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

[[li...]]

The URL in question is https://resources.tocris.com/pdfs/archive/gabarev.pdf

 

I'd question the values of clonazepam ! It doesn't show the often described 'intense affinity for the alpha 2 and 3 subunit'.

[[cs...]]

The URL in question is https://resources.tocris.com/pdfs/archive/gabarev.pdf

 

I'd question the values of clonazepam ! It doesn't show the often described 'intense affinity for the alpha 2 and 3 subunit'.

 

Thanks.  I will read this during this week.  I do see that table.  Yes, taking the relative affinities between diazepam and clonazepam doesn’t show what we would expect to see. 

Yes, this is the same tocris I thought it was.

 

 

 

[[li...]]

I could ask for a benzo that is pharmacokinetically 'clean', like lorazepam (but obviously wrong choice). But I guess that these do not exist, except for clonazepam and benzos that do not apply like oxazepam or temazepam.

[[li...]]

It seems that some locals in The Netherlands are also having problems with this clonazepam drug. A small epidemic, possibly. I'm not the only one for whom clonazepam is a unique drug.

 

Doctors here really believes 'it calms', and that's it. They have no clue. They are probably a few decades behind the times.

[[...]]

It seems that some locals in The Netherlands are also having problems with this clonazepam drug. A small epidemic, possibly. I'm not the only one for whom clonazepam is a unique drug.

 

Doctors here really believes 'it calms', and that's it. They have no clue. They are probably a few decades behind the times.

 

Really?  Do you have a link to share at all, Liberty?

[[li...]]

abcd,

 

It's in Dutch. Can you read Dutch ? There is a local forum, I could show you some stories ... No statistics, though.

[[cs...]]

Abcd posted this great link to a very interesting document on Neuroplasticity and drugs.

 

I recommend downloading the full pdf.  The table of contents is hyoerlinked and there’s a section on Benzodiazaphines

 

http://www.benzobuddies.org/forum/index.php?topic=205181.0

[[li...]]

Thanks. I take it you didn't find anything about clonazepam and the GABAA subunit affinity ?

 

Clonazepam is so different ...

[[cs...]]

Abcd posted this great link to a very interesting document on Neuroplasticity and drugs.

 

I recommend downloading the full pdf.  The table of contents is hyoerlinked and there’s a section on Benzodiazaphines

 

http://www.benzobuddies.org/forum/index.php?topic=205181.0

 

 

section I is very good.

 

It provides a great overview of several forms of Neuroplasticity

 

Short term synaptic plasticity (mostly presynaptic // w and wo retrograde signaling). See fig 2

Long term synaptic plasticity (LTP and LTD) (pre and postsynaptic // w and wo retrograde signaling) see fig 3

      Hebbian and anti-Hebbian. 

Developmental plasticity

Homeostatic plasticity (brief mention)

Metaplasticity

 

As a prerequisite, anyone who is interested in presynaptic vesicle pools and dynamics

 

Synaptic Vesicle Pools and Dynamics

AbdulRasheed A. Alabi1 and Richard W. Tsien1,2

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405865/pdf/cshperspect-SYP-a013680.pdf

 

 

[[cs...]]

Thanks. I take it you didn't find anything about clonazepam and the GABAA subunit affinity ?

 

Clonazepam is so different ...

 

No.  I will have to research it  Like we agree, the tocris info isn’t revealing what we’d expect.

We can see that clonazepam is massively potent compared to v or Librium.

 

taking relative affinities , relative to alpha1,

 

clonazepam affinity  for alpha3 is 1.5 times weaker than alpha1,and

affinity for alpha2 is 1.3 times weaker than alpha1

 

Clonazepam.  1    1.308  1.538.    (Alpha1 alpha2 alpha3)

 

For Valium they are all roughly the same.(and weak)

 

Perhaps it’s the differential binding itself , even though not what we expected, that’s causing the problem you are having.  (rather than the absolute nominal affinities  themselves).

 

since regional brain GABAaR subunit distributions differ between individuals, this might explain why some have such a hard time with clonazepam tolerance and dependency, and why some are predisposed to having issues with the drug.

 

Also:: The link on Neuroplasticity above tells us what we already knew.  Neuroplasticity is temporally dependent **and** brain region dependent.

[[Te...]]

dm123, can you please explain this so common people can understand (myself included)? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

MsAtomicBomb posted this in the Benzos in the News section.

 

Here's something else: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

Thank you!!!

[[li...]]

Neuroplasticity goes both ways ... good and bad ...

[[li...]]

I'm not sure, but hypothetically a combination of alpha1alpha3(beta)(gamma) subunits if (for example) the raphe nuclei could explain something ? That is, receptors that do not just contain alpha 1 or alpha 3 but both ? I was unable to find anything. A long time ago I did show you that chart about receptors, subunits in the brain.

 

Thanks. I take it you didn't find anything about clonazepam and the GABAA subunit affinity ?

 

Clonazepam is so different ...

 

No.  I will have to research it  Like we agree, the tocris info isn’t revealing what we’d expect.

We can see that clonazepam is massively potent compared to v or Librium.

 

taking relative affinities , relative to alpha1,

 

clonazepam affinity  for alpha3 is 1.5 times weaker than alpha1,and

affinity for alpha2 is 1.3 times weaker than alpha1

 

Clonazepam.  1    1.308  1.538.    (Alpha1 alpha2 alpha3)

 

For Valium they are all roughly the same.(and weak)

 

Perhaps it’s the differential binding itself , even though not what we expected, that’s causing the problem you are having.  (rather than the absolute nominal affinities  themselves).

 

since regional brain GABAaR subunit distributions differ between individuals, this might explain why some have such a hard time with clonazepam tolerance and dependency, and why some are predisposed to having issues with the drug.

 

Also:: The link on Neuroplasticity above tells us what we already knew.  Neuroplasticity is temporally dependent **and** brain region dependent.

[[cs...]]

dm123, can you please explain this so common people can understand (myself included)? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

MsAtomicBomb posted this in the Benzos in the News section.

 

Here's something else: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

Thank you!!!

 

Hi Terry,

 

Yes sure.  I missed that original post.

 

I will read it this week and let you know how we can apply it here.

[[cs...]]

Neuroplasticity goes both ways ... good and bad ...

 

Yes.  The Neuroplasticity link above points to the time dependent nature of Neuroplasticity specifically as it pertains to proper brain development and brain maintenance.  See section 1E and figure 4.  It’s differential according to brain region as well and cortical layer.  Aberrations cause developmental disorders like ADHD and early adult onset schizophrenia.

 

Synaptic pruning “cleans up the weeds” so to speak

 

Here’s a nice layman’s article on it

 

https://www.gemmlearning.com/blog/learning_science/why-synaptic-pruning-is-good/

[[Te...]]

dm123, can you please explain this so common people can understand (myself included)? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

MsAtomicBomb posted this in the Benzos in the News section.

 

Here's something else: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

Thank you!!!

 

Hi Terry,

 

Yes sure.  I missed that original post.

 

I will read it this week and let you know how we can apply it here.

 

Okay. Thanks so much!!

[[Sw...]]

Thanks Terry for finding these two articles and bringing them to our attention.  Not that I can fully understand them but at least I know we are inching forward on the protracted front.

 

Sweet pea

[[Te...]]

Inching forward. You've got it right, Sweet pea! 

[[cs...]]

dm123, can you please explain this so common people can understand (myself included)? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

MsAtomicBomb posted this in the Benzos in the News section.

 

Here's something else: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

Thank you!!!

 

Hi Terry,

 

Yes sure.  I missed that original post.

 

I will read it this week and let you know how we can apply it here.

 

Okay. Thanks so much!!

 

 

I read through the abstract.  I do understand what they are getting at.  It will take some background material to present the process as it’s quite complex.

 

Do you have access to the full document?  It would be great to read it.

Also, I found a tie in to high blood pressure that’s related to this theory as well.

 

RST I also found some links for the neuropathic pain via this theory.

 

 

 

[[Ca...]]

Hi Guys,

This is one thread where I have nothing to say, but Thanks...

Think its been about a year now..??

 

Obviously I cant get close to the full concepts, but I sure am connecting one or two dots...

 

Be well...

[[Re...]]

dm123, can you please explain this so common people can understand (myself included)? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

MsAtomicBomb posted this in the Benzos in the News section.

 

Here's something else: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

Thank you!!!

 

Hi Terry,

 

Yes sure.  I missed that original post.

 

I will read it this week and let you know how we can apply it here.

 

Okay. Thanks so much!!

 

 

I read through the abstract.  I do understand what they are getting at.  It will take some background material to present the process as it’s quite complex.

 

Do you have access to the full document?  It would be great to read it.

Also, I found a tie in to high blood pressure that’s related to this theory as well.

 

RST I also found some links for the neuropathic pain via this theory.

 

Hi dm123.

 

This is interesting.  I wish I had access to the whole article.  Maybe I should just bite the bullet and pay for it!  I have a lot of other symptoms besides neuropathic pain such as sweating, headaches, sleep difficulty, nausea, fatigue, muscle twitching and cramping, vision issues, cognition issues... etcetera.  Anyway, what I find very interesting is that I can experience the whole "withdrawal symptom cycle" in two ways: 1) by tapering (even with my micro cut-and-hold approach); and 2) by physical exercise or stress.  I can be holding on my taper and if I do even light physical activity, it will cause withdrawal symptoms exactly as though I had just cut my dose. 

 

I know that exercise has many affects on the human brain but I wonder how physical activity of any kind causes me to experience symptoms that are identical to those I endure after a dosage reduction.

 

The good thing is that we are gaining information day-by-day and that is going to eventually lead us to an understanding and,  ultimately, a solution.

 

-RST

[[li...]]

A bit different (see prior posts and pm?), perhaps even off topic

 

I´ve read a few articles about clonazepam withdrawal and motor hyperexcitability. I just wonder if my ´motor cortex (?) hyperexcitability´ isn´t (partly?) ´tolerance withdrawal´ and interdose withdrawal caused by the lorazepam experience. Well.

[[Te...]]

dm123, can you please explain this so common people can understand (myself included)? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

MsAtomicBomb posted this in the Benzos in the News section.

 

Here's something else: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

Thank you!!!

 

Hi Terry,

 

Yes sure.  I missed that original post.

 

I will read it this week and let you know how we can apply it here.

 

Okay. Thanks so much!!

 

 

I read through the abstract.  I do understand what they are getting at.  It will take some background material to present the process as it’s quite complex.

 

Do you have access to the full document?  It would be great to read it.

Also, I found a tie in to high blood pressure that’s related to this theory as well.

 

RST I also found some links for the neuropathic pain via this theory.

 

I asked MAB if she had the full document, but she hasn't responded.

 

Now my blood pressure is low. I don't understand this. It's been low all day and I've felt faint and dizzy. Had to stay iin bed, which is unusual for me. This constant yanking of my bp is devastating to the rest of my body and especially the kidneys. But I would like to read that tie in that you were talking about!

 

Thanks so very much!!! You're a gem!!!

[[cs...]]

dm123, can you please explain this so common people can understand (myself included)? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

MsAtomicBomb posted this in the Benzos in the News section.

 

Here's something else: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

Thank you!!!

 

Hi Terry,

 

Yes sure.  I missed that original post.

 

I will read it this week and let you know how we can apply it here.

 

Okay. Thanks so much!!

 

 

I read through the abstract.  I do understand what they are getting at.  It will take some background material to present the process as it’s quite complex.

 

Do you have access to the full document?  It would be great to read it.

Also, I found a tie in to high blood pressure that’s related to this theory as well.

 

RST I also found some links for the neuropathic pain via this theory.

 

Hi dm123.

 

This is interesting.  I wish I had access to the whole article.  Maybe I should just bite the bullet and pay for it!  I have a lot of other symptoms besides neuropathic pain such as sweating, headaches, sleep difficulty, nausea, fatigue, muscle twitching and cramping, vision issues, cognition issues... etcetera.  Anyway, what I find very interesting is that I can experience the whole "withdrawal symptom cycle" in two ways: 1) by tapering (even with my micro cut-and-hold approach); and 2) by physical exercise or stress.  I can be holding on my taper and if I do even light physical activity, it will cause withdrawal symptoms exactly as though I had just cut my dose. 

 

I know that exercise has many affects on the human brain but I wonder how physical activity of any kind causes me to experience symptoms that are identical to those I endure after a dosage reduction.

 

The good thing is that we are gaining information day-by-day and that is going to eventually lead us to an understanding and,  ultimately, a solution.

 

-RST

 

Hi RST

 

I will post a short version today for Terry that ties into her BP issues.

 

I’m holding off on posting the full post until I can get access to the full article.  To get into the neuropathic pain side of things requires a full understanding of the NO/ONOO- dynamics.

 

Certainly too much exercise is a form of oxidative stress and would fall into the NO/ONOO- dynamics but it would also fall into the stress pillar of the Benzodiazaphine model presented here.  The NO/ONOO- cycles are dependent on induction  of oxidative stress and mitochondrial dysfunction.  These are yet another form of stress on the cellular physiology.  In the short post I will post today, it’s clear that viruses, molds, bacterial infections,parasites and tumors can increase what are called iNOSs, which are one form of nitric oxide synthases stemming from immune system activation and an inflammatory cytokine response.

 

There’s another path in the NO/ONOO- model that incites calcium dependent NOSs (nitric oxide synthases) such as nNOSs and eNOSs.  These are increased when the intracellular Calcium influx increases vastly.  The Benzodiazaphine hypothesis link posted above postulates that first dysfunction in VGCCs, and then subsequent sensitization of NMDARs predispose individuals to this high influx of Ca2+ into the neurons and cells.  The abstract also mentions decompensation of GABAaRs as well, which would certainly increase the probability of depolarization and the firing off of VGCCs. 

 

There’s an overlap with the current Benzodiazaphine model in that the glutamatergic and GABAergic pillars are involved in this hypothesis, and the stress pillar is destabilized via oxidative stress and mitochondrial dysfunction.  Certainly negative stressors.

 

The main crux of the hypothesis is a persistent overproduction of Peroxynitrate (ONOO-) which , in and of itself is pro oxidant.  It oxidizes a substrate called BH4, which is essential for conversion of NOSs to NO.  When BH4 gets low, more and more of the NOS converts to superoxide rather than NO.  The problem with that is that superoxide very rapidly and forcefully reacts with any NO in tHe proximate tissues to form more Peroxynitrate.  You can see that a viscous cycle ensues perpetuating the oxidative stress.

 

If you are in this state, a small amount of exercise for you might be intolerable because of the cycle dynamics above, which have essentially lowered your resiliency to stress.

 

In addition all the Neuroplastic and neurogenic issues in the layman’s Benzodiazaphine model persist making recovery very long. Negative stress comes in many shapes and forms.

 

P.S.  I replied to your PM. 

[[cs...]]

dm123, can you please explain this so common people can understand (myself included)? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

MsAtomicBomb posted this in the Benzos in the News section.

 

Here's something else: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

Thank you!!!

 

Hi Terry,

 

Yes sure.  I missed that original post.

 

I will read it this week and let you know how we can apply it here.

 

Okay. Thanks so much!!

 

 

I read through the abstract.  I do understand what they are getting at.  It will take some background material to present the process as it’s quite complex.

 

Do you have access to the full document?  It would be great to read it.

Also, I found a tie in to high blood pressure that’s related to this theory as well.

 

RST I also found some links for the neuropathic pain via this theory.

 

I asked MAB if she had the full document, but she hasn't responded.

 

Now my blood pressure is low. I don't understand this. It's been low all day and I've felt faint and dizzy. Had to stay iin bed, which is unusual for me. This constant yanking of my bp is devastating to the rest of my body and especially the kidneys. But I would like to read that tie in that you were talking about!

 

Thanks so very much!!! You're a gem!!!

 

Hi Terry,

 

I will post a shorter post for you today.  I don’t want to post the full post until I can get access to the full Benzodiazaphine hypothesis document.

 

 

I’m very sorry about your BP swings and hope my post later today gives you some more insight into what going on with the HBP.