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Ketamine and Glutamate

Solipsis

Solipsis

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This thread is mainly about ketamine and glutamate-modulating drugs but extends to other NMDA antagonist dissociative anaesthetics as well.

As I understand it ketamine can exert neuro-protective effects by blocking the N-P complex channel to block excitatory glutamate to flood in. It seems that higher concentrations of glutamate entering the neuron can prompt the action of ketamine to be stronger, if there is a sudden event like cardiac arrest where carbon dioxide levels rise, glutamate can excite brain cells to death causing irreversible trauma for which the human body seems to have evolved a protective mechanism. Even without ketamine endogenous compounds can block the N-P complex thereby 'shutting down' certain circuits and in result producing NDE-like internal dissociated experiences. [main source: Ketamine - Dreams and Realities by Dr Karl Janssen]

My question is: would one expect glutamate-modulating (esp. increasing) agents to potentiate the action of ketamine? Would you need to go so far with this that it becomes dangerous regarding encitotoxicity? Is MSG active this way or does it not pass the BBB? If possible, what drugs could be used to increase glutamate?

This hypothesis is for theoretical purposes only at this moment. I would never subject myself to significant encitotoxicity that way or risk thereof.
 
If your interested in the Molecular mechanisms off the NMDAR's then it is essential you learn of hebbian plasicity and about the relevent subunits of the NMDARs. I understand that the primary effects of ketamine is to blocks NR2bs(at the synapes responisable for LTP and at extrasynaptic sites for blocking LTD induced by synaptic NR2A's). Because NR2bs are prefferentially extrasynaptic there main effects on blocking is to increase LTD at lower doses. At higher doses blocking LTP causes a complete shutdown of central regions of the brain.

Regarding your question
It is impossiable to be definitive to a question that is this broad. There are to many variables to arrive at a singular answer. For instance increasing glutamate in one area of the brain often leads to decreases in other areas. Ketamine's antidepressant effects is actually mediated by an dramactic increase in AMP mediated through extrasynaptic shutdown.
The main variables
what NMda antagonist(they mostly have different binding targets)
The concentration achieved in the brain( alters dynamics often from +to- or -to+
THe pro glutamate agent.

Both NMDA antagonist and Proglutamate agents can display neurotoxicity of varying degrees, while is some cases they may provide co-protection they generally will not and will lead to atleast additive neurotoxic effect


Extrasynaptic NMDARS oppose synapic NMDARS via CREB shutoff pathway(more general)


Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have
opposite effects on CREB (cAMP response element binding protein) function, gene regulation and
neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brainderived
neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium
channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate
exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway
that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic
activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial
membrane potential (an early marker for glutamate-induced neuronal damage) and cell death.
Specific blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss following
stroke and other neuropathological conditions associated with glutamate toxicity
Modafinil is a nice proglutamate
 
Thank you!

Modafinil a proglutamate? Thats convenient, I have that...
Seems like the combination with (S-)ketamine is an unpredictable one at best.
Can't remember having ever "accidentally" used the two in conjunction.
 
Wtf? Modafinil? I wondered the other day why the k didn't hit as hard as it usually does, and it occurred to me that i didn't take any modafinil that day.. I didn't give it any second thought, as it just seemed so unlikely with a connection there.

Normally i take moda/adra on a daily basis.

So yeah, just anecdotal, but surely not placebo. But still unclear, i'm on piracetam too, which has NMDA-activity.

But uh.. am i frying my brain more efficiently this way? 8)

(I started another thread kind of related to this subject earlier today, before i found this. If anyone knowledgeable would care to answer in it, it would be deeply appreciated)
 
No, if you do a search on BL you should be able to find multiple posts (some by myself) indicating that the -racetam drugs seem to block the effects of K.

In my book, anything that cancels the effects of K, through whatever mechanisms, is poison and should be disposed of in a waste management facility so as not to ruin the little lives of poor rats and roaches that live in our drains...
 
:)

I've seen that. I just meant that the situation involved more things than just K and modafinil, and by so harder to draw any conclusions from. I take much less piracetam on K-days, and just in the morning..
 
I think modafinils proglutamate effects are mediated via an antagonist effect on glutamate(there are many feedback systems). Very similiar to cocaine maybe via sigma-2. Stacking modafinil maybe dissassociative in its own right

I was reffering before to direct or closely indirect agonists(maybe partial) as being dangerous in ketamine use. Dissassociatives cause intense stimulation in the cingigulate? There is an article on erowids that is very well written regard contradiction with dextrametamorphan.
 
According to the Merck Manual, PCP produced a "bewildering array" of neurophysiological effects on the central nervous system. I would expect the same of ketamine.

As for ketamine proper, one of its most clinically significant aftereffects is something known as emergent psychosis. You can read a description of that phenom in the Physician's Desk Reference.

I can tell u this based on personal experiences: ketamine induced emergent psychosis is not something I want to have again.
 
IM'ed a vial (1.2 g) Ketaset in 24 hrs. Experienced transient psychotic, outrageous outbursts while working at the uni library. Think James Brown.

I feel good!

Lasted around, 6 mos.

For example, one time my boss was like well, Why are you 30 mins late to work this am? And I exclaimed, Oh well, I must have taken TOO MUCH ECSTASY last night!!!, which was of course coming from me a true statement.
 
Dresden said:
As for ketamine proper, one of its most clinically significant aftereffects is something known as emergent psychosis. You can read a description of that phenom in the Physician's Desk Reference.
Click to expand...

LOL.

"Emergent Psychosis" is actually nothing more than medical jargon for what drug users usually call "K-hole" :D. Sometimes this is also described by physicians as "nightmares".
 
It's been years since I read the monograph's boxed warning, and I think you are right that emergent psychosis is synonmous with the k hole term, but let me assure you, emergent psychosis associated with ketamine and ketamine induced psychosis are two distinct side effects.

Another time I took ketamine when I was 19, after first being introduced to it, and started listening to Tricky's Pre-Millenium Tension a lot. And chuckling under my breath. And asking my friend to cut off my nose. And fantasizing about ripping off a bum's arm and eating it. Think Michael Alig.

I needn't do ketamine, you see.

They used to call me Tricky Kid. I live the life they wish they did. I live the life, don't own a car, but now they call me Superstar. Tell 'em where u at, Tricky! Tell 'em where u at, bb!
 
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First of all, glutamate doesnt enter the cell, it opens the ion channel and it is extracellular calcium entering that leads to cell death.

Ketamine is not selective for any subtype of the NMDA receptor as afar as i know.

There are no specific glutatmate releasing agents as far as i know.

The brain is EXTREMELY sensitive to changes in glu levels, and if you did eat msg and it crossed the BBB then its set up to deal with that. ITs jsut an amino acid. The only sure fire way to increase extracellular glu would be to hit yourself in the head and burst open your neurones.

I dont even think your reasoning that increasing glu levels will give ketamine a better effect is valid. The receptor is so ubiquitous, potentiating release will not have any 'effect' in the way potentating dopamine release does.
 
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