Can anyone make sense of this to explain to a layperson?

[[cs...]]

Some food for thought around the the concept of downregulation.  To date, unless I am wrong, the most talked about concept of downregulation in BZD withdrawal/tolerance is modulation of the receptor conformation.  There is some interesting stuff in the following article about downregulation as a function of altered hyperpolarization that is not specifically due to altered receptor conformation.

 

https://www.researchgate.net/publication/319046545_Seizing_Control_of_KCC2_A_New_Therapeutic_Target_for_Epilepsy

 

“Glutamate Dephosphorylates S940, Decreasing KCC2 Surface Expression and Function:

 

Excess glutamate downregulates KCC2 and reduces the chloride extrusion capacity of neurons [60]. This downregulation depends on NMDA receptor-mediated activation of PP1, which dephosphorylates S940, as NMDA receptor and PP1 inhibition prevents glutamate-mediated S940 dephosphorylation and maintains hyperpolarizing GABAergic inhibition. Glutamate-mediated downregulation of KCC2 seems to also depend on the activation of the calcium activated protease, calpain, which cleaves the C terminus of KCC2, reducing its total and surface expression [111]. Interestingly, levels of glutamate are known to increase within the brain during a seizure [69], which we would expect to lead to dephosphorylation of S940. In support of this, induction of SE in mice causes dephosphorylation of S940 and a reduction in the surface expression of KCC2, potentially due to enhanced NMDA receptor activity [46]. A glutamate mediated reduction in S940 phosphorylation may therefore underlie the decrease in KCC2 surface expression seen in patients with epilepsy”

 

And…

“Seizures are bursts of synchronous neuronal hyperactivity typically lasting for several minutes. In some cases, seizures are prolonged and fail to terminate. These extended seizures are termed Status Epilepticus (SE) and are life threatening medical emergencies that can lead to long-term neurological deficits including epilepsy. GABAA modulators, specifically the benzodiazepine class, are the standard first-line treatment for SE. Many patients fail to respond to benzodiazepines [125,126] and many papers have established deficits in GABAA receptor subunit expression as the underlying cause [127,128]. More recently, it has been proposed that a reversal in the direction of Cl flow through GABAA receptors is responsible [86,129], potentially due to an impairment of KCC2 function. While these two papers did not study SE per se, they both linked the Cl  gradient with the efficacy of benzodiazepines. As we discuss in the main text, Cl  shifts are observed during seizures in vitro and in vivo. Thus, during SE we can expect similar shifts in Cl  gradients, and hence rapid reductions in benzodiazepine efficacy.”

 

Obviously the above material is from a paper on epilepsy but it offers some interesting correlations.  I find it particularly interesting in my case due to the influence of gabapentin on calcium concentrations and the significant role calcium plays in withdrawal syndrome / damage.  More interestingly, is this a piece of the puzzle for those of us suffering protracted withdrawal?

 

Here is another interesting paper looking at this area. If it seems too long or is confusing, at least read the last couple of sections.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760510/

 

-RST

 

RST, thanks for posting this.  I had read up a lot on KCC2 several months back, and wish I could find the paper on it.  It was on tolerance and dependency I think, but not sure.  It was interesting enough for me to print it out, but I don’t know where the copy is.  Nutty professor 

 

I just found a good substitute article

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243505/

 

 

quote

 

KCC2-MEDIATED SPINE MORPHOGENESIS

 

Knockdown of neuroligin-2 down-regulates expression of KCC2 and reduces GABAergic synaptogenesis, and interestingly, by affecting the KCC2 levels it also down-regulates the number of glutamatergic synapses (Sun et al., 2013).

 

Although there is no direct evidence yet on drug-induced structural changes through KCC2-dependent mechanisms, several studies demonstrated changes in expression levels of KCC2. Chronic treatment with the BZ agonist zolpidem up-regulated the KCC2 expression in mouse limbic forebrain (Shibasaki et al., 2013). Also the neurosteroid allopregnanolone transiently modifies KCC2 expression and protein levels during brain maturation in male rats (Modol et al., 2014). However, treatment with general anesthetics, midazolam, propofol and ketamine, does not alter the expression of KCC2 in rats during the first two postnatal weeks when developmental maturation of KCC2 expression is going on (Lacoh et al., 2013). Future studies should be directed to clarify whether KCC2-mediated mechanisms play a role in neuronal plasticity induced by GABAergic drugs (Kang et al., 2006), and which particular isoforms of KCC2 play role in structural changes, since a recent study suggests that KCC2a and KCC2b isoforms have different brain regional distributions and likely different roles in neuronal functions (Markkanen et al., 2014).

 

End quote

 

 

 

 

 

[[li...]]

dm123,

 

I get your point and we don't need to discuss it. In a way, everyone is invested in something.

 

My real point, aside form the almost continued messing with prescription drugs over years (two antimuscarinics, clonazepam, destructive lorazepam, bit of diazepam) the messing with my physical health is really the major problem.

 

The foundation for legitimate medical care ('medical treatment' 'informed consent', no, not just the benzo) was absent and was the fundamental issue. I had expected to be off in 2014 latest ! I guess the local healthcare system that is monopolized by the GPs wants me to be off the drugs and back in normal health first ! I did post on a local forum recently, didn't even mention the word benzo but there's that overwhelming belief that healthcare is good and that you need a GP ! A few people see things differently, but only a few. When I read the last printout of my medical records it was full of agression by that GP. Not surprising, GPs tend to get on a power trip in many situations. Give people power, and ... I think I'll drop him and go 'naked' ...

 

Someone else here took pheno in addition to clonazepam (not mentioning names), which makes sense but my situation is different.

 

I guess it's up to me to deal with the mess that is my health (I know what's wrong but getting something done is a different matter. 5 years is a long time.

And getting off clonazepam under high physiological stress ...

Being on Librium for years will cause its own problems. I'm not 'fine'.

[[ih...]]

Some food for thought around the the concept of downregulation.  To date, unless I am wrong, the most talked about concept of downregulation in BZD withdrawal/tolerance is modulation of the receptor conformation.  There is some interesting stuff in the following article about downregulation as a function of altered hyperpolarization that is not specifically due to altered receptor conformation.

 

https://www.researchgate.net/publication/319046545_Seizing_Control_of_KCC2_A_New_Therapeutic_Target_for_Epilepsy

 

“Glutamate Dephosphorylates S940, Decreasing KCC2 Surface Expression and Function:

 

Excess glutamate downregulates KCC2 and reduces the chloride extrusion capacity of neurons [60]. This downregulation depends on NMDA receptor-mediated activation of PP1, which dephosphorylates S940, as NMDA receptor and PP1 inhibition prevents glutamate-mediated S940 dephosphorylation and maintains hyperpolarizing GABAergic inhibition. Glutamate-mediated downregulation of KCC2 seems to also depend on the activation of the calcium activated protease, calpain, which cleaves the C terminus of KCC2, reducing its total and surface expression [111]. Interestingly, levels of glutamate are known to increase within the brain during a seizure [69], which we would expect to lead to dephosphorylation of S940. In support of this, induction of SE in mice causes dephosphorylation of S940 and a reduction in the surface expression of KCC2, potentially due to enhanced NMDA receptor activity [46]. A glutamate mediated reduction in S940 phosphorylation may therefore underlie the decrease in KCC2 surface expression seen in patients with epilepsy”

 

And…

“Seizures are bursts of synchronous neuronal hyperactivity typically lasting for several minutes. In some cases, seizures are prolonged and fail to terminate. These extended seizures are termed Status Epilepticus (SE) and are life threatening medical emergencies that can lead to long-term neurological deficits including epilepsy. GABAA modulators, specifically the benzodiazepine class, are the standard first-line treatment for SE. Many patients fail to respond to benzodiazepines [125,126] and many papers have established deficits in GABAA receptor subunit expression as the underlying cause [127,128]. More recently, it has been proposed that a reversal in the direction of Cl flow through GABAA receptors is responsible [86,129], potentially due to an impairment of KCC2 function. While these two papers did not study SE per se, they both linked the Cl  gradient with the efficacy of benzodiazepines. As we discuss in the main text, Cl  shifts are observed during seizures in vitro and in vivo. Thus, during SE we can expect similar shifts in Cl  gradients, and hence rapid reductions in benzodiazepine efficacy.”

 

Obviously the above material is from a paper on epilepsy but it offers some interesting correlations.  I find it particularly interesting in my case due to the influence of gabapentin on calcium concentrations and the significant role calcium plays in withdrawal syndrome / damage.  More interestingly, is this a piece of the puzzle for those of us suffering protracted withdrawal?

 

Here is another interesting paper looking at this area. If it seems too long or is confusing, at least read the last couple of sections.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760510/

 

-RST

 

Very interesting thanks,RST.

 

It’s not surprising that our brain changes are multi-factorial, GABA being so influential throughout the body. If only I had understood what I was messing with from the first Z drug.

 

You are all posting some new and highly relevant research & given that dysregulated glutamate is involved in a number of pathologies, maybe someone will find some form of relief for benzo damage via indirect research for seizure or some such

:smitten:

[[li...]]

A question to which I suspect noone has an answer.

 

I know that the alpha1 subunit can be downregulated quickly. Clonazepam has a strong effect on alpha 2 and 3. For me, it took a long time to develop physical dependence to clonazepam. I suspect that that type of downregulation (if that's even the correct phrase) happens much slower. Often, people can use high doses of clonazepam for a very long time, but you woudn't last long on 200 mg of diazepam a day.

 

Much guess is that it also takes much longer to undo the downregulation of alpha 2 and 3. Is anything known about that, science or anecdotes ?

 

Another point: I'm  by no means 'fine'. From what I've read, Librium causes its own dependence and withdrawal. There is no chance I could do such a thing quickly, aside form a 'detox' approach. years on that drug would cause its own issues I presume.

 

 

[[Re...]]

A question to which I suspect noone has an answer.

 

I know that the alpha1 subunit can be downregulated quickly. Clonazepam has a strong effect on alpha 2 and 3. For me, it took a long time to develop physical dependence to clonazepam. I suspect that that type of downregulation (if that's even the correct phrase) happens much slower. Often, people can use high doses of clonazepam for a very long time, but you woudn't last long on 200 mg of diazepam a day.

 

Much guess is that it also takes much longer to undo the downregulation of alpha 2 and 3. Is anything known about that, science or anecdotes ?

 

Another point: I'm  by no means 'fine'. From what I've read, Librium causes its own dependence and withdrawal. There is no chance I could do such a thing quickly, aside form a 'detox' approach. years on that drug would cause its own issues I presume.

 

 

Interesting questions.  I wonder about these issues, too, Liberty.  There has to be a way to antagonize these receptors into upregulation, but how to do so without something like flumazenil or low dose ketamine is beyond me.  Misery and time doesnt seem to be doing it......

 

-RST

 

 

[[li...]]

I don't want to whine, and I may have asked this a long time ago. If I were off the clonazepam, how long for those GPCRs to 'reset' ?

I can't taper on the base that I'm fine, I can just easily split doses, take a psychiatric pill for sleep or any of that.

 

One of the things I hate about both L and V is that it takes a long time to get that out of the body. And it's not 'if it doesn't help, it won't harm'. Unlike many other people here I never used anxiolytics. Just infrequent use of hypnotics and clonazepam.

 

I think I read that either clonazepam has a blood level during the 'duration of action' that is (up to) 10 times higher than during the rest of the half life, or that the 'unbound fraction of clonazepam' is ten times higher during the 'duration of action. It's not as if I'm in time during my taper or if I have had a doctor at beck and call all the time ... Benzo wise doctors ? None. The GPs and psychiatrists, as well as addiction doctors, are horrible. My GP was at about the level of about 1980, including not following the WGBO (law) that came into effect in 1995.

It's all very different when you're able to taper off when you need to. I wish my former GP has CT'd me (American style) in 2013 when he learned of my problems with the drug rather than this !

[[li...]]

'nother one.

 

Recently I had been thinking, and reflecting on some of my old posts.

 

Before that crazy lorazepam experiment I would often feel a bit better if I lowered the dose a bit. Although it has been quite some time since last the last time I made a cut, I'm pretty sure that's no longer the case and I'd get effects like time subjectively passing slower.

 

And it's obvious that this drug has a strong effect on the motor system. As an example, I recall that once while I was on either 1 or 1,25 mg and I had not exercised in the gym for quite a while, when I did exercise I experienced effects like time passing slower (by a lot!) and I managed to stop that (sort of) by stabilizing on 1.5 mg. Now, maybe all this seems nuts but it's an extremely dangerous drug. I did experiment with splitting the dose, not with good effects ! (obviously, other neurotransmitters) Obviously, those tapers were more agressive.

 

There are no 'benzo wise' docs here. Prior to that lorazepam I had never been on anti anxiety drugs before. Just the clonazepam and infrequent use of hypnotics.

 

So whatever I do, it's quite a 'thing' I have to deal with.

[[cs...]]

'nother one.

 

Recently I had been thinking, and reflecting on some of my old posts.

 

Before that crazy lorazepam experiment I would often feel a bit better if I lowered the dose a bit. Although it has been quite some time since last the last time I made a cut, I'm pretty sure that's no longer the case and I'd get effects like time subjectively passing slower.

 

And it's obvious that this drug has a strong effect on the motor system. As an example, I recall that once while I was on either 1 or 1,25 mg and I had not exercised in the gym for quite a while, when I did exercise I experienced effects like time passing slower (by a lot!) and I managed to stop that (sort of) by stabilizing on 1.5 mg. Now, maybe all this seems nuts but it's an extremely dangerous drug. I did experiment with splitting the dose, not with good effects ! (obviously, other neurotransmitters) Obviously, those tapers were more agressive.

 

There are no 'benzo wise' docs here. Prior to that lorazepam I had never been on anti anxiety drugs before. Just the clonazepam and infrequent use of hypnotics.

 

So whatever I do, it's quite a 'thing' I have to deal with.

 

Yes, i understand. And it gets very complicated.

 

[[cs...]]

Hi all,

 

I am posting a 2 part piece.  This piece is a summary of Neural Circuits modules 5-9.  The source material was too complicated to post to this forum.  Most of this two parter is written in my own words, so not the usual large amount of quoted material, in the hopes that the general message of how Neural circuit dynamics pertain to the model are clear.

 

This two part piece will pretty much finish up most of the development of the Benzodiazaphine model as i had originally planned it.  It’s an extensible model, and i am sure there will be many more pillars and components added in the future.

 

 

==============================================================

 

Neural circuits Dynamics in the context of the Benzodiazaphine model:  PART I

Who cares about how neural circuits are supposed to function anyways. What does this have to do with withdrawal, tolerance, and PWS??!

 

((((A surrogate for Neural Circuits Modules 5-9)))))

 

 

 

 

 

 

 

 

 

1.Introduction

 

 

Why this type of post on this blog?

 

 

I had contemplated not posting the additional modules for the Neural Circuit Dynamics part of the Benzodiazaphine model, due to the complexity of the material, and how difficult it is to understand and present it in this format.  However, in researching other challenges that often occur as part of  Benzodiazaphine PWS, I felt it necessary to post this informal paper below as an alternative or surrogate to posting the modules, in the hopes that it might help readers understand why connecting all the disparate clinical work into a cohesive model, is so important, and why neural circuit dynamics matter.  It’s my hope that this paper can serve as a surrogate for the more complex module source material.

 

 

Understanding PWS is not easy because it’s a very very complex syndrome!!  Autism and cancer, and CFS are all very similar to Benzodiazaphine PWS in this respect. And there’s simply no easy one-size-fits-all golden bullet cause or solution to these diseases and syndromes. Autism is a spectrum disorder with complex etiology that manifests itself in a number of different ways that depend on a person’s genetics, physiology, and many other factors.  In the same way, Benzodiazaphine PWS has a very complex etiology that is dependent on a number of pillars and component systems, and these systems and pillars all interact with one another in a complex fashion and in a way that is dependent on our individual physiology and intracellular genetics.  No magic bullet, at least for now……

 

 

In a much broader context, these additional modules to the Neural circuits paper were written many months ago ( and included as a component system in the Benzodiazaphine model even prior to page 40 of this blog).  This was prior to my researching the vestibular neural circuit physiology aspect of PWS, and having done research in this particular area of PWS makes me all the more certain that neural circuit dynamics is a very essential system component of the generic Benzodiazaphine model, especially as it pertains to PWS.  I’m very glad that it was originally included in the model (see page 40 for an overview of the model) all those months ago.  The model is applicable to various types of PWS symptoms, such as cognitive issues, stress resiliency issues, hormone imbalances, anxiety, and vestibular issues.

 

 

  Without this component, the concepts of entrainment, phasic neural dynamics, homeostatic plasticity and to a more general level, Neuroplasticity, would be missing in the model, for the most part. We wouldn’t fully understand how the pillars act on our nervous system in a real life body with interconnected neurons, interneurons, and the like.  In this context, it’s no wonder that many clinical studies that focus on very small individual neurons or small “dead” circuits in certain regions of the brain fail to reveal much in terms of substantive findings.  In fact, these studies often yield conflicting findings or no findings at all.  Add to this that many of the studies fail to consider pharmacokinetics of the various Benzodiazaphines, how the drug is administered, and if the drug is chronically administered or acutely administered, and how the Benzodiazaphine differentially affects different brain regions (think brain slices in clinical terms), and you have a recipe for a complete and utter mess of disjointed and inconsistent conclusions. 

 

 

And one more thing: neurons were meant to live along side other neurons.  To study them in relative isolation is a completely fruitless endeavor.  Future studies will have to clinically test Benzodiazaphines in the context of entire circuits, in vivo, a point that I will reiterate in the conclusion to this post.  Functional MRI imaging over time (temporal),  might add some insight into the mechanisms behind how chronic  Benzodiazaphine administration (and cessation) differentially affects neural circuits in specific regions of the brain.  However, it goes far beyond this as we will see.  Functional MRIs have serious shortcomings when it comes to understanding how our brain works.  There is a field of neuroscience that deals with “nanotools” that are useful for brain activity mapping in the context of neural circuits.  I’m going to present a bit on this in a later section, which will illuminate just how complex things get when trying to determine what goes on in a real life brain…….

 

The latest research is incorporating the study of very simple “live” neural circuits to assess the behavior of particular circuits under stress.  Incorporating Benzodiazaphine studies into this type of environment is many many years away.  It’s adding a massive layer of complexity and statistical control to an already complex and poorly understood area of cellular neurophysiology.  Nonetheless,  it’s the right way and this type of research will yield more consistent useful and applicable results when it comes to understanding Benzodiazaphine PWS and etiology.  And perhaps these “nanotools”, once sufficiently developed will be able to help us understand the effects of Benzodiazaphines on our neuroanatomy more precisely, and in a way that yields some innovative therapeutic approaches.

 

 

 

 

 

 

 

 

 

 

 

2.The pillars and individuality…..

 

 

Thus far there are 4 pillars that act on 4 different component systems.  There are 4 pillars belonging to the    glutamatergic, GABAERGIC, stress system/hormones, and the NO and NOS (NO synthase)  areas of our physiology.  A fifth one, pillar #5, the GPCRs, has yet to be added.  The GPCRs include, for example, serotonin, dopamine and acetylcholine systems (and many others).    These 5 pillars are referred to as pillars because they act on 4 different component systems, and the pillars affect each other, and in a sense they are what “makes” the 4 different component systems “work” (or not work, when one or more pillars are disrupted or dysfunctional).  They are what “support” the component systems and make them function the way they do.    They are pillars because when one is knocked out (or destabilized) the others can follow (just like a chair with a leg snapped off).  They all interact with one another, as explained in the earlier pages of this thread.  And they interact in a very complex and sometimes synergistic fashion.  The complexity and variability of the pillars themselves and how they interact with one another, between different people, help explain why we all respond to drugs like Benzodiazaphines uniquely and why we recover differently.  And as we will see, it goes way way beyond this (conceptually) when we think of things in terms of neural circuits.  Across different people, receptors are distributed a bit differently across the various regions of the brain.  Across different people, receptors are in different numbers in these different regions of the brain. (think GABAERGIC, glutamatergic. GPCR pillars).  Stress hormones are at different levels for different people and depending on their gender.  The environment in which we live and work in is different across different individuals (think stress system/hormone pillar).  We don’t all live in “enriched” environments.  And the pillars themselves interact in a very unique fashion between different individuals!!

 

 

And to bring it up a notch, let us talk about this in terms of neural circuits.  We will revisit this topic below, but for now think about this: Neural circuits  across different individuals tend to crash at different thresholds when put under very similar stressors!  So if our pillars are all unique and our hormone levels and neuromodulators are all at different unique levels, and our neural circuits respond uniquely to stressors, is it any wonder whatsoever why we all have unique responses to pharmaceutical drugs, and more importantly why we all recover in different timeframes and to different degrees after the drugs are washed out??!  After all, it’s the very same systems and pillars and environments, that are so very unique between individuals, that enable us to recover.  Thus our recoveries, likewise, are all very unique.

 

 

And one last thing for this section on pillars. There’s yet another pillar #6, for the immune system.  We will very briefly discuss how this fits into the neural circuit aspects of the model below.  Some immune system cytokines directly act as neuromodulators on neural circuits, and affect neuroplasticity and adaptation in the brain!  Everything is connected.

 

 

As for pillar #5, GPCRs, many of these are potent neurotransmitters in their own right, and they can act as potent neuromodulators when called to duty.  The neural circuitry if our grand physiology has these at its  disposal to maintain homeostasis in the face of significant perturbations.  Many of these neurotransmitters provide excitatory and inhibitory control of the neuron’s membrane potential. The levels of these neurotransmitters can be altered as part of the compensatory response to stresses on the neural circuit, when there are excitatory/inhibitory imbalances.  Benzodiazaphine tolerance presents the neural circuit with enormous stress and our physiology will strive to maintain homeostasis at all costs. This can mean that there will be disturbances in the “normal” levels of these other neurotransmitters, as the physiology seeks homeostasis.  And all these pillars affect one another as well.  From this perspective, many different feedback loops ensue, and this can make recovery quite challenging.

 

 

In the following sections I refer to these neuromodulators and neurotransmitters, and the pillars as “knobs and switches” that our physiology uses to maintain homeostasis.  And it doesn’t stop here.  There are fundamental mechanisms behind homeostatic plasticity that are additional “knobs and switches” that are available  to keep everything in balance.  These all act on neural circuits in a very dynamic fashion….lending to the term “neural circuit dynamics.”

 

 

 

 

 

 

 

 

 

 

 

3.And there’s more to this story……The component systems

 

 

When a single pillar is destabilized , this has a cascading affect on the component systems upon which they act because peer pillars are affected and because there are feedback loops that feed back from the component systems to the pillars, most notably (but not exclusively) the stress system/hormone pillar.  The pillars, in a sense, hold up the component systems with respect to proper physiological function, hence the use of the term “pillar”. 

 

 

It is ultimately the component systems (via the pillars) that make us feel the way we feel and function the way we function.  If Hippocampal neurogenesis is stunted there will be anxiety issues and cognitive dysfunction, if action potential dynamics are skewed towards excitatory signaling there will be nerve pain, if cellular integrity is adversely affected through the NO/NOS pillar dysfunction there will be excessive oxidative stress and mitochondrial dysfunction that can manifest itself in a number of different ways (fatigue, cog fog, depression).  Finally if neural circuit homeostasis is affected such that the neurons cannot effectively adapt to stress (ie, via homeostatic Neuroplasticity ), any neural physiological function can be affected from digestion (gut motility) to motor dysfunction to severe emotional swings (limbic and amygdala system circuits).  In short, if the component system(s) are adversely affected, we will not function properly and we will not feel right.  We will become sick, and according to the model we can remain sick if there are reinforcing feedback loops.(PWS)

It’s not just about the Action potential.  It’s not just about the GABAa receptor.

 

 

The 4 component systems are: Neuronal Action potential dynamics, Adult neurogenesis, Cellular integrity and homeostasis, and Neural Circuit dynamics. 

 

Neural Circuit dynamics helps us understand how neurons work together to create physiological function, and it helps understand:

-why its so important that neurons have a phasic relationship to each other (firing off at different times),

 

-how the receptors on neurons are affected by neuromodulators and neurotransmitters in response to stress so that the circuit can continue to function (homeostatic plasticity), and

 

-at a much more general level, how neuroplastic changes occur in response to perturbations or stressors on the circuit.(homeostatic plasticity)

 

 

Also think about this: Neuron dendrites and the spines on the dendrites will shrink if they cannot form synapses with their peer neurons. Much like the human being as a social creature who will not thrive when socially isolated, neurons plastically adapt when isolated.  And when they are able to make connections they plastically adapt if potentiation is too excessive (pruning and/or decrease in spine size) or if it is too weak (increase in spine size).  So studying neurons in isolation seems quite futile in this respect when trying to discern the effect of Benzodiazaphines on them, because they don’t live in isolation and they will not behave the same when isolated.

 

 

 

 

 

 

 

 

 

 

4.Accommodation (compensation )and pharmaceuticals……

 

 

This accommodative nature of the neurons in a neural circuit forms the backbone of why neural circuit theory is so important in the context of Benzodiazaphine wd and PWS.  Neurons accommodate stress to maintain their phasic firing relationship and thus to maintain physiological function of the circuit when faced with stress.  As we will see, phasic firing of neurons is very highly dependent on inhibitory and excitatory signaling in each of the neurons.  Things that disrupt inhibitory and excitatory signaling or things that disrupt the balance between excitatory and inhibitory signaling are very detrimental to the function of the neural circuit.  The circuit can withstand and accommodate quite a bit of stress before the phasic relationship between the neurons completely breaks down. At this point physiological function breaks down (deteriorates ) and eventually the circuit can crash (ie, become non responsive).  Please note that circuits rarely get “cooked”, ie rendered permanently nonresponsive. 

 

 

 

 

 

 

 

 

 

 

5.Back to individuality…..and forget about pharmaceuticals for a moment!

 

 

So now, let us take this up, way up, another notch.  Let’s forget about pharmaceuticals for just a moment ( a peaceful moment ).  Remember earlier when I said that we are all different, with different pillars and hormone levels and receptor densities, etc.  The amazing thing is that with all the massive variation between us (remember no drugs) our circuits maintain the same physiological function from one individual to the next.  How is this even remotely possible?

 

 

  The neural circuit has all these knobs and switches (neuromodulators, neurotransmitters, receptor densities, conductance densities , etc) at its disposal to insure that even though we are quite different physiologically , all the knobs and switches are maintained at uniquely individual levels so that the output of the circuit is pretty much the same from one person to the next.  This IS what circuit homeostasis is at the very core.  All biological systems will seek this homeostatic function at all costs.  Part of it is  hardwired in the genetic coding, because many things are ultimately controlled intracellularly (where all the gene regulation stuff occurs) in response to external stimuli.  And it’s based on whether or not the phasic relationship between the firing off of the neurons in the circuit is maintained (and lots of other things), because that’s what determines physiological function.  So if the neuron “senses” too much glutamate receptor activation and too much sodium coming into the membrane it can regulate the glutamate and other receptors dynamically to maintain a membrane potential that insures that the circuit as a whole continues to operate “properly”.  Artificially messing around with certain receptors imposes a stress on this process, and the neurons can accommodate stress only to a point.

 

 

So back to individuality : This means if assuming a non-drug healthy individual, that his leg motor system will function pretty much in the same way as the other person’s across the room.  These knobs and switches allow us to function the same across person to person, even though the knob settings and switches are all at different levels.. This is called compensation or accommodation.  And it works both ways. Once we stress the system, or introduce drugs into the system, the neural circuit has to accommodate the stress through the very same knobs and switches. And it can do this pretty well for quite a bit of stress.  But at some point things break down when the drug use escalates (drug stress is relentlessly decompensating the receptor(s)).  And we all break down uniquely because our knobs and switches, the very same elements that make it possible for similar physiological function to exist across different people (compensation), are all uniquely genetically different at accommodating stress at threshold.  We each have our own threshold or breaking point because those very knobs and switches are different in terms of how far they can adapt.  But its those very same knobs and switches that make us operate all pretty much the same with “normal” levels of stress.

 

Thus we compensate for our different physiology when things are fine and stress is under control, but when things are pushed too far (excessive stress on the circuit) we all compensate to different degrees,  and we all have different capacities to accommodate the stress before crashing.  This is an important point, because it explains why we all function the same , but when stress (drugs) is introduced we all start to react and breakdown differently.  And now lets take a look at the crash scenario with drugs a bit more closely.

 

 

 

 

 

 

 

 

 

 

 

6.And now back to our crash scenario and let us sadly introduce drugs back into the equation……

 

 

Neural circuits recover once the stressor is removed, more often than not.    And they tend to recover quite rapidly providing that there are no feedback loops that perpetuate the initial imbalance.  In reality, the absence of feedback loops during and post withdrawal is the exception to the rule.  It usually doesn’t work out this way.  Think about this: the stress from the withdrawal process itself is horrendous.   

 

 

It’s more common than not, to have some perpetuating feedback loops that make full recovery slow and difficult.  The model tells us this.  Negative stress is one such feedback loop and it can manifest itself as a direct result of impairments in Neurogenesis and adverse neuroplastic changes in the brain.  Negative stress can be from the withdrawal symptoms themselves, due  to  a poor environment (not an “enriched” environment), etc.  Is it any wonder that these types of feedback loops form???!

Other feedback loops involving internal stressors like oxidative cellular stress and mitochondrial dysfunction can also be involved.  Hormone imbalances can perpetuate stress system dysfunction (think HPA axis dysfunction and point the finger at the hypothalamus not the adrenal glands or the pituitary), which is another loop perpetuated by brain dysfunction.  And this poorly understood  “aberrant adult neurogenesis “ can be slow to correct, and this perpetuates dysfunction particularly in the hippocampus.  Adult neurogenesis depends on a healthy GABAERGIC pillar.

 

So the big question is, do Benzodiazaphines stress neural circuits, or in more precise terminology, can Benzodiazaphines destabilize the phasic relationship between the neurons firing (and to a more global extent, the firing relationship of the neurons between different neural circuits, because many neural circuits are interconnected)?  Intuitively, the answer is yes.  But intuition is not enough……

 

There is a large dependency of neural circuit functionality on inhibitory signaling.  I will not get into the clinical and scientific work in this area, other than to explain the very simple oscillator circuit below. Inhibitory signaling is what makes it possible  for the neurons in a neural circuit to fire out of phase (properly).  Oscillatory circuits, an elemental building block of many neural circuits,  are possible only because of inhibitory signaling.  At its simplest:

 

 

Neuron A inhibits neuron B only when neuron A is firing off

Neuron B inhibits neuron A only when neuron B is firing off

 

This is a basic neural circuit oscillator, based on inhibitory feedback (think of the inhibitory (GABA) axon terminal of A projecting out to B and the inhibitory (GABA) axon terminal of B projecting out to A).

 

  (There is also something called an H conductance current that’s generated in each neuron after it is inhibited.  This is a depolarization (excitation) that occurs inside each neuron after it is inhibited (repolarized and hyperpolarized).  It’s an intracellular process. This keeps the circuit running independent of external excitatory stimulation. However, the main point is how the reciprocal inhibition creates the different phased shift alternating firing between the two neurons)

 

 

  Benzodiazaphines blunt and disrupt this inhibitory signaling and when tolerance is reached the inhibitory signaling becomes compromised and less efficient.  In the simple oscillator circuit above one can clearly see that as inhibitory signaling degrades, the oscillator alternating firing effect will start to break down.

 

 

Benzodiazaphines present an enormous stressor to neural circuits because those other knobs and switches mentioned earlier have to adjust to pick up the slack from the compromised inhibitory receptors.  Remember, homeostatically the circuit will strive to maintain a phase shifted firing off of the neurons at all costs.  (This means it will do anything to maintain physiological function). And when the main inhibitory signaling is compromised, the other knobs and switches (other neuromodulators and neurotransmitters) have to increasingly accommodate, as the main inhibitory signaling becomes less efficient and wanes.  So Benzodiazaphine tolerance, in and of itself is an enormous stressor on the neural circuits. 

 

 

This same concept holds true for  compromised GABAaR receptors during a rapid withdrawal resulting in PWS.  The same accommodation described above occurs, and the neural circuit is less able to accommodate the same amount of exogenous stress as it would have without the Benzodiazaphine history.    Benzodiazaphines are also a very potent stressor because they typically affect all of the neurons that have GABAaRs, and GABAaRs are very very prevalent in the CNS. 

Remember, without drugs, compensation is at work, and all the knobs and switches are adjusted between each one of us to provide more or less consistent physiological function.  And we can handle normal stressors to the circuit pretty consistently across individual to individual.  When excessive blanket stressors like drugs are introduced, the whole thing is a different ball game.  A completely different ball game.  In the case of Benzodiazaphines a very important knob or switch is kind of broken, and it is done across many neurons at the same time.

 

 

Neurons can dynamically alter conductance densities across the receptors (ie, the ion flows across the membrane of the neuron) to accommodate stress (this is done via intracellular processes involving gene regulatory processes, etc).  If the receptors themselves are impaired by drugs, how can the neuron adjust its membrane potential to accommodate the stress??! 

 

And this whole discussion is not just about GABA.  There are other neurotransmitters, many types of receptors types on the neuron, and there are many many different neuromodulators (100s) that can be relied upon to maintain neural circuit homeostasis, ie the proper phasic firing off of neurons in the circuit.(homeostatic plasticity).  These are the knobs and switches I mentioned earlier.

But the accommodation mechanisms only go so far, especially when a VERY important and pervasive receptor like GABAaRs are knocked out for the count.  If the decompensation of the GABA receptor continues to deteriorate, and if the  stress on the circuit relentlessly continues, at some point the circuit, with all its accommodative processes at hand,  the circuit simply can no longer maintain proper phasic relationship between its neurons.  It can no longer compensate in the face of this stressor, and becomes more susceptible to even minor stressors.  There is no more reserve.  The circuit eventually crashes.

 

 

The circuit can meander along prior to the crash with suboptimal function…..with periodic crashes between attempted recoveries as stress waxes and wanes and as GABAa receptor function varies.  But while in tolerance the propensity is to veer towards further circuit dysfunction.

 

 

 

 

 

 

 

 

 

7.So what about post withdrawal syndrome.  If the drug is washed out, shouldn’t things just bounce back?

 

 

  When this problem persists after drug washout, it becomes a post withdrawal syndrome. The model explains why this persists, ie  through the feedback loops (some were mentioned above) that make it very very difficult for the pillars to stabilize, even after drug washout.  If the pillars cannot stabilize the component systems won’t run smoothly and we remain sick, with symptoms and with compromised physiological function. 

 

Remember, in the absence of the drug and with “normal” stress on the circuit there is accommodation and the circuit continues to function more or less properly.  It’s only when it can no longer accommodate, that it crashes.  Now if we remove the stress, and there are no other collateral feedback loops stressing the circuit it can and will recover quite rapidly.  Homeostatic plasticity is quite a rapid accommodation (4 hours, but can take as long as 24-48 hours).  There’s a lot of research in this area. It’s only when there are reinforcing feedback loops, that the circuit continues to run in a degraded and compromised state.  These feedback loops happen to involve many of the same neurotransmitters and neuromodulators that are these “knobs and switches” that I refer to above.  If these pillars get into a state of decompensation its very difficult to stabilize even after the drug (Benzodiazaphine) is washed out.  It’s no longer just a “GABA problem”.

 

These feedback loops must be understood, and dealt with directly for resolution of PWS.  There’s no permanent nerve damage, there’s no permanent damage to the receptor that the drug was binding to, but there is “damage” to the homeostatic balance between several systems and pillars in the model that are no longer working like they should be.  And the feedback loops are instated because of a very serious insult, in the case of Benzodiazaphines, to the GABAERGIC pillar.  But in a larger sense, it can be any pillar that causes a PWS.  If it’s a virus or stress this would be called CFS.  If it’s the Benzodiazaphine wd that is the culprit then its PWS.  If its emotional stress, it is a “nervous breakdown”.  And this leads to our next topic…..general applicability of the model to pharmaceutically induced protracted withdrawal symptoms.

 

[[...]]

Oh yay, Dm, now you're talking!   Just skimmed the first couple of paragraphs and I swear I could understand more than three words in a row, lol.  Will definitely try and make my way through this one, I'm sure you spent an extraordinary amount of time/effort putting this together for all of us kindergartners. 

[[li...]]

That's a good one, of course not quite at your usual theoretical level.

 

I think you sort of mentioned it - drug stress (any kind, withdrawal-like/tolerance withdrawal/interdose withdrawal) combined with 'other' systemic or non-systemic stress that lasts for a long time can be quite devastating.

 

What I mentioned earlier - effects like serious time distortion, intensely elevated treshold for falling asleep, all prior to the lorazepam- was after intense exercise (objective effects stronger than subjective effects) during a taper, while somewhat untrained, some interdose withdrawal.

[[Re...]]

That's a good one, of course not quite at your usual theoretical level.

 

I think you sort of mentioned it - drug stress (any kind, withdrawal-like/tolerance withdrawal/interdose withdrawal) combined with 'other' systemic or non-systemic stress that lasts for a long time can be quite devastating.

 

What I mentioned earlier - effects like serious time distortion, intensely elevated treshold for falling asleep, all prior to the lorazepam- was after intense exercise (objective effects stronger than subjective effects) during a taper, while somewhat untrained, some interdose withdrawal.

 

Outstanding description, DM.  Really great summary.  My whole post-benzo experience on gabapentin is a great case study for your analysis.  Not understanding all the interlinked systems resulted in me making unfortunate decisions.  For example, pushing to get exercise for its health benefits actually damaged my system more than helped.  Now, any stressor will further unbalance my system.  I have no reserve left and this is tolerance.  Now, how to break this cycle is the issue.  I could quit work and sell my house and try to spend a few years focusing on recovery.  But other than that, I don't know what else would work for me.  Great work, though.

 

-RST

[[li...]]

dm123,

 

Just great. If I had read this mid 2014 I would never have been in this mess !

 

I hope you'll publish this one day. And if doctors would even learn a few key points, a lot of suffering and many misdiagnoses could be prevented.

[[Su...]]

dm123,

Thank you for this!  it all makes sense -- Oh Not that I Understand it all  -- but I do get the gist of what we are dealing with, and with how my body adjusted over the years.  And there are lots of terms and systems to google and get a more accurate understanding of.

 

It also validates -- I believe- the idea of long holds to try to get the body to some kind of stability before tapering again. I tapered from a very unstable place and had all the things one would expect. Out of sheer terror and resignation I decided on a long hold (I'm very lucky to have a doc who simply follows my lead)  Now that i am down this far, and feeling pretty well on day 43 I intend to hold until I feel really well to allow things to adjust, understanding that I will again stress all the systems when I begin to taper again.  I just think it is from a less stressed place to begin with, which sounds positive if I'm understanding you thesis here.

 

I took these years with NO, yup no, problems -- and now i realize that I also had come off various benzos 5X in my life over the last 40 years.  All that  being said to remind myself,  and anyone else who is struggling that I/we have had a strong physiology, that our body fights for homeostasis, and that with that in mind I can taper.

 

Sorry for the long post!  It's just that this post spoke to me so strongly!  Is so hope filled.

Again I thank you for all the great work that you do here!  Yes I too hope you publish some day in the area that we are all struggling so hard to deal with.

 

All the best to everyone!

SS

[[li...]]

dm123,

 

A rather specific question. Part of my problems would be the downregulated alpha 1 subunit. That started with the lorazepam, and that diazepam didn't help either ...

 

Diazepam itself is such a mess ... pharmacokinetics, pharmacodynamics, metabolites. It seems to interfere with feedback mechanisms, posibly the neurotransmitter acetylcholine ...

 

Would you happen to know of ANYTHING that acts somewhat selectively on the alpha 1 subunit and that could be used as a supplement to clonazepam, and that is not a mess in terms of metabolites etc. ? Either as a PAM/POM, or as something completely different ?

[[cs...]]

That's a good one, of course not quite at your usual theoretical level.

 

I think you sort of mentioned it - drug stress (any kind, withdrawal-like/tolerance withdrawal/interdose withdrawal) combined with 'other' systemic or non-systemic stress that lasts for a long time can be quite devastating.

 

What I mentioned earlier - effects like serious time distortion, intensely elevated treshold for falling asleep, all prior to the lorazepam- was after intense exercise (objective effects stronger than subjective effects) during a taper, while somewhat untrained, some interdose withdrawal.

 

Hi,

 

Yes, the model is based on extensions to generic stress.  Homeostasis, in this respect, can be thought of as a the body trying to re-establish balance after a perturbation or stress.  Allostatic load is worth looking into if you would like to learn more about how the body deals with the incessant never ending accumulation of various stressors over time.  Stress must be dealt with, otherwise it accumulates and has the potential to disrupt all the component systems in the model, as well as adversely affect the other pillars in the model.  It’s a feedback loop.

 

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

 

Some of those symptoms that you list are classic tolerance symptoms that develop insidiously over time.  Tolerance is exasperated by interdose withdrawals, in particular with the high potency short half life Benzodiazaphines (i include clonazepam in this group).  Persistent interdose withdrawals day to day can lead to a slowly evolving neuro kindling effect.  That is what happened to me and i am very grateful that it has improved quite a bit.  Nerve pain is a classic sign of neuro kindling.

[[cs...]]

Oh yay, Dm, now you're talking!   Just skimmed the first couple of paragraphs and I swear I could understand more than three words in a row, lol.  Will definitely try and make my way through this one, I'm sure you spent an extraordinary amount of time/effort putting this together for all of us kindergartners. 

 

Hi abcd, i hope its more palatable.

 

I agree, there is no point in posting things if no one can understand it.  I am hoping this part 1 and the next part 2 will be more accessible to the forum.    These two parts form a climax to a very long winded story  .   

 

The objectives are to cast light on why were are so different in some ways and why we are very similar in other ways relative to PWS etiology.  Part 2 will bring up yet more questions that need answering.  It will point us in the direction that clinical research needs to take in order to learn more about Benzodiazaphine PWS.  Much more work needs to be done in the formal clinical research.

[[cs...]]

That's a good one, of course not quite at your usual theoretical level.

 

I think you sort of mentioned it - drug stress (any kind, withdrawal-like/tolerance withdrawal/interdose withdrawal) combined with 'other' systemic or non-systemic stress that lasts for a long time can be quite devastating.

 

What I mentioned earlier - effects like serious time distortion, intensely elevated treshold for falling asleep, all prior to the lorazepam- was after intense exercise (objective effects stronger than subjective effects) during a taper, while somewhat untrained, some interdose withdrawal.

 

Outstanding description, DM.  Really great summary.  My whole post-benzo experience on gabapentin is a great case study for your analysis.  Not understanding all the interlinked systems resulted in me making unfortunate decisions.  For example, pushing to get exercise for its health benefits actually damaged my system more than helped.  Now, any stressor will further unbalance my system.  I have no reserve left and this is tolerance.  Now, how to break this cycle is the issue.  I could quit work and sell my house and try to spend a few years focusing on recovery.  But other than that, I don't know what else would work for me.  Great work, though.

 

-RST

 

RST, I understand exactly where you are coming from.  As many of you have read, Elon Musk ran into some issues with ambien.  The problem with Benzodiazaphines (including z drugs) is that they make our nervous system more fragile and less able to adapt to stress.  That’s the main point of the Part 1 above.  He wore himself out over the course of 2 years, and the z drug made things worse.  Sometimes it takes up to 1-2 years of extreme stress (which can be in any form: viruses, bacterial infections, mold, work and relationship stress,  and pharmaceutical stress) for the nervous system to buckle. 

 

What you say is true. I know you are supporting a family and have a mortgage to pay.  These things are very difficult and the choices that we have to make are even more difficult. 

 

I do hope that if there are any medical doctors reading this, that they realize the destruction that these drugs can cause, and i hope that they become more conservative in their liberal use of these drugs.

[[fr...]]

  So in neuro kindling is the only recourse to taper while so very sick and unstable.  My nerve pain is slowly killing me and I see no way forward.  Very scared and hopeless.

[[cs...]]

dm123,

Thank you for this!  it all makes sense -- Oh Not that I Understand it all  -- but I do get the gist of what we are dealing with, and with how my body adjusted over the years.  And there are lots of terms and systems to google and get a more accurate understanding of.

 

It also validates -- I believe- the idea of long holds to try to get the body to some kind of stability before tapering again. I tapered from a very unstable place and had all the things one would expect. Out of sheer terror and resignation I decided on a long hold (I'm very lucky to have a doc who simply follows my lead)  Now that i am down this far, and feeling pretty well on day 43 I intend to hold until I feel really well to allow things to adjust, understanding that I will again stress all the systems when I begin to taper again.  I just think it is from a less stressed place to begin with, which sounds positive if I'm understanding you thesis here.

 

I took these years with NO, yup no, problems -- and now i realize that I also had come off various benzos 5X in my life over the last 40 years.  All that  being said to remind myself,  and anyone else who is struggling that I/we have had a strong physiology, that our body fights for homeostasis, and that with that in mind I can taper.

 

Sorry for the long post!  It's just that this post spoke to me so strongly!  Is so hope filled.

Again I thank you for all the great work that you do here!  Yes I too hope you publish some day in the area that we are all struggling so hard to deal with.

 

All the best to everyone!

SS

 

Hi SS,

 

Yes i understand what you are saying and you have understood the major takeaway from the post.  That’s what matters.    If people understand how things happen, it doesn’t necessarily give us one size fit all therapeutics, but it does tell us how to live, what to avoid and how to taper successfully.

 

Symptom based taper is the safest way to approach any Benzodiazaphine taper.  Symptoms are the body’s way of telling us that things have not settled down yet, things are not yet balanced, things are not in homeostasis (to use the scientific term).  For whatever reason: drug serum levels have not stabilized yet, emotional stress, etc.  It doesn’t matter.  It’s all stress that the body has to acclimate to prior to the next cut.

 

I have learned quite a bit from my own taper, and like you, its getting low. I won’t feel safe until I’m completely off.  My body’s response for the most part is deterministic and predictable, but every now a cut can throw me for a loop. 

 

As RST mentioned above, its far more than just the taper that’s involved when it comes to stress and withdrawal and ultimate recovery.  There are lifestyle challenges, there are mortgages to be paid, there are families that need to be supported. It’s all piling on more emotional (and sometimes physical ) stress.  And the main point is that we have to factor in all of these things because they do affect our ultimate recovery.

 

I am glad you are doing better.  THere was another thread on half lives and valium and valium metabolites.  I’m tapering with librium, which is is similar to valium in many ways, and i have found a 26-30 day cut recovery period (for me) is sufficient. It varies a bit, from cut to cut, but it is around that ballpark.  The metabolite takes around 30-60 days to clear out , depending on ones physiology, etc.  So these numbers make sense from a clinical standpoint.  But we still have to factor in how generic stress affects our taper.  And that’s the point i wanted to make with part 1 above.

[[cs...]]

dm123,

 

A rather specific question. Part of my problems would be the downregulated alpha 1 subunit. That started with the lorazepam, and that diazepam didn't help either ...

 

Diazepam itself is such a mess ... pharmacokinetics, pharmacodynamics, metabolites. It seems to interfere with feedback mechanisms, posibly the neurotransmitter acetylcholine ...

 

Would you happen to know of ANYTHING that acts somewhat selectively on the alpha 1 subunit and that could be used as a supplement to clonazepam, and that is not a mess in terms of metabolites etc. ? Either as a PAM/POM, or as something completely different ?

 

Hi liberty, i unfortunately don’t know of any drugs like this.  As you know there are z drugs. These types of drugs would not help a taper and would worsen it.  You don’t want to potentiate the GABAaR with another PAM that is additive to the drug you are trying to taper. It’s distrubing steady state. 

 

I can’t recommend drugs like this, as i am not a doctor.  And i think it will make the taper worse.

 

I would split up the dose to AM and PM, and equally titrate up until you are out of tolerance and then taper directly from the clonazepam in equal AM/PM amounts like IntendtobeOff.  THere are people on BB who know a lot about a liquid microtaper.

 

Best

Dm123

 

 

[[cs...]]

  So in neuro kindling is the only recourse to taper while so very sick and unstable.  My nerve pain is slowly killing me and I see no way forward.  Very scared and hopeless.

 

Hi freeme,

 

It would be to stabilize serum levels of the benzodiazphine (and the soma) and then try to slowly taper.  Is your nerve pain consistent or is it improving slowly with time.  It’s best not to look at day to day or even week to week changes, but focus on the long term trend.  Also, i know you are on soma, and i don’t know much about the drug, but it does act on the GABAaR.  I just looked it up and it has a half life of 2-3 hours so it might be making steady state difficult to achieve.  Do you take the soma multiple times a day?

[[Ma...]]

I have seen the smartest guys in the room thread here, but most of it is way over my head  I am however interested in this quote from dm123

 

Tolerance is exasperated by interdose withdrawals, in particular with the high potency short half life Benzodiazaphines (i include clonazepam in this group).  Persistent interdose withdrawals day to day can lead to a slowly evolving neuro kindling effect.

 

I ave only been tapering a few weeks and still waiting for appointments for a prescribing physicam for tapering In the meantime my dosing is something like this  four doses per day of slightl under .25 mg X Those time have been

 

3 AM  9-11 AM  3-5 PM  9 PM 

 

I have been playing with moving 9 PM to 8 and 3 AM to  2 Mostly due to the fact that #AM just seems too late for more good sleep

 

 

My question is however about the other two late morning late afternoon doses I try to stretch these out to an 8 hour interdose window and often suffer some symptoms in doing so in the hope that my evening doses will be more effective for sleep But it sounds like what you are saying is that could be causing me problems

[[li...]]

dm123,

Thank you for this!  it all makes sense -- Oh Not that I Understand it all  -- but I do get the gist of what we are dealing with, and with how my body adjusted over the years.  And there are lots of terms and systems to google and get a more accurate understanding of.

 

It also validates -- I believe- the idea of long holds to try to get the body to some kind of stability before tapering again. I tapered from a very unstable place and had all the things one would expect. Out of sheer terror and resignation I decided on a long hold (I'm very lucky to have a doc who simply follows my lead)  Now that i am down this far, and feeling pretty well on day 43 I intend to hold until I feel really well to allow things to adjust, understanding that I will again stress all the systems when I begin to taper again.  I just think it is from a less stressed place to begin with, which sounds positive if I'm understanding you thesis here.

 

I took these years with NO, yup no, problems -- and now i realize that I also had come off various benzos 5X in my life over the last 40 years.  All that  being said to remind myself,  and anyone else who is struggling that I/we have had a strong physiology, that our body fights for homeostasis, and that with that in mind I can taper.

 

Sorry for the long post!  It's just that this post spoke to me so strongly!  Is so hope filled.

Again I thank you for all the great work that you do here!  Yes I too hope you publish some day in the area that we are all struggling so hard to deal with.

 

All the best to everyone!

SS

 

Hi SS,

 

Yes i understand what you are saying and you have understood the major takeaway from the post.  That’s what matters.    If people understand how things happen, it doesn’t necessarily give us one size fit all therapeutics, but it does tell us how to live, what to avoid and how to taper successfully.

 

Symptom based taper is the safest way to approach any Benzodiazaphine taper.  Symptoms are the body’s way of telling us that things have not settled down yet, things are not yet balanced, things are not in homeostasis (to use the scientific term).  For whatever reason: drug serum levels have not stabilized yet, emotional stress, etc.  It doesn’t matter.  It’s all stress that the body has to acclimate to prior to the next cut.

 

I have learned quite a bit from my own taper, and like you, its getting low. I won’t feel safe until I’m completely off.  My body’s response for the most part is deterministic and predictable, but every now a cut can throw me for a loop. 

 

As RST mentioned above, its far more than just the taper that’s involved when it comes to stress and withdrawal and ultimate recovery.  There are lifestyle challenges, there are mortgages to be paid, there are families that need to be supported. It’s all piling on more emotional (and sometimes physical ) stress.  And the main point is that we have to factor in all of these things because they do affect our ultimate recovery.

 

I am glad you are doing better.  THere was another thread on half lives and valium and valium metabolites.  I’m tapering with librium, which is is similar to valium in many ways, and i have found a 26-30 day cut recovery period (for me) is sufficient. It varies a bit, from cut to cut, but it is around that ballpark.  The metabolite takes around 30-60 days to clear out , depending on ones physiology, etc.  So these numbers make sense from a clinical standpoint.  But we still have to factor in how generic stress affects our taper.  And that’s the point i wanted to make with part 1 above.

 

Stupid question and one you're likely not able to answer ...

 

In my case: symptoms of what ? Not just 'the benzo'. The entire body has been affected, there are a few major components. Maybe something could be done, medically. Even though I pretty much fired that GP, the local healthcare system is restrictive. What if some of my physical issues cause distress or impairment of function ? Clonazepam can dampen certain forms of physical distress (and cause that too) in ways no other benzo can. Yeah, I get the feeling 'stupid question'. Most docs everywhere would say something like 'taper the clonazepam first'. And in an unhealthy way, it can promote sleep. Tapering while in physical distress and lacking sleep is not ideal ... primary cause: multiple medical errors, iatrogenic damage.

[[cs...]]

dm123,

 

Just great. If I had read this mid 2014 I would never have been in this mess !

 

I hope you'll publish this one day. And if doctors would even learn a few key points, a lot of suffering and many misdiagnoses could be prevented.

 

Hi liberty,

 

I will try.  I wish every doctor knew about this.  They wouldn’t prescribe it.

 

Dm123