Long-term Consequences of Dissociative Use - Revisited

[dopamimetic]

The only paper I know of about this topic is now around 7 years old and while they https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713393/

Shouldn't the lowered shizo like NMDA density many are raving about induce a negative tolerance to dissos while we see a positive one, and one which reaches stratospheric dimensions?

From my own not-so-scientifical experiences, both is true. This makes the 'loss of magic' phenomenon many experience at some point when over doing dissociatives.

Yet, I found alcohol to be more euphoric than it was for a long time, and less sedative than ever - together with feeling not unlike early lower 2nd plateau DXM trips.. Which I do blame more the opioids for than dissos but this might be a bias.

Do either dissos and/or opioids (the latter might explain why so many people in metha maintenance begin to abuse benzos at some point) lower the production of GABA or mess with it in another way??

I know that ketamine is associated with loss of 'rapamycin' which apparently means GABAergic interneurons but never read anything about opioids when they are known to increase nmda density.

 

[allone]

yeah im also curious about this too, more specifically about the current status of olney's lesions associated predominantly with DXM use, but also ketamine and maybe other related compounds. whats the current status on this? is there official conclusion in association or still speculation??

 

[dopamimetic]

Was wondering about whether these lesions described in the paper linked above are in fact Olney's lesions in humans or something different. What they neglected a bit is that some/many? of the probands were also using methamphetamine and norepinephrine is a relevant factor for this as clonidine was already mentioned in White's FAQ to protect against.

I feel that things went downwards at least much faster when I started opioids. It became much more psychotic and things remained after stopping opioids. But this is subjective. Seems to be more emotional than cognitive but then again this was always my problem.

Any hints on what concrete symptoms one would have to expect from such degenerative changes? Somebody able to interpret the paper and MRI images?

 

[atara]

Olney's lesions are, at worst, rare in humans if not absent.

The problem with amateurs reading studies is that they always look for keywords and concepts which they recognize rather than looking for the meaning that the authors intended to convey. Sure, you can say one thing or another about NMDA receptor density based on fluorescence assays, but this sentence, right in the abstract, is pretty unambiguous:

"Cortical atrophy was usually evident in the frontal, parietal or occipital cortices of addicts."

You're not going to see any NMDA receptors on the fluorescence assay if the neurons carrying them atrophy or die. This isn't hard to find. It's in the abstract. It's clearly telling you not to abuse ketamine. I don't know how to read the words "cortical atrophy" without concluding "bad".

Everyone gets concerned about "neurotoxicity", as in a cascade of chemical reactions initiated by the drug that leads to the death of a neuron. But people tend to ignore atrophy, when someone is intoxicated so often for so long that persistent changes in neuronal metabolism and the CSF cause neurons to die slowly. Benzodiazepines cause no neurotoxicity, but atrophy is quite evident in scans of long-term users.

The brain is metabolic as well as computational. Neurons need to maintain homeostasis to survive. Drugs don't merely affect the way cells communicate with each other; they also affect the way the cell uses energy and repairs itself. From Wikipedia:

"The main problem with the utilization of NMDA receptor antagonists for neuroprotection is that the physiological actions of the NMDA receptor are essential for normal neuronal function."

Potential symptoms of dissociative overuse include reduced ability to form memories or learn new skills. However, focusing on the symptoms is not helpful. Assuming that you will not be able to learn is a self-fulfilling prophecy. The one reliable conclusion that can be drawn is that ketamine should not be used so often.

 

[dopamimetic]

Yeah, I knew about the consequences regarding learning and cognition but that's not what I have any issues with, and this confuses me. What I get is some weird ADD kind of sensory overwhelming, rigid emotions, dysphoria which I never read about. Would say learning is no different as it was always.

Have kind of a negative tolerance btw, to the dissociation as such. 200mg DXM are enough for a partial dissociation with floating w/ eyes closed while the euphoric effects seem to require more now.

 

[atara]

What I get is some weird ADD kind of sensory overwhelming, rigid emotions, dysphoria which I never read about.

These are also symptoms of mild hypoglycemia. Do you notice any correlation with your eating habits?

edit: https://www.sciencedirect.com/science/article/abs/pii/0006899389910743

200mg DXM are enough for a partial dissociation with floating w/ eyes closed while the euphoric effects seem to require more now.

I think some of the pleasure of sense-distorting drugs comes from the reflecting action of mind, the second nen so to speak. When you feel sparks and see lights for the first time, it's new and exciting, but eventually you get used to it and it isn't as fun anymore. This isn't because of a neurochemical change because that part of the pleasure was never from a neurochemical impulse in the first place; it happens because the mind is functioning normally.

 

[dopamimetic]

These are also symptoms of mild hypoglycemia. Do you notice any correlation with your eating habits?

That's a good question as I am pretty notorious about forgetting to eat until my body screams for food but blood values were always within normal ranges and I'd say while malnourishment exacrebates the symptoms, they are and maybe even were always there. Nmda antags are the best at masking them and yeah I got diagnosed with ADD but stims only work for a few days.

Agree with that becoming used to drug effects will be a factor but less so when it is about obvious things like relaxation, talkativeness vs. subjective toxicity. DXM has turned from a heavy stim into a sedative.

 

[atara]

but blood values were always within normal ranges

You use a glucose monitor?

Maybe address the problem by setting some scheduled mealtimes.

 

[dopamimetic]

You use a glucose monitor?

Maybe address the problem by setting some scheduled mealtimes.

Sorry this was misleading, I meant routine blood tests by the doc, I am not sure but think it included glucose (knowing that you need to check it more than once a few months and they drew blood in the early morning before breakfast so low glucose wouldn't surprise).

You might be into something here, I forgot about but thought I should have my thyroid checked in the past but morphine masked these things. Eating doesn't help unfortunately but I remember becoming very tired after food when I couldn't sleep before. Need to get over my aversion against these profs in white coats I guess.

 

[Cotcha Yankinov]

Everyone gets concerned about "neurotoxicity", as in a cascade of chemical reactions initiated by the drug that leads to the death of a neuron. But people tend to ignore atrophy, when someone is intoxicated so often for so long that persistent changes in neuronal metabolism and the CSF cause neurons to die slowly. Benzodiazepines cause no neurotoxicity, but atrophy is quite evident in scans of long-term users.

This!

Many of the long term consequences of GABA-A agonists/PAMs have been linked to disruption of sleep, and NMDAr do provide a very important role in the circadian pacemaker, the SCN -- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888256/

NMDAr input onto dendrites provides an important neurotrophic effect, and they can tend to atrophy and withdraw if those NMDAr are blocked. Last I think I read in an EJ Nestler textbook a while back that they were still trying to work out how the specific synapses involved in LTP were tagged for protein delivery. Anyways, I believe the retraction of dendrites is thought to be responsible for some NMDAr antagonist related brain volume loss. The brain is like a muscle I suppose, use it or lose it.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697127/ - see figure 4.

Some effects of ketamine in MDD patients and abusers are also related to alterations in genetic transcription, GAD67 and parvalbumin expression are known to be altered by ketamine and are involved in the generation of NMDAr antagonist animal models of schizophrenia. So while the monoamine release downstream of NMDAr blockade and those AMPA/mTOR activating metabolites of K might be helpful and neurotrophic for some MDD patients at therapeutic dosages, I couldn't say the same for addicts or those without that specific MDD pathology.

Its believed that NMDAr drive some of the communication between cortical regions, and there are some papers on depersonalization being related to alterations in function of said NMDAr in areas like BA39. I have a feeling there are only specific circumstances in which stopping brain regions from communicating with each other is helpful in the long term.

I assume the more psychotomimetic dissos like PCP worsen the "dopamine" related pathology, as chronically elevated levels of dopamine in human brains seems to be capable of causing effects that don't necessarily disappear that moment the drug has cleared. I think some DeltaFosB isoforms can stick around for ~2 months. And we do know that many of these drugs of abuse cause cortical atrophy, especially of the orbitofrontal cortex. Any drug that raises mid-brain dopamine - I'd bet we can probably apply the addiction literature to it to some degree.

There seems to be some debate within the ketamine clinics with regards to psychoactive doses, some believe that the psychoactive effects are helpful, while other clinics want to keep the dose as low as possible to avoid psychoactive effects. Here is a paper linking psychoactive effects (dissociation) to the beneficial effects, for what its worth -- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858990/

I think these guys might prefer to skip the trip and go straight to HNK, no fun

Development of (2R,6R)-Hydroxynorketamine

NCATS scientists helped discover that a key metabolite of ketamine, (2R,6R)-hydroxynorketamine, replicated ketamine’s antidepressant effects in mice.

ncats.nih.gov

One old theory about the lack of typical Olney's lesions/vacuoles in higher primates is that they don't form easily because the opioidergic system kicks in protectively and helps shut down excessive excitatory activity sooner in higher primates than it does in other mammals. The NMDAr normally turn on GABA cells and, when NMDAr are blocked, increases in downstream excitatory activity can be seen. This includes release of glutamate.

Sorry for the novel! Been a while since I could nerd out. Long time no talk Dopa!
CY