Yes, appreciate that. But it's possible that supplements which reduce NMDA activation, or boost GABA activation, may help. If you look at the theory of central sensitivity syndrome (CSS), the idea is that pain may be amplified to a higher level than normal in the central nervous system, and I believe NMDA activation from high glutamate is implicated in this CSS amplification. I can't remember the details, as it has been a while since I looked into CSS.
However, the idea of glutamate/NMDA activation being behind pain amplification makes sense, since the NMDA receptor is basically the volume or gain control on a neuron. The more you turn up NMDA, the more the neuron amplifies its inputs, and thus creates a stronger output.
My theory is that if this excessive NMDA activation (and neuron output amplification) occurs in the circuits of the brain that mediate anxiety, then this excessive amplification may cause ramped up anxiety, and you will suffer from generalized anxiety disorder, as I did.
But if this excessive NMDA activation occurs in CNS circuits which are involved in pain signal transmission, then maybe instead you get ramped up pain.
Anyway, some of the supplements in my list of 29 I believe work by reducing NMDA activation, so possibly they might work for pain. The high-dose transdermal magnesium helps block NMDA receptors. Oral magnesium will not work, as bowel flushing prevents you from taking high doses. (I have not tried memantine, which blocks the NMDA receptor, so I cannot compare magnesium to that; but I found transdermal magnesium had noticeable effects on anxiety).
The N-acetyl glucosamine I suspect works because it may reduce brain inflammation, and inflammation in the brain produces copious amounts of glutamate, which activates the NMDA receptor. So if you use anti-inflammatories which work in the brain and CNS, you are targeting the root cause of the NMDA activation, which is the glutamate produced from brain inflammation.
What about this drug that's normally used for alcohol withdrawal... I'm wondering if it could help with dependence on other gabaergics
PharmacodynamicsEdit
The
pharmacodynamics of acamprosate are complex and not fully understood;
[11][12][13] however, it is believed to act as an
NMDA receptor antagonist and
positive allosteric modulator of
GABAA receptors.
[12][13]
Its activity on those receptors is indirect, unlike that of most other agents used in this context.
[14] An inhibition of the
GABA-B system is believed to cause indirect enhancement of
GABAA receptors.
[14] The effects on the NMDA complex are dose-dependant; the product appears to enhance receptor activation at low concentrations, while inhibiting it when consumed in higher amounts, which counters the excessive activation of NMDA receptors in the context of alcohol withdrawal.
[15]
The product also increases the endogenous production of
taurine.
[15]
Ethanol and benzodiazepines act on the central nervous system by binding to the GABAA receptor, increasing the effects of the inhibitory
neurotransmitter GABA (i.e., they act as
positive allosteric modulators at these receptors).
[12][4] In chronic alcohol abuse, one of the main mechanisms of
tolerance is attributed to GABAA receptors becoming downregulated (i.e. these receptors become
less sensitive to
GABA).
[4] When alcohol is no longer consumed, these down-regulated GABAA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to
physical withdrawal symptoms;
[4] since GABA normally inhibits
neural firing, GABAA receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer
inhibitory postsynaptic potentials occur through GABAA receptors), leading to neuronal over-excitation (i.e., more
action potentials in the postsynaptic neuron). One of acamprosate's mechanisms of action is the enhancement of GABA signaling at GABAA receptors via positive allosteric receptor modulation.
[12][13] It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control
tinnitus, hyperacusis, ear pain and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.[
medical citation needed]
In addition, alcohol also inhibits the activity of
N-methyl-D-aspartate receptors (NMDARs).
[16][17] Chronic alcohol consumption leads to the overproduction (
upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of
delirium tremens and
excitotoxic neuronal death.
[18] Withdrawal from alcohol induces a surge in release of excitatory
neurotransmitters like
glutamate, which activates NMDARs.
[19] Acamprosate reduces this glutamate surge.
[20] The drug also protects cultured cells from excitotoxicity induced by
ethanol withdrawal[21] and from glutamate exposure combined with ethanol withdrawal.
[22]
The substance also helps re-establish a standard sleep architecture by normalizing stage 3 and REM
sleep phases, which is believed to be an important aspect of its pharmacological activity.
[15]
