - and this is purposedly toxic, so I wonder about implications about permatolerance and such.. :/

 

[Vastness]

Did you ever get a depressive rebound from dissociatives? This I am really unsure about. DCK certainly gives this to me, 2F less but too. Overall I lost a good part of my energy while sober and acquired increased feelings of tension, hopelessness etc and subjective inflammation (headache, muscle ache etc) when discontinuing NMDAi's which seems to be upregulated receptors - they do upregulate, which I mentioned in another thread that it confuses me with the theory of model psychosis and downregulated NMDAr's being propsychotic - and this is purposedly toxic, so I wonder about implications about permatolerance and such.. :/

Definitely I did and do get a depressive rebound from many dissociatives, have done for a long time, again the majority of my binges have been on ketamine but I've been aware of this aftereffect in myself for a long time, although it hasn't stopped me doing them. Subjective feelings also include lack of energy, irritability, basically just major frustration and irritation at the fact that I have to do anything other than just continue to binge on ketamine like I really want to do.

In fact, I'm reminded that this is how I have framed my general listlessness, lack of motivation and apathy recently in therapy - just a general unwillingness to really DO ANYTHING other than just sit around taking ketamine... I've recently thought that I have some kind of adult onset ADHD (OK, "adult noticed", whatever, as someone informed me once that there is apparently no such thing as "adult onset" ADHD ) due to my apparent lack of ability to consistently motivate myself to do anything useful without some kind of phamacological aids... and I wonder if dissociatives have played a part... these feelings pre-date my heavier use of dissociatives definitely, but, yeah... I think dissociatives definitely have not had a good effect on me historically. I am a lot better at manageing these aftereffects within the last year or so and I have also cut down on my usage a lot. And as ever - what came first, the chicken or the egg? Was I self-medicating existential apathy with dissociatives, and experiencing harsh rebound effects due to an unresolved inability to deal with these feelings, amplified by general post-dissociative emotional instability? Or were these feeling I was self-medicating for with occasional dissociative binges actually induced by dissociative use themselves? I think in reality it's probably a bit of both, the tendency towards lack of motivation both pre-dates and was exacerbated by dissociative use to some extent, and equally the harshness of the aftereffects was amplified by an undeveloped ability to properly deal with these feelings - and the development of this ability was not helped by using dissociatives, but by periods of relative sobriety and regular therapy. I'm sure if I did enough dissociatives even now though I'd be quite capable of undoing this good psychological work, so to speak, if I really put my mind to it, everyone's capacity for psychoemotional self-regulation has it's limits, and is vulnerable to sufficiently intense efforts to aggravate one's neurochemical stability via exogenous psychoactives...

Honestly I have no clue from a receptor standpoint what to make of all this and as much as I'd like to I can't even speculate on your own question about downregulation/upregulation and how it relates to permatolerance, psychotomimetic effects, and the like... I will have to do some reading though. I don't know anything about peripheral NMDA receptors either although I will have a read about that too for my own curiousity.

Answering the rest of your post somewhat in reverse - to my knowledge there is no reason to think the diarylethylamines share the same toxicities as the arylcyclohexylamines, I posted a thread speculating about the toxicological properties of these compounds a while back and someone else speculated that intutively they should be less toxic as they are more structurally similar to some endogenous compounds, although I don't know how accurate this is. I personally felt them to be easier on the body - and considering the very long duration of ephenidine - the best one, IMO - this is maybe worth something, although also maybe not.

Interesting that you say that opioids limit dissociative tolerance somewhat - this actually may be relevant to my own experience as I've probably quite often combined tianeptine with ketamine, not really deliberately, just from having taken tianeptine earlier in the day and deciding to do a little ketamine in the evening. And I have felt myself to have managed to mostly avoid permatolerance until very recently - while I have not been taking any tianeptine - although I have been taking kratom - but maybe the effects of kratom and tianeptine are not equivalent here. I have noted before when it's obvious I was feeling something from both that there was a definite synergy and it definitely made it more enjoyable... I wonder if perhaps permatolerance set in longer ago than I previously thought but I have been kind of unintentionally masking this with co-administration of tianeptine quite often.

I have also experienced somewhat psychotic effects on the tail end of some ketamine binges, I actually put this down to changing effects from overuse but possibly again the tianeptine-ketamine combo might be a factor I have kind of overlooked... effects generally consist of having multiple "virtual conversations" as I call them going on in my head, like I have phantom people around me talking, and sometimes I'll actually respond out loud to something and immediately snap back to reality... or other times I'll be kind of weirdly unsure who else is with me (I am almost always alone), and have actually called "HELLO...!?" into my empty flat before to verify if anyone else was indeed there. Inevitably usually once I actually act in response to one of these delusions rather than just letting them kind of play out in my head, I immediately snap back to reality and realise I'm just experiencing a particularly harsh comedown. I can't remember if tianeptine has been a factor in all of these particularly psychotic sessions, as not all my comedowns are like that, sometimes it's just a gradual fade back to a more uncomfortable reality but without the delusional mental element... but it could be.

 

[dopamimetic]

Whoa, you are the first person to share the exact same symptoms, experiences etc. Especially the struggling with sobriety and the multiple conversation thing, this can grow into really hearing voices but the core is multiple streams of thought which I concluded is more of an interaction than really psychosis as it mostly remains to be an isolated auditory phenomen (a very disturbing one although, ID rather choose visual effects I guess) and there were the trials of nmda antagonists against tinnitus, again I am not sure but it might be related to my left side tinnitus as I got these things sometimes more or only on that side.

It's almost completely gone, yet sometimes just before falling asleep I get one second stream of thought again which even answers to my thoughts so I am wary about learned psychotomimesis or toxicity a bit but really think it is either worsened or triggered by opioids and heavy sleep deprivation, maybe only together as this never happened before opioids (which happen to be anticholinergics, and you get the same thing with DXM + benadryl. Coincidence?)

Had the same experience with abruptly snapping out of it when realizing it isn't real but only when more mild. Sometimes it would keep repeating the last phrase over and over for minues which is verrry weird. Antipsychotics worsen this btw, only the antihistaminergic ones (quetiapine, truxal, etc) do help a little in histamine-selective doses but again appears to be plausible as I remember to have read about dopamine regulating excess glutamate, wich antagonism does diminish and is involved in tardive dyskinesia.

I wonder about the same chicken and egg point. Disso use certainly makes things worse while sober and better while on them.
Given that in rats single doses lead to upregulation and the relative toxicity of NMDA mediated effects, well thinking about it doesn't feel too good.. As you say though, I agree that K is among the worst here and with the DCKs it mimics somewhat more stimulant rebound which is much more manageable and supposedly less toxic.
In times of opioid withdrawal, where supposedly you have increased NMDA density as morphine increases them too, it in fact is worse. Somehow even while on morphine, but mostly with K and O-PCE, in a different way MXE ... it indeed might be healthy to take a little dose of benzodiazepine at the tail end of a disso trip. According to the DXM FAQ, clonidine could do it too and really I had a strong experience from stopping memantine+clonidine (the latter for sleep, and against tension) abruptly and stupidly doing (very little) 3-MeO-PCP triggered an intense manic phase, the only one I've ever had..

I got diagnosed with adult ADD, and tended to like sometimes to do a bit of stims together with dissos. No healthy combo for sure but curiously not too bad either, might be something about dopamine+glutamate ... I never did any stim while in rebound as this sounds like hell but really I wouldn't be too surprised if it could actually help in moderation. Or dopamine agonists. Because memantine for sure inhibits rebound from MXE, never tried with others unfortunately. I thought it would be the continued NMDA antagonism but I am pretty unsure these days as with tolerance memantine became mostly a dopaminergic but still greatly helps (and, of course, has a rebound itself, argh).
Whatever, my experience is that the use of dissociatives isn't that problematic in terms of toxicity but the rebound after higher doses or ceasing of chronic use is.

I had the theory about NADPH oxidase and excessive superoxide generation because the latter seems to be involved, and DXM happens to be an inhibitor of said enzyme together with a friend who does excess doses of DXM and only gets SNRI related side effects but no rebound.. I have mixed low doses of DXM with arylcyclohexylamines with mixed results, some nice experiences and some very weird ones, memantine + disso is certainly very weird, it induces other sort of auditoral disturbances but that too was while on opioids. Guess the affinity to the oxidase isn't too high or it isn't relevant, one day I had acquired apocynin which selectively inhibits NADPHo but was seized..

Naltrexone appears to reduce NMDAr density. I'd be happy to read some experiences, until then I am too afraid of these kind of opioid inverse agonists as a brief contact with naloxone while on just 30mg/d memantine was hellish. Would be interesting if LDN/ULN has similar effect - somehow it appears to be oppositing but as still limits opioid tolerance like dissociatives do, maybe it has potential. Never ever read anything about naltrexone+disso. In chronic alcoholics it is dysphoric though which doesn't sound too good since ethanol too has nmda antgaonistic properties. And now that I think of, fuck alcoholics show similar rigidity and irritability, just with GABAergic symptoms like excess energy and aggression on top. Might be that too much of alcohol side effects / rebound / withdrawal is associated with GABA as of course GABAergics counter-act glutamate too. DXM fully inhibits hangover from alcohol to my experience which I always found strange, given that they say it is a metabolite that is directly toxic but maybe it is toxic through excess glutamate..

Never combined tianeptine with anything but its an interesting substance that just is much too short acting. Never had the sulphate though. As the 'voices' appeared even with just 60mg XR morphine, much less so but still there on methadone and briefly on bupe, I guess tianeptine might be able to do it too.
Not sure but bromadol seemed to be devoid of this effect as was ah-7921. As it seems to be partially a learned condition it might just have been that it was less of a problem back then as morphine was the only opioid of recent times when it was worst, would also say it is the worst one as it initially felt pretty weird ish different than other opioids and has some kappa affinity. Might be that I have increased kappa receptors and/or the phenomen is dynorphin mediated..

Guess many questions are just still open

 

[dopamimetic]

Whoa again, somehow out of nowhere the thought that DMT and dissociatives will make a good combination like somewhat a chemical yin and yang, popped once to my mind while in dissoverse ... but didn't actually try it as serotonergic psychedelics are highly anxiogenic to me but it for sure is a very interesting substance. Crazy that excitatory 5-ht2a agonism is neuroprotective, I've thought the opposite from inverse agonism being antipsychotic but well I absolutely dislike anything antipsychotic and with psychedelics promoting growth factors it sounds resonable again ...

Can you use sub-psychedelic doses of DMT or do you need to ... hole (for the lack of a better term, like said I've never done it but apparently it involves loss of contact with everyday reality)?
Is my theory true that using psychedelics together with dissociatives abolishes their possible anxiogenesis? It is weird, as I have had positive experiences with psilocybin but I guess this was in a time when I wasn't on a SSRI and didn't have tolerance to one. Ever since I got hooked on venlafaxine psychedelics became nothing but weird speedy anxiogenics.

Interesting about lack of hangover not influencing the desire to do more, I'd have thought that if something is strong enough to 'repair' the damage done it would also target this. But yeah dissociatives are the most reinforcing drug class I know of ... maybe like nicotine (sth which I can go against cognitively though, telling myself that it is nothing but an addiction, but still even after months of not smoking I can't forget it in stressful moments)

Oh, now that I think about that. Very probably the DCKs are serotonergics, granted MXE too is a strong one but given that it's probably a metabolite which causes hangover it's possible that it happens in a phase after SSRI activity weared off. But I know that SSRIs aren't exactly psychedelics. They do activate 5-ht2a though to a certain degree, on venlafaxine + very little (75mg) DXM I got some visual morphing stuff back when I lacked tolerance ...

Guess this warrants new experiments?

 

[Vastness]

Am always very interested to hear about your Ketamine+DMT experiences, @PYTH, it does sound like something I'd be into for sure and I will likely try myself soon. I was going to try DMT last weekend but ended up scaring myself off trying new drugs after an unplanned 3-MeO-PCE binge, and now I'm going to leave it for a few weeks before trying any dissos again (although I probably will try DMT alone sooner, once I've psyched myself up to do it, LOL... I feel like I should try it alone first although honestly, I also feel in a sense that that's kind of just to "get it out of the way" before I can start combining it with ketamine or another dissociative ).

I do find that dissociative and psychedelic combos always leave me with a much better aftermath, I would even call it an afterglow most of the time, in a way that just using dissociatives alone does not... however it obviously (unsurprisingly) doesn't change the physical toxicity, and hence I have felt bladder twinges and other general weirdness even after the most wholesome, holy feeling trips, but these feelings are accompanied with a more positive "oh well, I'm sure this will pass and it was worth it for that, I just need to be healthy for a while now!" kind of feeling, rather than the regret, self loathing, "urgh, why do I do this to myself, I'm so stupid, addicted, I think I want to use some more even though I know it's harming me" kind of feeling that the negative physical aftereffects usually induce psychologically.

I got diagnosed with adult ADD, and tended to like sometimes to do a bit of stims together with dissos. No healthy combo for sure but curiously not too bad either, might be something about dopamine+glutamate ... I never did any stim while in rebound as this sounds like hell but really I wouldn't be too surprised if it could actually help in moderation. Or dopamine agonists.

Interesting - what stims specifically, if you don't mind clarifying? And, you don't think it's harmful? I did a little amphetamine and ketamine on one occasion, and it didn't feel very healthy for sure. Also the studies I've seen where ketamine did seem to induce neurotoxic changes in humans (always heavy abusers over long periods of course) were always in polydrug users, usually combining with stimulants, which lead me to think it could possibly be a little more neurotoxic. Although I know there's a lot of talk of NMDA antagonist co-administration with some stimulants inhibiting tolerance build up to same stimulant... so maybe it's a dosage thing... I dunno.

Would you say that your ADD diagnosis, and presumably medication, helped, as far as the kind of existential apathy that dissociative aftermath worsens, that we've discussed here? Or was the ADD kind of uncoupled from this, in a sense, an additive factor but something needing to be addressed separately?

Interested also in the fact that opiate withdrawal increases NMDA receptor density - this should mean that tolerance to dissociatives goes down during withdrawal? Or up? Confused given what you said previously about opiates and dissociatives being synergistic... I just had a quick google and I see it is studied that opiate tolerance is inhibited by NMDA-antagonists... this means that opiates are reducing NMDA receptor density? If withdrawal increases it... so if someone had a tolerance to opiates already... would NMDA antagonists have less subjective effect...? I do have a bit of a kratom tolerance right now for sure, and ketamine recently was surprisingly ineffective... tianeptine I get the sense is a lot more selective to mOR, perhaps this also means it lacks some of the NMDA related changes?

 

[dopamimetic]

Yeah, had the same question before about these neurotoxic changes being only in polydrug users (as in polytoxicomanic, which are the ones which the rehab people get to know and will use for studies I guess) which tend to have bad habits about general lifestyle, bad knowledge about the substances they take, use reckless cocktails and such. For sure I wouldn't recommend using stims together with dissociatives to anybody at this time, as the norepinephrine appears to be a relevant factor in toxicity and clonidine was able to abolish that. NE lowers seizure threshold, DA doesn't to my knowledge(?) and I am pretty sensitive to stims in general, I was referring more to therapeutic than recreational doses. Think I liked most the fluorinated amphetamines which are generally less 'heavy' (which tends to mean less NE for me) than classic amphetamines, methylphenidate felt toxic somehow but it does so alone. Like say, 5mg of d-amph should be fine though and while I am really, really unsure I would say that indeed it helped with rebound, at least avoiding the depression, the scattered brain and to a lesser extent the noise thing but then again when using both usually I continued redosing thus generally avoiding rebound - maybe it is that NRA tolerance makes the rebound less pronounced.

I got diagnosed early as an adult, to that time I was abusing DXM though so it's difficult to decouple things from each other. NMDAi's indeed help with stim tolerance, stims alone never worked out in the longer term for me. So continue using the same doses as without isn't the best thing.

In times of opioid withdrawal you get tolerance to the dissociation, yeah but I based on a paper I posted recently somewhere here that morphine or dizocipline both alone increased NMDA density while naltrexone decreased it and morphine+dizo wasn't mentioned suggesting they together make less changes (= less tolerance). Afaik it is specific to the mu opioid receptors of which many have direct connections with NMDA ones but the strange voice phenomenon might direct that kappa receptors could be involved too.
Opiate tolerance is for sure negatively manipulated by NMDA antagonists but their subchronic use leads to upregulation and thus possibly increased tolerance again. The other way round appears to be less researched and I found nothing about the influence of opioids on NMDA tolerance so this remains anecdotal for now and somewhat hard to grasp for now..

Guess these days when people say opioid receptors they mostly mean mu, as we have few widespread agonists for the others. Interested in them and remember salvia divinorum having a dissociative afterglow but it's been 15 years since so no guarantee.

I'd say as long as you are on an effective dose of opioids, you will exhibit less tolerance development to NMDA antagonists yet not necessarily reduced tolerance. They are very complex and I read somewhere that they have different patterns with different degrees of antagonism, like lower doses increasing tolerance and high ones decreasing it (might be partially and appears to be incorrect though as dissos unfortunately don't have negative tolerance independent of dose. A few people reported weird, partially negative tolerance experiences but only with DXM.)

Think I am confused about receptor regulation as I and people often correlate tolerance with receptor density which probably is true but not the conclusion that it takes equivalently long for them to re-regulate than it takes for tolerance to develop or diminish. Things like adenosin receptors being mostly absent after sleep but there when tired indicates this is a very quick process and tachyphylaxis too. Such regulation can happen in minutes I guess and thus during a rebound you will have different sensitivity and receptor patters than some hours later ... things like DeltaFosB will be involved here I guess ...

 

[Vastness]

I can't be sure but I'm pretty sure sarcosine has negative effects on my experience with nicotine and - possibly - kratom. I've been going through a nicotine vaping phase - although I was going to stop for a while anyway, as I typically do - but yesterday a few times when I tried to vape I almost immediately felt this kind of "loud silence" like an uncomfortable pressure or buzzing, inside my own head. I've read that sarcosine can induce a kind of "inner tension" and nicotine definitely amplifies this, as such I have no desire at all to try vaping today, which I suppose is a good thing.

I also can't be totally sure if this is just tolerance - as I say I am deeper into a kratom phase than I would like - but I'm pretty sure that my kratom doses have been less enjoyable the last few days, even with heavier doses... again, could be tolerance, I really need to take a break. I want to say also that, strangely, just as the effects seem to be muted, also the withdrawal seems to be somewhat muted as well... I have not been feeling as terrible as I can remember feeling at other times... but my feelings about this are a bit more tenuous as I tend to have strange and variable reactions to a lot of opiates anyway. However I mention it as I wouldn't be too surprised if there was some interaction given the somewhat overlapping receptor interactions of these 3 classes (opiates, dissos, and indirect NMDA agonists).


EDIT: Something in another thread just reminded me of something I remember you saying and meant to ask for clarification on, but forgot, so had a read back through this convo just now to find it...

2F-DCK is the one I like second, to me it was about half as potent as DCK, similar but different ... one of the less manic ones too, certainly less toxic than K

When you say "certainly less toxic", are you referring to body toxicities, ie, bladder, kidney, etc, or is this more of a perceived, psychological toxicity?

Curious as I wasn't/am still not really aware of how much the relative toxicities of ACHs other than K have been studied, I know MXE has been shown to have bladder toxic effects in rats, at least, and it has been surmised that norketamine is the more toxic ketamine metabolite (personally I think there is evidence to suggest this although it hasn't been formally confirmed). So I wonder if you can shed some light on the metabolites and relative toxicities of the others?

Speaking for myself, I can't remember ever experiencing bad physical aftereffects from the PCP analogues, although obviously these are a whole lot more potent, so that could be why. I THINK that I've experienced it, but less, from MXE, and also DCK although in retrospect I think the latter case could well be down to a bad synthesis. Again though as ever I may be biased purely from the vastly larger amount of K I've done in my life compared to any other disso.

 

[dopamimetic]

Somehow it doesnt surprise me at all to read sarcosine leads to inner tension, I have had this sort of feeling when sober for as long as I can remember (childhood PTSD) and dissociatives, and/or age worsens it the same manner as e.g. impulsivity gets better with time. I have really worried about either some weird, destructive neurological disorder, there are some which are mediated by NMDA/glutamate and share symotoms but probably the bets are on the dissociatives and increased receptor density. Just what are the implications of permatolerance for health?

Know there's speculation that weak partial agonism of Nmdar's should have similar effects to antagonism but I don't buy it.

Yeah have weird and unpredictable results to opioids too. Guess doing dissos contributes heavily to that but also I tend to find too much of a dose of them dysphoric for example especially w/o tolerance. Morphine was certainly the weirdest and the synthetic RCs (O-DSMT, bromadol, lesser AH-7921) the most constant.

Granted my statements are mostly based on subjective experiences, unfortunately I know much too little about chemistry and metabolism to predict specific metabolites and toxicity
Have read about MXE, there's also a chart with at least 9 metabolites so it is quite different from K. When I say the DCKs are less toxic I refer to good batches, there was an awful lot of bad DCK from China with alarming long-term but even short term physical effects that must have had something in it which accumulates over time and doesnt cross the BBB. Mostly the early batches I guess.

MXE was toxic in rats but imho this is nothing we wouldn't have known without this study as apparently the arylcyclohexylamine just isn't an ideal structure from a toxicity point of view(?) ans rats have different, much faster metabolism requiring huge doses so really not answering the question whether MXE is less toxic than K. Guess you could compare the doses and intensity between that one and a similar paper about K though. My hunch is that they won't differ much weight by weight but dose-wise.

Then again the only real acute physical side effects I had were once from 25g of illicit K within a week or two (the 'K cramps' where I somewhat blame impurities for) and said batches of DCK (strange phenomen of 'gummi legs' sth while sober in mind, worsening to things like impaired speech, tremor, once collapsed after redosing a regular amount - not w/o warning but which addict ever listened to such? Things faded away over literally months, back then I was suicidal, didnt care much and thought it was from excessive use as I got similarly impaired speech from DXM+sodium valproate - where probably valproate was the cause also worsened psychotomimesis, don't do it.. and all never happened again with even more of DCK and of 2F).
MXE felt quite easy on the body but less so than 2F, that one even recently appeared to be almost devoid of both rebound and physical side effects but I am sensitive to it, 15mg showing some effects.
The most worrying side effect I have and this appears to be semi permanent and reappears quickly on a binge is a frequent urge to pee. It seems to be inflammation related and somewhat improves with memantine, or NSAIDs.

Might be that the closed ring of PCPs is less toxic (?), just unfortunately I don't like their mental effects. Just for sure it is not a direct effect of NMDA antagonism but of the structure and thus very probably related to the absolute amount, so inverse to the potency of an agent.

Curious about whether there are other researched srructures with nmda antagonist activity than the obvious arylcyclohexylamines and the somewhat neglected diarylethylamines (sbdy please synth isophenidine)?

 

[Vastness]

Interesting as ever. Interested specifically that you say there was an awful lot of bad DCK from China a while back, I had some from China that came in squarish white crystals like table salt, which did indeed seem to have toxic effects - it induced the first long term (more than a twinge, lasting more than a few days) bladder awareness issues I've had, as well as a lasting low mood akin to general post-dissociative apathetic haze but somehow, worse. I eventually flushed that bag as I was not in a good place. There's at least 1 other member here who I saw reported a particularly "caustic" batch who went on to develop serious lasting bladder pain, apparently, although they apparently were using multiple other dissos and did not attribute the same significance to this as I did (am discussing currently in the Dissociatives Organ Damage thread in the Psychs&Dissos forum).

I had another batch recently which came an an off-white yellowish powder which I did not experience nearly the same aftereffects from despite dosing about as much in a single night as I did over about a week the last time.

As far as the "gummy legs" effect, I DID experience this, to SOME extent, I think, although actually it could have been because I didn't sleep and had taken a shit ton of benzos in an effort to sleep (and also in anticipation of post-disso binge uncomfortableness). I took it this time in combo with 4-HO-MET however so overall my experience was pretty positive both during and after... anyway my experience this time was far less severe, but, it was my impression that DCK actually is notorious for a long trailing comedown which includes physical unsteadiness- do you think that this is indeed the case? Just wondering how concerned I should be about a bad synthesis. My recent source is supposedly NOT Chinese in origin but a fairly reputable European country, and by all appearances they seem legit, at least as far as one can ever judge in this perpetually grey underworld of prohibition and clandestine syntheses...

Interesting also that you say you get weird effects from opioids. To elaborate on my own experience a little, I do not find opioids nearly as reinforcing as some do, and have always had apprently fairly mild withdrawals (I say this about a week into a 10-15g a day kratom habit, hehe... but previously I've taken kratom usually in 5g doses, 2 or 3 x daily, for maybe 10-15 days before running out and quitting with minimal downsides). Tianeptine I also notice an immediate unpleasant kind of crash if I take it continuously for a while (usually 40-60mg sulphate a day) but nothing too unmanageable. Even diamorphine, which I tried really just to check it off my list, I was not blown away by, it was kind of nice and dreamy but not Trainspotting-style mega euphoria. Oxycontin I found distinctly dysphoric and unpleasant, really nothing enjoyable about it at all, tried it once and will not repeat. Tramadol I do enjoy - although I have not tried it in a while, and the pro-seizure and weird serotonin activity scares me a little.

Tianeptine and kratom are definitely effective adjuncts for whatever psychological maladies I feel the need to self-medicate for, they do both induce a motivation and clearheadedness which augments the drive of stimulants (which on their own are not actually necessarily that motivating, focus enhancing, sure, but the task of directing that focus to a given task is sometimes still a barrier to taking full advantage of them). Certain opiates remove this barrier to being able to properly direct my attention - this also has a useful social function, when combined with gabaergics, which on their own may remove anxiety but are not necessarily "pro-social" as many people find them, and just as often make me more comfortable just chilling asocially, removing the drive to practice social bravery that I usually have as a small voice somewhere in my head whether I act on it or not (I'm talking about alcohol and phenibut, primarily, here, benzos I really try to avoid for anything but recreation and recreational parachutes but I expect the effect would be the same).

In fact alcohol has a pretty rapidly dysphoric effect without an opiate mediator - I read a while back that in certain people alcohol has some opiate receptor interaction which really amplifies the crash when alcohol starts to wear off, typically leading to being "unable to stop drinking" and more prone to alcohol problems and whatnot, which I probably would be if I wasn't so substance aware, didn't have whole litany of other options at my disposal, and wasn't also something of a hypochondriac which gives me a strong aversion to drinking too much.

The "inner tension" effect from sarcosine seems less pronounced at 1g / day than 2, for sure, I have vaped a few nicotine vapour tokes today and have felt the edge of something uncomfortable but have been very careful with it. I feel like it does, maybe, somewhat, increase my desire for dissos also, which maybe is unsurprising... or maybe it's just this discussion. But I'm trying to hold off as I've also taken a few racetams today as well so it would probably just be a waste of drugs and health and would ruin the experiment.

Do you have any formal training or education in any kind of drug science btw? Since you seem to have some clue what you're discussing and obviously are a moderator of N&PD, so would make sense... :giggle: although even if you don't and are self-taught would be interested to know more about how you learned, if it's any more than what we all do, just peruse science articles, reddit broscience, and try to muddle through the literature as best we can... Would like to run a few more science things by you regarding my speculations on ketamine bladder toxicities, obviously I can read papers and whatnot but I have no bioscience background so I often wonder if what I think I understand is actually just complete misunderstanding of the data.

 

[dopamimetic]

Interesting finding about sarcosine and nicotine, I am curious about the relation with choline, a transmitter I happen to know little about.. but of which too much is said to be tensious and dysphoric, antagonism is delirant, antidepressive (my experience w/ 500mg of diphenhydramine was weird though. Dysphoric, relaxed, anxiogenic, lack of dry mough and insects, strange gummi-like physical discomfort. Never tried any more anticholinergice besides akineton after 1mg of haloperidol triggered dyskinesia and it gave me insomnia, some euphoria which might have been just the reversal of the dysphoria but I think it was actual euphoria).

Yep, the DCK from Europe is better than the Chinese. The first I have had was a specifically bad batch, yellow and slightly oily yet dry enough to insufflate it. This was the one with prolonged physical comedown/after-effects (said gummi legs, but very different to diphenhydramine, kinda like slow sea waves in lack of a better description). But now that I remember more, I have to say that this too was during I was prescribed sodium valproate which was the weirdest substance ever in some way, smoking half of a cig would floor me in overwhelming euphoria, and it certainly was pro-psychotic. Got on it by accident, I was taking memantine for over a year which greatly levelled out both the acute comedown, after-effects as well as the chronical tension and anxiety. Then I had a crazy batch of 3-MeO-PCP, never really liked this chem but too either there are extremely different isomers out there or I got some other arylcyclohexylamine as the three times (from different sources) I've tried it, every time was completely unlike the previous experiences. One time was strongly dissociative yet not psychedelic. Second time was very psychedelic yet less psychedelic. Third time triggered the only manic episode I've ever had.. but the worst batch of any I remember was big rocks of DCK which were very impure (white with yellow spots) and had these horrible, slowly building effects which lasted for months, completely without any correlation to the duration and metabolism of DCK. Was the same time when I developed that urge to urinate frequently, unsure about coincidence as it was also a time of heavy use. Certainly caffeine worsens the residual of this effect and memantine tends to abolish it.

Finally somebody with the same strange reaction to opioids indeed I've never found them to be particularly euphoric and too tried diamorphine 'to know it', it definitely is nicer than morphine yet still nothing compared to the dissoverse (the combination of both has something unique I have to admit, if there weren't these strong, strange auditoral hallucinations they'd make an ideal suppression of negative emotions). Even before any real experience with opioid I thought that dissociatives offer the very exact effects I would have thought opioids give you (intense, heavily euphoric and warm confidence, comfortability, mental silence, cozyness etc) just together with some others like stimulation and hypomania while the opioids tend to be more sedating and - yeah - less euphoric, less warm, less cozy, much less zen-like. More psychotic. More mentally and less effective painkillers. Having a worse, yet nowhere close to other (addicts) experiences withdrawal - sth I never really knew if I should attribute to that I did never use needles (some say though that intranasal is equally direct and indeed things like K, 2FDCK etc. have an instant rush w/o any delay) nor did I use astronomic doses of them but these would have killed me I guess as somehow opioids have weird tolerance pattern. Methadone was the prescription one I tolerated best yet still not completely devoid of psychotomimetic effects - which disappear with opioid use and tolerance(!) and the majority of dissociatives lack (!!). None ever besides DXM+DPH had similar auditorial hallucinations and never ever did something persist besides the auditoral things, as long as on opioids, and said physical effects from bad batch. And the urge to pee.

Similar for alcohol. Many years ago I liked drinking, but it never really changed my introversion into extroversion like it does for others or dissociatives are able to. Back then low dose codeine + DXM felt very euphoric, physically strange (strong muscle relaxation I'd say) ... and I really, really don't know but I keep having the bad feeling that these first DXM trips changed something to the worse in me. Might have been a natural development that would have come so or so, or not. Yet I feel that the first maybe 5-10 DXM trips had more permanent influence than all of it and the aryls I've done years later, possibly you shouldn't dissociative beyond the age of 25 or so, similar to you shouldn't do reuptake inhibitors before or early smokers show a different tolerance pattern than people who start to smoke late as adults. Need to read more about this. But maybe dissociatives are just the better opioids, heroin users for sure are attracted to the euphoric RC dissos if they happen to get contact with them which usually isn't the case given the ignorance of most dealers and consuments, but too they all get psychotic features.

GABAergics are strange too. When they put me on lorazepam with 17 for social anxiety and another shitty doc quit these avg 2mg/d cold turkey after 2 months, I went through a period of intensivied anxiety and tension (not unlike disso rebound yet the other way, with them it's much tension and less anxiety, the lora was much anxiety and less tension). Alcohol for sure gives me a rebound but no longer-term effects and benzos do the same nowadays. They probably do worsen the whole thing but using benzos for 1-2 months straight and quitting them turkey is no problem. Alcohol has become mainly a sedative w/o real euphoria or stimulation, a nasty rebound and benzos tend to feel cognitively limiting, sedative and even pro-depressive, dysphoric.

Guess NMDA antags are the only chemicals I know of which have the properties of giving you an anxiolytic and euphoric, stimulating, partially empathogenic high. Qualitatively different but comparable to opioids+stimulants and, curiously more similar, to the legendary 4,4'-dimethylaminorex - indeed the only other one which fits into the anxiolytic, euphoric pro-social category. Never did MDMA though but I am very wary of its rebound.

Tianeptine and kratom are both chemicals I'd like to investigate further, both atypical opioids with more stimulating than sedative nature (?) in a certain range of doses which is intrigung as I happen to like most the acute, stimulating effects of both methadone and morphine. The kind of effects you get when you have tolerance, but did less for a few days and then upping the dose again. An unique relaxing yet stimulating high somewhat remotely similar to acute high doses of pregabalin or yeah dissociatives without the weirdness. Guess part of it is histaminergic as it comes together with the itch and histamine is both wakefuless-promoting as well as undergoes rapid desensibilisation and I don't get intense itching, mostly I don't get it at all.

Well I happened to find peace with my interest for psychoactives much too late for me to do any carreer about them, as people kept and keep trying me to convince that I was an addict, reckless and would have a serious substance problem etc.pp. I tried to convince myself for long and indeed only know of one person with a similar curiousity and ability to remain (more or less) functional under the influence while most other consuments I met were the scene kind of reckless, ignorant and morally bad style of character ... none of them used dissociatives and none of them out of a medical neccessity though, the latter ones tend to be more knowledged and more functional. I suspect more of my kind to be hiding out there, many more than any politician or counseler would ever imagine but as long as these stupid legislations and social stigmata don't change we'll never know and never change for sure. Chicken and egg. But I think to know that the style of people seen in addiction clinics is a minority despite popular belief.
I would love to get to know open-minded professionals to learn more specific stuff or do anything productive with the acquired knowledge but it's just a hobby currently.. being labelled as a non-functional mental trainwreck (which I am in the longer run without NMDA antagonists) it's difficult to get a job, so I have plenty of time though and plenty need (together with limited access to) for chemical destraction given that for the last maybe 8 years the most time I had some idiotic legal problems and possible prison time hanging above my head - German speaking area, after some Asian and Arabian countries the worst part of the world to do research chemicals. Happen to learn and comprehend things quickly as long as they fascinate me, makes me really sad to see my life completely wasted out off artificial, stupid limitations & consequencies following early-life mistakes, dysfunctional family, misdiagnosis, ignorance, criminalization of non-violent, non-amoralic things like interest and self-medication but that's how the world works I guess..

For sure thinking and discussing about dissociatives triggers the desire to do some. A feature pretty unique to NMDA antagonists for me at least, it is present with other drugs but to a much less degree, more 'empty' with them, less fueled by curiosity and mostly absent while on Dissos, on lower dosages I keep a somewhat healthy interest in doing things (more so than with just stims), they make all the little things in life very magic from time time like a trip back to childhood with an adult mind and most if not all excesses were out of acute negative emotions, lack of good equipment like exact milligram balances or equipment for volumetric dosing etc., fucked up batches. Sometimes hypomania but most of that would have been avoidable too as I can control it as long as it's not too intense for too much time. Just un/luckily I don't get any physical incapatition which both avoided psychiatry as well as lead to some legal problems.
Even excess doses of K don't incapacite the least of my body, standing in the way of more intense and profound experiences, being potentially dangerous and being unable to hole frustrates the hell out of the curious me.

Plan to research 2F-/DCK + DMT/tryptamine soon I guess
The only disso which ever was incapaciting to some degree was DXM on which I learned to remain functional and doesn't show these effects anymore .... increased peripheral NMDA receptor density, and implications of that in negative emotions/sensations anyone? And the 3-MeO-PCxy's which have the ability to become strong enough to loose contact with reality at least w/ eyes closed below an anesthetic dose. The weaker ones knock me out at some point without any real warning or physical symptoms other than some confusion - with and without morphine.

 

[Vastness]

I must admit I kinda ballsed up the sarcosine experiment and am probably going to abort. After looking up the sarcosine half life this last Sunday I determined it would be out my system enough to indulge in just a little DCK, it's just so long since I had it. I ended up doing just a little for the next 2 days, in combination with kratom for the last (actually the last 2 days I also did some 4F-MPH which may have something to do with the negative aftereffects I am about to describe). I decided the day before last this would have to be the last day as otherwise I was going to rocket my permatolerance even more (even though I was keeping it to strictly "functional" doses) and also that I was gonna have to stop doing kratom so often because I was surely developing a tolerance and withdrawing was going to suck. Nicotine also has a pro-depressant effect on me I notice almost every time I decide to go back to vaping it for a while so as a result I cold-turkeyed everything yesterday but was also almost unable to get out of bed. This is the second withdrawal from kratom I've had in the past few months after considering myself basically immune to withdrawals before that, obviously quite naively. Today I did dose kratom in the morning out of an unwillingness to feel diabolical for another day but I'm going to rapidly taper now and try to avoid it. Kratom seems to be not equivalent to tianeptine for me in "forgivability factor". I am pretty sure sarcosine is pro-depressive to an extent, obviously I mentioned it did seem to reduce the effectiveness of kratom doses and probably lead to me dosing more, and obviously I did renege on my previous decision to abstain from dissociatives for some time. Not the first time I've reneged on a decision regarding drug us of course but I can't help but think sarcosine had a destabilising influence here.

I really identify I think with a lot of what you say as far as reaction to GABAergics, definitely alcohol, and maybe opiates although I have tried less of them. Kratom is indeed primarily stimulating up to a certain dosage range - and these are the effects I primarily seek in it - in higher doses and I believe with redoses the sedating effects become more pronounced, and I think this is why kratom has a "ceiling effect" for me where after a certain amount in a day redosing becomes progressively more sedating and more dysphoric. Tianeptine for me does not seem to have this ceiling and also seems a lot less prone to inducing dysphoria. I've tried higher doses but did not find them overwhelmingly pleasant, not necessarily dysphoric, but just somewhat uninterestingly sedating, kind of dreamy and nice in a way but also not something I had any desire to repeat, especially obviously as dosing like this too often will ruin the functionality of lower doses which I find so useful. I think that I do find them to be "emotionally silencing" in some ways even in lower doses however which is not necessarily a negative for me as, like many people with somewhat depressive tendencies, or perhaps emotional dysregulation in general, I would sometimes characterise my default state as being one of "too many emotions". But tianeptine at least definitely does make me a little "colder" in some ways, and I can definitely identify with your description of opioids - at least in this quite specific instance - being somewhat "pro-psychotic" - I think kratom is just a bit messier overall, which makes sense obviously as it is natural and pharmacologically "dirtier", it might be more recreational in some ways but this is probably not necessarily a desirable property for me as far as my reasons for taking it (which are primarily in pursuit of functional benefits).

It's quite easy, it seems, for me to remove the euphoric effects from benzodiazepines. I don't find very many benzos recreational although diazepam and etizolam are 2 of the better ones in this aspect - however - strangely - I have found that racetams actually make both a lot less recreational, although the sedating effects remain. I've done this enough times now and experimented deliberately enough that I think I can say this, for me, is not in dispute - piracetam definitely nullifies most of the enjoyable effects from benzos - I imagine actually the same might be true for other GABAergics although I haven't experimented enough to say this definitively, and it might even be less noticeable for whatever reason. I would say that with increasing tolerance the psychologically enjoyable effects are the quickest to disappear, while sedation remains.

Anyway as I say I seem to have been a little destabilised the last week or so and I primarily blame sarcosine and nicotine - maybe I'll try again with sarcosine at a later date but I'm gonna have to give myself time to reorient a little.

What you say about the bad DCK batch is interesting also, I can't really remember if mine had yellow spots although it might have done - although I would say it seems there might be enough circumstantial evidence here to point to at least a working hypothesis that a particularly bad batch of DCK was a significant contributor to lasting bladder issues in potentially at least 3 members of this forum.

Interestingly I did get some bladder pain in my brief low dose dalliances with DCK the last few days - but I think only on days where I also took phenibut, in fact only on 1 day in particular - it's hard to be sure of course but I'm sure it felt somewhat different to the lasting bladder aggravation I've had from ketamine and/or other dissociatives before. In fact one time most recently, I was noticing that I was feeling a definite bladder irritation, and drinking a ton of water, and then suddenly - it just stopped - this might be down to the anaesthesia reaching a critical threshold, so to speak - or it could be down to the remnants of my earlier phenibut dose finally reaching a sub-critical level. Obviously this doesn't entirely indemnify DCK from being a contributor to the effects since even the small ~5mg bumps I was doing did seem to aggravate this - but I've been aware before that phenibut seems to aggravate post dissociative bladder issues to an extent, and obviously it is a very caustic substance. But usually bladder issues for me are something that peak in intensity a few days after the fact, rather than mid session, so again, this recent experience seems to have been of quite different character, I want to say less concerning, but I'm aware of some bias I have towards wanting to a reason not to worry at all about my dissociative usage.



EDIT: Oh, one other thing I just remembered, I am almost positive nicotine amplifies bladder irritation issues experienced post-disso, and possibly during disso as well. I can't remember exactly now but I read that the norketamine metabolite shares a much higher affinity than it's parent metabolite for the same nicotinic ACh receptor which plays a key role in arterial hardening and atherosclerosis that nicotine induced - this receptor is also involved in pro-fibrotic activity and this was part of my working hypothesis for thinking that norketamine was indeed a more toxic metabolite than ketamine. Obviously it does also seem that this effect is shared by other dissos but I would bet that activity at this specific ACh receptor plays a big part in the bladder damage, and affinity for this receptor I would also bet is positively correlated with increased incidences of bladder damage.

EDIT again: Receptor I was thinking of above is the α7 nACh receptor.

 

[dopamimetic]

Just a quick response, will write more later - might indeed be that you're right about the alpha 7 nACh receptor, somehow I never found nicotine to actually worsen the bladder issues yet do I seem to have got them only mild, vaping/smoking certainly is pro-depressive especially in times of rebound and too less serotonin (SSRI withdrawal, heavy precipitation of brain zaps even with cigarettes which contain additional MAOIs), in other times though it is more of a stimulant but that is with heavy tolerance to it ... but now, memantine which seems to abolish the frequent urge to pee, is - an alpha7 antagonist. It too makes nicotine less intense and while withdrawing from it the opposite is true. DXM too is an alpha7 antagonist btw.

 

[Vastness]

Kept meaning to reply to this to update further and also enquire about your own experience with memantine, which I remember you mentioning a few times elsewhere. and I am very curious about. You are actually prescribed memantine, correct? Did you titrate up to your current (to me fairly high) dose or just jump right in? Do you notice any cognitive deficits?

When I've tried memantine now and then, I've started low and tried to titrate up, like 2.5mg, 5mg, 7.5mg, 10mg, up a maintenance of 10mg or something, I can't remember if that's right, it's been a while since, but I was initially going for possible neuroprotective benefits. I did find it to a be a bit brainfoggy unfortunately so usually discontinued use soon after. I would love if there was a barrier through which I could break after which the brainfog resolved but the desirable NMDA modulation remained.

That's interesting about the alpha7 antagonism of memantine, although since I wrote that I'm now a little less sure of my earlier hypothesis as ketamine, it seems, is in fact a negative allosteric modulator of this a7 nACh receptor, and norketamine is the same, although it has a higher affinity for that receptor and therefore presumably, more antagonism... Looking into it a bit deeper, both ketamine, norketamine, dehydronorketamine and other metabolites, and memantine, are all listed as antagonists. So perhaps something more complex is at play here. With further experimentation though I'll say definitively that both phenibut and nicotine increase bladder awareness for me induced by arylcyclos, so there is SOMETHING going on... I'm just not qualified to say what. Nicotine is an insidious addiction for sure, I really get very little good out of it but occasionally I'll just vape until I remember that actually I don't really enjoy it that much... unless perhaps I'm on some heavy doses of stimulants.

Getting back to sarcosine for a moment - I think that while NMDAis apparently might have some opiate anti-tolerance effects, sarcosine in fact might have the opposite, inducing a harsh rebound disprorportionate to dose or frequency of usage when combined with opiates, even an atypical one such as kratom, while reducing subjective positive effects. That said however, kratom and any harder stimulant does seem to induce a pretty severe crash in myself - after a week of using low doses of amphetamine in combination with kratom I had another week I could barely get out of bed. And my recent sarcosine-triggerred harsh withdrawal which this time only lasted a few days was also preceded by combining 4F-MPH with kratom. I am aware of the downstream dopaminergic effects of opiates, but I haven't really seen this massive propensity for downswings reported elsewhere so I'm wondering if it's something that is not usual. My dad did develop parkinson's at a fairly young age (mid fifties) and died of complications related to this disease so I am a little concerned, I guess, about any indicators that my own dopamine system might be more fragile than most.

I must say this DCK batch I've been lucky enough to get my hands on is pretty fantastic and I'm really enjoying using it as an actual functional compound which is something I haven't really done before. It's not a miracle drug by any means, today I am combining with 4F-MPH again and have been reasonably productive. And - for me at least - it is just SUCH a fine line between dosing JUST ENOUGH to get that sweet, functional, stimulating, clearheaded anxiolysis... and going over that line to the point that it becomes a little cognitively disabling.

That said - a few days ago I did go over the line pretty royally, eventually abandoning my work plans. And the next day while I did feel an edge of that post-ACH depressive weirdness, it was also closer to that of a psychedelic afterglow. I think DCK is really closer to a true psychedelic than ketamine itself, and if I don't vape, smoke, or take phenibut, the bladder issues actually have been getting progressively better, which is an absolute first for me with any ACH. I did have a small 3-MeO-PCE binge I think over a week ago now which aggravated my bladder slightly in the days after (although 3-x-PCxs, as I've noted are not the worst for this, this particular PCE is less potent so doses were higher) and it's like my DCK doses initially were aggravating that but as that recedes, any temporary irritation is also receding. Touch wood I'm not placeboing myself or just in a perpetual state of bladder anaesthesis... but again... my doses are fairly low, so I don't think this is the case. I know the immunosuppressant properties of DCK are still somewhat up for debate but so far to me it feels like the healthiest ACH I've had the pleasure of imbibing. I'm gonna have to call time on even my low dose functional indulgences soon enough as I'd like to keep this around for a while, annoyingly I was literally just able to snap this up before the vendor underwent some kind of management change which apparently just fucked them, so not sure when I'll be able to get any more. But anyway, this is definitely a far different experience to my last opportunity to sample Chinese manufactured DCK which caused significant negative aftereffects, wobbly legs, and whatnot, and makes me even more confident that some kind of bad synthesis is to blame for those negatives.

 

[dopamimetic]

Well, memantine is a truly weird one. Guess I'd have given it up a long time ago if it wasn't the only one that is prescribable and half-way usable... with my tolerance, it went out of balance and became more of a dopaminergic, which isn't always what I want - racing thoughts and similar, given the long half life certainly not too desirable. Heavily fucks up my sleep. But then again it's besides opioids maybe the most useful pharmaceutical for me, is a very clean disso but with dosing high enough it becomes pretty strong, with 140mg or so I even drifted away with eyes closed but was also hypomanic from all the dopamine. They should make a variant that is a stronger NMDA antagonist and less of a dopaminergic but guess we won't see this for some while which is why I nevertheless am pretty happy with memantine.. finally something that could be scripted and the guys at the airport don't find suspicious (even when I'm no way in the age for Alzheimer's but thankfully they just don't know the med).

I'd say it is an unique disso-like substance on its own. It certainly doesn't share the sustained antidepressive effect of some arylcyclohexylamines which is a pity but, for me, it is still useful and I suspect it to have potential for PAWS. Combines well in low dose with some lisdexamph or mph, also with opioids and maybe keeps their tolerance at bay. Unfortunately it isn't a complete anxiolytic like morphine or DCK which I am back on low doses of morphine, sigh ...

Yeah it is a problem to find and maintain a functional dose on dissociatives. Would be great to be able to properly weigh the doses or even make a retard formula but the only way I know of (which comes pretty handy btw) is to fill some into a saline nasal spray. Good aid to dose while in public (just have some answer ready for the guy/girl who will notice your notorious bad cough.... kinda like the DXM shopping years ago. Fuckin CH managed to make it Rx only last year.)

How does your sarcosine experiment work out? I am thinking about giving agmatine a try, maybe it boosts dissociatives and/or helps with opioid tolerance. Too sad that we don't have any peripherally selective NMDA antagonist.. and that these bastards will shut down 2F-/DCK sooner or later... have to order a load of that but atm I lack the money, and a safe storage place for it.... after recently somebody (unfortunately the guy I rented my room from) threatened me with police unless I'd let him search my room for drugs, and flushed all my stash. Fuck Nixon.