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The use of SAMe and other serotonergic means to alter glutamate reception


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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.

 

Ramcon1

Your personal neuroscientist, reminding you to hang in there, and if you are going thru hell, keep going!

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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 SAMe, and other serotonergic supps and meds from the threads in the protracted 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,

 

Ramcon1

 

 

*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.

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Well ramcon, 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.

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Ramcon,

 

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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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.

 

Ramcon1

 

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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,

 

ramcon1

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Took,

 

I am convinced that after a few months to a year off tops, all of our issues are glutamate.  I would not preoccupy my thought process with antagonizing GABA or what will affect GABA, think instead, what will reduce the number and potential of glutamate receptors?  That is why I like lithium so much.  It SHOULD do what we want it to do, make glutamate hang out in the synapse just a little longer, and have the receptors respond by reducing.  Will it happen for us?:  Who the heck knows, but I think it is worth a shot for that reason alone.

 

I stand behind what I said about 50-50, I think some will be calmed, others revved, but that is just my "gut feeling."

 

Ramcon1

YPNS. RYTHIT, AWYAGTH, KG!

 

Ram,  just for clarification let's lay out your thesis here.  So you believe that the Glutamate receptors are stuck in upregulation due to the initial downregulation of the GABAA receptors.  And you also believe that, regardless of the current state of the GABAA receptors, that finding a way to suppress and even reduce the numbers of Glutamate receptors will bring a reduction in our symptoms.  Have I got that right?

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Took,

 

Almost.  My thesis is that taking benzos floods the synapse with Chloride ions (Cl-) released from the GABA-A ligand gated ion channel.  These Cl- ions halt many cascades, many of which by neutralizing the Ca+2 ions in the synapse.  All of that part is actually not theory.  That is 100% proven fact.

 

Then my thesis is that the body responds by looking to maintain homeostasis.  So in response to, "oh, we have too many Cl- ions," your GABA-A receptors "respond," by downregulating.  This is standard benzo healing thinking.  But also in response to, "where did all of those Ca+2 ions go?" your NMDA (and potential other types of glutamate receptors) upregulate.

 

And my thesis continues that the body is designed to upregulate.  We "learn" anything in our mind and nerves by upregulating NMDA, and in general we are designed to build and rebuild.

 

But why should something we "rebuilt" dissipate? The answer is, I don't think it will, and that is the story of protracted withdrawal.  That is the part of my thesis that is not proven, but I can feel it.  In my mind and in my nerves and in my bones, like 2+2 is 4 I believe that to be true, and my neurologist agrees with me. 

 

And to be clear, I do not think we need to "suppress" glutamate.  We need to give those NMDA receptors a damn good reason to disappear.  I think if we could be put in a medically induced coma given an IV with glutamate to the point just below going into a seizure we would be cured in a month. 

 

In the absence of that, there is a lot of good research that an increase in serotonin at the synapse would do it.  I have been hesitant to discuss that at length because in general most people here would not be open to taking an SSRI after having such a bad experience with at least one psyche med, and I do not blame them.  And you can increase serotonin with supps, but that method is so fraught with peril that until I can get clean and try it on myself, I am not posting that method at all!  I just bought a higher level biochem book to help me work out the bugs.

 

The Lithium idea shows promise because it seems that is will simultaneously reduce Ca+2 gated reactions, AND slow glutamate transport out of the synapse.  By having glutamate in the synapse but reducing the downstream reactions, it could "trick" the body into downregulating NMDA.  It is postulated but not proven, that kidney damage not withstanding, that is the reason biopolar patients who respond well to Lithium often get better the longer they are on Lithium while other meds tend to "peter out."

 

And finally, when we achieve this, we will not have reduced our symptoms, we will be cured, and by cured I mean "restored to neurotypical."  We will be able to eat what we want when we want, and do what we want when we want.

 

At least that is the thesis.

 

Ramcon1

YPNS, RYTHIT, AWYAGTH, KG!

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I did not want to throw this out there because I know it is going to be very unpopular as most here are very anti psyche med, with good reason.  But I know Sky does not do PM's, and I want her to hear this, so please everyone else don't beat the crap out of me for what I am about to say:

 

As per benzobuddies, I am not a doctor, and this is not a prescription. But, "if I were you," and still had major issues at 5 years AND lithium was not an option, my plan B is Zoloft/sertraline.  Before anyone bites my head off, hear me out.

 

I have found many papers showing how serotonin at the synapse will reduce the number and current flow of NMDA receptors over time.  We are VERY sensitive creatures for sure so we have to be really careful.  Zoloft/sertraline is one of the few (only?) SSRI that is available as a liquid.  It is also the only one that slows glutamate transport out of the synapse, in a way similar to lithium ions.  So it has two mechanisms that could be helpful, three if you count the benefit of slightly more serotonin in general.  To do this veeeeeeeery slowly, one could get a few diabetic syringes, break off the needles, and literally take liquid sertraline "homeopathically," a few milligrams a day, increasing very slowly over a few months. And it should not take much.  People take 200-300 mg for depression and anxiety, and I think for us, working up to 25-50 mg tops should do the trick.

 

Homeopathic literally means "self disease," so the application of something makes the nerves just a little "sick."  Then they heal.  Then I apply a little more.  Repeat.  The "little sick," is anyone for whom Zoloft has worked really well for depression or anxiety all say they felt a little worse before they felt better, and they were not sensitive like us, thus why I would need to use the worlds tiniest doses to make this work.

 

Most importantly, if I got to 50 mgs in say 3 months, stayed there for 6 months and did not feel any better, I could back out in 3 months and should be "no worse for the wear."

 

I say "should."  Is there a 1 in 1000 chance I will be worse?  Sure.  As we have learned, anything can happen.  But I am looking at it this way, right now my life suuuuuuuuuuuuuuuucks.  I am disabled and unstable, and I am sure I am not the sickest person here.  I am looking at it as I literally have nothing to lose.  I like lithium better, and plan to try that first, but if I do not tolerate the lithium like Sky, I am going to try liquid Zoloft.

 

Again, I am not "prescribing" anyone to do anything and I am not trying anything on myself until I have logged a few months "clean," but those are my plans A and B.

 

(Actually homeopathic Zoloft is my plan "C." I have a plan B that uses a combination of supplements to raise serotonin that is more fraught with peril than the Zoloft.  If it works I will have a new med to patent, but I still do not have the chemistry worked out yet.)

 

Ramcon1

YPN, RYTHIT, AWYAGTH, KG!

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Hi again Ramcon,

 

I am healing somewhat,

so I'm  only trying to help others, plus  I dont post often,

however just giving my experiences

in the hope they help someone.

 

I agree re the serotonin  effects, which might help adjust

our systems so  I  personally use probiotics for this and noticed

it improved things for me in many areas.

 

https://www.fasebj.org/doi/abs/10.1096/fj.14-259598

 

however

I had to research and adjust these many probiotics

to ones that dont affect histamine production,

as that causes inflammation in many areas for me,

and that was another improvement once I got  my histamine levels sorted,

plus the baking soda to heal the gut lining along

with its other benefits for me, however its trial and error

I have found and listening to ones own body's reactions

as we heal over time.

 

So this is a journey for me, and not just one thing will fix it for all

our differing symptoms as this forum shows.

 

I wish everyone finds what works for them, however I believe

we must listen to our own bodies, as many times I have tried things

recommended on here, only to find no matter how scientifically they

are presented they caused me many problems often causing setbacks.

 

It is never just one thing that needs adjusting no matter how we think

it is just one thing required to  heal that  one area and we will be healed,

and then another  different area pops up

needing to be attended to now over and over again

which is why one "cure" probably wont be found.

 

these are just my experiences that I post and believe we are all different

and need different things to heal our differing damages.

 

I am grateful that I do see much healing has happened,

and I live in the hope that

eventually my good weeks will become good months and then good years.

 

Good luck with your trials Ramcon,

I do hope you find something that gives you relief,

as I know how desperate I was way back 5 years ago

and trudging along the road to some healing with my knapsack of belief

heavy on my back as I proceeded on this journey.

 

Good luck with everything 

I wish you well with your scientific  research

and I do hope you come up with something that helps you.

 

Sky

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First Sky,

 

Using probiotics that produce serotonin is a REALLY good idea.  I would not be surprised if you do not feel a lot better soon.  Good luck. I am amazed at how well this thread is going.

 

Colley,

 

I would expect that starting at 25 mg (Zoloft/sertraline) would be a sh!t show for some (most?) of us here. But.  That fact actually gives me confidence that it could work.  Remember what I posted about "homeopathic."  Do you live in the US?  If you do, there is generic, (cheap) liquid sertraline at 20 mg/ml, so on a diabetic syringe, 5 "units" (0.05 ml) is 1 mg.  If I choose to do this, I would literally start at 2-4 mgs.

 

Think about this:  Did it rev up your issues?  Because if it did, that is exactly what I want it to do to me, only in teeny tiny increments.

 

Ramcon1

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Colley,

 

Too bad about the sertraline liquid and Canada.  Two things.

 

First, one could get 25 mg tablets, buy a milligram scale and do some algebra.  That is how I am doing my diazepam taper.  There are a few good scales on Amazon.  I use this one:

https://www.amazon.com/American-Weigh-GEMINI-20-Portable-MilliGram/dp/B0012TDNAM/ref=sr_1_3?crid=2I287RKB0A32P&keywords=gemini+milligram+scale&qid=1567614026&s=gateway&sprefix=gemini+mill%2Caps%2C711&sr=8-3

 

It is not really accurate to 1 mg, 0.001 g, more like 10 mg, or +/- 0.005 g, and usually has a slight "bias heavy," but that is close enough. A "real" scale accurate to 1 mg would cost about $1000, so for $30 we can't bitch too loudly.  We just have to be realistic about our expectations, and if we are, it does work.  For example, my 2 mg diazepam pills weigh about 153 mg. Allowing for bias and precision, I measure 0.018-0.028 for an average 0.023 mg pill, which translates to about 0.25 mg diazepam, which is my unit of cut.  That could be used as a method of increment or cut, again using algebra and a scale on any pill.

 

Second tryptophan is THE key, but unlocking that door is exactly what is fraught with peril. Even in a healthy person, most of tryptophan will go down an excitation pathway to things like quinolinic acid, not serotonin. It can be "metabolically coaxed" to serotonin, but anyone who can consistently unlock that door will be rich as the inventor of a truly effective truly natural antidepressant and sleep aid.  To say it is challenging is an understatement.  I am going to give it a shot after my taper, but a 1/2 dozen things have to happen juuuuuuuuuuuuuuuust right for it to do what we need it to do.

 

For that reason, I will probably try lithium first, and if I do not do well with it, decide between liquid zoloft, and the metabolically coaxed tryptophan challenge.

 

Ramcon1

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Colley,

 

Too bad about the sertraline liquid and Canada.  Two things.

 

First, one could get 25 mg tablets, buy a milligram scale and do some algebra.  That is how I am doing my diazepam taper.  There are a few good scales on Amazon.  I use this one:

https://www.amazon.com/American-Weigh-GEMINI-20-Portable-MilliGram/dp/B0012TDNAM/ref=sr_1_3?crid=2I287RKB0A32P&keywords=gemini+milligram+scale&qid=1567614026&s=gateway&sprefix=gemini+mill%2Caps%2C711&sr=8-3

 

It is not really accurate to 1 mg, 0.001 g, more like 10 mg, or +/- 0.005 g, and usually has a slight "bias heavy," but that is close enough. A "real" scale accurate to 1 mg would cost about $1000, so for $30 we can't bitch too loudly.  We just have to be realistic about our expectations, and if we are, it does work.  For example, my 2 mg diazepam pills weigh about 153 mg. Allowing for bias and precision, I measure 0.018-0.028 for an average 0.023 mg pill, which translates to about 0.25 mg diazepam, which is my unit of cut.  That could be used as a method of increment or cut, again using algebra and a scale on any pill.

 

Second tryptophan is THE key, but unlocking that door is exactly what is fraught with peril. Even in a healthy person, most of tryptophan will go down an excitation pathway to things like quinolinic acid, not serotonin. It can be "metabolically coaxed" to serotonin, but anyone who can consistently unlock that door will be rich as the inventor of a truly effective truly natural antidepressant and sleep aid.  To say it is challenging is an understatement.  I am going to give it a shot after my taper, but a 1/2 dozen things have to happen juuuuuuuuuuuuuuuust right for it to do what we need it to do.

 

For that reason, I will probably try lithium first, and if I do not do well with it, decide between liquid zoloft, and the metabolically coaxed tryptophan challenge.

 

Ramcon1

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Sky,

 

So right about histamines.  I have "itchy days," and tinnitus is all histamine.

 

At least you gave me independent confirmation I am taking the "right" probiotic.  I take Therbiotic Complete Powder:

https://klaire.com/k-tcp-therbiotic-complete-powder

 

It has all of the ones you suggested except infantis and gasseri, and none of the ones on the not good for histamine list.

 

While we are on the topic, VSL3 is really popular and really powerful, but produces a boatload of D-lactate of which many of us have to be concerned, so watch out for that one.

 

The biggest problem I have with the probiotic I take is yes, the more I take the better I feel, but when I stop histamine, I get REALLY backed up.  I have tried every laxative known to man since I quit smoking and every one revs me up or gives me really bad side effects.  I do ok with a small amount of coffee, but usually that just doesn't "do the trick."  I wish there was a probiotic that got things moving without raising histamine.

 

Thanks again,

 

Ramcon1

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LTP is a major culprit (if you will :D), here.

 

However, this would only partially explain something like the paradoxical effect seen when eventual benzo dosing results in glutamate upheaval, as well as certain other triggering factors like other meds, exercise, etc.

 

The brain seems to make changes with certain variants of glutamate decarboxylase - limiting activity of at least one. Less glutamate converted into GABA would increase extracellular pools of roaming glutamate, but short of autoimmune disorder this wouldn't likely be too damaging.

 

Rather, scattered, de-coupled GABA receptors ill-equipped with effectively taming LTP-induced high excitatory neurotransmission (possibly) via altered genetic expression is more likely.

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FnF,

 

Don't make the same technical mistake I made in the beginning of my research: thinking any of this has to do with the GABA-Glutamine-Glutamate cycle.  That has absolutely no effect on the amount of glutamate or cations present in the synapse at any given time.  That is tightly controlled by the EAAT's.  That is why tobacco, while mostly a source of glutamate, so you would think would speed healing, actually impedes it because while it provides glutamate, it is a complete pharmacopia and boosts the EAAT's at the same time.  That is also how antibiotics kindle protracted members, they boost EAAT, and the glutamate receptors "remember," "Oh reduced glutamate! Great!  Let's go back to the way we were before and make 100 more of ourselves!"

 

That is why we need to not only normalize, but scrub those receptors away, and the RNA that encodes their replication!

 

Ramcon1

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All,

 

Think about it this way: Benzos do one thing.  They attach onto your GABA receptors causing them release GABA and open a channel and let negatively charged Chloride anions through (Cl-)  That is it.  Everything that happens from there is how our bodies adapt to that unnatural activation and outpouring of Cl-.  GABA receptors are everywhere, most notably near other receptors so the Cl- anions can say "stop."  Stop transmitting other things.  Stop whatever you are doing. 

 

Previous thinking had us believe we are sick because our GABA receptors start to disappear as we trigger those Cl- anions with benzos, and that may be a part of it, especially in the "tolerance" phase.  But I am not in tolerance, the same little dose of Valium calms me, and a little bit more makes me sleepy.  Certainly anyone here in the protracted section is no longer dealing with "tolerance," so what is going on?

 

Because of the excessive GABA and Cl- anions, our glutamate receptors respond by increasing in number, and by a long elaborate mechanism, those that open ion channels open easier, and as FnF mentioned LTP, or Long Term Potentiation, means they let more Calcium cations (Ca2+) thru.  The glutamate receptors are also everywhere, and glutamate and its Ca2+ cations tell everything to "go go go," and are the source of ALL of our protracted pain.

 

So to get well, to find an active cure, we need to find something that will reduce the number of glutamate receptors and the Ca+2 cations they let thru.  Of the glutamate receptors, those called NMDA are the most powerful.  Some of the studies I have read talk about methods that reduce NMDA "receptor count" and "EPSC" and "EPSV," Excitory Post Synaptic Current / Voltage.  That is the Ca+2 cations.  Reducing those things is "scrubbing away the receptors."

 

Then the papers talk about RNA activity.  RNA is how our DNA tells our nerves what to do.  When you reduce RNA activity for the transcription (signaling) to nerves to make NMDA proteins, you have "scrubbed away the memory" of those NMDA receptors at the genetic level. Then we are truly cured.

 

Upregulating GABA receptors is relatively easy.  The body is designed to grow.  Downregulating glutamate receptors is much harder, and that is why some people are sick for a long time. Slowing RNA activity is harder still, and that is why NMDA are "kindled," as in some one who is "well" does something that pokes his NMDA receptors like alcohol, an antibiotic, a flu shot, whatever, and his NMDA receptors go back to the sick state.  They do not grow back "wrong," they just "remember" the state of having too many, and letting too much current thru, and we kindle.

 

That is the entire depth of my knowledge at this point, except for the methods we are discussing like serotonin, glutamate itself, and lithium.  Those are discussed in this thread.  Right now those SEEM to be the best shots for the protracted.  Will they work?  I have no idea.  Exactly how does all of this happen?  I had to take a break from studying neuroscience to refocus on biochem because I do not know enough biochem to take my understanding deeper.  But that is my job right now, and I am on it. 

 

I hope that explanation was helpful to anyone trying to understand our goals.

 

Ramcon1

(YPN, RYTHIT, AIYGTH, KG!)

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Colley and All,

 

I have tried a few NMDA antagonists and inverse agonists, and so have other buddies.  For reasons I cannot explain, in me they revved me up, and others had no benefit.

 

Inhibitors are a different story.  If you have ever been in a wave and taken a drink of alcohol and had the wave "magically vanish," that is the alcohol inhibiting the current flow through your NMDA.  The problem with that of course is the rebound, which happens in neurotypical people too, but can be quite severe in the sensitive among us.  Plus, alcohol abuse isn't going to help us heal. But the fact that it DOES make us feel better in that instant just proves that lowering the current long term is a big part of the key to the cure.

 

Ramcon1

(YPN, RYTHIT, AIYGTH, KG!)

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Yep... SAM-E isn't the greatest. I take a really low dosage and it's probably not enough to do much but you never know... it may have some benefit over time.

 

At the moment I'm only taking 100mg in the morning but I've taken as much as 400mg. I also added some Pharma-GABA at night to help with sleep quality as I wake up multiple times during the night... I'm not sure if the Pharma-GABA will mess with my GABA receptors like Benzos did but from what I've read, there's little research to prove that supplemental GABA crosses the blood brain barrier. I'm hoping it might have a positive effect on the rest of the receptors that live throughout my body and / or my CNS.

 

Anyway, I don't want to hijack this important thread with what I'm doing. I take several vitamins and supplements which could interfere with eachother and / or healing... unfortunately I always feel I have to try something new/different do to the lack of meaningful progress on the mental side of things. I don't want to take antidepressants so I believe I need to try these things...

 

Good luck everyone!

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Buddies,

 

This is my guide to trying SAMe.  Like my lithium post, it is very "presecriptive," so again, this is what I would do if I were you and having a tough time after many months clean.  It is, in fact, what I intend to do:

 

Based on posts about SSRI and SAMe, a lot of us "feel" serotonin poke our NMDA receptors and present as anxiety, anger, stiffness etc.  These feelings are why serotonin would, if we could bare it, club those NMDA receptors back to normal.  But that is a huge if.  I was originally thinking that I might try liquid Zoloft and literally take a few milligrams, so I could just barely feel it, and then take a few more, building to 25-50 mg max.  But the discussion in the lithium method got me thinking.

 

Zoloft is artificial. SAMe is a chemical that normally occurs in our bodies, and is THE methyl donor for us undermethylators.  I did some digging and found a capsule that, like the lithium in my previous post, does not contain any of our triggers, not even rice flour:

 

https://www.amazon.com/Now-Stabilized-Same-200mg-Capsules/dp/B07H4PZCKH/ref=sr_1_10?keywords=s-adenosyl+methionine+capsules&qid=1572114004&sr=8-10

 

This brand is pure.  It goes out of its way to say that it does not contain any of the “other things” that normal people would not feel, but we might find a trigger.  When I do this, this is what I will get.  It is also a capsule which means it is powder so you can empty the capsules and weigh the powder:

https://www.amazon.com/Relentless-Improvement-High-Purity-Excipient-Formulation/dp/B07BSMQPDW/ref=sr_1_2_sspa?crid=3UV8G7W5IXAZI&keywords=lithium+orotate&qid=1571852532&sprefix=lithium%2Caps%2C139&sr=8-2-spons&psc=1&spLa=ZW5jcnlwdGVkUXVhbGlmaWVyPUEzS01VM1FUVEQwR05RJmVuY3J5cHRlZElkPUEwMTM1NjU5MzZNS0VNTEowNVdGSCZlbmNyeXB0ZWRBZElkPUEwNjQyNDc5Mk9VSjBCNTZWSTMzJndpZGdldE5hbWU9c3BfYXRmJmFjdGlvbj1jbGlja1JlZGlyZWN0JmRvTm90TG9nQ2xpY2s9dHJ1ZQ==

 

You will need large, empty capsules to fill:

https://www.amazon.com/PurecapsUSA-Clear-Vegetarian-Capsules-Joined/dp/B00I7DVEJS/ref=sr_1_2_sspa?keywords=empty+vegetarian+capsules&qid=1571850888&sr=8-2-spons&psc=1&spLa=ZW5jcnlwdGVkUXVhbGlmaWVyPUFDUEpGUFRJTVlINzYmZW5jcnlwdGVkSWQ9QTA2NDcxMjYzOE5CQkNIOVc2MTQ4JmVuY3J5cHRlZEFkSWQ9QTAwMDAwNDAyOFpDS1JVMzFSTFRUJndpZGdldE5hbWU9c3BfYXRmJmFjdGlvbj1jbGlja1JlZGlyZWN0JmRvTm90TG9nQ2xpY2s9dHJ1ZQ==

 

Tiny spoons for measuring and filling:

https://www.amazon.com/Norpro-Stainless-Measuring-Spoons-smidgen/dp/B0009X1P9S/ref=sr_1_4?crid=27YSLSSIXL2UO&keywords=measuring+spoons+smidgen+pinch+dash&qid=1571850673&sprefix=measuring+spoons+smid%2Caps%2C134&sr=8-4

 

And a REASONABLY accurate milligram scale

https://www.amazon.com/Smart-Weigh-GEM20-Precision-Milligram/dp/B00ESHDGOI/ref=sr_1_1_sspa?crid=1BW30LCGBPR31&keywords=gemini+milligram+scale&qid=1571851012&sprefix=gemini+mill%2Caps%2C131&sr=8-1-spons&psc=1&spLa=ZW5jcnlwdGVkUXVhbGlmaWVyPUEzRFRYSVVLSVMyNlo0JmVuY3J5cHRlZElkPUEwNjU1NzUyMVhZSk4zQVdEWERBRCZlbmNyeXB0ZWRBZElkPUEwNzMxNDUxTTNGSTYzNk1TVjNBJndpZGdldE5hbWU9c3BfYXRmJmFjdGlvbj1jbGlja1JlZGlyZWN0JmRvTm90TG9nQ2xpY2s9dHJ1ZQ==

 

Not sure about shipping, but all of that will cost about $60 without shipping.

 

Each capsule contains a certain amount of powder, but the important thing is that the powder contains 200 mg of SAMe.  If you get a different brand that is a tablet instead of a capsule, that is ok, but it could contain stuff we do not want, and you will need to cut the tablets.  I like capsules, so I can weigh powders, but if all you can get is tablets, then buy the scale, but do not buy the empty capsules.

 

If you get the SAMe capsules, empty 1 capsule onto the scale and see what it weighs.  If you get tabs, weigh the tabs. Do a few to get an average weight.  Then either weigh out a bunch of powder until you get 1/8 of a capsule, and fill the empties, or cut tablets until you get 25 mg SAMe. 

 

The scale is accurate to about +/- 0.003g (+/- 3 mg), so do not worry about its being exact.  For example if the capsule content weighs about 0.200 g (200 mg) you will find it will vary from 0.180 g to 0.220 g.  That is accounting for manufacturing variation and scale accuracy. So in this example, you weigh out about 0.050 g (50 mg).  So anywhere from 0.045 to 0.055 g is acceptable.  If you have powder from capsules, you can use the tiny spoons to put that amount in the capsule.  Remember that 0.050 g or whatever 1/8 capsule of POWDER (or tablet) weighs = 25 mg SAMe. Use algebra.  If you have problems with algebra, send me a PM.

 

Once you have prepared a few days wait for a day when you have nothing to do, and take one in the morning.  It might make you calm.  It might rev you up.  It might do nothing.  I want you to take it in the morning so you are awake and can feel what it does.

 

If it makes you calm, move the dose to night. 

If it revs you up, keep it in the morning. 

If it revs you up A LOT, halve the dose. 

If it does nothing, double the dose.

 

Once you feel it do SOMETHING, hold there.  Take that dose until you no longer feel it do anything.  That might be a week. That might be a month.  If it still makes you calm after a month, increase the dose until you feel just a little drowsy during the day.  Just barely.  Hold there until you no longer feel drowsy during the day.

 

Then you keep building SAMe until you can take about 400 mg or two whole capsules.  Some references sight using more, and if anyone has any ideas about an ideal dose, please reply.  When you can stay on that dose for several months, you might notice significant improvement.

 

That is the theory.    Now here is the catch.  It looks very good, and I mean VERY good on paper.  That DOES NOT MEAN IT WILL ACTUALLY WORK AT ALL.  If I had a dollar for everything that I thought would work on paper, I would have a lot of dollars.

 

If anyone actually does this, please let the rest of us know.

 

Good luck,

 

Ramcon1

(YPNRYTHIT, AIYAGTH, KG!)

 

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[24...]

Ramcon some more links with information re glutamate  for you to study.  Good luck  :thumbsup:

 

I do take this and have for many months from a compounding chemist, and it works great for

many types fo pain and sleep for me.  :thumbsup:

 

 

Palmitoylethanolamide Inhibits Glutamate Release in Rat Cerebrocortical Nerve Terminals

 

http://accurateclinic.com/accurate-education-palmitoylethanolamide-pea/

 

https://www.dovepress.com/effects-of-the-glial-modulator-palmitoylethanolamide-on-chronic-pain-i-peer-reviewed-fulltext-article-JPR

 

https://www.customcompounding.com.au/drug-manufacturer-to-launch-commercial-version-of-natural-painkiller-palmitoylethanolamide-pea/

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394492/

 

https://gencorpacific.com/featured-ingredients/levagen

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Sky,

 

Glad you found us.  I PM'ed everyone else but your PM's are off.  I like PEA.  I am in the middle of some other research right now, but I will get back here.  Can you do me a favor?  If a week or 10 days go by, can you post again reminding me to look at your links?  They look good, both the PEA and the others, but I can get overwhelmed and forget if I don't get poked now and again.

 

Be well,

 

Ramcon1

YPN . . .

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[24...]

Sky,

 

Glad you found us.  I PM'ed everyone else but your PM's are off.  I like PEA.  I am in the middle of some other research right now, but I will get back here.  Can you do me a favor?  If a week or 10 days go by, can you post again reminding me to look at your links?  They look good, both the PEA and the others, but I can get overwhelmed and forget if I don't get poked now and again.

 

Be well,

 

Ramcon1

YPN . . .

 

OK . no worries,  i  sent you a link re it all  many months ago.

 

I just thought others might find the links useful also when reading this.

as we are all individually  looking for things that might help us and our many differing symptoms on this journey.    :thumbsup: 

 

They are doing sleep studies on it in Australia

 

https://www.facebook.com/7NEWSsydney/videos/535926803896666/

 

short video on 7 news Australia

 

If you wish to make a seperate thread on chewing the fat for discussion Go ahead.

 

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