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Hi Terry congratulations on getting off benzos.

 

Wonderful video.

 

  I wrote a little transcript summary after watching the video.  I added a few things.  You might also want to read some of Perseversence's papers in this same section Chewing the Fat for more information.  Her papers are quite good.  I hope this summary helps you understand what these horrible benzodiazaphines do to our wonderfully God-given- and-designed physiology.

 

----------

Pre synaptic neuron

 

action potential comes in to the presynaptic cell, hits the voltage gated calcium terminal, this  allows calcium to come into the presynatic neuron, when calcium comes in it causes the fusion of the vesicles in the pre synaptic neuron, the vesicles  contain GABA  , vesicles are released across the synaptic cleft, bind to a receptor on the post synaptic membrane --->

 

Post synaptic neuron

 

the post synaptic receptor can be a GABA receptor (on the post synaptic cell membrane) which will let in extracellular chloride through its channel into the post synaptic neuron, or if glutamate is released presynaptically, it can be a glutamate receptor (on the post synaptic cell membrane) which will let in extracellular sodium through its channel into the post synaptic neuron.  ---->

 

 

Action potential

 

Each of these ionic infusions into the post synaptic neuron will have either a positive (sodium) or negative inhibitory  (chloride) effect on the overall action potiential of the post synaptic neuron (post synaptic potential),  thus resulting in a net positive or net sub threshold action potiential in the post synaptic neuron.  They occur at the same time on a given post synaptic neuron as shown in the video.  (He shows 2 pre synaptic neurons acting on the post synaptic neuron).  If it's  an overall sub threshold action potential,  the post synaptic neuron will not fire, thus creating an overall inhibitory post synaptic potential (IPSP), post synaptically.

 

If it's overall positive, then this can elicit another action potential on an axon in the post synaptic neuron. The axons have sodium channels, and an overall positive action potential the exceeds the threshold can elicit sodium to flow through these channels on the axon.

 

If it's overall action potential does not reach threshold, there will not be an action potential on the axon, and this sodium will not flow into the channels on the exiting axon.

 

GABA receptor subunits

 

GABA, benzodiazaphines, and barbiturates all uniquely bind to different subreceptors on the GABA receptor, and barbiturates actually have a different mechanism of action on the chloride flow through the channel.

Since barbiturates and benzodiazaphines bind to different subunits on the receptor, they can have additive effect on the chloride ion channel flow, and thus additive CNS depressant effects physiologically.  (Barbiturates and benzodiazaphines have a very different mechanism of action on the chloride channel and you can find more info on this by googling). The newer Z drugs bind very selectively to the BZ1 receptor subunits location, but the net effect is that they have a profound effect on the chloride ion flow into the receptor/cell.  So during a benzodiazaphine taper , these Z drugs or barbiturates are not a good idea.  They are all positive allosteric modulators of the receptor....

 

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The newer Z drugs bind very selectively to the BZ1 receptor subunits location, but the net effect is that they have a profound effect on the chloride ion flow into the receptor/cell.  So during a benzodiazaphine taper , these Z drugs or barbiturates are not a good idea.  They are all positive allosteric modulators of the receptor....

 

Just curious why is it that Z drugs should not be taken at the same time as a benzodiazepine? I did take both these drugs for about one and 1/2 years not knowing it was not a good idea to combine the two drugs. It's a long story how I ended up on both drugs...fortunately, I found out I needed to get off both drugs and I have no desire to look back.

 

I had a serious reaction to Ambien(z-drug)...that horrific reaction to Ambien is what led me to take Ativan (Ativan helped to bring the burning throat pain in control that Ambien had caused. Also Ativan helped with insomnia, since, ironically, Ambien was not working as it had when I first began taking it....clearly I had become tolerant to my dosage).

 

These drugs are so dangerous...I wish I had known their potential to cause damage to our receptors. :(

 

Thank for explaining the video. This subject is fascinating...our brains are amazing....what more can be said?  :)

 

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THANK YOU VERY MUCH, dm123!!

 

I will have to read it tomorrow, as it's time for bed. I was afraid no one would answer.

 

 

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The newer Z drugs bind very selectively to the BZ1 receptor subunits location, but the net effect is that they have a profound effect on the chloride ion flow into the receptor/cell.  So during a benzodiazaphine taper , these Z drugs or barbiturates are not a good idea.  They are all positive allosteric modulators of the receptor....

 

Just curious why is it that Z drugs should not be taken at the same time as a benzodiazepine? I did take both these drugs for about one and 1/2 years not knowing it was not a good idea to combine the two drugs. It's a long story how I ended up on both drugs...fortunately, I found out I needed to get off both drugs and I have no desire to look back.

 

I had a serious reaction to Ambien(z-drug)...that horrific reaction to Ambien is what led me to take Ativan (Ativan helped to bring the burning throat pain in control that Ambien had caused. Also Ativan helped with insomnia, since, ironically, Ambien was not working as it had when I first began taking it....clearly I had become tolerant to my dosage).

 

These drugs are so dangerous...I wish I had known their potential to cause damage to our receptors. :(

 

Thank for explaining the video. This subject is fascinating...our brains are amazing....what more can be said?  :)

 

 

Hi BlueRose, I feel the same way. 

Congratulations on getting of benzodiazaphines.

 

The more I learn about human physiology, the less I know.  I noticed you stated the below, and just some geek humor is added to your phrase below:

 

"I wish I had known their ACTIONpotential to cause damage to our receptors."

 

I focused on that part of your reply to try to explain my first hand experience of how all this actually feels in real life.

 

I too fell into the same trap.  At my worst I was taking ambien, lunesta, and lorazepam.  I would alternate the ambien and lunesta.  One can take them at the same time.  I don't think it does permanent damage, but one will have a much more difficult time stabilizing, when taking both of these types of drugs together.  The whole problem with taking any positive allosteric modulator (PAM) in addition to the Benzo, which is also a PAM of the GABAa receptor, is that they are additive in terms of what they do to suppress the action potential in the post synaptic neuron.  I'm so glad you asked the question, because in the context of the video, if one understands what these terrible drugs are doing to our physiology, one will realize how important it is to avoid all PAMs during and after taper.

 

Since benzodiazaphines and z drugs both inhibit the post synaptic action potential, that graph/curve in the video will drop way down.  The body always seeks homeostatic balance.  Z drugs  add a transient peak to the blood levels of PAMs in the serum.  This translates to a very transient and jerky suppressive action potential in the post synaptic neuron.  The body will seek homeostasis at all costs.  You can see this in tons of different biological processes in the human body.  This is just one example of the beautiful and elegant design.  The body just wants to survive.  Over inhibitory action potentials in that post synaptic neuron translate to over suppression of the CNS.  The body will do anything and everything it can to upregulate other biological processes to keep alive once it is able to (i.e., once the drug starts clearing in the serum).  The body hates dysregualtion, sharp transient peaks and troughs, and unstable serum levels of hormones, neurotransmitters, etc.    This is the foundation of an adaptive process called kindling, or compensatory regulation of an opposing system to counteract what we are doing when we ingest these drugs. 

 

Fooling with GABAa receptors has such a profound effect on the body because they are so widespread and because they form a such a  large part of our physiological well being. We are talking about something similar to yin and yang.  Kindling, particularly with alcohol binging, is very well established.  There are tons of clinical papers in this area.  We have basically 2 states, an excitatory state and a calming and relaxing state.  With the added transient peak of serum  from the z drug that modulates the GABAa receptor, the body is even more inclined to try to counter regulate the strong inhibitory action potential when the drug clears.  This is why a benzodiazaphine tolerant state and withdrawal state are so intense.  The body can do this by upregulating and sensitizing the glutamate system.

 

Real life:

I felt this very profoundly.  As the lorazepam became more ineffective and I started to reach tolerance, I refused to increase the dose and instead added lunesta, then ambien to the mix.  I would get a few hours of sleep from them, but the next day was horrible.  Not only was I tolerant to the lorazepam, but as the short lived lunesta wore off in the morning, the tolerance got much worse than it was before.  When the lorazepam cleared, it was even worse.  Unfortuntely, I  was prescribed lorazepam as a single dose all at night.  This was the worst thing to do.  Spreading it out would have been much better even if it meant increasing the overall dosage.

 

These horrible symptoms that  I felt  were the body’s way of counterbalancing the inhibitory effect of the drugs.  Kindling is a sensitization of glutamate receptors like the NMDA and AMPA receptors.  By upregulating  the glutamate receptor system, the body is counteracting the CNS depressant effect of the drugs.  Hyper excitability, nerve pain, nerve shocks, brain zaps, increased anxiety, restlessness, are all hallmarks of kindling.  Interdose kindling is exasperated by adding z drugs to short lived benzodiazaphines, and vise versa…...    For anyone in this mess I sympathize.

 

Possible Solution

I’m not a medical doctor so

-Find a Benzo wise doctor.

-crossover to a very long acting Benzo, if you can tolerate it.  In my case it was Librium. 

-titrate the dose up until symptoms dissipate

-Next step fast taper the ambien and lunesta.  Full stabilization is very difficult when taking z drugs. 

-Once the z drugs are out, in  a few weeks one should feel much better

- start the Aston style slow taper of Librium. 

 

I feel first hand that the video  is solid science and not quackery.  I think that the key takeaway I have from this experience is to keep serum levels as stable as possible.  That way the body will not be so vigilant in upregulating other systems to achieve homeostasis.  Avoid PAMs outside of the Benzo that you are tapering from, during your taper. 

 

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Only a bit related, what about drugs that act on acetylcholine (anticholinergic drugs, antimuscarinic drugs) ? Acetylcholine can be relevant for action potentials.

 

Would you say that for that same reason it's better to abstain from those drugs ? I know, that's MY question.

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Only a bit related, what about drugs that act on acetylcholine (anticholinergic drugs, antimuscarinic drugs) ? Acetylcholine can be relevant for action potentials.

 

Would you say that for that same reason it's better to abstain from those drugs ? I know, that's MY question.

 

Hi liberty, every time I hear or think about acetylcholine, I'm afraid to weightlift.    :). It's amazing how many chemical processes occur to get a muscle to contract.

 

Yes, as you know, the nicotinic Ach receptors are ligand ion based gated channels, like the above mechanism.  There is a lot of physiological similarity across a wide variety of receptors. I think the muscarinic receptors are G protein coupled. (?).  I do see where you are going on antimuscarinics as therapeutically "anti" excitable potentials, given that we're are in an overly excitable state.

Same with anticholinergic drugs.

 

My uncle had some dementia and i researched a drug called namzaric (donepezil + memantine) for the family.  It does the opposite of what you are asking by reversibly inhibiting the breakdown of ACh(donepezil) , ie acting as a  reversible acetylcholinesterase inhibitor,this increasing ACh;  the memantine blocks NMDA receptors (kind of like ketamine).  The donepezil is excitatory in a way, increasing alertness, etc. The memantine is antagonistic to NMDA receptors and is supposed to reduce neuronal excitotoxicity in Alzheimer's, etc, but clinically the proof of this is weak. I know there have been discussions on ketamine in these threads, but these drugs sound quite dangerous outside a medically supervised environment.

 

As I am not a medical doctor, I don't know about the answer to your question, but the muscaranic receptors as G protein, are quite different than the nicotinic ACh receptors, that work in a similar fashion as the glutamate and GABA receptors, i.e. Ionic channel. I have not researched any correlations of the GABA system with the ACh system, but they do affect one another.  In that respect I would be careful.

 

https://www.ncbi.nlm.nih.gov/pubmed/3226360

 

I am going to post an addendum to my post above with some kindling references, and much to my surprise a drug called Acamprosate used in alcohol detox.  It was approved in 2004, and I am surprised that it has not been mentioned much under alternative therapies.  I haven't tried to search for it on BB,  but it looks interesting, but they really don't know how it works :(

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Only a bit related, what about drugs that act on acetylcholine (anticholinergic drugs, antimuscarinic drugs) ? Acetylcholine can be relevant for action potentials.

 

Would you say that for that same reason it's better to abstain from those drugs ? I know, that's MY question.

 

Liberty, do you know if any of those drugs in the Wikipedia PAMs and orthosteric agonists list are anticholinergic or antimuscarinic?

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ADDENDUM TO CLOSE OUT THIS THREAD

 

just some additional references on kindling that many have already seen, but viewed form the perspective of the original you tube video.

This acamprosate seems very interesting.

------

 

Kindling

https://en.m.wikipedia.org/wiki/Kindling_(sedative%E2%80%93hypnotic_withdrawal)

 

"

Acamprosate, a drug used to promote abstinence from alcohol, an NMDA antagonist drug, reduces excessive glutamate activity in the central nervous system and thereby may reduce excitotoxicity and withdrawal related brain damage.[12]"

 

 

 

"Adaptational changes at the GABAA benzodiazepine receptor complex do not fully explain tolerance, dependence, and withdrawal from benzodiazepines. Other receptor complexes may be involved; in particular, the excitatory glutamate system is implicated. The involvement of glutamate in benzodiazepine dependence explains long-term potentiation as well as neuro-kindling phenomena. Use of a short-acting benzodiazepine at night as a sleeping pill causes repeated acute dependence followed by acute withdrawal. There is some evidence that a prior history of CNS depressant dependence (e.g. alcohol) increases the risk of dependence on benzodiazepines. Tolerance to drugs is commonly believed to be due to receptor down-regulation; however, there is very limited evidence to support this, and this hypothesis comes from animal studies using very high doses. Instead, other mechanisms, such as receptor uncoupling, may play a more important role in the development of benzodiazepine dependence; this may lead to prolonged comformational changes in the receptors or altered subunit composition of the receptors.[1]"

 

 

"Repeated benzodiazepine withdrawal episodes may result in similar neuronal kindling as that seen after repeated withdrawal episodes from alcohol, with resultant increased neuro-excitability. The glutamate system is believed to play an important role in this kindling phenomenon with AMPA receptors which are a subtype of glutamate receptors being altered by repeated withdrawals from benzodiazepines. The changes which occur after withdrawal in AMPA receptors in animals have been found in regions of the brain which govern anxiety and seizure threshold; thus kindling may result in increased severity of anxiety and a lowered seizure threshold during repeated withdrawal. Changes in the glutamate system and GABA system may play an important role at different time points during benzodiazepine withdrawal syndrome.[1]"

 

 

https://en.m.wikipedia.org/wiki/Kindling_model

 

Dm123: Repeated stimulation( subthreshold action potential (Benzo) followed by ever increasing compensatory high action potential in the post synaptic neuron, for example) leads to excessive increasing overstimulation and over sensitization of the glutamate system (receptors, exogenous glutamate etc), ultimately lowering thresholds to stress, seizures, anxiety, etc.  At this point we feel terribly sick and vulnerable.

 

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Thank you for the detailed response. I actually tapered off both drugs as my ticker counters show below…over 3 years off now from each drug.

 

I read some of your previous posts and see that you are quite learned on this gabba receptor subject….and even some, beyond the “basics”….if I can ask how is it that you are able to articulate such a complex subject-our brains-so that the average person can get a glimpse of or begin to  think we “understand” it?

 

I appreciate your contribution on this subject....and thanks again for answering my question. I have often wondered about this subject, given there are some of us who have taken both drugs at the same time. :(

 

By the way, your explanation in a previous post(and the posts on this thread) on kindling was/(is) excellent....I definitely fit the profile from what I had previously suspected on whether I kindled or not. I did not space my doses throughout the day....and now I understand how damaging that was.

 

But like you, I refused to increase my dose even though one of my many doctors during this nightmare increased my prescription as high as 3 mgs of ativan...if I recall correctly. I only went as high as 1.5 mgs daily.....and I was so miserable...but refused to increase. I'm glad I didn't. These drugs are DIFFICULT to get off of.

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Only a bit related, what about drugs that act on acetylcholine (anticholinergic drugs, antimuscarinic drugs) ? Acetylcholine can be relevant for action potentials.

 

Would you say that for that same reason it's better to abstain from those drugs ? I know, that's MY question.

 

Liberty, do you know if any of those drugs in the Wikipedia PAMs and orthosteric agonists list are anticholinergic or antimuscarinic?

 

I'm not sure if I understand. I did see a few drugs that act on acetylcholine that are PAMs, but those are not used in clinical practice for as far as I know.

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Only a bit related, what about drugs that act on acetylcholine (anticholinergic drugs, antimuscarinic drugs) ? Acetylcholine can be relevant for action potentials.

 

Would you say that for that same reason it's better to abstain from those drugs ? I know, that's MY question.

 

Liberty, do you know if any of those drugs in the Wikipedia PAMs and orthosteric agonists list are anticholinergic or antimuscarinic?

 

I'm not sure if I understand. I did see a few drugs that act on acetylcholine that are PAMs, but those are not used in clinical practice for as far as I know.

 

Hi liberty, yes, that is what I was getting at.  Since there are no clinically relevant drugs that act on ACh and are PAMS, we at least know the GABAa receptor won't directly be modulated by the drugs you were asking about.  I don't know enough about anticholinergics but do know they indirectly affect the GABA and dopamine systems.

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Hi BlueRose,

 

I'm glad this thread discussion is helping you understand what may have happened to you.  I had to keep researching until I figured it out for myself, months ago.  The effects of the benzodiazaphine were so profound, I had to understand what happened once I realized that the benzodiazaphine was why I felt so sick.  It took me a while just to discover that. >:(

 

I have a few degrees in engineering, business finance, and chemistry, but I only consider them useful with respect to how these disciplines teach you how to research,learn, and assimilate new material.  Reading all those books helps you articulate well in writing.  I think that, and the science background has helped a great deal in understanding these concepts and articulating them to others.  I am self taught in human physiology and health, and I consider that my most valuable degree.  I am not a medical doctor, and I don’t want to be one.

 

I wanted to add another addendum, number 2,  to this thread To help fellow BBs understand the importance of homeostatic balance in human physiology.  I think it will help complete the tread.  I'm hoping this thread will thrive.  I wish we could rename this thread.  :)

 

---------

 

ADDENDUM NUMBER 2: other areas of physiologic homeostasis as they pertain to benzodiazaphine tolerance and withdrawal.

 

I've read all of Perserverance's wonderful papers, and these are just some summary highlights of her paper describing how benzodiazaphines cause anxiety, both during chronic administration, and during the tolerance and withdrawal phases.

 

Here is a link to her paper

 

http://www.benzobuddies.org/forum/index.php?topic=110964.0

 

I focused on a few areas from this paper in the context of the body's tireless efforts to maintain counter regulatory homeostasis when bombarded with benzodiazaphines.  The points regarding AMPAr (AMPA receptor) upregulation align well with the glutamate upregulation that I mentioned in the earlier posts.

 

1. Upregulation of AMPAr and glutamate system due to membrane voltage potential troughs and peaks in the post synaptic neuron.

Note the sudden drop of chloride is what sets off the counter regulatory response.  This is more extreme in the context of withdrawal , i.e. Cold turkey, but interdose withdrawals can be a catalyst as well.  Note the subsequent rise in voltage (as the drug is withdrawn), activating the NMDA and voltage gated Calcium channels.  This is a homeostatic response of our physiology, and makes us feel very ill.

 

Quotes

"

“In summary, the present study provides evidence that AMPAR facilitation of NMDAR-mediated hippocampal pathways contributes to expression of anxiety-like behavior during withdrawal from prolonged BZ exposure.” [8]

AMPA potentiation may occur with rapid discontinuation of BZDs after changes to GABAAR subunit gene expression have occurred.  This is because rapid discontinuation of the BZD does not allow time for the changes to GABAAR gene expression to reverse as happens with a slow gradual taper.  The sudden removal of the drug after dependence has set up may result in a sudden drop in chloride influx into the neurons.  The lack of the negatively charged chloride influx results in an increase in the neuron membrane voltage potential.  The rise in voltage may in turn activate NMDA and voltage gated calcium channels and subsequently allow calcium to enter the neurons.

 

End quote

 

2. We are all familiar with the concept of downregulation of the GABAa receptor itself.  The paper gives us more insight into how much the body acclimates to  counteract the bombardment of the receptor with benzodiazaphines .  This is a counter regulatory effect to maintain inhibitory and excitatory homeostasis.

 

I don’t know if maintaining steady state in this situation will help in this area, as it does with kindling and upregulation of the glutamate system.  My doctor said there is very little we can do for this, other than to let nature take its course once the benzos are tapered off. The last part of the quote explains why a slow taper is better than an abrupt taper.

 

There are conformational changes to the receptor leading to changes in the subunit configuration, , uncoupling (described below), downregulation of endogenous endozepine binding sites (leading to a lower anxiety  threshold ), and even changes to GABAr gene expression.

 

 

Quotes

BZD administration has been shown to cause reductions in BZD binding sites through subsensitivity, or uncoupling, of GABAARs. Mechanisms underlying GABAAR uncoupling may include: receptor down-regulation; changes in receptor gene expression; and changes to receptor subunit configurations that result in reduced GABA potentiation:

 

 

“…uncoupling mechanism involves an initial increase in receptor internalization [down-regulation] followed by activation of a signaling cascade that leads to selective changes in receptor subunit levels. These changes might result in the assembly of receptors with altered subunit compositions that display a lower degree of coupling between GABA and benzodiazepine sites.” (10)

 

 

On the GABAAR, the BZD binding site is coupled to the GABA neurotransmitter binding site. When BZDs bind to the GABAAR they alter the receptor conformation (3 dimensional shape).  This results in an increase in the receptors binding affinity (tendency or strength of binding(37)) for the neurotransmitter GABA.  This keeps the GABAAR GABA-bound for longer periods of time, which in turn causes an increase in the total number of the receptor ion channel openings.(38,39) In this way, BZDs modulate the receptor's activation by enhancing the effect of the neurotransmitter GABA.  This process is known as positive allosteric modulation.(36) Scientists think that chronic potentiation of GABA might result in subsensitivity, or uncoupling between the BZD site and the GABA site on the GABAAR:

 

Long-term BZD administration has been shown to cause GABAAR uncoupling through down-regulation and changes to GABAAR gene expression- where the neurons essentially swap out GABAARs with subunits that bind BZDs with ones that don’t:

 

The BZD binding site on the GABAAR may also serve as the binding site for natural peptides known as endozepines.  Therefore, BZD induced down-regulation of GABAARs that are BZD sensitive might also cause a reduction in endozepine binding sites, which could theoretically reduce the natural capability of the brain to reduce anxiety:

 

There is still much to discover about endozepines. Some inhibit diazepam binding and may therefore be anxiogenic while others appear to act like diazepam and enhance GABA activity (as explained in the Manual, Chapter 1). It seems likely that the balance between different endozepines acting at the GABA-A receptor may determine an individual's susceptibility to anxiety and response to benzodiazepine drugs by acting as 'fine-tuners' of GABA-A function.” (21)

 

In contrast to abrupt BZD cessation, gradual tapering allows the neurons to reverse changes in GABAAR subunit gene expression as the dosage declines.  Therefore switching the patient from a BZD with a short half-life to one with a longer half-life in addition to a gradual tapering schedule may help prevent sudden changes in the membrane potential of the neurons (30) which may help prevent LTP-like occurrences from setting up.

 

End quote

 

3. HPA axis dysregulation.  These are compensatory responses to overstimulation of the subthreshold action potential state of the post synaptic neurons when dosing benzodiazaphines.  Perseverance also has a separate paper on this.  .I experienced this first hand.  I was on up to 30 mg of hydrocortisone a day during the worst of the kindling phase.  Early on, with benzos,  I was not producing any AM cortisol, via blood serum testing.  Subsequently put on hydrocortisone, kept on hydrocortisone , kindled, endogenous cortisol rose, but they kept me on HC.  After stabilized on long lasting  Benzo I was able to taper the HC rapidly.  Note the rebound in HPA activity with withdrawal.  Another compensatory response, after the cortisol has been suppressed so thoroughly by benzos.  During the kindling phase, I am guessing cortisol is jumping all over the place, based on my own personal experience.  Too low and too high cortisol have profound neurophysiological and neuropsychological effects.

 

Quotes

BZD administration has been shown to inhibit CRF and CRF receptor 1 (CRF1) receptor function:

 

“Previous studies revealed that chronic administration of the anxiolytic alprazolam reduced indices of CRF and CRF1 receptor function.” (24)

 

“Chlordiazepoxide attenuates stress-induced activation of neurons, corticotropin-releasing factor (CRF) gene transcription and CRF biosynthesis in the paraventricular nucleus (PVN)” (25)

 

However when BZDs are discontinued, studies have shown an increase in CRF transcription and a rebound increase in HPA Axis activity:

 

“Spontaneous withdrawal from the triazolobenzodiazepine Alprazolam [Xanax] increases cortical Corticotropin-Releasing Factor mRNA expression…The elevated HPA axis activity exhibited during alprazolam withdrawal may represent not only the endocrine stress response to drug withdrawal but also a rebound increase in HPA axis activity after removal of the suppressing influence of chronic benzodiazepine administration.” (24)

 

“Benzodiazepines profoundly suppress the basal and stress-related activation of the hypothalamic pituitary-adrenocortical (HPA) system and discontinuation of these drugs results in rebound activation.” (26)

 

Studies have correlated increased levels of CRF and CRF1 activity with anxiety and decreased levels with anxiolysis:

 

“CRHR1-deficient mice show decreased anxiety-related behavior…transgenic mice overexpressing CRH show increased anxiety-related behavior…central administration of CRHR1 antisense ODNs inhibit CRH- and social defeat–elicited anxiety-related behaviors and evoke anxiolytic-like effects in certain anxiety tests… selective (nonpeptidergic) CRHR1 antagonists NBI-27914, CRA1000, CRA1001 (all anilinopyrimidines), and CP154526 (a pyrrolopyrimidine) inhibit the anxiogenic action of CRH [under stressed conditions]” [28]

 

And this....

 

As previously mentioned, BZD induced changes to GABAAR gene expression may cause uncoupling of the GABAA-benzodiazepine receptor complex.  Research suggests that this may also be associated with HPA Axis hyperactivity [Note- Flumazenil binds to the BZD receptor site on the GABAAR(2)]

 

End quote

 

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Excellent, dm123!!

 

It's unfortunate that we in the benzo community have this but it isn't seen by doctors. I'm still angry at the doctor who ignorantly told me that after a month's time the benzo would be out of my body and no symptoms left. I had been hospitalized for hyponatremia, obviously caused by benzos. I still have low salt.

 

 

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dm123,

 

Any idea what chronic (physical, but also some mental) stress will do in this context ?

 

' membrane potential of the neurons' Can you describe that in a few words ?

 

Also, I learned that one strong antimuscarinic drug in particular seemed to suppress HPA activity ... for a while .. but then, the cognitive effects ...

 

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I'm sorry, liberty, but that is definitely not my field of expertise. dm123 could probably explain it. Hopefully he'll be back soon.
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Excellent, dm123!!

 

It's unfortunate that we in the benzo community have this but it isn't seen by doctors. I'm still angry at the doctor who ignorantly told me that after a month's time the benzo would be out of my body and no symptoms left. I had been hospitalized for hyponatremia, obviously caused by benzos. I still have low salt.

 

Hi Terry, I hope it helps you understand why you are feeling the way you do.  Yes, I was hyponatremic as well, which further strained my adrenals.  While I was on HC, they also put me on fludrocortisone to stabilize my sodium levels and give my adrenals a break.  At that time,  I did not know that it was the benzos causing all the adrenal issues and electrolyte imbalances.  I'm off the fludro as well.  Very powerful mineral corticosteroid.

 

 

Since you are in PWS try to do everything you can to pamper those adrenal glands.  As you know, adrenal function is tightly coupled to sodium levels via aldosterone.

 

 

I want to add a quick ADDENDUM 3 in light of liberty's question about ACh drugs as adjunctive meds during withdrawal.  I'm continuing on the theme that one  should always consider making decisions with homeostasis in mind.

 

  I'm hoping that this document can be dynamic, with others contributing their knowledge in this area of homeostasis and benzodiazepines.

 

ADDENDUM 3: Adjunctive medications during withdrawal

 

Since I am not a medical doctor I cannot give out medical advice on whether or not to take a certain drug.  However, given the three points above in ADDENDUM 2, I would say that any PAMs or orthosteric agonists should be completely avoided during and after a taper. I say this because they act directly on the GABAa receptor in such a way to potentially alter the conformation and subunit configuration of the receptor itself.  This is listed as point 2 in ADDENDUM 2, above.  From Pers’s original paper:

 

Quote

On the GABAAR, the BZD binding site is coupled to the GABA neurotransmitter binding site. When BZDs bind to the GABAAR they alter the receptor conformation (3 dimensional shape).  This results in an increase in the receptors binding affinity (tendency or strength of binding(37)) for the neurotransmitter GABA.  This keeps the GABAAR GABA-bound for longer periods of time, which in turn causes an increase in the total number of the receptor ion channel openings.(38,39) In this way, BZDs modulate the receptor's activation by enhancing the effect of the neurotransmitter GABA.  This process is known as positive allosteric modulation.(36) Scientists think that chronic potentiation of GABA might result in subsensitivity, or uncoupling between the BZD site and the GABA site on the GABAAR:

 

End quote

 

  I’ve posted several listings of these PAMs, for those who are interested.  I’m trying to spread the word to as many BBs as possible, to avoid unnecessary additional pain.  I hear of people using kava and other adjunctive meds that are known to be PAMs. 

 

I realize  that these are Wikipedia listings, and as such, are not the most reliable.  I did extensive research for one post/thread regarding if niacin is truly a PAM of the GABAa receptor.  I worked backwards from the reference in the Wikipedia listing (reference 29).  I could not find clear clinical or research evidence of its role as a PAM.  One study came close, but was not a full confirmation.  Many of the studies on niacin were done with analogues, and not niacin itself.  Some of the studies were outdated, and some clinical conclusions used the word “may” act on the receptor.    Please refer to that thread if you are interested.

 

I did not want to quote the full details of  point number 2 above,  from Perseverance's source material, because it's not all positive news.  Point 2 above, according to my doctor, and according to the research that I have done, is the most difficult area for the body to heal, and the least understood by clinicians.  The Ashton manual gives us some insight, so even back then Professor Ashton had an idea that this was going on.     

 

I think that many of the PWS cases might be experiencing  significant recovery in this area.  Since some part of this area is due to altered  gene expression of the receptor itself,  this would explain the large variation we see in people with respect to both the severity and duration of PWS.  We all have unique genetics. Since the whole area of downregulation is mostly theory, these conclusions are theoretical as well.

 

I think that other meds that affect numbers 1 and 3 are, in general ok, but talking to your healthcare provider about concerns is always recommended.  I say this because in my own experience, even though my HPA axis was severely affected, once I got off of the HC it did bounce back fairly quickly.  Cutting out the fludrocortisone  was much more difficult to adjust to, and my sodium is still borderline low, but there is recovery.

 

One drug that many BBs are using adjunctively during withdrawal is gabapentin.  Most clinicians and doctors really don’t know how it works so effectively, but I suspect it affects mostly area 1, quelling the glutamate upregulation by acting on the volted gated Calcium channels(i.e., EDIT 7/20/17: I am going to research this area more thoroughly.  I don't know if it is acting on the presynaptic voltage gated calcium channels, or if it is acting post synaptically on voltage gated channels in the axons, or both.  In either case, it seems to lessen the chance that the voltage gated channel fires off by somehow directly acting on these types of channels.  It does not seem to be acting on any of the ligand  gated ion channels post synaptically (i.e., the GABAa or glutamate ion channels) which is good.  In the end, the action potiential won't get through, and the signal won't get propagated through the axon.  See ADDENDUM 4 below for more info on different types of channels). That’s where most of the theory on the effectiveness of this drug is pointing to.

 

  If gabapentin does modulate these types of channels, then in light of the original discussion above on action potentials, it makes sense why it is so therapeutic during withdrawal and glutamate upregulation.

 

 

From Wikipedia

https://en.m.wikipedia.org/wiki/Gabapentin

 

Note:

Its  affinity for GABA receptors is thought to be very weak.

 

Quote

Gabapentin was initially synthesized to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid (GABA), but is believed to act on different brain receptors.[citation needed]

Some of its activity may involve interaction with voltage-gated calcium channels. Gabapentin binds to the α2δ subunit (1 and 2) and has been found to reduce calcium currents after chronic but not acute application via an effect on trafficking[58] of voltage-dependent calcium channels in the central nervous system.[59] Another possible mechanism of action is that gabapentin halts the formation of new synapses.[60]

 

End quote

 

And from the same reference.

Note: a 1 mM concentration for affinity to the GABA receptor is huge.  One would have to ingest a very very large amount to get any binding to GABA receptors.  It does not appear to be relevant to area number 2.

 

Note: it does modulate GAD and BCAT enzymes, so it does effect endogenous GABA production.  I haven’t researched this yet to confirm just how much of an effect it has in GABA synthesis. References 63 is an in vitro study.

 

Note: Another reason why it appears to help so much in the area of number  1 is because interacts with NMDA receptors.  I have not looked up and read the citations that Wikipedia cites to confirm in what way and to what extent it does this. This is another area that needs more research.

 

Quote

The mechanism of the anticonvulsant action of gabapentin has not been fully described. Several possible mechanisms for pain improvement have been discussed.[61] Though similar in structure to the endogenous neurotransmitter GABA, gabapentin has not been shown to bind to GABA receptors at concentrations at or below 1 mM.[62] Gabapentin modulates the action of glutamate decarboxylase (GAD) and branched chain aminotransferase (BCAT), two enzymes involved in GABA biosynthesis. In human and rat studies, gabapentin was found to increase GABA biosynthesis, and to increase non-synaptic GABA neurotransmission in vitro.[63]

Gabapentin has been shown to bind to the α2δ-1 subunit of voltage gated calcium ion channels, which contributes to its pain attenuation effects in diabetic neuropathy and post-herpetic neuralgia. Other neurophysiological findings indicate that gabapentin also interacts with NMDA receptors , protein kinase C, and inflammatory cytokines.[62][64]

End quote

 

 

 

 

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dm123,

 

Any idea what chronic (physical, but also some mental) stress will do in this context ?

 

' membrane potential of the neurons' Can you describe that in a few words ?

 

Also, I learned that one strong antimuscarinic drug in particular seemed to suppress HPA activity ... for a while .. but then, the cognitive effects ...

 

 

Hi liberty,

 

Regarding membrane potentials in a few words:

Regarding the membrane potential of the neurons. I think this is referring to the cell membrane potential.  Neurons are made of cells.  Here we are interested in the post synaptic cell membrane.  There is a difference in the electrical potential between the inside of the cell, and the outside of the cell.    For a more complete story see ADDENDUM 4 below. I’m sure there are a lot of electrical engineers out there who might find this interesting.

 

Regarding stress, it will create havoc on number 3, the HPA axis, and will dysregulate hormones and neurotransmitters.  In that respect,  it will also indirectly affect number 1 above.  I think benzos and PAMs are unique in the great damage that they cause us with number 2.  Only a man made pharmaceutical could cause number 2. Kind of like nuclear weapons.    I never felt like I do now, even during years of work stress.  It only started after benzos.  I’m convinced that for me, number 2 above is the problem, and benzos caused that. 

EDIT: please also read up on the works of Hans Selye, allostasis, and homeostasis.  Physiological  Homeostasis is the main theme of this thread..  He is considered the father of stress research and allosteric adaptation of the body to human stress.  I consider benzodiazaphines as a stress physiologically, once we enter withdrawal and tolerance so his work applies to us.

This link is a great staring point

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808193/

 

 

Regarding your third question, why do you want to suppress the HPA axis via ACh pharmaceuticals? Low thyroid and adrenal function are horrible.  One thinks that low cortisol will lead to a more relaxed state, but from first hand  experience I can tell you that with low cortisol you get terrible anxiety and fear .    I think balance is the key, but I know it’s hard to attain whilst on

 

ADDENDUM 4

 

EDIT ADD: The concept of resting potential in the first link below is very important.  When we ingest benzodiazaphines, we are overly suppressing the resting potential inside the post synaptic neuron (making the voltage more negative) and doing so for an abnormally long time..  Because the body always strives to restore homeostasis, it will upregulate the glutamate system (item 1), uncouple binding sites in the GABA receptor, downregulate the GABA receptor, alter gene expression of the GABA receptor, all leading to conformational changes in the receptor itself (3 dimensional changes in its shape), making it much less effective (item 2) as a modulator of the chloride channel.  The end result is what the body wants, to raise the voltage potiential inside the post synaptic neuron.  Unfortunately, since benzodiazaphines are so effective in lowering the voltage inside the neuron, the body's correction will overcompensate.  This can lead to unstable and oscillating voltages inside the neuron, which translate to very erratic and horrible excitatory currents through the axon.  The quote below describes this very well.  Ligand and voltage gated ion channels feed off of each other, and the feedback can cause very large oscillations , as the body tries to maintain steady state resting potential.

 

Quote

 

In neurons, the factors that influence the membrane potential are diverse. They include numerous types of ion channels, some of which are chemically gated and some of which are voltage-gated. Because voltage-gated ion channels are controlled by the membrane potential, while the membrane potential itself is influenced by these same ion channels, feedback loops that allow for complex temporal dynamics arise, including oscillations and regenerative events such as action potentials.

 

End quote

 

 

-membrane potentials

 

Regarding the membrane potential of the neurons. I think this is referring to the cell membrane potential.  Neurons are made of cells.  Here we are interested in the post synaptic cell membrane.  There is a difference in the electrical potential between the inside of the cell, and the outside of the cell.  I know this is more than what you asked, but if you read the first few paragraphs of this article below,  you will get a good idea of what we are talking about.  I like the analogy of a battery and a resistor.  You can think of these ionic channels as a battery stuck in the cell membrane.  In electrical engineering they teach you about electric circuits.  A battery with a negative and positive terminal basically forces electrons through a potential gradient to complete an electrical circuit, so that a current (i.e.,  - charged electrons) flow through the wires.  The current flows from the positive terminal of the battery in a loop to the negative terminal of the battery. The battery is actually doing work or generating power as it does this, because opposite charges attract and same charges repel. The wire has what is called resistance, and that determines how much work the battery has to do to “push” those electrons (-) through the wire from its + terminal in a loop back to its negative terminal. At this point there is a voltage potential or gradient established to get that current flowing through the wire

 

In reading the link below, we are more concerned about chemically gated or ligand gated ion channels.  This would be , for example the GABA receptor’s chloride channel or the glutamate receptor’s sodium channel mentioned earlier in this thread.  These are channels that are opened by ligands, for example GABA or glutamate. 

 

Also note in the links below, the terms depolarization and hyperpolarization.  Also resting potential.  Since the chloride ion has a net negative charge, when GABA (2 of them actually) locks into that ligand gated receptor and opens up the channel, an influx of negatively charged extracellular chloride ions flow into the inside of the cell, hyperpolarizing it, i.e. Lowering the volatage from its resting potiential (it becomes more negative, like in That graph in the video at the beginning of this thread).    If glutamate locks into a post synaptic ligand gated channel, an influx of extracellular sodium ions(+)  will flow into the inside of the cell.  The resting potential of a cell is negative and this will depolarize the inside of the cell making it much less negative, like the upward sloping part  of the graph in the video. If it’s enough of a + flow, and if there are many more glutamate receptor channels opening than there are GABA receptor channels opening , the inside of the cell can actually go positive.  By the way, the channels only let through an ion at a time, and the channels rarely let through the “wrong” ion when they are open.  This is despite the fact that all these ions have only minute differences in their size(radius).  Amazing!

 

  Depolarization is significant because it acts as a catalyst to the eventual action potential in the post synaptic neuron.  This is the net charge +  impulse inside the post synaptic neuron,  shown in the video.  If it’s high enough it will activate what is called a voltage gated sodium channel in the axon.  The axon will transmit this electrical signal or impulse to the next neuron.  This is where the drawing part in the video ends.  This is why we feels zaps and anxiety and nerve pain.

Quote

 

Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals.

 

End quote

 

 

 

The links below go into far more detail as to how the channels are actually opened,etc. it’s very fascinating.  The first link goes into the electrical circuitry analogue of this biological process.

 

-Membrane potential

https://en.m.wikipedia.org/wiki/Membrane_potential

-Ligand gated ion channels (chemical)

https://en.m.wikipedia.org/wiki/Ligand-gated_ion_channel

-Voltage gated ion channels

https://en.m.wikipedia.org/wiki/Voltage-gated_ion_channel

 

Other links of interest

 

-Membrane transport proteins, or transporters

 

Two main types of Transport proteins: The difference between channels/pores and carriers(ion transporter/ pump proteins)

Quote

Ion transporter/pump proteins (carriers)actively push ions across the membrane and establish concentration gradients across the membrane, and ion channels allow ions to move across the membrane down those concentration gradients. Ion pumps and ion channels are electrically equivalent to a set of batteries and resistors inserted in the membrane, and therefore create a voltage between the two sides of the membrane.

End quote

Quote

A carrier (i.e., ion pump) is not open simultaneously to both the extracellular and intracellular environments. Either its inner gate is open, or outer gate is open. In contrast, a (ion) channel can be open to both environments at the same time, allowing the solutes it transports to diffuse without interruption. Carriers have binding sites, but pores and channels do not.[2][3][4] When a channel is opened, millions of ions can pass through the membrane per second, but only 100 to 1000 molecules typically pass through a carrier molecule in the same time.[5]

End quote

 

https://en.m.wikipedia.org/wiki/Membrane_transport_protein

 

 

 

 

 

-Ion channels in more detail : generation of the action potential  We are focused on this

 

 

We are focusing on α-helical protein channels such as voltage-gated ion channels (VIC),  and most importantly ligand-gated ion channels(LGICs)

 

Note with just a channel open, the ions will flow down concentration gradient according to the existing membrane potential and the difference in ion concentration. This is the direction of flow unless ATP or active transport gets involved.  See ion pumps below for more info on how this is done.

 

When a channel is open, ions permeate through the channel pore down the transmembrane concentration gradient for that particular ion.

Quote

 

Ion channels can be classified by how they respond to their environment.[16] For example, the ion channels involved in the action potential are voltage-sensitive channels; they open and close in response to the voltage across the membrane. Ligand-gated channels form another important class; these ion channels open and close in response to the binding of a ligand molecule, such as a neurotransmitteR

End quote

 

Quote

The rate of ion transport through the channel is very high (often 10^^6 ions per second or greater).

Ions pass through channels down their electrochemical gradient, which is a function of ion concentration and membrane potential, "downhill", without the input (or help) of metabolic energy (e.g. ATP, co-transport mechanisms, or active transport mechanisms).

End quote

 

Quote

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells

End quote

 

In this discussion we are focused on chemical or ligand (GABA or glutamate) based gating, or voltage based gating.

Quote

In many ion channels, passage through the pore is governed by a "gate", which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force.

End quote

 

 

 

Types

Quote

Ligand-gated ion channels are channels whose permeability is greatly increased when some type of chemical ligand binds to the protein structure. Animal cells contain hundreds, if not thousands, of types of these. A large subset function as neurotransmitter receptors—they occur at postsynaptic sites, and the chemical ligand that gates them is released by the presynaptic axon terminal. One example of this type is the AMPA receptor, a receptor for the neurotransmitter glutamate that when activated allows passage of sodium and potassium ions. Another example is the GABAA receptor, a receptor for the neurotransmitter GABA that when activated allows passage of chloride ions.

 

Voltage-gated ion channels, also known as voltage dependent ion channels, are channels whose permeability is influenced by the membrane potential. They form another very large group, with each member having a particular ion selectivity and a particular voltage dependence. Many are also time-dependent—in other words, they do not respond immediately to a voltage change but only after a delay.

End quote

 

Quote

Ion pumps influence the action potential only by establishing the relative ratio of intracellular and extracellular ion concentrations. The action potential involves mainly the opening and closing of ion channels not ion pumps. If the ion pumps are turned off by removing their energy source, or by adding an inhibitor such as ouabain, the axon can still fire hundreds of thousands of action potentials before their amplitudes begin to decay significantly.[8] In particular, ion pumps play no significant role in the repolarization of the membrane after an action potential.[3]

End quote

 

In neuronal cells, an action potential begins with a rush of sodium ions into the cell through sodium channels, resulting in depolarization, while recovery involves an outward rush of potassium through potassium channels. Both these fluxes occur by passive diffusion.

 

Passive diffusion, not ATP

With ion channels, passive diffusion is what moves the ions though the channel, not ATP.  ATP is used with ion pumps.

Quote

Passive transport is a movement of ions and other atomic or molecular substances across cell membranes without need of energy input. Unlike active transport, it does not require an input of cellular energy because it is instead driven by the tendency of the system to grow in entropy. The rate of passive transport depends on the permeability of the cell membrane, which, in turn, depends on the organization and characteristics of the membrane lipids and proteins.

 

Diffusion is the net movement of material from an area of high concentration to an area with lower concentration. The difference of concentration between the two areas is often termed as the concentration gradient, and diffusion will continue until this gradient has been eliminated. Since diffusion moves materials from an area of higher concentration to an area of lower concentration, it is described as moving solutes "down the concentration gradient" (compared with active transport, which often moves material from area of low concentration to area of higher concentration, and therefore referred to as moving the material "against the concentration gradient")

End quote

 

https://en.m.wikipedia.org/wiki/Ion_channel

https://en.m.wikipedia.org/wiki/Passive_transport

 

 

 

-Carriers: Ion pumps (ion transporters), and ATP: maintenance of the membrane potential These transport those ions through the membrane and it's through a concentration gradient. 

Active transport

An ATP utilizing transporter or pump will use ATP to transport ions through  a concentration gradient (low to high).  Used ATP has been converted to potential energy in this case.

An ATP producing transporter or pump will transport ions through a concentration gradient (high to low) "downhill" and in the process generate ATP

Quote

In biology, an ion transporter (or ion pump) is a transmembrane protein that moves ions across a

plasma membrane against their concentration gradient through active transport.

End quote

 

Types of ion transport

Quote

There are two forms of active transport, primary active transport and secondary active transport. In primary active transport, the proteins involved are pumps that normally use the chemical energy in the form of ATP. Secondary active transport, however, makes use of potential energy, which are usually derived through exploitation of an electrochemical gradient. This involves pore-forming proteins that form channels across the cell membrane. The difference between passive transport and active transport is active transport requires energy and moves substances against their respective concentration gradient, whereas passive transport requires no energy and moves substances in the direction of their respective concentration gradient.

End quote

 

Maintenance of the membrane potential

Quote

A major contribution to establishing the membrane potential is made by the sodium-potassium pump. This is a complex of proteins embedded in the membrane that derives energy from ATP in order to transport sodium and potassium ions across the membrane. On each cycle, the pump exchanges three Na+ ions from the intracellular space for two K+ ions from the extracellular space. If the numbers of each type of ion were equal, the pump would be electrically neutral, but, because of the three-for-two exchange, it gives a net movement of one positive charge from intracellular to extracellular for each cycle, thereby contributing to a positive voltage difference. The pump has three effects: (1) it makes the sodium concentration high in the extracellular space and low in the intracellular space; (2) it makes the potassium concentration high in the intracellular space and low in the extracellular space; (3) it gives the intracellular space a negative voltage with respect to the extracellular space.

 

 

Another functionally important ion pump is the sodium-calcium exchanger. This pump operates in a conceptually similar way to the sodium-potassium pump, except that in each cycle it exchanges three Na+ from the extracellular space for one Ca++ from the intracellular space. Because the net flow of charge is inward, this pump runs "downhill", in effect, and therefore does not require any energy source except the membrane voltage. Its most important effect is to pump calcium outward—it also allows an inward flow of sodium, thereby counteracting the sodium-potassium pump, but, because overall sodium and potassium concentrations are much higher than calcium concentrations, this effect is relatively unimportant. The net result of the sodium-calcium exchanger is that in the resting state, intracellular calcium concentrations become very low.

End quote

 

 

Regulation of ion transporters

Quote

Ion transporters can be regulated in a variety of different ways such as phosphorylation, allosteric inhibition or activation, and sensitivity to ion concentration. Using protein kinases to add a phosphate group or phosphatases to dephosphorylate the protein can change the activity of the transporter.[7]

Whether the protein is activated or inhibited with the addition of the phosphate group depends on the specific protein. With allosteric inhibition, the regulatory ligand can bind into the regulatory site and either inhibit or activate the transporter.

End quote

 

Quote

Specialized transmembrane proteins recognize the substance and allow it to move across the membrane when it otherwise would not, either because the phospholipid bilayer of the membrane is impermeable to the substance moved or because the substance is moved against the direction of its concentration gradient.[4]

End quote

 

https://en.m.wikipedia.org/wiki/Ion_transporter

https://en.m.wikipedia.org/wiki/Active_transport

https://en.m.wikipedia.org/wiki/Passive_transport

 

-Neurotransmitter extracellular clearance transporters

 

Neurotransmitter transporters overview

https://en.m.wikipedia.org/wiki/Neurotransmitter_transporter

Quote

Normally, transporters in the synaptic membrane serve to remove neurotransmitters from the synaptic cleft and prevent their action or bring it to an end. However, on occasion transporters can work in reverse, transporting neurotransmitters into the synapse, allowing these neurotransmitters to bind to their receptors and exert their effect.

End quote

 

Glutamate transporters

https://en.m.wikipedia.org/wiki/Glutamate_transporter

A note about NAC: 

Quote

Drugs which help to normalize the expression of EAAT2 in this region, such as N-acetylcysteine, have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.[28]

 

 

The EAATs are membrane-bound secondary transporters that superficially resemble ion channels.[1] These transporters play the important role of regulating concentrations of glutamate in the extracellular space by transporting it along with other ions across cellular membranes.[2] After glutamate is released as the result of an action potential, glutamate transporters quickly remove it from the extracellular space to keep its levels low, thereby terminating the synaptic transmission.[1][3]

End quote

 

GABA transporters

https://en.m.wikipedia.org/wiki/GABA_transporter

GAT2 also transports taurine, while BGT1 transports betaine

Quote

GAT1 a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft.[5]

 

Deletion of the GAT2 gene in mice does not appear to have any dramatic effects on brain function in a normal situation. The only difference noted so far is a slight elevation of brain Taurine levels.[2] This was an unexpected finding, but is in agreement with the notion that GAT2 permits efflux of GABA and taurine from the brain to circulating blood through the blood brain barrier.[3] GAT1 and GAT3 have higher concentrations in the brain and have higher affinity to GABA. This makes them more likely than GAT2 to influence the activity of neurotransmitter GABA in the brain.[1]

 

GABA transporter type 3 (GAT3) uses sodium (Na+) electrochemical gradients to mediate uptake of GABA from the synaptic cleft by surrounding glial cells.[1]

End quote

 

Kinases

https://en.m.wikipedia.org/wiki/Kinase

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Thanks so much, dm123!! I'm going to print these out so that I can show them to my nurse practitioner, who I hope will show them to the doctors in her practice. This is such valuable information and cuts to the core of what these drugs cause in the body. I'd have to read very slowly and look everything up for it to make sense to me!
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dm123,

 

'Regarding stress, it will create havoc on number 3, the HPA axis, and will dysregulate hormones and neurotransmitters.  In that respect,  it will also indirectly affect number 1 above.  I think benzos and PAMs are unique in the great damage that they cause us with number 2.  Only a man made pharmaceutical could cause number 2. Kind of like nuclear weapons.    I never felt like I do now, even during years of work stress.  It only started after benzos.  I’m convinced that for me, number 2 above is the problem, and benzos caused that.

EDIT: please also read up on the works of Hans Selye, allostasis, and homeostasis.  Physiological  Homeostasis is the main theme of this thread..  He is considered the father of stress research and allosteric adaptation of the body to human stress.  I consider benzodiazaphines as a stress physiologically, once we enter withdrawal and tolerance so his work applies to us.''

 

I my situation I suffered in a severe way from what was originally one health problem, interfering with sleep, leading to exhaustion. I could not get any medical help at the time.

I did notice it was a very bad thing combined with the clonazepam. While the original problem was solved, others occurred ...

 

My situation is that I have to deal with an incompetent GP who is a gatekeeeper (referrals are necessary). And a horrible medical culture, at least at the GP level. That's the national system, it cannot be bypassed.

 

By now I am quite familiar with Selye's work ...

 

So I am very messed up, but I already knew that.

 

'Regarding your third question, why do you want to suppress the HPA axis via ACh pharmaceuticals? Low thyroid and adrenal function are horrible.  One thinks that low cortisol will lead to a more relaxed state, but from first hand  experience I can tell you that with low cortisol you get terrible anxiety and fear .    I think balance is the key, but I know it’s hard to attain whilst on benzos…..'

I did not want that. the incompetent GP prescribed an antimuscarinic drug to deal with a health problem, and I had to deal with the consequences.

 

I did learn that exercise was (up to a point) helpful in recovering from that drug, but at a price ... HPA axis activity etc. !!!

 

Without the GP and this archaic system I wouldn't have gotten into this mess. Thing is, my health is poor and while an antimuscarinic drug would help with some serious issues, but there is a price !!!

 

(serious as in seriously interfering with a taper)

GPs just reaching for symptom pills ... horrible.

 

 

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Hi liberty,

 

I'm sorry to hear what happened to you.  Our stories are very very similar.  Alsmost the same.

 

 

Single main health issue.....

 

Exhaustion, then pituitary/hypothalamus shut down, cortisol to zero, thyroid out, HC, etc.....you know what I mean.

 

I posted a nice article on exercise and anxiety response under the Exercise thread in this section.  Take a look if you have a chance.  It's the best thing for getting through this taper, in my opinion.  It's painful, but helps develop a stronger resiliency toward stress and glutamate upregulation.

 

Also that link to allosteric framework in my previous post.  It's very interesting.

 

 

Yes, pills are not the answer to these complex problems.  I assume you are in a country with socialized healthcare?  I'm sorry you can't fire your GP :)

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Thanks so much, dm123!! I'm going to print these out so that I can show them to my nurse practitioner, who I hope will show them to the doctors in her practice. This is such valuable information and cuts to the core of what these drugs cause in the body. I'd have to read very slowly and look everything up for it to make sense to me!

Hi Terry, great.  I hope it helps.  Make sure to print out a copy with the most recent edits.  Good luck.

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And once our cells are damaged, there could be an immune response to those damaged cells.  Read fellow bb,  Hope4us's latest posts.  Docs found tons of autoantibodies attacking her brain and body causing further symptoms and damage.  Docs gave her immunoglobulin, but not sure how it worked out for her since she hasn't posted since last year. 
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Hi all,

I want to bump into this thread to help me know what is going on with me, and all of us.  Thanks for all the research and willingness to share! :thumbsup: :thumbsup: I'm almost half way through a taper, but it's just half way...

I hope everyone is doing well.

SS

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Hi SufferingSixity

 

Congrats on halfway point.  It feels great, doesn't it. :) :)

 

Thanks for bumping.

 

Perhaps one of the admins can pin it in this Chewing the Fat along with the other articles so that it gets more visibility.  Also,perhaps re-title it as "Physiological Homeostasis and Benzodiazpahines: Tolerance, Withdrawal, and Recovery"

 

Spread the word about those orthosteric agonists and PAMs! to your fellow newbie BBs.

 

Knowledge is power, and unity is power!    Soon, we, as a group, can get these drugs reclassified to Schedule II in the U.S.  ......especially the shorter acting ones like lorazepam, xanax, and clonazepam.  They serve no medical therapeutic purpose outside of the hospital.  The only exceptions are for seizure disorders, and  for systemic genetic defects in the GABA system and neuromuscular diseases, etc.

 

I'm not trying to intentionally make it harder to get an Rx, but Schedule II will make the docs and naturopaths think twice about prescribing these drugs so indiscriminately for things like anxiety.  Publicity will help as well.  Opiates are already seeing a significant drop off rate in the number of prescriptions.  I know this fosters illegal distribution of the drug, but reclassification of benzodiazaphines is a good start.  Nothing is perfect.

 

Best wishes.

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