Trying to understand why MXE is having these effects

[vortech]

I swear I wish a lab team would take me in and study my brain when I'm on MXE because it is a regular experience for me on this drug to feel some truly amazing things up there.
Anyway, while I have a great number of theories and unanswered questions regarding MXE, for this post I will focus on one effect. After two years of regular use, I feel like my brain is working much more sharply and in tune. Memory recall is more complete and responsive, access to my vocabulary is vast and always on cue in the moment, and I feel like I can process lots of abstract information and unconventional problems and reach the best conclusion very quickly.
My question is why it could be having these effects. What I know is that MXE is an NMDA receptor antagonist. I also know that there are a breed of smart drugs and nootropics that act as NMDA receptor agonists. Is it possible that MXE improves my cognition after prolonged conditioning by causing my brain to counter-balance the antagonism as the tolerance to the drug builds, so that when I'm not on the drug it is effectively equivalent to being on a drug that acts as an NMDA receptor agonist?
If this is not a reasonable explanation, what other pharmacological actions of MXE could explain an increase in 'sharpness'?

 

[endotropic]

I swear I wish a lab team would take me in and study my brain when I'm on MXE because it is a regular experience for me on this drug to feel some truly amazing things up there.
Anyway, while I have a great number of theories and unanswered questions regarding MXE, for this post I will focus on one effect. After two years of regular use, I feel like my brain is working much more sharply and in tune. Memory recall is more complete and responsive, access to my vocabulary is vast and always on cue in the moment, and I feel like I can process lots of abstract information and unconventional problems and reach the best conclusion very quickly.
My question is why it could be having these effects. What I know is that MXE is an NMDA receptor antagonist. I also know that there are a breed of smart drugs and nootropics that act as NMDA receptor agonists. Is it possible that MXE improves my cognition after prolonged conditioning by causing my brain to counter-balance the antagonism as the tolerance to the drug builds, so that when I'm not on the drug it is effectively equivalent to being on a drug that acts as an NMDA receptor agonist?
If this is not a reasonable explanation, what other pharmacological actions of MXE could explain an increase in 'sharpness'?

You mention that you've noticed these effects over two years of use, and I assume that you're seeing these effects in your day to day life and not just when high. If you're under the age of 30, the effects that you're describing could just be the effect of your brain finally approaching a mature state of development. I experienced the same sort of cognitive gains throughout my early 20's, irrespective of drug use.

My second best guess is that all of the effects that you've mentioned are the dead opposite of the cognitive loss that depressed individuals experience. NMDA antagonists should reverse those effects as a consequence of improving your mood.

 

[vortech]

Correct, I am seeing these effects in my day to day life outside of drug-induced states of consciousness.
The fact that I have indeed seen vast improvements in my mood, energy and disposition over these two years could be the likely explanation for the perceived increase in acuity.
I am 31 years old.

 

[MyDoorsAreOpen]

The effects you're describing ring true for me as a person who used DXM every day for 2.5y. I think there's something to the theory that NMDRAs (in concert with other neurotropic effects like serotonin and/or NE reuptake inhibition, DA agonism, mu and kappa agonism, GABA agonism other "soothing" effects on a depressed brain that are specific to, and to a large degree differentiate, different drugs in this class) do a lot to shut down the thought loops and and viscious cycles of mentations that keep a person feeling disempowered, helpless, and depressed. Now, if the person doesn't promptly get up off his ass and make sure the underlying causes that led him to feel this way aren't cut out for good, this will be only a temporary solution, and the feelings of learned helplessness (i.e. depression) will become reentrenched and working their neuron-stunting mojo in no time. Clinically, I have good feelings about short (but perhaps intense) courses of NMDARAs in a medically-supervised setting as a once in a lifetime or rare jolt out of a very depressed state. It's similar to how I feel about electroshock therapy; I'm a whole lot leerier about a clinician prescribing either one to patients at regular frequent intervals over long periods of time, before a LOT more research is done.

 

[ebola?]

Clinically, I have good feelings about short (but perhaps intense) courses of NMDARAs in a medically-supervised setting as a once in a lifetime or rare jolt out of a very depressed state. It's similar to how I feel about electroshock therapy; I'm a whole lot leerier about a clinician prescribing either one to patients at regular frequent intervals over long periods of time, before a LOT more research is done.

Why so cautious as to suggest "once in a lifetime" administration? Thus far, clinical trials show maintenance of efficacy for a few weeks. It seems to me that reinstating the anti-depressant effect periodically would be key. Also, we're beginning to tease apart the relevant mechanism (something happens downstream, possibly involving neural adaptation, increasing neuroplasticity localized to the pfc and hippocampus). I mean, we still don't really know how SSRIs work (insofar as the actually do), and it might be a downstream mechanism that converges with that induced by NMDA agonism. So with this mechanism, high-dose regimens might actually be counterproductive, but we don't yet really know.

ebola

 

[MyDoorsAreOpen]

^ OK, maybe I was being a little overly cautious with that recommendation. I think you basically answered your own question -- we need more research. My concern with frequent use of NMDARAs is twofold. First, all anecdotal reports (including my own) seem to suggest that tolerance to these agents, once acquired, appears to be permanent. Secondly, there are serious concerns with I have with gumming up the pathway of long-term potentiation for extended periods of time, especially when it comes to learning and memory.

It's a bit of a conundrum -- there seems to be a direct relationship between a very sharp memory the the tendency to get depressed. More often than not, I find in clinical practice, those who are depressed are those who cannot forget, and cannot ignore the clear logical connections that le[a]d to their misfortune. It's been amply demonstrated that high intelligence, which correlates with a sharp working memory, also correlates with the predisposition to become depressed. I've long said that if my life were totally bleak, I'd much rather be dumb than smart. At least the dumb can delude themselves into thinking there's still hope for them. A smart and educated person who's totally fucked, meanwhile, can see exactly why they're fucked.

I should add here that in my observation, the so-called "depression" that's considered one of the hallmark negative symptoms of schizophrenia (and to a lesser extent, the depressive phases of bipolar disorder, especially in some individuals who are prone to psychosis in the manic phases, and whose bipolar is more "schizophrenia flavored", if I can be a bit crass) is really an entirely different mental state than the depression of unipolar / major depression. The former could more correctly be called abulia, a completely "neutral" mood, the absence of any emotion, painful or joyful. The only emotion I've seen most florid schizophrenics express in large amounts is fear. They don't feel much if any joy, but nor much anger or sadness either. This is generally exactly as I feel during the "coast" of a strong ketamine experience. It's not euphoria by any means, but it's a whole different, and far preferable, state to how I've felt in the throes of major depression brought on by life stressors before I ever touched any drugs. And I'm certain, in both NMDARA usage and in schizophrenia, that this lack of emotion is directly related to a broken or interrupted mechanism for putting together logical causal chains and using these as the basis for emotion-tinged memories. Why? Because long-term potentiation via NMDA and AMPA receptors is what comprises the "trodden trail" of fire-together-wire-together between the brain's emotional centers and those that encode memory.

Maybe at the neurochemical level, ignorance truly is bliss

 

[arctica]

On a side note, depression itself can make you just as stooopid as burning out your receptors on various chemicals. My IQ has dropped ~20 points in my present depressive episode (mostly on the math side, in accordance with the literature on the subject), and a recent QEEG showed that the idling speed of my brain is about 20% under what is normal for a woman my age (I assume this is the psychomotor retardation I've been experiencing). In other words, I have the brain of a 70-year-old woman at 34, not that I needed something else to cry about. Perhaps my docs are blowing sunshine up my ass, but they claim that I should be able to regain whatever it was I lost when the depression goes into remission, as opposed to losing 20 IQ points from a traumatic brain injury, which is apparently more permanent.

ETA: While I certainly have depressive ruminations and anxiety at off-the-charts levels, I've noticed that dissociatives (e.g., N2O) have caused the most intense (sometimes frightening, though very transient) feelings of being stuck in "thought loops." Does anyone else notice increased thought loops on dissociatives?

An example: the first time I tried nitrous, I looked at my friend, and he started repeating digits over and over "0, 2, 0, 2, 0, 2, 0, 2, 0, 2, 0, 2, 0, [...] and after some confusion about the significance of the digits, the rest of the sentence finally clicked: "zero to nitrous fiend in 20 seconds." It was entirely an auditory hallucination. I've had the same feeling inside my head, though, where I get hung up on the first part of a thought, and it's almost like a thought stutter until finally things click into place and the rest of the thought comes through.

 

[ebola?]

It's a bit of a conundrum -- there seems to be a direct relationship between a very sharp memory the the tendency to get depressed. More often than not, I find in clinical practice, those who are depressed are those who cannot forget, and cannot ignore the clear logical connections that le[a]d to their misfortune. It's been amply demonstrated that high intelligence, which correlates with a sharp working memory, also correlates with the predisposition to become depressed. I've long said that if my life were totally bleak, I'd much rather be dumb than smart. At least the dumb can delude themselves into thinking there's still hope for them. A smart and educated person who's totally fucked, meanwhile, can see exactly why they're fucked.

I find this observation intriguing, particularly as hippocampal atrophy commonly occurs as depressive illness progresses. So it could also be that as depression progresses, the encoding of new experiences interfere less and less with focus on memories of regret. Now, working memory capacity is another matter, implemented by distinct neural circuits, relating to other aspects of experience.

This is generally exactly as I feel during the "coast" of a strong ketamine experience. It's not euphoria by any means, but it's a whole different, and far preferable, state to how I've felt in the throes of major depression brought on by life stressors before I ever touched any drugs. And I'm certain, in both NMDARA usage and in schizophrenia, that this lack of emotion is directly related to a broken or interrupted mechanism for putting together logical causal chains and using these as the basis for emotion-tinged memories. Why? Because long-term potentiation via NMDA and AMPA receptors is what comprises the "trodden trail" of fire-together-wire-together between the brain's emotional centers and those that encode memory.

I can see the connection between these emotional states, but I'm still skeptical of the inferred physiological cause, as we don't yet know enough about the physiology of schizophrenia, or even why negative and positive symptoms 'hang together' for some of those afflicted but not others.

 

[Moredopamine]

Maybe you just 'think' your cognitive capacities have increased at this point in your life. A lot of how you view your intellectual performance is emotional in nature. Maybe if you had some hard evidence that you have become cognitively superior after your use, then this might be worthy of some more serious investigation.

For example, after taking amphetamine, I 'feel' intellectually superior, but my performance of various cognitive tasks (such as those testing working memory, visuospatial skills, etc) doesn't improve at all. It's all in the head, I think.

 

[oar9fi]

I know that ketamine is being researched to treat a condition known as Reflex Sympathetic Dystrophy where, after an injury, pain receptors become sensitized and stuck in an activated state. It manifests as burning pain when there is no actual stimulus. They just create "noise." I imagine a similar effect happens in other neurons.

By turning off some of the unnecessary neural pathways (in both central and peripheral neurons), you are able to get a kind of better signal to noise ratio. Just a guess...

 

[arctica]

I know that ketamine is being researched to treat a condition known as Reflex Sympathetic Dystrophy where, after an injury, pain receptors become sensitized and stuck in an activated state. It manifests as burning pain when there is no actual stimulus. They just create "noise." I imagine a similar effect happens in other neurons.

By turning off some of the unnecessary neural pathways (in both central and peripheral neurons), you are able to get a kind of better signal to noise ratio. Just a guess...

This is interesting to me, with respect to my recent QEEG findings and the definite antidepressant effect I immediately get from ketamine:

One of the irregularities found was:

Excess Beta and High Beta, predominantly across the frontal lobes, but upon a more detailed look, also the cingulate as well as nearly globally at certain frequencies. Excess beta is correlated with high anxiety, emotional deregulation (especially in the frontal lobes), and rigid thinking and rumination (along the cingulate). With this much excess Beta it is likely the brain is working very hard which could create mental and physical fatigue, low adrenal levels, and possibly excess cortisol levels. It is common to see depression mixed with anxiety with beta like this.

Is it possible that the ketamine is knocking out some of the signaling pathways responsible for the excess beta/high beta?

 

[Chris Timothy]

Even though MXE might indeed technically harm the cerebral forest, nothing makes a bush grow like gently pruning it.

 

[arctica]

This is interesting to me, with respect to my recent QEEG findings and the definite antidepressant effect I immediately get from ketamine:

One of the irregularities found was:

Is it possible that the ketamine is knocking out some of the signaling pathways responsible for the excess beta/high beta?

Apparently, the answer is NO. I had another QEEG performed yesterday after 20+ neurofeedback sessions (2/week) and ~10 weeks of ketamine treatment and it appears that while the alpha-theta reversal is improved, the excess beta/high beta is definitely worse, and at some frequencies, is almost global in nature.

 

[Reverend Random]

Didn't read the thread yet, but here's a phenomenological study of methoxetamine that came out recently. It might be of interest to some. Full article here.