Glutamate scavengers against excitotoxicity from withdrawal?

[blowpipe]

As far as I know withdrawing from GABAergics (benzos, ethanol etc)/possibly NMDA antagonists is excitotoxic because of increased glutamate-driven overstimulation. So in order to minimize neuronal death, why not use glutamate scavengers like oxaloacetate? They basically decrease the concentration of Glu in the blood, thus possibly decreasing the overstimulation. There are studies which show that such scavengers help decrease neurodegradation caused by Glu, but which in turn is caused by other events, so I'm wondering if the same approach would work for drug withdrawal. If it worked, would it ease the symptoms of said withdrawal?

http://www.nature.com/jcbfm/journal/v34/n2/full/jcbfm2013186a.html
http://www.ncbi.nlm.nih.gov/pubmed/22711471

 

[TriputoryHeadicine]

As far as I know withdrawing from GABAergics (benzos, ethanol etc)/possibly NMDA antagonists is excitotoxic because of increased glutamate-driven overstimulation. So in order to minimize neuronal death, why not use glutamate scavengers like oxaloacetate? They basically decrease the concentration of Glu in the blood, thus possibly decreasing the overstimulation. There are studies which show that such scavengers help decrease neurodegradation caused by Glu, but which in turn is caused by other events, so I'm wondering if the same approach would work for drug withdrawal. If it worked, would it ease the symptoms of said withdrawal?

http://www.nature.com/jcbfm/journal/v34/n2/full/jcbfm2013186a.html
http://www.ncbi.nlm.nih.gov/pubmed/22711471

I like how you think Blowpipe.

B12 is highly effective, and should be taken by every for so many great reasons. B vitamins should be taken all together so they don't throw off each others' levels- too much of 1 imbalances the others.

Cannabidiol, AKA CBD is my favorite, because it makes things SO much more comortable. I love talking about healthy use and abuse, hit me up if you ever wanna chat.

 

[sekio]

As far as I know withdrawing from GABAergics (benzos, ethanol etc)/possibly NMDA antagonists is excitotoxic because of increased glutamate-driven overstimulation.

Maybe in the heaviest of GABAergic addictions it could be irrparably toxic. But honestly, I strongly suspect feeling crap from the withdrawals is not necessarily an indicator of damage , there are many more variables at work, and the brain is quite plastic. As far as I know "NMDA antagonist withdrawal" is not toxic or even much of a concern. There's, at worst, a few hours of comedowns and a day or two as your body eliminates the 2nd or3rd order dissociative metabolites.

Would taking gluamate help? I don't think so. Taking extra could be expected to dp very little as your brain must actively transport it in. So increasing concentration of glutamate/oxaloacetate is a No.

 

[blowpipe]

I've encountered mixed opinions on the extent of neurodegradation from GABAergic withdrawal. I'm not addicted and not going to enter withdrawal - this is just out of pure curiosity. My primary concern is excitotoxicity, not the subjective symptoms of withdrawal. I'm aware that NMDA antagonist WD is not necessarily excitotoxic, but then again I recently came across a study that suggested that ketamine use results in neurotoxicity (what the study was escapes me right now).

Did you take a look at the articles I linked? The point is not taking glutamate, but taking a substance that decreases the concentration of glutamate, such as oxaloacetate or pyruvate. Taking glutamate would be a move in the opposite direction, but as you said it would have minimal impact.

I'll re-state the idea behind this thread. The articles describe how taking agents that decrease glutamate help prevent/decrease damage to the brain resulting from glutamate "outbursts" following an injury or poisoning. Since possible neurotoxicity of a (heavy) GABA withdrawal is mediated by glutamate, I thought maybe the same treatment could be used. Decrease in WD symptoms would just be a plus if it all worked.

 

[serotonin2A]

If oxaloacetate or pyruvate were effective at reducing excitotoxicity in humans then they would be given to stroke patients, but they are not. They have multiple biochemical effects, and they could potentially even mske things worse through their other effects.

 

[Cotcha Yankinov]

A lot of the pathophysiology of ALS is glutamate related (too much glutamate essentially) so this is an arena with a little research behind it. A drug Riluzole was interesting I remember, here's something from wiki on it.

"Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.^[12][13] Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.^[14] However, the action of riluzole on glutamate receptors has been controversial, as no binding of the drug to any known sites has been shown for them.^[15][16] In addition, as its antiglutamatergic action is still detectable in the presence of sodium channel blockers, it is also uncertain whether or not it acts via this way. Rather, its ability to stimulate glutamate uptake seems to mediate many of its effects.^[17][18] In addition to its role in accelerating glutamate clearance from the synapse, Riluzole may also prevent glutamate release from presynaptic terminals.^[19] These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves."

Then there is stuff like gabapentin that we don't know all about how they work yet but it seems to mess with glutamate decarboxylase and increases GABA synthesis without having actual GABA affinity. Apparently not too helpful for alcohol WD seizures but it is an anti-epileptic med itself and WD from it can sure cause seizures so idk.

Interesting approach and very interesting studies though, I was wondering if the blood concentration of glutamate would be important since peripheral serotonin levels don't correlate very well to neuronal levels but the second study says "Our method causes a rapid decrease of blood Glu levels and creates a gradient that leads to the efflux of the excess brain Glu into the blood, thus reducing neurotoxicity."

The main excitotoxicity from GABA withdrawals is during the seizures themselves, so trying to reduce the amount of glutamate that's available to overfire would make complete sense but I've never heard of this angle being used in epilepsy (until now I guess). Though let me put it out there that just because we haven't done it yet doesn't mean it won't work, whatever the tradeoff of a oxaloacetate like substance would be messing with all your synthesis cycles and everything it might be a therapeutic option that is just yet unexplored (medicine sucks sometimes, trust me). I'm wondering if reducing glutamate is helpful for minimizing gliosis reactions from WDs. Excitotoxicity leads to mitochondrial death and production of ROS so minimizing the glutamate available to overfire and make ROS in the first place makes sense for not only saving the specific cells but it also makes sense to impede the harmful gliosis, not that gliosis is all bad but it has its ups and downs.. I should mention I think gliosis would be a reaction to the ROS/inflammation from the glutamatergic storm and wouldn't necessarily be excitotoxicity itself but would be another bad long term effect from excitotoxicity. Interesting idea, any guinea pigs for oxaloacetate/pyruvate though? 0.0

 

[dopamimetic]

This is a very important topic in my eyes, as so much of the enormous distress resulting from various drug withdrawals as well as tolerance development & loss of effects (most pronounced of course with opioids & GABAergics, but there is also a strong connection with dopamine / psychostimulants and through downstream mechanisms everything is interconnected in the brain) seems to be somewhat related to an imbalance in excitation and glutamate being crucial here.

If you search on PubMed for NMDA antagonism & opioid tolerance / benzodiazepine withdrawal / stimulant tolerance - there is so much exciting evidence. And it actually works, as many anecdotal reports confirm as well as my own experiences. Blocking NMDA at a reasonable degree (sub-dissociative) relieves so much distress, literally erases tolerance development to psychostimulants, lessens the rebound so much, gets one off opioids (low-dosed but enough still) without going through the terrible withdrawal and all this.

It even helps with those horrible brain zaps from SSRI withdrawal. Granted, I seem to have a natural, genetic prevalence for excess glutamate, and it is very possible that it won't work for every single person. But even if it does only work for 50%, or 25%, it would be a huge benefit. Every single person who can get around withdrawal, protracted PAWS with disabling depression, dysphoria, fatigue etc. is worth it. And I highly guess there are many people with excess excitation, also being predisposed to PAWS, who because of this even begin to use sedatives / narcotics.

--

A seriously interesting link I've just found through this thread is the NADPH oxidase. I don't understand the whole complexity yet, but it seriously raised my interest to see that NADPH & oxaloacetate are interconnected.
Dextromethorphan is a NADPH oxidase inhibitor. There are links to thyroid disorder, irritable bowel syndrome, and of course - excess glutamate, even ALS. So DXM is not only a dissociative, but it directly helps in scavenging glutamate by inhibiting NADPH oxidase, eventually leading to more oxaloacetate ... and there is this nice little vanillin-related Apocynin which acts as a selective NADPH oxidase inhibitor & an antioxidant. The relieving effects of DXM without all the psychotomimesis? Would be too good to be true, I have to be misinterpreting somewhat ...

--

And it even continues:
The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses.
Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. (The link to inflammation & IL-6. Wow!)

It is just so confusing. Does now inhibiting the NOX2 help or activating it? Maybe even both is true, depending on the genetics?

IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase.
Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

Repetitive adult exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex.

Oh fuck. But they say it's reversible in the adult brain - of course if everything is normal. With genetic predispositions this can be different. So ketamine would actually make things worse & DXM the opposite because it additionally inhibits NADPH oxidase to its dissociative effects...!? Well, would make some sense why memantine (purely lowering glutamate & showing some anti-inflammatory effects) is more a sedative & the arylcyclohexylamines are strong relievers, but also hypomania-inducing and have a somewhat excitatory rebound (because NADPH oxidase gets upregulated and after the NMDA blockade wears off, one has more glutamate than before... but also while under the influence, the overall glutamate rises, leading to a sum of less NMDA : more AMPA activity --> the pro-cognitive effects of racetams / AMPAkines. Makes perfect sense somewhat in why I'm processing information so much faster whilst on arylcyclohexylamines when they should actually inhibit memory. Or, to be exact, after an initial adjustment phase of 1-2 days ... with initial dissociation from the pure NMDA blockade and then eventually the NADPH oxidase increases and AMPA activity rises.)

So in the end, we need to inhibit NOX2 & the Apocynin could actually be a miracle in relieving depression from glutamate excess??
Or memantine & unifiram would be so incredibly nice to have this mood-lifting, depression- and anxiety-erasing nootropic-alike sobering effect chronic low-dosed MXE induces on a legal, sustainable and non-dangerous way..