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

[[Lo...]]

I would like to get the drug rescheduled as class II, especially short acting benzos.  The science is clearly pointing me to the conclusion that short acting benzos have NO therapeutic value.

 

I would agree with this. The short acting benzodiazepines have a capacity of assaulting the various GABA receptors much more quickly than they can recover. In sensitive individuals, even a rebound to normal GABA system functioning after a single dose might take a while, which causes the initial destabilization, making a confused individual think they need to keep taking these meds.

[[Le...]]

Following...

[[li...]]

dm123,

 

I'm going to need more time if I want to make sense of this ... A lot of very complicated stuff.

 

'Chronic changes in neuronal activity regulate the numbers of GABAAR expressed on the neuronal cell surface

-Chronic changes in neuronal activity regulate the levels of GABAAR β3-subunit ubiquitination

-Identification of major sites for ubiquitination within the GABAAR β3 subunit

- Decreasing β3 subunit ubiquitination increases receptor accumulation on the neuronal cell surface

- Ubiquitination of the β3 subunit modulates GABAAR insertion into the plasma membrane

- The effects of neuronal activity on GABAAR cell surface expression levels are mediated via β3 subunit ubiquitination'

 

Bold (and the rest), a bit vague.  Is this about the number of GABAA receptors, not the binding site at the GABAA receptor ? An increase or decrease ? I take it it is a decrease (reading back and forth).

 

(in my case, interdose withdrawal, tolerance withdrawal (increased neuronal activity at times) there might even be an increase of the receptors ! (?)

 

To other people: probably best not to show this to your doc, he/she is likely to say it's mental, refer you to a psychiatrist or that He/she is the doctor !!!

I think the only person who got a positive response from her doc was Perseverance. I probably even made a mistake to use the word HPA axis to my former GP  !

[[...]]

Thanks so much fro this thread and all the research dm123!

 

I couldn't absorb all the information , but what I read is interesting.

 

I do find myself left feeling rather hopeless though ! I know there's neuroplasticity.... But it's scary to think that changes could be permanent , tho it seems that everyone does recover  eventually .

 

I would love to see more research , ( wouldn't we all!) being done on how we can actually recover from these changes , what would help us ?

 

I also have a question about gabapentin , which you touched on earlier ..... With the limited information on how it actually works , would you think it's ok to take during benzo WD ?

I was on it before benzos , and still on it , but I think about taking more to help ease WDs .

 

Many thanks again ,

MiYu

[[...]]

One other question ... Where would I find the list of PAMS? Thanks! MiYu

[[Ca...]]

Gone a bit beyond my capabilities, but it needs to be precice...

Just hopeing for a great simple summary to connect the dots after you have finishd..?

 

Again thanks...

 

And yes, Gabapentin?? -I take as needed (not often) for physical nerve damage.

But it does help benzo WD SX too...

[[Te...]]

If I were to give information here to doctors and nurses, dm123, what in particular would I give them in order that they TRULY UNDERSTAND what goes on with having benzos in the system? And thank you again for all of your valuable research!

 

What would make the most impact, in other words, so finally they would GET IT!

Hi Terry,I'm not sure.  The more research I do on this, the more damning the evidence is for these drugs.  Pers put together a document for doctors.  I don't remember the title but it's pinned above, and nice and short.

 

I think ADDENDUM 6 alone says a lot.  There's so much more , unfortunately.  There are metabotropic Glutamate receptors, and serotonin, ACh and dopamine receptors that are effected as well, and of course what is truly behind kindling.

 

I truly feel that we are in an era like the tobacco industry was in 50 years ago.  The science is all there, everyone knows what the drugs do to our physiology, but the regulatory standards of care are simply not in place yet.  We have a lot of work to do.  Knowledge always is power....

Yes, I agree. Thank you for providing all of this information. And I certainly feel, also, that benzos need to be classified as a Schedule II drug. Knowledge is indeed power.

[[cs...]]

Thanks for all the great research you've done, dm123. This has been one of the best threads I have seen here in a long time. Good, solid research backed up with a lot of studies and references. I find it very useful myself as I go through this process . Thanks again 

Thanks LPfree2015, I am glad it helps.  That was and is my main objective, to help us understand why we are so severely affected, and perhaps in the process, we might discover some great adjunctive therapies, with the science to back them up  . They don't have to necessarily be pharmaceutical.

[[cs...]]

I would like to get the drug rescheduled as class II, especially short acting benzos.  The science is clearly pointing me to the conclusion that short acting benzos have NO therapeutic value.

 

I would agree with this. The short acting benzodiazepines have a capacity of assaulting the various GABA receptors much more quickly than they can recover. In sensitive individuals, even a rebound to normal GABA system functioning after a single dose might take a while, which causes the initial destabilization, making a confused individual think they need to keep taking these meds.

Right on the mark.  Short acting benzos are the ultimate Rx for doctors who want high appointment turnover (lots of patients), and quick fixes to often complex problems that can be solved otherwise, with a bit of effort. When you go back to them and ask them for help getting off they just say you can stop.  At least that's what my Dr told me.  The science is so damning.  There's so many papers that I have gone through, and yet there are literally hundreds more.  No one  wants to, or is bothering to look at the whole picture.  One has to do this, because this is the only way to approach a framework that models what our actual bodies are going through.  So many physiological systems are affected it truly is mind boggling.  The most difficult areas to model are those of interdose  wd and interdose tolerance wd, which is what I hope this thread helps to shed some light on.

 

Anyone who is reading this, please don't cold turkey.  The scientific evidence in that is clear cut.  I have read it over and over again..... it depends on your genetics somewhat, but it's not worth the gamble.

 

Also avoid all PAMs, orthosteric agonists, and even second order modulators of the GABAa receptor (this includes EGCG found in green tea, etc)

There is also something called allosteric agonists.  Those should be avoided. .  I have not tried to find a list of these for GABAa, but their mechanism is a bit different than allosteric modulators(in our case Positive AMs are the ones to avoid)

[[cs...]]

dm123,

 

I'm going to need more time if I want to make sense of this ... A lot of very complicated stuff.

 

'Chronic changes in neuronal activity regulate the numbers of GABAAR expressed on the neuronal cell surface

-Chronic changes in neuronal activity regulate the levels of GABAAR β3-subunit ubiquitination

-Identification of major sites for ubiquitination within the GABAAR β3 subunit

- Decreasing β3 subunit ubiquitination increases receptor accumulation on the neuronal cell surface

- Ubiquitination of the β3 subunit modulates GABAAR insertion into the plasma membrane

- The effects of neuronal activity on GABAAR cell surface expression levels are mediated via β3 subunit ubiquitination'

 

Bold (and the rest), a bit vague.  Is this about the number of GABAA receptors, not the binding site at the GABAA receptor ? An increase or decrease ? I take it it is a decrease (reading back and forth).

 

(in my case, interdose withdrawal, tolerance withdrawal (increased neuronal activity at times) there might even be an increase of the receptors ! (?)

 

To other people: probably best not to show this to your doc, he/she is likely to say it's mental, refer you to a psychiatrist or that He/she is the doctor !!!

I think the only person who got a positive response from her doc was Perseverance. I probably even made a mistake to use the word HPA axis to my former GP  !

 

Hi liberty,

Your great question was the inspiration of ADDENDUM 7

 

We all know more than they think we know.  That's our power from this point forward.  We can now make fully informed decisions about what we put in our bodies.  I'm not that same person 3 years ago, one who trusted docs.

 

it's about the number of GABAa receptors that ultimately make it to the surface.  Once you grasp it, let us know.  It's a great and very thorough study, and they did their due diligence to make sure that something else was not causing the result by using that mutated beta3 GABAa receptor.  Once you understand it, your eyes will light up.  So complex, yet so basic....

 

I gave a lay man's summary in the middle of the ADDENDUM 7

 

" You try to put the neuron to sleep by excessive inhibitory potentials, and the neuron responds by producing less GABAa receptors that make it to the surface,  You excite and stimulate the neuron, as painful as it is, and the neuron responds by slowing the degradation of subunits(inside the cell) thereby increasing the number of assembled receptors that make it to the surface.  This gives a whole new appreciation to the term downregulation, and gives us insight into one of the mechansims that the cell uses to achieve this."

 

It's so complex, yet so basic  .....

 

[[cs...]]

Thanks so much fro this thread and all the research dm123!

 

I couldn't absorb all the information , but what I read is interesting.

 

I do find myself left feeling rather hopeless though ! I know there's neuroplasticity.... But it's scary to think that changes could be permanent , tho it seems that everyone does recover  eventually .

 

I would love to see more research , ( wouldn't we all!) being done on how we can actually recover from these changes , what would help us ?

 

I also have a question about gabapentin , which you touched on earlier ..... With the limited information on how it actually works , would you think it's ok to take during benzo WD ?

I was on it before benzos , and still on it , but I think about taking more to help ease WDs .

 

Many thanks again ,

MiYu

 

Hi MiYu,

See also my most recent responses.  I agree. The purpose of all of this data is not to confuse.  If you read one ADDENDUM a week, and build on the concepts slowly, you will start to understand in great depth what this stuff does to us.  In conjunction with how I feel, I'm getting confirmation of what I'm seeing in the research. 

I'm not a doctor of medicine, so I can't give you medical advice.  However, my Benzo wise doctor did state that gabapentin is ok.  You will find tons of threads on it here on BB.  You will then be able to make an informed decision.  Also see my older posts if you get a chance on PAMs and orthosteric agonists, etc.  these have to be avoided during taper.  I'm choosing to stay clear of them the rest of my life, if possible.

Please go slow on your taper, based on symptoms.  Don't let anyone push you along.  The body needs time to do its miracle of healing.....and heal we do, all on our own unique timelines.

 

  I do have pending research in many areas.  One is on general and local anethetics.

 

From what I've read, they all potentiate the GABAA receptor.  If anyone has any links on this area, and whether or not there are any safe anethetics please let me know.  I want to know about it in case I need surgery some day.

[[cs...]]

One other question ... Where would I find the list of PAMS? Thanks! MiYu

 

Hi MiYu

 

I responded to this from your last post, without seeing this post. 

You are right on.  You can click on read all my posts and find a few postings on this.  Also a simple list is on Wikipedia under GABAa receptor.  More exhaustive lists I posted earlier.

Stay away from PAMs.  You might feel better for a short time, but you will be worse off in your tapering progress.  It's not worth it.  There are other meds out there if needed.....

[[cs...]]

Please Spread the word to any newbies.  They cannot have PAMs.

[[...]]

Tried searching through your posts but couldn't find the list of PAMs.  Would this be accurate, from Wikipedia?

 

https://en.wikipedia.org/wiki/Category:GABAA_receptor_positive_allosteric_modulators

 

What are your thoughts on the use of PAMs post-taper?

 

Also, wondering if you've come across anything of special interest regarding the differences between each individual benzo? 

[[cs...]]

Tried searching through your posts but couldn't find the list of PAMs.  Would this be accurate, from Wikipedia?

 

https://en.wikipedia.org/wiki/Category:GABAA_receptor_positive_allosteric_modulators

 

What are your thoughts on the use of PAMs post-taper?

 

Also, wondering if you've come across anything of special interest regarding the differences between each individual benzo?

 

I am going to post an unedited list for the PAMs as reference in the following post.  Please feel free to redirect people to this list.

 

I'm personally not going to use any PAMs post taper.  I'm not sure how severe your symptoms were at their worst, but I don't ever want to go back there.... that plus this accumulation of research I've seen.  I don't have any studies to post on this because I haven't looked yet.    If it's anything like alcohol's effect on GABAa receptors, it's best to leave it alone.  If there is anything I can do to protect those GABAa receptors I'm going to do it.  Also exercise is important.

 

I'm glad you asked the last question. I've thought about that a lot lately.    I have not taken the time to research it, but in the studies, they use all sorts of benzodiazaphines......  I've noticed a definite trend in looking through many posts on this site.  I notice that many of the sufferers here have used clonazepam or xanax, next on the list is lorazepam (my case before crossing over).  I notice anecdotally, that a lot of the Valium users have used a long time, and although they have built up tolerance and titrated up over the years,  the tolerance seems more manageable, if you know what I mean.  I don't know if Valium users hit extremes in interdose wd, like we see (and feel) with the shorter acting benzos.

 

From personal experience, I think interdose wd and interdose tolerance wd are a continuum of the same process of worsening dysfunction of a whole bunch of different physiological systems, that I hope we can discuss here.  The most obvious was ADDENDUM 6, the GABAa receptor.  But there are a lot of other systems affected.  I don't think I ever got to serious tolerance , but I hit interdose wd after around 2 years, and had to split the dose , rather than taking all at night.  I was Rx'Ed to take all at night.  The worst thing to do.  It fosters and speeds up the kindling process.  It literally physiologically breaks you down to the point where your body can no longer accommodate the changes required to maintain homeostasis.    I started to hit tolerance at the time of crossover, i.e. I probably would have had to increase total daily dosage had I not crossed over. 

 

  These are the types of empirical studies that we need, and that are lacking.  Great question......

[[Lo...]]

https://en.wikipedia.org/wiki/Category:GABAA_receptor_positive_allosteric_modulators

 

This is quite interesting to me. I see Fluoxetine on this list, yet I don't see either Sertraline or Venlafaxine. Out of my own reasons, due to taking Fluoxetine and Ativan together for a while, I wonder if Fluoxetine has any direct/indirect effect on GABAa receptors. There have been claims that Fluoxetine may potentiate ativan, but I have not found any study or any research done to substantiate that claim. Makes me wonder if some of the SSRI's missing on a wiki page are just that, an omission, or if there was more research done on Fluoxetine that made it go up to that list.

 

http://www.drugsdb.com/rx/ativan/ativan-drug-interactions/

[[...]]

You know, I'm wondering also if one of the other worst things to do is erratic dosing, the way I was doing it.  Can never be 100% sure but it's my best guess seeing as I CT'd many a time before without so much as a hiccup.  See my sig.

 

You should add your siggy, dm, it helps to know who we're talking to.    I gather you're still tapering though, so I wish you luck and certainly hope all your great efforts here serve you well.  Slow and easy does it. 

[[cs...]]

 

PAMs, NAMs, and SAMs

 

Note: I did a post on niacin as a PAM, and the evidence was lacking.  Just my opinion based on the research.  Megadosoing niacin is quite a different thing.  I'm not sure about that.  It's included in the lists below

 

 

 

Main link

 

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

 

More complete list of PAMs

https://en.m.wikipedia.org/wiki/Category:GABAA_receptor_positive_allosteric_modulators

 

Note valerian, lavender oil, skullcap, bromides, avermectins(ivermectin, the antiparasitic), neuroactive steroids including progesterone, testosterone are all PAMs

 

 

Needs the ligand (i.e., GABA)present to have its effect on chloride channel?

Orthosteric agonists? Y

Allosteric agonists? N

Orthosteric antagonists? Y

PAMs? Y

negative allosteric modulator? (NAMs)? Y

Second order modulators? Y since PAM needs to be present and PAM requires ligand.

non-competitive channel blockers?N

 

 

https://www.quora.com/What-is-the-difference-between-an-agonist-and-positive-allosteric-modulator

 

 Orthosteric agonists and antagonists: bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site). Agonists activate the receptor, resulting in increased Cl−conductance. Antagonists, though they have no effect on their own, compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl− conductance.

 

 Allosteric agonists: bind to allosteric sites on the receptor and activate the receptor in absence of orthosteric ligands.

 

 

 First order allosteric modulators: bind to allosteric sites on the receptor complex and affect it either in a positive (PAM), negative (NAM) or neutral/silent (SAM) manner, causing increased or decreased efficiency of the main site and therefore an indirect increase or decrease in Cl− conductance. SAMs do not affect the conductance, but occupy the binding site.

 

 Second order modulators: bind to an allosteric site on the receptor complex and modulate the effect of first order modulators.

 The modulatory activity can be first-order or second-order (or both). Second-order[disambiguation needed] modulators alter the modulatory activity of first-order modulators. (−)‐Epigallocatechin‐3‐gallate is one such example of a second-order modulator at GABAA receptors.[2]

 

 

 Open channel blockers: prolong ligand-receptor occupancy, activation kinetics and Cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner.[26]

 

 Non-competitive channel blockers: bind to or near the central pore of the receptor complex and directly block Cl−conductance through the ion channel.

 

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

A channel blocker is the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce a physiological response in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.

 

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

Due to its interactions with the inhibitory neurotransmitter GABA, picrotoxin acts as a stimulant and convulsant. It mainly impacts the central nervous system, causing seizures and respiratory paralysis in high enough doses.

 

 

Examples

 Orthosteric agonists: GABA, gaboxadol, isoguvacine, muscimol, progabide, piperidine-4-sulfonic acid (partial agonist).

 Orthosteric antagonists: bicuculline, gabazine.



Positive allosteric modulators: barbiturates, benzodiazepines, certain carbamates (ex. carisoprodol, meprobamate, lorbamate), thienodiazepines, ethanol (alcohol), etomidate, glutethimide, kavalactones,[27] meprobamate, quinazolinones (ex. methaqualone, etaqualone, diproqualone), neuroactive steroids,[28] niacin/niacinamide,[29] nonbenzodiazepines (ex. zolpidem, eszopiclone), propofol, stiripentol,[30] theanine, valerenic acid, volatile/inhaled anesthetics, and lanthanum.[31]



Negative allosteric modulators: flumazenil, Ro15-4513, sarmazenil, amentoflavone, and zinc.[32]



Second-order modulators: (−)‐epigallocatechin‐3‐gallate.



Non-competitive channel blockers: cicutoxin, oenanthotoxin, pentylenetetrazol, picrotoxin, thujone, and lindane.

 

 

Effects

Ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. Some such as muscimol and the z-drugs may also be hallucinogenic.[citation needed] Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion.[citation needed] Some of the subtype-selective negative allosteric modulators such as α5IA are being investigated for their nootropic effects, as well as treatments for the unwanted side effects of other GABAergic drugs.[33]

[[cs...]]

https://en.wikipedia.org/wiki/Category:GABAA_receptor_positive_allosteric_modulators

 

This is quite interesting to me. I see Fluoxetine on this list, yet I don't see either Sertraline or Venlafaxine. Out of my own reasons, due to taking Fluoxetine and Ativan together for a while, I wonder if Fluoxetine has any direct/indirect effect on GABAa receptors. There have been claims that Fluoxetine may potentiate ativan, but I have not found any study or any research done to substantiate that claim. Makes me wonder if some of the SSRI's missing on a wiki page are just that, an omission, or if there was more research done on Fluoxetine that made it go up to that list.

 

http://www.drugsdb.com/rx/ativan/ativan-drug-interactions/

 

Hi LPfree2015, I think the later.  A lack of research.  Hydrocortisone, which they had me on while on lorazepam is not on the list but is thought to be a PAM.  it's not officially a neurosteroid.

[[cs...]]

You know, I'm wondering also if one of the other worst things to do is erratic dosing, the way I was doing it.  Can never be 100% sure but it's my best guess seeing as I CT'd many a time before without so much as a hiccup.  See my sig.

 

You should add your siggy, dm, it helps to know who we're talking to.    I gather you're still tapering though, so I wish you luck and certainly hope all your great efforts here serve you well.  Slow and easy does it. 

Yes I'm well on my way, but don't want to post as sig due to Benzo fear of jinxing it.  Worse thing for me was all at nightly dosing. 

[[Lo...]]

You know, I'm wondering also if one of the other worst things to do is erratic dosing, the way I was doing it.  Can never be 100% sure but it's my best guess seeing as I CT'd many a time before without so much as a hiccup.  See my sig.

 

I like that you brought this up, abcd. Sometimes, I wonder if there's such thing as "proper dosing". Yes, while the dosing may be proper in the medicinal and social context, I can't keep but wonder if any type of PRN dosing in certain people can shift up the tolerance so slighty, that some of the gaps/CT's or whatever you want to call them leave us with some sort of minor tolerance that we are not even aware of. Perhaps the first two or three CT's go without any problems, and even if the symptoms may not be present, a couple of stops may raise our tolerance to perhaps 0.05mg/day. Of course, this baseline anxiety upshift may be invisible to us, but if the tolerance goes to 0.05mg/day after the stop #1, and then to 0.09mg/day after stop #2 and to 0.12mg after stop #3, it could be possible that we reach a certain baseline anxiety threshold at which our minds start going "Hey, what is going on here?". Some people may be much stress-resilient than the others and may still be living their life no problem with 0.25mg or 0.5mg tolerance while being off the pills, but some may start getting panicky reactions at 0.09mg tolerance (while off) and start dosing a touch more frequently because of their belief that this 0.09mg tolerance/baseline is their "high levels of natural anxiety that have to be medicated".

 

I just keep wondering about this a lot, and if this holds a key why quite a few people get off these pill with few problems and not restart them again.

 

Another scenario comes to mind is that someone may be off of their benzo, but still at a 0.09mg tolerance, that keeps slowly decreasing. But guess what? More stress comes into their life and their stress tolerance is a touch lower. This will now make the stressful event look slightly more stressful than it is, so the perception of the stressful even becomes greater, while the actual and perceived ability to cope may be lessened, thereby leading to a belief in one's mind that a benzo needs to be taken again.

[[Be...]]

dm, did you do any research about the link between benzo's and dementia?  I was recently diagnosed with Memory Impairment and Amnesia by the doc.  My mental functioning declined significantly as soon as I got off the benzo's.  I'm almost certain these benzo's and Z-drugs caused my dementia.  I know there's a strong association between benzo's and dementia.  I've got the bad genes for early onset dementia.  My father and uncle got it in their 50's and now I've got it. 

[[cs...]]

You know, I'm wondering also if one of the other worst things to do is erratic dosing, the way I was doing it.  Can never be 100% sure but it's my best guess seeing as I CT'd many a time before without so much as a hiccup.  See my sig.

 

You should add your siggy, dm, it helps to know who we're talking to.    I gather you're still tapering though, so I wish you luck and certainly hope all your great efforts here serve you well.  Slow and easy does it. 

 

Hi abcd, I forgot to add, part of the research I'm doing involves getting to the root cause of what kindling does to our physiology.  In addition to this, a study of epileptogenesis, i.e. The evolution of spontaneous seizure disorders, is helping.  Alcohol studies are also being looked at.  In ADDENDUM 6 part II you can clearly see that alcohol in and of itself messes with the subunit configurations of extra synaptic and synaptic GABAa receptors.  The reason why I bring that up is because alchohol and benzodiazaphines mess with the phosphorylation of GABAa receptors.  They do it in such a way that there is an increase in endocytosis or absorption of particular subunits back into the cell. One is left with increased absorption of alpha1 subunits in the synaptic region and increased absorption of delta subunits extra synaptically.  This leads to reduced inhibitory efficiency.

 

Kindling of repeated seizures produces similar changes in phosphorylation, resulting in a decrease in synaptic receptor populations with beta3 subunits.  Erratic dosing fosters kindling.  This is through altered phosphorylation.  We also know that short half life benzos by their very nature lead to interdose wd at some point, and this, in and of itself is a more subltle form of kindling. 

 

All these things combine to form a more subltle model of changes that we see in he majority of people here. Changes that occur over time.  So we know that erratic dosing does cause these effects in the GABAa receptors through alchohol (binge drinking) and classic seizure kindling studies.  But the flip side of the model is the effects on the many other systems in the brain and CNS, as well as peripheral systems that are affected.  It's not just GABAa receptors.

 

The model for interdose wd has to include all of these areas above, as well as a group of receptors called GPCRs.....    also, different benzos affect our physiology differently, and that makes the clinical studies harder to interpret into a coherent and consistent model.

 

[[cs...]]

dm, did you do any research about the link between benzo's and dementia?  I was recently diagnosed with Memory Impairment and Amnesia by the doc.  My mental functioning declined significantly as soon as I got off the benzo's.  I'm almost certain these benzo's and Z-drugs caused my dementia.  I know there's a strong association between benzo's and dementia.  I've got the bad genes for early onset dementia.  My father and uncle got it in their 50's and now I've got it.

 

Hi BecksBlue, I have not, but it's something that looks interesting, and I can take a look.  I do know from reading the literature that abrupt stopping the Benzo is very dangerous to neurons, as they get very depolarized, especially if the person has built up tolerance to the benzos, and the GABAaR efficiency is very poor ( this Aggravates the problem)

 

I read your signature.  How fast did you taper?  I can tell you from first hand experience, that at one point I too combined a few z drugs with the short acting Benzo, and it continued to potientiate my hyper excitable state.  I know that taking these 2 types of drugs together speeds up kindling, and one such effect of kindling is less GABAa receptors at the surface.  I think there are a lot of other things that happen to our physiology in addition to GABAa receptor dysfunction.  That's what I'm looking at.  Systems that affect the dynamics of the action potential curve become dysfunctional, as we kindle.

[[cs...]]

Tried searching through your posts but couldn't find the list of PAMs.  Would this be accurate, from Wikipedia?

 

https://en.wikipedia.org/wiki/Category:GABAA_receptor_positive_allosteric_modulators

 

What are your thoughts on the use of PAMs post-taper?

 

Also, wondering if you've come across anything of special interest regarding the differences between each individual benzo?

 

I am going to post an unedited list for the PAMs as reference in the following post.  Please feel free to redirect people to this list.

 

I'm personally not going to use any PAMs post taper.  I'm not sure how severe your symptoms were at their worst, but I don't ever want to go back there.... that plus this accumulation of research I've seen.  I don't have any studies to post on this because I haven't looked yet.    If it's anything like alcohol's effect on GABAa receptors, it's best to leave it alone.  If there is anything I can do to protect those GABAa receptors I'm going to do it.  Also exercise is important.

 

I'm glad you asked the last question. I've thought about that a lot lately.    I have not taken the time to research it, but in the studies, they use all sorts of benzodiazaphines......  I've noticed a definite trend in looking through many posts on this site.  I notice that many of the sufferers here have used clonazepam or xanax, next on the list is lorazepam (my case before crossing over).  I notice anecdotally, that a lot of the Valium users have used a long time, and although they have built up tolerance and titrated up over the years,  the tolerance seems more manageable, if you know what I mean.  I don't know if Valium users hit extremes in interdose wd, like we see (and feel) with the shorter acting benzos.

 

From personal experience, I think interdose wd and interdose tolerance wd are a continuum of the same process of worsening dysfunction of a whole bunch of different physiological systems, that I hope we can discuss here.  The most obvious was ADDENDUM 6, the GABAa receptor.  But there are a lot of other systems affected.  I don't think I ever got to serious tolerance , but I hit interdose wd after around 2 years, and had to split the dose , rather than taking all at night.  I was Rx'Ed to take all at night.  The worst thing to do.  It fosters and speeds up the kindling process.  It literally physiologically breaks you down to the point where your body can no longer accommodate the changes required to maintain homeostasis.    I started to hit tolerance at the time of crossover, i.e. I probably would have had to increase total daily dosage had I not crossed over. 

 

  These are the types of empirical studies that we need, and that are lacking.  Great question......

 

I wanted to post the conclusion to this excellent paper, which illustrates that regarding different benzos, the two most important things are what subunits they affect (this could play a big role in tolerance development), and the half life of the Benzo, which can greatly affect interdose wd, kindling, phosphorylation, and ultimately GABAa expression.

 

 

Since almost all the benzos that are rx'ed to the public attach to that same Bz binding site, this leaves half life as the only thing we can work with for now relative to reducing tolerance, and kindling effects on our physiology.  Another factor in tolerance appears to be The effects that the Benzo has.  From the bold below, certain effects like sedation (temazepam) build tolerance quickly, whereas others build much more slowly.  This, I think, is in large part  where (i.e., the brain region and peripheral tissues)  the Benzo is most physiologically active.  I know lorazepam penetrates certain brain regions deeper than the other benzos(reference required).  Clonazepam provides much greater anitseizure efficiency than some of the others.

Here is the link

https://www.hindawi.com/journals/aps/2012/416864/

 

Here are the quotes from the conclusion

 

More on bretazenil

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

 

Quote

 

In the present paper, we summarized the rather inconsistent data regarding changes in several neurotransmitter systems to explain the development of tolerance. Specifically, we addressed possible changes at the level of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that one tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. This is not unlikely, given that tolerance is a heterogeneous process that occurs at different rates for the various effects and also depends on the profile of the (subtype selective) benzodiazepine. Adaptations could then occur on different time scales depending on the receptor subtype and brain region involved. In line with this hypothesis, tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects most probably do not develop at all. It is intriguing that anxiolytic effects of classical benzodiazepines may not decline during prolonged treatment. In addition to subtype selectivity, additional factors may be important for a (subtype-selective) benzodiazepine to cause tolerance, including GABAA receptor potency (efficacy) and in vivo receptor occupancy over time. The finding that partial agonists with an overall but comparable lower efficacy at all α subunits of the GABAA receptor such as bretazenil did not result in anticonvulsant tolerance raises the possibility that chronic clinical use of these compounds is associated with a lower tolerance.

 

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Quote

 

An important question is how the development of tolerance of benzodiazepines could be reduced. One interesting suggestion could be—rather than intermittent use that can be defined by an individual—to develop benzodiazepine dosing schedules with varying daily doses including placebos. This could result in continued clinical efficacy (obviously depending on the indication) and utilize the placebo effect. The other possibility to reduce tolerance is the currently developing and promising body of literature on subtype-selective GABAA receptor PAMs. From the literature we reviewed, it appears that α2/α3 subtype selective compounds do not lead to tolerance or withdrawal symptoms. However, the underlying mechanism (reduced α1 efficacy or a generally reduced efficacy profile) is unknown. Also, it is presently unclear whether this lack of tolerance also applies to α1- and α5-selective GABAergic positive allosteric modulators, although a broad and unspecific tolerance resulting from selective (and often low potency) compounds seems unlikely.

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Quote

In conclusion, the development of tolerance following chronic benzodiazepine treatment is a complex process in which multiple processes may simultaneously act to cause varying rates of tolerance depending on the studied effect and the administered drug. There is no convincing evidence that subtype-selective compounds acting at the benzodiazepine site lead to tolerance at a level comparable to classical benzodiazepines. If this is indeed the case, one consequence may be that such subtype-selective compounds are unlikely to engender clinical tolerance, which would be a clinically significant improvement over classical benzodiazepines.

 

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