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Progressive damage years post-excitotoxicity? (AMPAr-mediated, GABA antagonism)

Limpet_Chicken

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So, I'd like to know if there is potential for continuing damage years AFTER an initial, severe excitotoxic insult (it nearly killed me, twice)

The setting was acute, severe and extremely protracted barbiturate withdrawal. At first, cared for in intensive care after ODing when plasma levels of a very long-lingering but nevertheless not at all phenobarb-esque subjectively, and damned abusable barb mounted up and got me. I'd built up a dependence on the stuff and whilst I didn't like the fact, I KNEW I had more than enough to taper. Only problem was the OD, someone snitched on me and I got jailed. Did a cold turkey 'detox' and damn near died again, after months of protracted severe DTs, during which I didn't eat, didn't know food was there, and I doubt I could have got it down me anyway if I did. No way in hell with THAT fight or flight response.

Barbs both have the well known GABAergic agonist effects, and additionally they bind in an antagonistic mode to AMPA type ionotropic glutamate receptors. And perhaps of interest, They have a weird long-lasting (even on electrophysiological patch-clamp conditions it takes PROLONGED washout to reduce say, pentobarbital maximal inhibition to say, 70-75% of its masximal, as the ligand binds in such a manner as not to easily un-bind)


Now, I used to be, well, a lot more brilliant than I am. It feels as though its THERE, I just can't access it, like a scratched hard drive with the read head skipping over when searching for data. Memory severely impaired, difficult to find words in speech, I often have to circumlocute mentally to find the correct term, I can't remember what, but I had to go from the etymology of a word embodied by the concept that I wished to convey, in ancient greek, and derive it thus, from the english of the equivalent latin term.

And substituting similar sounding phonetically but mispelled words in typing, and having to correct from rote. Along with ataxia, seizures, Recently I started, to slowly lose the ability to feel hunger and thirst. Its a struggle to eat and drink at all now, theres no drive to. And I rarely take psychostimulants, although I am actually considering it to get along. Memantine, although I have been struggling to try persuade my doc to give me a script more or less restores me from a ghost of my former self to being fully alive again. Other NMDA antagonists do to a degree but not with the same utility as memantine. If I can get it or find a source for it elsewhere, think combining it with an AMPAkine to offset the awful memory loss might be worth a shot?

Its getting to the point of dangerous, the memory loss. Forgot the cap was off a bottle of SOCl2 recently, for example until the stench began to penetrate the filter of my mask, and my eyes were stinging like they were drying off after a bath in chloroacetone.
 
Mindfulness meditation could certainly help, it's positive effects on memory and focus are documented.

Being lost in thought is no good for cognition.
 
The brain should be able to deal with excitotoxic insult and heal over time, certainly it would be very unusual etiology for the damage to present itself years after the fact.

What sort of exposure controls are you dealing with in your, ahem, workspace? Solvent vapor inhalation can be enough to dull someone mentally and emotionally if it's on a repeated, regular basis. Let alone thionyl chloride or any of those nastier things.

Another thing that must be considered is to what extent you are practicing unregulated pharmacy: things like chloromorphide have not been characterized fully as to their toxic effects in man. There also may be an aspect of opioid dependency if you use it regularly (you'd know that, I'm sure :)).
 
No the damage was immediately presenting. Its just that over time, it has gotten more and more and more severe.

I do wear protective gear sekio. That account about the SOCl2, it was just to illustrate how bad things in terms of memory things had got now. I turned to screw the cap on a 10l jug of MeOH lest it be kicked over. And then promptly, once my vision was no longer fixed on the thionyl chloride, I couldn't remember it was there anymore. As soon as I couldn't SEE it there, it was as if it did not exist. And I wasn't breathing in the miasma of fumes either, it was simply what alerted me to realize, rush over to seal the bottle so I wasn't losing reagents and stinking my workspace out. Not to mention to remind me to change the filter as soon as I could. Was just trying to illustrate how BAD things have gotten, and it seems to be progressing.

I've only taken alpha-chloromorphide a small handful of times, enough to characterize its effects, and mostly, because whilst its the precursor to desomorphine, I do not seem to recall or be able to find (and I don't just mean here) reports of it actually going into people. The only reference I had to go on was '10x the strength of morphine' in wikipedia. So expected some activity. Which there proved to be, if you read my report here on it in ADD? But it was nothing like morphine WHATSOEVER, the only, the one-and-only, similarity it has, is that it can relieve opioid withdrawal induced by temporary cessation of morphine in a subject so physically dependent. But had the trial been double-blind with my not knowing if I was recieving an active substance or saline, I would have guessed at a modafinil given what I have read of the effects of that drug, mixed with a small amount of a dopaminergic, although I've never taken modafinil. One of the queerest, most peculiar things that have ever gone into me, it really was. And I can't say I'd be too happy pushing it too far to see how far it could go though, due to the appearance of clonus in the distal extremities; and of course, since I have seizures, the last thing I wish to do is to provoke one. They are most unpleasant when they happen of their own accord, so I certainly don't want to CAUSE one.

As for opioid dependency, whilst not to alpha-chloromorphide, yes, I am. I don't have a great deal of choice in the matter since its to treat a longstanding injury that can be very, very painful and would without pain medication drastically limit my mobility and independence. What there is of it to begin with, because I cannot drive, and must walk or get anywhere I'm going by cycling or public transport, the last of which I can ill afford. I can't rely on getting a lift everywhere, sometimes I can do but not every time I want to go somewhere. So I need to be able to walk long distances. If I can't I'd be more or less housebound. And without pain control I can't lie down either, not on my sides, back or front, so I'd not be able to sleep either.

Its that whilst medication (aside of course from things being experimented with, which are used from time to time in determination of results, or occasionally if something particularly interesting and useful is hit upon, rather than constantly, on a per-compound basis) is a two edged sword, I really, really would be a lot worse off without it. And whilst it remains static in quality and quantity, the memory-cognitive and attending issues seem to be degenerating. And things like becoming unable to feel thirst, or to feel hunger, those are outside the sphere of what opioids etc would do.

Edit-and sure my pharmacy is regulated. By me=D
 
Have you considered that it may not be safe to work with chemicals like thionyl chloride if you believe that you are suffering from cognitive impairement? I get that chemistry is an interesting hobby, but if things are really as bad as you describe (not being able to remember that you opened the bottle) then you probably shouldn't be working with reagents like that one.
 
Yes. And I know it. In fact I have a hunch one day I'll probably be found in the lab, once someone evntually smells the stink of decomposition coming out of there. I'd just rather that was a lot later, than sooner. Which is why I'm attempting to get things done about it. But if its going to happen anywhere, then better sooner and some real time left to me, than much later, going like my mother did. She starved herself to death, eventually. Deliberately.
 
Sleep deprivation is indeed cumulative, if you're looking for a reason as to why things are getting worse over time.

As I recall the pain from your foot is from an accident - is there a component of causlagia or nerve sensitization? Opoids are well known to make true nerve sensitization (like seen in causlagia/CRPS/RSD) worse in the long run because the opoid agonists bind to Toll Like Receptors on the microglia that maintain a pain amplification state. On the other hand, low dose naltrexone for neuropathic pain is very promising, with Dextro-naltrexone apparently showing very little activity at the opoid receptors but still blocking toll like receptors.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576/

What of the issues with laying down - what is the cause of the pain there?

Just thought I'd point out that chronic pain leading to sleep deprivation is a sure fire way to hammer cognition.
 
The pain in my foot is very recent. I just must have nicked it, or broken the skin slightly somehow, because it took infection and that ate a big hole in my foot, about an inch wide, blistered up all good and proper, hurt like a fucking right royal motherfucking cunting bastard of a cunt. The foot pain is simply due to the fact there was a severe localized infection and also, due to the fact that because of the infection I could no longer take my clobetasol and mometasone, so I'm shedding and I'm consequently scratty, irritable and grumpy as a box full of rattlesnakes.

What is CRPS? I've had the crAps before, but methinks thats not quite what your meaning. RSD?

The other pain, I originally got fucked up, when I fell in a kneeling kind of position, as a child. Unfortunately I was playing, as kids are wont to do, in an abandoned factory, and what did I go flying down on, but a brutal great shard of upright broken glass, which went straight through into my knee, impaling me in the patellar tendon and carrying on through in between the shin and kneecap to go into the knee joint. I had to pull it out as best I could, then snap it off when I couldn't withdraw it further, and walk home several miles to seek help. This I did, and I had the remains, at least all they found, taken out of my knee in hospital.

When I was recovering, I was surrounded by a bunch of chavscum pikey filth that beat the shite out of me, proper kicked my fucking head in, knocked me down and stamped on my face, stamped on my knee, stamped on my head. Basically used my kneecap, the fucked up one, as a trampoline. It only ended when I managed to get a knife out and start wildly slashing at them, threatening to kill the next fucking bastard that I could get my hands on. They were going to do the same to me, and imo would have killed me otherwise. Fucked me up and more or less, as far as they were concerned, left me for dead.

Its never been the same since. I've had knee surgery done, that stopped it locking immobile so often and lessened the frequency of it simply collapsing, it doesn't collapse from under me much at all now, but it did nothing whatsoever for the pain, and in fact they made that worse, not to mention left me with some nerve damage. Thats caused a permanent, unceasing spasticity in my calf muscle, from which the only respite I get, is to be found in heavy doses of tizanidine, I'm taking just short of the maximum allowable daily dose of the stuff. The muscle spasticity manifests not only as stiffness but constant burning like fury, quite literally, it feels not very far different, from when I grabbed hold of something as a wee kid that I hadn't realized I'd left covered in concentrated perchloric acid. Only in a different place. Or a time I spilled thionyl chloride, when it first rotted through my glove and began to eat my hand down to the muscle surface (gloves were leather, which is why the one that took the splash rotted). And the violent, violent spasm in my calf....jesus fuckin christ dancing on the bloody cross! shit ME.

Paraesthesia and neuropathic pain down the side of my leg from after the surgery, which was years ago as well. Originally got baclofen for it, but I'm a nonresponder.

As for the laying down, the change in my walking gait from the fubar knee caused a bilateral trochanteric bursitis, As a result I EVENTUALLY managed to get a doc that was sympathetic enough to give me some pain relief, having had to go without, and being repeatedly told 'oh, go take some paracetamol, or ibuprofen, that will help you', despite being told I'd tried that and neither alone nor both NSAID and APAP did a fucking thing. I use topical diclofenac for the tendonitis and it helps a bit but now I'm on heavy doses of morphine. I was on oxy 80s before that and had been tried on fentanyl patches but came rushing (in a manner of speaking) back to the surgery the day after, begging for my oxy script back. I got it again. Lol I'd picked up one on a tuesday, and I think they tried me on the fent on the wednesday at the time, then I was back the day after tellling the doc to restore me to taking oxy 80s. They for some reason, actually just gave me another prescription, rather than what I thought they were to do, which was change it on the system. Thankfully didn't ask for the patches back because they had all been opened up, loaded into a couple of rigs and belted up. But I don't like oxy much AT ALL. So I got them to change me to morphia, which I have been on for a long time now. Along with a miserly quantity of shitty oxy for breakthrough and gabapentin, which I find total crap, for the neuropathy.

And to add to all that, my GI tract is giving me hell, to the extent I'm due to get a camera stuck down there for a gastroscopy soon this month. Because of severe stomach cramping and intermittently, awful, awful awful vomiting. Just will. not. stop. I'm on about 9 different stomach meds for barf prevention and cramps, everything I CAN take, bar cholestyramine I am already taking. no antidopaminergics though because I cannot tolerate in the slightest antidopaminergic shit like domperidone, metaclopramide or those abominations of the phenothiazine class, et cetera. They are as much poison to me as alpha2 adrenoreceptor antagonists. I now have a script, begrudgingly upon the part of my doctors, for ondansetron, after I got admitted the second (I think, either second, third or fourth time) to hospital, vomiting bile, and blood-streaked foam. And eventually being given a shot of ondansetron in hospital, and it was a fucking...well...wow. From spewing blood and bile in the foetal position to as chipper as the remnants of, to quote my uber-sexy goddess-of-snark friend w/ Rett's, aka the rettdevil herself, 'post ictal shitty', would let me (the term, which I daresay, I am borrowing from her and using to describe exactly what she meant it to describe. I.e post-ictal shitty. There's no better way to put it:P...hehe that lass has one hell of a hilarious turn of phrase and could snark the silver tongue off of the devil his own self (and WHAT a hottie too=D)
 
It's possible that you have causlagia, a variant of CRPS that involves nerve damage rather than solely inflammation/sensitized nerves. CRPS is basically when the nerves get very sensitized and amplify the signals way too much, hyperalgesia/allodynia. Spasm is extremely common with CRPS. Gabapentin doesn't seem to help those with CRPS, most people are refractory to those typical meds. I'm curious if you did get a chance to push the dose with the Gabapentin though. Below 1200mg a day might not do too much.

But at any rate, there are other drugs used for treating CRPS that you may look into. Ultra low dose naltrexone has been found to potentiate morphine analgesia and reduce tolerance buildup (microglia are responsible for some tolerance). The doses of naltrexone used for CRPS are usually 2-3mg but I have a feeling that would produce some precipitated withdrawal. As I recall naltrexone at doses .125-.25mg helped with opiate withdrawal. Can't recall what doses were used to potentiate morphine analgesia.
 
I've already been bugging my doc for some naltrexone and a memantine script. The latter, when I managed once to find a source, it was absolutely life restoring. Yet I keep being knocked back, despite the fact that it:

Lowers my opioid tolerance.
Helps a great deal with the neuropathic pain.
I seem to have fewer seizures.
My memory and cognitive difficulty go from being difficult to prepare a basic meal with more than one central item of food unless it requires a microwave and something out of a tray in which case I can put one thing in, cook it, and if I don't accidentally burn it to a frazzle forgetting it, do it again then heat the two on a plate.
Not be miserable and depressed so much about this.
Less myoclonus.

The disabling, life-restricting, crushing, crippling aesthenia is more or less gone.

Even had to explain to him that I also want it to guard against potential for anything like excitotoxicity from DM-235, and have been holding back on making my first batch of it until I can get that memantine :(

I keep repeatedly being knocked back. Although I think I MIGHT be making the very beginnings of a little progress, just hints of maybe being closer to being able to persuade my GP to give me that script.

I'm scripted 900mg three times a day of gabapentin, but its not of much help, I've tried to use it recreationally as well before, even at like 10g or so it does nothing much whatsoever.
 
I haven't. Not yet anyway. And whilst IDRA-21 is not one I am enthusiastic about actually, I do plan on it. DM-235 is the one I have in mind. I just need to get on the memantine again first. I don't wish to accidentally cause excitotoxicity, although the AMPAkines as a whole seem pretty safe, at least not outright poisons like say, domoic acid (a marine diatom is the source of this biotoxin, it causes noxious algal blooms and can accumulate in shellfish, causing potentially permanently crippling 'amnesic shellfish poisoning' if it doesn't kill the victim outright, after the shellfish feed on such nasty little blighters and bioconcentrate the poison, then themselves get scooped up, boiled alive and munched on, giving some poor bastard their own payback, with one hell of a vicious rate of interest. Making payday loan companies look like mother fucking theresa:P

(domoic acid is an orthosteric AMPA receptor agonist, it basically causes a massive inflood od Ca++ into cells and allows those mussels, clams etc. to serve the consumer hippocampus mariniere, cooked in the shell.)

(is it messed up of me that I cannot help but get this mental picture come to mind of a mussel, waving a clump of byssus thread, with a little fist at the end and clapping its valves like a mouth, speaking with an oddly identical voice-over to stewie griffin from the show ''family guy'', yelling 'HAH you barstahd, you damn well chew on THAT and see how YOU like being cooked you son of a bitch!!!)


IDRA-21 is probably one of the least favourably looked upon (as personal options to ingest) AMPAkines actually. These are related to cyclothiazide, the thiazide diuretic and this presents multiple reasons why it would be perhaps not the most suitable option)

I looked into cyclothiazide and cyclothiazide derivatives whilst doing some of my boning up on the AMPA-NMDA side of the ionotropic glutamatergic system and it turns out that cyclothiazide itself, not only is non-BBB penetrant but that is a good thing, because cyclothiazide is also a GABAa antagonist or inverse agonist.), plus additionally I'd rather avoid the thiazides because of it being difficult to feel thirst, I can't afford to get dehydrated and its hard enough to keep consuming sufficient liquid as it is. 'nesquik' milkshake powder is a godsend to me, I love the cococolate one, and can just add half a tub of milkshake powder to a 2l container of milk once someone else has consumed enough for me to fit the powder in and shake the thing like it was a 6 months pregnant theresa may. I've had two of those today.

And Styx take it I'm out of fucking milkshake powder, BOLLOCKS. Because I could murder for another big bottle of cold chocolate milkshake. I'm not exactly thirsty but I can still take sensory delight in it in the autie sense. Love that stuff going down.


Of the AMPAkines, DM-235 and PEPA are the ones that interest me most. The former I can synth the moment I get myself on memantine again to guard against potential toxicity and PEPA is interesting becaues it discriminates selectively between flip and flop isoforms of AMPARs.

PEPA is different where AMPAkines are concerned, because unlike most of them, it doesn't so much potentiate glutamatergic responses but it inhibits AMPAr desensitization,

DM-235/sunifiram on the other hand, I just need to buy a new scale, so I can weigh out the ingredients. Not to mention the compound itself. I was a klutz and melted my scale, and I certainly do not trust the household kitche digital scale to weigh down to a few mg.
 
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