Novel Zephyr
Greenlighter
I would like to propose a neurologically hypothetical explanation of PTSD, for critique; so I can better discern whether it's worth more of my time.
Kynurenic acid, a molecule that naturally occurs in the central nervous system, acts almost exclusively by blockage of NMDA receptors. Alcohol, as well as certain cannabinoids and opiates, have secondary actions as NMDA blockers. I propose that the endogenous purpose of its antagonism is to forestall propagation of psychologically destructive adaptations. This is why we give drugs with its effect to people before operation or surgery, rather than simply strapping them in place so tightly that they can't move. Likewise, I propose that it alone offers a means to dissociate from the sorts of trauma that cause PTSD, and that the side-effects of NMDA antagonists are responsible for modern medicine's failure to develop effective pharmacological treatments for PTSD.
A study, which can easily be found by exploring the references on kynurenic acid's Wikipedia page, demonstrated that mice, whom researchers had genetically engineered to produce minimal amounts of this molecule, exhibited drastically improved cognitive function. They offer minimal explanation about why this happened, from a neurological standpoint; but I've been reflecting on it for months, and believe that I've discovered why.
Piracetam, a drug that (for over four decades) has demonstrated virtually no effects on mammals except improvement of cognition, immediately increases activity of AMPA receptors, and (after weeks of administration) increases acetyl-choline receptors' density in the frontal cortex. Acetyl-choline receptors are a more generic (and useful) type of the sort that allows nicotine to improve cognitive function, for very brief spans of time, and forestall dementia with chronic use.
Both AMPA and NMDA receptors are activated by glutamate, the most abundantly occurring neurotransmitter in the mammalian CNS; however, unlike NMDA receptors, activation of AMPA receptors does not drastically increase neurons' own excretion of glutamate (a profoundly neurotoxic phenomenon). I propose that cognitive deficits, caused by frequent and thorough antagonism of NMDA receptors, arise from downstream reduction of AMPA receptors' activity (through reducing excretion of glutamate), and consequently lowering the density of acetyl-choline receptors, in a manner opposite of piracetam's effects.
(This becomes quite hypothetical, though, because the source that I found, about piracetam's downstream increase of acetyl-choline receptor density, did not demonstrate that this phenomenon was mediated by increase of AMPA receptor activity; however, after years of searching, I have found no other immediate, pharmacologically significant effects of administrating piracetam. I will doubt this connection when I discover a reason to do so.)
Assuming that I am correct (about the possibility that NMDA antagonists' side-effects are mediated by down-regulation of acetyl-choline receptor density), however, then I propose three means by which such side-effects could be mitigated (without preventing the emotionally dissociative effects sought by blockage of NMDA receptors), none of which have demonstrated clinically significant side-effects. One, of course, would be administration of piracetam. The second would be to increase choline intake; it's a naturally occurring component of our diets (though its concentration is very poor in most foods), which is necessary for the body's production of acetyl-choline, and which most Americans consume at approximately 5% to 10% of an ideal daily quantity. The third would be administration of a reversible acetyl-cholinesterase inhibitor, such as Huperzine A or Donepezil (i.e. "Aricept"), which typically have negligible side-effects, even at high doses.
Ketamine and ibogaine (NMDA antagonists) have been demonstrated to treat otherwise refractory cases of depression. I propose that such cases (when ketamine or ibogaine works, but all else fails) are not technically cases of "depression" (at least as modern psychiatry tends to define the term), but instead misdiagnosed instances of PTSD. As well, I propose that the side-effects (such as loss of coordination, memory and coherence), which typically arise from frequently and thoroughly blocking NMDA receptors (even for other psychiatric purposes, like treatment of dementia), will be negated by the three aforementioned means of increasing acetyl-cholinergic activity.
Tangentially, I'd also like to conjecture that the CNS up-regulates production of kynurenic acid, or a similarly endogenous NMDA antagonist, when exogenous sorts are not administered during episodes of emotional trauma. During a few years of events, in mid later childhood, which later resulted in my diagnosis of PTSD, I naturally experienced episodes that remarkably resembled second and third plateau DXM trips. Long after the trauma (and seemingly consequential psychotic reactions) ended, however, I continued to experience relatively deficient cognitive functions; though what I'm about to describe may of course be placebo, I feel as if the last few weeks of taking choline, piracetam and Huperzine A have begun restoring my capacity for attention to a degree that I have lacked since earlier in childhood.
Kynurenic acid, a molecule that naturally occurs in the central nervous system, acts almost exclusively by blockage of NMDA receptors. Alcohol, as well as certain cannabinoids and opiates, have secondary actions as NMDA blockers. I propose that the endogenous purpose of its antagonism is to forestall propagation of psychologically destructive adaptations. This is why we give drugs with its effect to people before operation or surgery, rather than simply strapping them in place so tightly that they can't move. Likewise, I propose that it alone offers a means to dissociate from the sorts of trauma that cause PTSD, and that the side-effects of NMDA antagonists are responsible for modern medicine's failure to develop effective pharmacological treatments for PTSD.
A study, which can easily be found by exploring the references on kynurenic acid's Wikipedia page, demonstrated that mice, whom researchers had genetically engineered to produce minimal amounts of this molecule, exhibited drastically improved cognitive function. They offer minimal explanation about why this happened, from a neurological standpoint; but I've been reflecting on it for months, and believe that I've discovered why.
Piracetam, a drug that (for over four decades) has demonstrated virtually no effects on mammals except improvement of cognition, immediately increases activity of AMPA receptors, and (after weeks of administration) increases acetyl-choline receptors' density in the frontal cortex. Acetyl-choline receptors are a more generic (and useful) type of the sort that allows nicotine to improve cognitive function, for very brief spans of time, and forestall dementia with chronic use.
Both AMPA and NMDA receptors are activated by glutamate, the most abundantly occurring neurotransmitter in the mammalian CNS; however, unlike NMDA receptors, activation of AMPA receptors does not drastically increase neurons' own excretion of glutamate (a profoundly neurotoxic phenomenon). I propose that cognitive deficits, caused by frequent and thorough antagonism of NMDA receptors, arise from downstream reduction of AMPA receptors' activity (through reducing excretion of glutamate), and consequently lowering the density of acetyl-choline receptors, in a manner opposite of piracetam's effects.
(This becomes quite hypothetical, though, because the source that I found, about piracetam's downstream increase of acetyl-choline receptor density, did not demonstrate that this phenomenon was mediated by increase of AMPA receptor activity; however, after years of searching, I have found no other immediate, pharmacologically significant effects of administrating piracetam. I will doubt this connection when I discover a reason to do so.)
Assuming that I am correct (about the possibility that NMDA antagonists' side-effects are mediated by down-regulation of acetyl-choline receptor density), however, then I propose three means by which such side-effects could be mitigated (without preventing the emotionally dissociative effects sought by blockage of NMDA receptors), none of which have demonstrated clinically significant side-effects. One, of course, would be administration of piracetam. The second would be to increase choline intake; it's a naturally occurring component of our diets (though its concentration is very poor in most foods), which is necessary for the body's production of acetyl-choline, and which most Americans consume at approximately 5% to 10% of an ideal daily quantity. The third would be administration of a reversible acetyl-cholinesterase inhibitor, such as Huperzine A or Donepezil (i.e. "Aricept"), which typically have negligible side-effects, even at high doses.
Ketamine and ibogaine (NMDA antagonists) have been demonstrated to treat otherwise refractory cases of depression. I propose that such cases (when ketamine or ibogaine works, but all else fails) are not technically cases of "depression" (at least as modern psychiatry tends to define the term), but instead misdiagnosed instances of PTSD. As well, I propose that the side-effects (such as loss of coordination, memory and coherence), which typically arise from frequently and thoroughly blocking NMDA receptors (even for other psychiatric purposes, like treatment of dementia), will be negated by the three aforementioned means of increasing acetyl-cholinergic activity.
Tangentially, I'd also like to conjecture that the CNS up-regulates production of kynurenic acid, or a similarly endogenous NMDA antagonist, when exogenous sorts are not administered during episodes of emotional trauma. During a few years of events, in mid later childhood, which later resulted in my diagnosis of PTSD, I naturally experienced episodes that remarkably resembled second and third plateau DXM trips. Long after the trauma (and seemingly consequential psychotic reactions) ended, however, I continued to experience relatively deficient cognitive functions; though what I'm about to describe may of course be placebo, I feel as if the last few weeks of taking choline, piracetam and Huperzine A have begun restoring my capacity for attention to a degree that I have lacked since earlier in childhood.
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