Author Topic: The Use of Lithium to alter glutamate reception  (Read 1996 times)

[Buddie]

The Use of Lithium to alter glutamate reception
« on: November 06, 2019, 05:39:17 pm »
Ok Buddies,

This is part of a thread that came from the "Protracted" area, where we were discussing ideas to actively reverse the damage benzos has caused us.  This was one of the ideas, and we will move the best of the posts on that topic here.

If you were not part of the original thread, give us a day to move the topics.  It is now 12:30 pm Eastern US time on Tuesday Nov. 6.  Please wait until Midnight Thursday Nov 8 wherever you live to make any comments on this topic.

Thank you all for your cooperation.

[...]
Your personal neuroscientist, reminding you to hang in there, and if you are going thru hell, keep going!
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #1 on: November 06, 2019, 06:21:56 pm »
Dear Buddies,

The idea that most of our pain is due to glutamate reception is not an original idea I had.  Other buddies have had it, and there is research to support it.  I will bring the discussion of how this could be done with Lithium from the protracated area where someone first brought it up.  But I want to start these two threads centered on glutamate with this opening:

My thesis statement is:

Although every case of Protracted Benzodiazepine Withdrawal Syndrome (PBWS) is unique, a cure that applies to almost every case is still possible.

Mutuuaria has posted:
“I believe the reason there is no collective consensus about what "works" is because we don't share the exact same pathologies. There can be no collective "treatment" that works for everyone, only individual treatments that work for individuals.”

I respect mutuu, and her opinion(s).  The part of that statement with which I firmly agree is “we don’t share the exact same pathologies.”  In fact I think the pathologies of those who suffer PBWS vary wildly from individual to individual.  But I still believe a cure that works for nearly everyone is possible because benzos can do only one thing: open an ionotropic GABA-A receptor to release negatively charged chloride anions (Cl-). Period.  That is all they do.  The dozens (hundreds?) of different things that happen to us all result from that one thing.

The reason there are so many different issues, and that each case is unique is that GABAergic nerves enervate every organ and body system and our CNS, and everyone’s genetics and epigenetics of those systems is different, which means literally almost anything is possible.

The very next thing that happens downstream is the Cl- anions immediately remove the positive charged (usually calcium, Ca+2) cations from the synapse.  If this happens once or a dozen times, no big deal.  But do this on a continuous basis, and the body responds by upregulating the number of glutamate receptors to receive the fewer cations, and probably also lowers their firing potential and duration the stay open, aka Long Term Potentiation (LTP) as well.  While this is the secondary effect, I think it is the longer lasting effect and the reason some of us are sick for so long.

Could I be wrong?  Yes, but I do not think so.  Ionotropic glutamate receptor upregulation is required for learning and so the mechanisms are well established.  But downregulation not normally required in nature, so why would it happen on its own?  Very, very, slowly to the painful, regular, presence of what is perceived as excess cations?  This might happen, and this would explain protracted success stories.

I have found a common term across a variety of disorders that have nothing to do with PBWS; “hypervigilance.” This is associated with the neurological conditions of Irritable Bowel Syndrome (IBS, which has “visceral” hypervigilance) Temporal Lobe Epilepsy (TLE), and Autism Spectrum Disorder (ASD), and the psychiatric conditions Generalized Anxiety Disorder (GAD) and Obsessive Compulsive Disorder (OCD), and those are just the main ones for which there is a tangible research consensus.  One only has to google any of those terms with “hypervigilance” and look at the plethora of articles that pop up.  Better still, google them with “glutamate,” and/or “NMDA, and AMPA.” and you will quickly see from where my thesis comes.  (I would add “prostatitis,” “chronic Lyme’s Disease,” and others, but those are speculative on my part and I have found no correlating research.)

Examples:
IBS
https://www.ncbi.nlm.nih.gov/pubmed/27356126
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817711/
TLE
http://www.biomed.cas.cz/physiolres/pdf/62%20Suppl%201/62_S21.pdf
ASD (autism)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134390/
PTSD
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482215/
OCD
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205262/

And I have already posted but to bring this full circle:
PBWS (US!)
https://www.jstage.jst.go.jp/article/jjp/81/1/81_1_1/_pdf/-char/en
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

Pain, stiffness, bloating/distention, anxiety, disruption of the HPA axis and everything that flows downstream from there, dozens if not hundreds of possible health issues, all stemming from upregulated ionotropic glutamate receptors.

Consequently, since it was upregulation that caused our issues, I postulate that if one could coax downregulation, in a relatively short period of time, the majority of downstream issues should also be corrected.

One could argue that if my hypothesis were true, there would be a cure for those other things too.  My answer to that is: there will be.*

There are published ways to make those ionotropic (and metabotropic too) downregulate with intervention, and that is the focus of my research.  I have been a human guinea pig, but even the baby steps involved in these methods have, to put it in the most technical terms, revved the B’Jesus out of me.  But I have posted and will state again, that in my own personal case, I think Florida is right.  I may be banging my head up against a wall until I log a few months clean of benzos.  If only because I cannot coerce downregulation by one mechanism while coercing upregulation by another.

So that is it in a nutshell, my buddies.  If you agree, chime in.  If you can find a hole in this logic PLEASE chime in.  I want to find where I might be making a mistake.  But if you find a hole, please make it a logical one, and post a link for supporting evidence that this logic is flawed.

Thank you all in advance for your input.

Be well and good luck,

[...]


*I did not want to interrupt the flow of the post, but this works as a foot note.  I remember about 4 years ago I read an article in which a woman found a doctor who had discovered a treatment for multiple myeloma.  His “cure” involved taking a person’s own “killer” T cells and “programming” them by a process called CAR T-cell therapy to attack multiple myeloma cells.  Her mom was in the final stages of the disease.  She approached him and begged him to treat her mom who was going to die soon anyway. Unbelievably, he did and she made a full recovery.  I remember thinking at the time, “Well I guess that is that.  Cancer, or at the very least blood cancer is cured.”  It was not yet perfected and they are still tweaking it, and medicine has as usual been slow, but they are getting there:
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy

My point is it had never been done before, and it all started with one guy looking to treat one disease.  Somebody had to be first.
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #2 on: November 06, 2019, 06:26:23 pm »
Well [...], I think you hit the nail right on the head. It's not just the downregulation of the GABA receptors. The upregulation of the glutamate system is probably responsible for half our problems. So I'm interested in what you mean by "the cure". I suppose everyone is different in some ways, but the differences are nothing compared to the similarities - or what would be the point of even having this forum? We all have GABA, we all have glutamates, we all have receptors for both and systems that are activated by them, we all have brains - or at least most of us. We're not so different after all. So go for it.
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #3 on: November 06, 2019, 06:28:40 pm »
[...],

Good thoughts & research !

A cursory search reveals a LOT of research has been done regarding the "GABAA System Hypotheses"
and very little regarding the Glutamate System Hypotheses with regard to withdrawal symptoms after benzodiazepine discontinuation.  No doubt Glutamate is equally as important as Gabaa in the other half of the equation.  Could it be our preoccupation with GABAA is a case of "can't see the forest for the trees"?


Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/#B107


4.3. Glutamate System Hypotheses

4.3.1. General

".....From the previous sections, we conclude that compensatory changes solely arising from the GABA system may at most partially explain the tolerance arising following chronic treatment with benzodiazepines. Glutamate is an excitatory neurotransmitter acting on glutamate receptors. Together with the GABA system, they constitute the two fast-acting and opposing neurotransmitter systems that can modulate synaptic plasticity. In support, close neuroanatomical connections exist between GABAergic and glutamatergic neurons [108, 109]. With a presence in at least 30–50% of all synapses in the CNS, inhibitory GABA and excitatory glutamate together coordinate the balance in the brain's excitability. Therefore, it is not surprising that as these two opposing and fast-acting neurotransmitter systems form a delicate balance,
chronic (increased) activation of the GABAergic system during benzodiazepine treatment may pertubate glutamatergic transmission. The basis of benzodiazepine tolerance could then lie in sensitization of the glutamatergic system—a putative process that could account for the withdrawal symptoms after chronic benzodiazepine discontinuation
[5, 110]. Such sensitization is reminiscent to adaptive glutamatergic processes as seen in kindling experiments, although it should be noted that kindling only occurs with intermittent and not after continuous treatment [111]. Glutamatergic sensitization could thus play a role in the development of tolerance as well as withdrawal symptoms upon cessation of treatment. Glutamatergic changes after benzodiazepine withdrawal will not be discussed here, but there are indications that the glutamatergic system plays a role in withdrawal states with accompanying increases in anxiety and seizure activity (for review see [5]). However, glutamate receptor mRNA and protein changes may be dynamic during withdrawal, with unchanged levels during the early phase of withdrawal but changes occurring several days later [112]. This consequently complicates the interpretation of withdrawal studies and their significance for our understanding of benzodiazepine tolerance.





A glutamatergic hypothesis of drug dependence: extrapolations from benzodiazepine receptor ligands.

https://www.ncbi.nlm.nih.gov/pubmed/11224351
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[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #4 on: November 06, 2019, 06:29:51 pm »
Buddies,

For better or worse, I have studied what you brought up so long and hard it is in my bones, and I can "discuss" it without thought.  I prefer "opinions are like elbows," because everyone has a couple, they do not all stink, but "they can accidentally poke someone leaving them bruised and annoyed." ;-)  I was preoccupied with GAD for a while and the GABA-Glutamine-Glutamate cycle.  But upon further study, while GAD makes sure there is enough GABA to be used as needed, and if we the sensitive eat too much free glutamine, that cycle turns it into glutamate via GAD's opposite glutaminase.  But the presence of glutamate in the synapse is not controlled by GAD or glutaminase, but buy the Excitory Amino Acid Transporters (EAAT).

EAAT suck glutamate out of the synapse where it is causing a flow of cations from the postsynaptic neuron, and transport the glutamate into adjacent glial cells where it is inactive.  This is actually how one can be kindled on a long course of antibiotics, specifically beta lactam antibiotics.  They boost the heck out of EAAT.  I did that by accident.  Twice. And boy did I feel the rebound!  So we must be careful with glutamate modulators, like alcohol, tobacco, (and firearms ;-) ) and antibiotics. It is the presence of glutamate in the synapse controlled by EAAT, and for our specific case, the lack of cations caused by the excess anions from benzos that have resulted in the upregulation of our ionotropic glutamate receptors.

LTP is the result of upregulation.  The mechanism is complicated and it involves first the creation of more AMPA receptors which fire at a lower potential and then more NMDA receptors which let more cations thru.  How this happens is well studied.  It is related to kindling because the more AMPA receptors you have the more primed your nerves are to give you more powerful NMDA receptors on a dime.

And "the cure" is not designed to scare or provide false hope.  I am not telling anyone that I have a method to cure anyone.  This is a discussion only that it is possible.  I know in my mind and in my bones there are ways to permanently remove ionotropic glutamate receptors.  Stop LTP and kindling and reverse our damage in months rather than years, or more importantly, at all in the case of the veterans still suffering after such a long time.  But I have also stated that everything I have tried has revved the B'Jesus out of me.  So I put this here looking for holes and ideas as to why it should succeed or fail.

PS.  The non linear recovery of waves and windows is our body's ability to deal with glutamate and cations.  Eat some (free glutamate or calcium), or have some triggered in you by circumstances and you get a wave.  As your body downregulates on its own, as most do, you deal with the glutamate and cations better.  Have a period where you have low glutamate, for whatever reason, and you have a window.

I am very cloudy headed today, so that is all I have for now.

Thanks again for your replies.

[...]
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #5 on: November 06, 2019, 06:44:13 pm »
Buddies,

If you are on this thread, you have at least a passing interest in glutamate reception.  I have asked this twice before, but so far no one has volunteered.

This is an experiment that will provide definitive proof that you personally have too many NMDA receptors that are letting too much current through.

Take a period when you have nothing to do for 4 days.  Go out and get yourself a box of your favorite flavor of sugar free jello sweetened with nutrasweet/aspartame.  Follow the directions with the slow prep (no ice cubes) method and make yourself a really big bowl of two large packets.  As your last meal of the day eat the whole bowl, or as much as you can.

The boiling water will liberate the aspartic acid from the aspartame.  The only receptor in your body that can receive aspartic acid is NMDA, and if you are NMDA upregulated it will hit you . . .

LIKE A MACK TRUCK.

You will have pain, stiffness, and anxiety like you have never felt in your life.  It does no permanent damage and wears off completely in 3-4 days.

I have done that experiment on myself, twice just to be sure, and I am sure.  I have posted twice for guinea pigs, and so far no one has volunteered.

Do I have any takers here?  Anyone?

Be well and good luck,

[...]
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #6 on: November 06, 2019, 06:45:36 pm »
[...], Have you ever tried Lithium Orotate to down regulate NMDA receptors? I take lithium orotate 5 times a week and it does wipe out my anxiety. So maybe the NMDA receptors are the problem.

Also. I just ordered some Sesamin. There's a study that says sesamin down regulates the NMDA receptors in the amygdala. We shall see.
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[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #7 on: November 06, 2019, 06:47:38 pm »
All,

I am definitely going to dig deeper into lithium, but here is just something I have picked up along the way.  Lithium orotate is a supplement, and lithium carbonate is the psyche med "mood stabilizer" often used for bipolar disorder.  There is no "real" difference between the two.  They are both salts of lithium.  The difference is mostly in the dose.

Here is the best chart I have been able to find showing the equivalent doses of elemental lithium ion in orotate, carbonate, and naturally occurring in diet and water:

https://psycheducation.org/treatment/mood-stabilizers/the-big-three-for-bipolar-depression/lithium/lithium-orotate/#Microdosing_how_much_actual_lithium_in_each_form

The study you posted only discusses the lithium ion, not the dose or the source.  It maybe be that we need the lowest psyche med dose of 150 mg (28 mg lithium ion from the chart) or that a few 120 mg orotate tablets (5 mg each from the chart) are sufficient or even better.  It is hypothesized that orotate is more bioavaliable because it occurs in nature.  This author showed no difference at all, but the study is old:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1666891/pdf/brjpharm00512-0006.pdf

I think when I try it (6 mos?) I will try orotate, if for no other reason than I can start slower.  If it ends up that I need 5 pills, then the drug will probably be a lot cheaper.

I hope that was useful.

[...]
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #8 on: November 06, 2019, 06:51:07 pm »
Well, before everyone goes running out to dose themselves with lithium, take a look at this Wikipedia article:

Lithium toxicity

It's one thing to discuss all the theories and possibilities. That's interesting and useful.
It's quite a different thing to encourage people to experiment on themselves with these untested "cures".
I think we should knock it off.

A REALLY good point from redevan.  We are talking about LOW DOSE lithium ions, topping out at 28 mg.  People who take the doses of lithium required to treat bipolar disorder are always in danger of toxicity.  We do not want to get any where near those doses to effect glutamate receptor change.

[...]
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: The Use of Lithium to alter glutamate reception
« Reply #9 on: November 06, 2019, 06:55:48 pm »
An Excellent guide discovered by [...]:

Lithium
https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

"Lithium enhances inhibitory neurotransmission by downregulating the NMDA receptor and inhibiting the myoinositol second messenger system directly."
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.