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

[[li...]]

Muscle rigidity is not uncommon between daily doses. For how long and to what extent, that varies.

 

It's important to realize that clonazepam has antimyoclonic properties, and it was effective as a muscle relaxant right up to the lorazepam. Then, the downregulated GABA receptors (?) took care of something ... it was never quite the same. The antimyoclonic properties are not mediated by GABA.

 

And after exercise ... muscle rigidity is hardly uncommon.

 

EDIT: written quite late, before going to bed and a few hours after the evening dose. I did exercise a few days ago. Right now I feel muscle rigidity, most obviously in my arms but also neck and elsewhere.

I think it's those very thin muscle fibers, after a fashion there must be a lot of strain on those (action potential?), signals to the motor cortex or whatever. Muscle mass close to zero. Not good. It's worse now than 7 months ago.

Those medical experiments over the last five years didn't work out well ...

[[cs...]]

I forgot to post Neural Circuits Module 4(PART 4) to this thread due to all of the other topics that came up in the last several months......  I am posting it below.

 

Table of contents to this thread

 

Pages 1-40 are the theoretical building blocks of the basic Benzodiazaphine model from the theoretical and clinical research

 

Page 40 has the summary of the Benzodiazaphine model Pillars 1-3 and Component systems 1-3 upon which the pillars act.

 

Pages 53-56:  added the 4th Pillar of NO and NOS system and a 4th component system called “Cellular homeostasis and cellular integrity”, based on earlier research i had done on NO and the NO/ONOO- cycle, as well as a MAB posted article. (Thanks MAB)

 

GPCRs will be a 5th pillar that needs to be added to the model.

 

Page 48 is Neural Circuits Module 4(PART3), where we last left off on the Neural Circuits component system of the Benzodiazaphine model (of page 40).  (Neural Circuits Modules 1-3 are posted piecemeal in the preceeeding pages)

 

 

 

 

Here is Neural Circuits Module 4(PART4), the last part of Module 4(Brain Neuroanatomy).

It’s heavily quoted material and the details are not important.  The flow and the connections between the different regions of the brain covered in PARTS 1-4 are what is important to understand.

 

Here’s module 4(PART4).

 

Be well...

Dm123

 

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

 

 

(4.7)Basic brain architecture: the cerebral primary motor cortex, premotor cortex,  and frontal lobe (the “cerebral cortex”)

 

 

 

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

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

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

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

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

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

 

These terms in the links above are often used interchangeably, but they are not all referring to the same region of the brain.  The frontal lobe is a superset region of the brain, and one of 4 major lobes in the cerebral cortex.  The last stop for the reward circuitry is the frontal lobe, and the last stop for the motor circuitry is the dorsal frontal lobe commonly referred to as the primary motor cortex.  These regions are generically referred to as cerebral cortex in this post, for simplicity.

 

 

 

 

 

 

 

(4.7.1)Frontal lobe (motor and reward)

 

 

This is the last stop on the brain circuit route for the risk/reward systems. It also houses the primary motor cortex.

 

 

Quote

 

 

The frontal lobe, located at the front of the brain, is the largest of the four major lobes of the cerebral cortex in the mammalian brain.

 

The frontal lobe is located at the front of each cerebral hemisphere and positioned in front of the parietal lobe and above and in front of the temporal lobe. It is separated from the parietal lobe by a groove between tissues called the central sulcus, and from the temporal lobe by a deeper groove called the lateral sulcus (Sylvian fissure). The most anterior rounded part of the frontal lobe (though not well-defined) is known as the frontal pole, one of the three poles of the cerebrum.[1]

 

The frontal lobe contains most of the dopamine-sensitive neurons in the cerebral cortex. The dopamine system is associated with reward, attention, short-term memory tasks, planning, and motivation. Dopamine tends to limit and select sensory information arriving from the thalamus to the forebrain.

 

 

End quote

 

 

Quote

 

 

The frontal lobe plays a large role in voluntary movement. It houses the primary motor cortex which regulates activities like walking.

The function of the frontal lobe involves the ability to project future consequences resulting from current actions, (i.e., risk reward) , the choice between good and bad actions (or better and best) (also known as conscience), the override and suppression of socially unacceptable responses, and the determination of similarities and differences between things or events.

The frontal lobe also plays an important part in integrating longer non-task based memories stored across the brain. These are often memories associated with emotions derived from input from the brain's limbic system. The frontal lobe modifies those emotions to generally fit socially acceptable norms.

 

 

End quote

 

 

 

 

 

 

 

(4.7.2)Primary motor cortex (dorsal portion of the frontal lobe) (motor)

This region of the brain is involved in the pure motor circuit.

 

 

Quote

 

 

The primary motor cortex (Brodmann area 4) is a brain region that in humans is located in the dorsal portion of the frontal lobe.[/b] It is the primary region of the motor system and works in association with other motor areas including premotor cortex, the supplementary motor area, posterior parietal cortex, and several subcortical brain regions, to plan and execute movements. Primary motor cortex is defined anatomically as the region of cortex that contains large neurons known as Betz cells. Betz cells, along with other cortical neurons, send long axons down the spinal cord to synapse onto the interneuron circuitry of the spinal cord and also directly onto the alpha motor neurons in the spinal cord which connect to the muscles.

 

 

….

 

 

As the motor axons travel down through the cerebral white matter, they move closer together and form part of the posterior limb of the internal capsule.

 

They continue down into the brainstem, where some of them, after crossing over to the contralateral side, distribute to the cranial nervemotor nuclei. (Note: a few motor fibers synapse with lower motor neurons on the same side of the brainstem).

After crossing over to the contralateral side in the medulla oblongata (pyramidal decussation), the axons travel down the spinal cord as the lateral corticospinal tract.

Fibers that do not cross over in the brainstem travel down the separate ventral corticospinal tract, and most of them cross over to the contralateral side in the spinal cord, shortly before reaching the lower motor neurons.

….

 

The primary motor cortex receives thalamic inputs from different thalamic nuclei. Among others:

- Ventral lateral nucleus for cerebellar afferents

- Ventral anterior nucleus for basal ganglia afferents

 

End quote

 

 

 

 

 

 

 

(4.7.3)Premotor cortex (motor)

 

This region of the motor cortex is involved in the pure motor circuit .

This is a very complex region of the brain that is still not fully understood. It is heavily involved with movement control.

 

Quote

 

 

The premotor cortex is an area of motor cortex lying within the frontal lobe of the brain just anterior to the primary motor cortex. It occupies part of Brodmann's area 6. It has been studied mainly in primates, including monkeys and humans. The functions of the premotor cortex are diverse and not fully understood. It projects directly to the spinal cord and therefore may play a role in the direct control of behavior, with a relative emphasis on the trunk muscles of the body. It may also play a role in planning movement, in the spatial guidance of movement, in the sensory guidance of movement, in understanding the actions of others, and in using abstract rules to perform specific tasks. Different subregions of the premotor cortex have different properties and presumably emphasize different functions.

 

 

End quote

 

 

 

 

 

 

(4.7.4)The motor cortex (motor)

 

This region is a superset of the primary motor cortex and premotor cortex.

 

Quote

 

 

The motor cortex is the region of the cerebral cortex involved in the planning, control, and execution of voluntary movements. Classically the motor cortex is an area of the frontal lobe located in the posterior precentral gyrus immediately anterior to the central sulcus.

 

 

….

 

 

The motor cortex can be divided into three areas:

 

 

1. the primary motor cortex is the main contributor to generating neural impulses that pass down to the spinal cord and control the execution of movement. However, some of the other motor areas in the brain also play a role in this function. It is located on the anterior paracentral lobule on the medial surface

 

2. the premotor cortex is responsible for some aspects of motor control, possibly including the preparation for movement, the sensory guidance of movement, the spatial guidance of reaching, or the direct control of some movements with an emphasis on control of proximal and trunk muscles of the body. Located anterior to the primary motor cortex

 

 

3. the supplementary motor area (or SMA), has many proposed functions including the internally generated planning of movement, the planning of sequences of movement, and the coordination of the two sides of the body such as in bi-manual coordination. Located on the midline surface of the hemisphere anterior to the primary motor cortex

 

-The posterior parietal cortex is sometimes also considered to be part of the group of motor cortical areas; however it is best to regard it as an association cortex rather than motor. It is thought to be responsible for transforming multisensory information into motor commands, and to be responsible for some aspects of motor planning, in addition to many other functions that may not be motor related.

 

-The primary somatosensory cortex, especially the part called area 3a, which lies directly against the motor cortex, is sometimes considered to be functionally part of the motor control circuitry.

Other brain regions outside the cerebral cortex are also of great importance to motor function, most notably the cerebellum, the basal ganglia, pedunculopontine nucleus and the red nucleus, as well as other subcortical motor nuclei.

 

 

End quote

 

 

 

 

(4.7.5) Summary of cortical motor control regions of the brain and their connections to other regions of the brain

 

 

 

 

Quote

 

 

The motor areas are located in both hemispheres of the cortex. They are shaped like a pair of headphones stretching from ear to ear. The motor areas are very closely related to the control of voluntary movements, especially fine fragmented movements performed by the hand. The right half of the motor area controls the left side of the body, and vice versa.

 

 

Two areas of the cortex are commonly referred to as motor:

 

 

 Primary motor cortex, which executes voluntary movements[citation needed]

 Supplementary motor areas and premotor cortex, which select voluntary movements.[citation needed]

 

 

In addition, motor functions have been described for:

 Posterior parietal cortex, which guides voluntary movements in space

 Dorsolateral prefrontal cortex, which decides which voluntary movements to make according to higher-order instructions, rules, and self-generated thoughts.

Just underneath the cerebral cortex are interconnected subcortical masses of grey matter called basal ganglia (or nuclei). The basal ganglia receive input from the substantia nigra of the midbrain and motor areas of the cerebral cortex, and send signals back to both of these locations. They are involved in motor control. They are found lateral to the thalamus. The main components of the basal ganglia are the caudate nucleus, the putamen, the globus pallidus, the substantia nigra, the nucleus accumbens, and the subthalamic nucleus.

 

The putamen and globus pallidus are also collectively known as the lentiform nucleus, because together they form a lens-shaped body. The putamen and caudate nucleus are also collectively called the corpus striatum after their striped appearance.[54][55]

 

 

End quote

 

 

 

 

(4.7.6)Prefrontal cortex (front part of the frontal lobe) (PFC) (planning, not necessarily motor)

 

 

In mammalian brain anatomy, the prefrontal cortex (PFC) is the cerebral cortex which covers the front part of the frontal lobe (Frontal lobe: see section 4.7.1, above).

 

Quote

 

 

This brain region has been implicated in planning complex cognitive behavior, personality expression, decision making, and moderating social behavior.[3] The basic activity of this brain region is considered to be orchestration of thoughts and actions in accordance with internal goals.[4]

 

 

End quote

 

 

 

 

[[li...]]

Thanks, very good.

 

Possibly a piece of the puzzle, for me and someone else: https://www.ncbi.nlm.nih.gov/pubmed/19846281

 

'The effects of lorazepam on extrastriatal dopamine D(2/3)-receptors'

'The sedative effect of lorazepam was associated with a decrease in D(2)/D(3) receptor BP(ND) in the DLPFC.' Motor cortex or not, jumping from clonazepam to lorazepam or backwards may be very bad for this reason if not for others.

[[Re...]]

You’ve put so much information in there for consideration, dm123.  Once again, thanks for your great contribution to our collective knowledge.

 

As I review each module I gain a greater appreciation for the interconnected nature of everything in our bodies.  This is helping me a great deal.  First of all, it has tempered my initial search for a 'cure' in the form of some 'thing' that could specifically target alpha receptors for upregulation by inducing mRNA synthesis of a higher proportion of A-1 subunits.  (That being said, I have read somewhere that there is some evidence that the 'A' bacosides in Bacopa Monnieri (BM) may effect such an outcome.  However, any commercial source of BM I find contains bioactive products such as 'B' bacosides, bacosaponins, etc with other CNS influencing properties.  I cannot find a source of 'A' bacosides only.  It would be interesting to isolate that compound and give it a try.)  That being said, your papers have really demonstrated that even the best intentioned manipulation of one part of a system can produce an unanticipated (and undesired) cascade of negative effects across multiple systems. 

 

I’ve been talking with you (dm123) here, and the rest of this group, about my kind of unique situation for a while now.  I mention it here only as a case study of which I am most familiar but I think there are interesting pieces due to my somewhat atypical experience.  First of all, there is the question of what residue of lorazepam / diazepam damage exists 16 months after my last dose?  This is an unknown as I am currently taking gabapentin and Effexor.    The next question is what is the current effect of my gabapentin dose (144mg; 48mg TID)?  I seem to be in a tolerance state.  Further, how has my withdrawal experience been influenced by exercise induced perturbations of my HPA axis – each one seemingly making my HPA more and more sensitive to any kind of physical stress?  Also, there is the mold issue.  How much is this further compounding HPA dysregulation and inducing inflammation?  Last week, I was diagnosed as having small fibre neuropathy.  This may explain why some of the burning pain is so intense.  But the real question is what is causing the nerve damage to begin with.  As I’ve also just been diagnosed with psoriasis – an autoimmune / auto-inflammatory disease.  Then, add the potential of low BH4  / elevated peroxynitrite and we can see that it’s a recipe for a lot of discomfort.  Throw in high anxiety and all it does to our body and I think it’s no surprise I ended up in a bad place.  In retrospect, some of these issues were becoming evident in the summer before I was prescribed lorazepam for insomnia.

 

So, going forward, so much of dm123’s work has helped me see the potential interrelatedness of my issues and how benzodiazepines may have exacerbated the previous conditions.  Now, I don’t find it shocking that my body so quickly deteriorated after short-term exposure to lorazepam.  For a long time I struggled with “why”/  Now feel that some of this ‘jigsaw puzzle’ is being pieced together.  I also feel there are strong clues here as to why I cannot heal.  Going forward, I need to figure out how to manage the chronic auto-immune activity of psoriasis (and the potentially compounding effects of mould) as well as (potentially) the NO/ONOO- cycle without causing further perturbations to my CNS.  It’s no surprise to me that the NO/ONOO- cycle may be so important in all of this when one realizes that a critical component of that cycle is Ca+.  Don’t forget, influencing movement of Ca+ ions through VGCC is thought to be a fundamental mechanism of action of gabapentin.  That’s a strong correlation.  For me, microscopic reductions of gabapentin lead to slow increases in withdrawal sensations after about 3-4 days that tend to slowly increase over the following 2 to 3 days to become severe and then they remain heightened for longer and longer periods of time with each cycle.    I am of the opinion now that my protracted withdrawal syndrome can be explained by more than just the benzodiazepine issue.  I think benzo’s were just the straw that broke the camel’s back.  Even though I was athletic and active before my benzo debacle, I was starting to decline in ways I just ignored and put down to age and challenging physical activity.  Now, piecing this all together to create a regime to move forward is the next big challenge. 

 

BTW, thanks to Liberty for great links and contributions and everyone else who takes part. 

 

Hugs to everyone.

 

-RST

 

 

[[li...]]

Actually, where the HPA axis is concerned ... :

 

´limbic hypothalamic axis sensitization´ the ´limbic´ may be worth looking into.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637449/

 

´LIMBIC REGULATION OF HYPOTHALAMO-PITUITARY-ADRENOCORTICAL FUNCTION DURING ACUTE AND CHRONIC STRESS´ not a bad article.

https://www.nikigratrix.com/wp-content/uploads/2013/06/Limibic-Kindling.pdf

 

https://books.google.nl/books?id=wpQ-DgAAQBAJ&pg=PA72&lpg=PA72&dq=corticosterone+hpa+axis+reprogramming+-prenatal+-neonatal&source=bl&ots=MQy6ZYYuQT&sig=eeiNcJ7IbayZq0wu2fL84vlso9A&hl=nl&sa=X&ved=2ahUKEwi_iKDqobvcAhWEY1AKHeGvBOc4ChDoATAAegQIABAB#v=onepage&q=corticosterone%20hpa%20axis%20reprogramming%20-prenatal%20-neonatal&f=false

 

https://onlinelibrary.wiley.com/doi/abs/10.1002/cne.23815

 

Maybe a bit much. But repeated stress ...

 

[[Re...]]

Actually, where the HPA axis is concerned ... :

 

´limbic hypothalamic axis sensitization´ the ´limbic´ may be worth looking into.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637449/

 

´LIMBIC REGULATION OF HYPOTHALAMO-PITUITARY-ADRENOCORTICAL FUNCTION DURING ACUTE AND CHRONIC STRESS´ not a bad article.

https://www.nikigratrix.com/wp-content/uploads/2013/06/Limibic-Kindling.pdf

 

https://books.google.nl/books?id=wpQ-DgAAQBAJ&pg=PA72&lpg=PA72&dq=corticosterone+hpa+axis+reprogramming+-prenatal+-neonatal&source=bl&ots=MQy6ZYYuQT&sig=eeiNcJ7IbayZq0wu2fL84vlso9A&hl=nl&sa=X&ved=2ahUKEwi_iKDqobvcAhWEY1AKHeGvBOc4ChDoATAAegQIABAB#v=onepage&q=corticosterone%20hpa%20axis%20reprogramming%20-prenatal%20-neonatal&f=false

 

https://onlinelibrary.wiley.com/doi/abs/10.1002/cne.23815

 

Maybe a bit much. But repeated stress ...

 

Thanks, Liberty.  More for my reading list!!!!!!  I need to study up on the HPA and HPA dysregulation.  It seems any physical activity really does a number on me.  I wonder about the increase in free radicals due to acute exercise or physical exertion being a problem alongside the potential nitrogen pathway issue.  So much to learn.......

 

All the best,

 

-RST

[[Re...]]

Also came across this study on another forum regarding the influence of BH4 at supra-optimal levels, which may be an issue in certain circumstances.

 

http://biopku.org/pdf/choi58.pdf

 

-RST

 

 

[[cs...]]

Thanks, very good.

 

Possibly a piece of the puzzle, for me and someone else: https://www.ncbi.nlm.nih.gov/pubmed/19846281

 

'The effects of lorazepam on extrastriatal dopamine D(2/3)-receptors'

'The sedative effect of lorazepam was associated with a decrease in D(2)/D(3) receptor BP(ND) in the DLPFC.' Motor cortex or not, jumping from clonazepam to lorazepam or backwards may be very bad for this reason if not for others.

 

Yes, and keep in mind this was a short term test with healthy volunteers.  In tolerance and withdrawal (and perhaps PWS) one would expect paradoxical results from those presented in the citation above.  Unfortunately, much of the clinical testing either fails to take this into account as an oversight, or perhaps much of the clinical testing focuses too much on the short term effects of Benzodiazaphines.  As we all know,  after 2 weeks, there are many many changes in both collateral systems (as the brain and nervous system seek to reestablish homeostasis) and in the gene regulatory processes of the GABAaR receptor itself.

 

It’s great that they are looking beyond the striatal neurons in this study, but I’m not suprised at all by the findings. Cortical and thalamic neurons are part of a larger neural circuit that originates in the cortex and striatal regions of the brain.    The motor circuit traverses through the GP, then through the SNr, then to the thalamus , which then exerts its influence on the motor neurons in the cortex.  The cortex then exerts its influence through the brainstem and descending spinal cord neurons. 

[[cs...]]

You’ve put so much information in there for consideration, dm123.  Once again, thanks for your great contribution to our collective knowledge.

 

As I review each module I gain a greater appreciation for the interconnected nature of everything in our bodies.  This is helping me a great deal.  First of all, it has tempered my initial search for a 'cure' in the form of some 'thing' that could specifically target alpha receptors for upregulation by inducing mRNA synthesis of a higher proportion of A-1 subunits.  (That being said, I have read somewhere that there is some evidence that the 'A' bacosides in Bacopa Monnieri (BM) may effect such an outcome.  However, any commercial source of BM I find contains bioactive products such as 'B' bacosides, bacosaponins, etc with other CNS influencing properties.  I cannot find a source of 'A' bacosides only.  It would be interesting to isolate that compound and give it a try.)  That being said, your papers have really demonstrated that even the best intentioned manipulation of one part of a system can produce an unanticipated (and undesired) cascade of negative effects across multiple systems. 

 

I’ve been talking with you (dm123) here, and the rest of this group, about my kind of unique situation for a while now.  I mention it here only as a case study of which I am most familiar but I think there are interesting pieces due to my somewhat atypical experience.  First of all, there is the question of what residue of lorazepam / diazepam damage exists 16 months after my last dose?  This is an unknown as I am currently taking gabapentin and Effexor.    The next question is what is the current effect of my gabapentin dose (144mg; 48mg TID)?  I seem to be in a tolerance state.  Further, how has my withdrawal experience been influenced by exercise induced perturbations of my HPA axis – each one seemingly making my HPA more and more sensitive to any kind of physical stress?  Also, there is the mold issue.  How much is this further compounding HPA dysregulation and inducing inflammation?  Last week, I was diagnosed as having small fibre neuropathy.  This may explain why some of the burning pain is so intense.  But the real question is what is causing the nerve damage to begin with.  As I’ve also just been diagnosed with psoriasis – an autoimmune / auto-inflammatory disease.  Then, add the potential of low BH4  / elevated peroxynitrite and we can see that it’s a recipe for a lot of discomfort.  Throw in high anxiety and all it does to our body and I think it’s no surprise I ended up in a bad place.  In retrospect, some of these issues were becoming evident in the summer before I was prescribed lorazepam for insomnia.

 

So, going forward, so much of dm123’s work has helped me see the potential interrelatedness of my issues and how benzodiazepines may have exacerbated the previous conditions.  Now, I don’t find it shocking that my body so quickly deteriorated after short-term exposure to lorazepam.  For a long time I struggled with “why”/  Now feel that some of this ‘jigsaw puzzle’ is being pieced together.  I also feel there are strong clues here as to why I cannot heal.  Going forward, I need to figure out how to manage the chronic auto-immune activity of psoriasis (and the potentially compounding effects of mould) as well as (potentially) the NO/ONOO- cycle without causing further perturbations to my CNS.  It’s no surprise to me that the NO/ONOO- cycle may be so important in all of this when one realizes that a critical component of that cycle is Ca+.  Don’t forget, influencing movement of Ca+ ions through VGCC is thought to be a fundamental mechanism of action of gabapentin.  That’s a strong correlation.  For me, microscopic reductions of gabapentin lead to slow increases in withdrawal sensations after about 3-4 days that tend to slowly increase over the following 2 to 3 days to become severe and then they remain heightened for longer and longer periods of time with each cycle.    I am of the opinion now that my protracted withdrawal syndrome can be explained by more than just the benzodiazepine issue.  I think benzo’s were just the straw that broke the camel’s back.  Even though I was athletic and active before my benzo debacle, I was starting to decline in ways I just ignored and put down to age and challenging physical activity.  Now, piecing this all together to create a regime to move forward is the next big challenge. 

 

BTW, thanks to Liberty for great links and contributions and everyone else who takes part. 

 

Hugs to everyone.

 

-RST

 

Hi RST, thanks for your very well articulated post.

 

I’m glad that the model is revealing how things are all tied into each other.  That was my main intention in establishing the model.... so that we can at least determine how one change affects processes in another system.  It helps us understand why we feel the way we do, and why, in some cases, symtoms go into a protracted state.  Knowing doesn’t necessarily reveal those “Magic bullet” therapies, and i imagine that much like cancer, the ultimate treatment for Benzodiazaphine PWS will consist of a very targeted multifaceted approach that seeks to reestablish homeostasis to the various systems indicated in the model.  Once homeostasis is achieved, protracted feedback loops can be mitigated and eventually will burn out.

 

As the model indicates, long after the last Benzodiazaphine is ingested there can be perpetual feedback loops that prevent the body from achieving symptomatic recovery.    Ive mentioned it several times, stress is a big player.  And it is not only the types of stress that are important, but also how resilient we are to stress.

 

The inhibitory and excitatory systems when in balance enable the body to handle an enormous amount of stress.  Once these pillars are destabilized, we become vulnerable to all sorts of stressors that would we may not have even noticed prior to getting sick.  The exercise tolerance is a good example of this.  I had a very similar experience, and its very very difficult to reestablish resiliency, when one cannot even exercise.    Resiliency is built up via challenge, and when we cannot challenge the systems, it is a double edged sword because not challenging the system in and of itself, weakens resiliency further.

 

...And challenging the system by overexerting throws one into further disarray because the systems cannot recover from the challenge stressor the way a normal person can.  Exercise is a positive stressor, but in this scenario, it can become very negative if resiliency is severely compromised.

 

The compromised HPA axis is first and foremost the center of the stress system.  If that is dysregulated, resiliency will be poor. 

 

As you mentioned, you felt it coming on a year before taking the benzodiazphine.  My case an acute infection followed by mold exposure and then endocrine failure.  So we are very similar in that we weren’t well going into the initial dose of Benzodiazaphine .  The Benzodiazaphine selectively destabilizes the inhibitory pillar over time as tolerance rapidly builds.  Once that pillar decompensates, and given that stress resiliency is poor, once can see how things can rapidly deteriorate and become perpetual.

 

Benzodiazaphines do more harm than good.  I agree with your last few sentences.  We are very similar in that respect.  Very athletic, and an initial insult was made much worse by the Benzodiazaphine.  And the perpetual nature of the situation goes far beyond serum Benzodiazaphine levels......

 

Best, and please keep us updated on the small fiber neuropathy. 

 

Dm123

[[cs...]]

Actually, where the HPA axis is concerned ... :

 

´limbic hypothalamic axis sensitization´ the ´limbic´ may be worth looking into.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637449/

 

´LIMBIC REGULATION OF HYPOTHALAMO-PITUITARY-ADRENOCORTICAL FUNCTION DURING ACUTE AND CHRONIC STRESS´ not a bad article.

https://www.nikigratrix.com/wp-content/uploads/2013/06/Limibic-Kindling.pdf

 

https://books.google.nl/books?id=wpQ-DgAAQBAJ&pg=PA72&lpg=PA72&dq=corticosterone+hpa+axis+reprogramming+-prenatal+-neonatal&source=bl&ots=MQy6ZYYuQT&sig=eeiNcJ7IbayZq0wu2fL84vlso9A&hl=nl&sa=X&ved=2ahUKEwi_iKDqobvcAhWEY1AKHeGvBOc4ChDoATAAegQIABAB#v=onepage&q=corticosterone%20hpa%20axis%20reprogramming%20-prenatal%20-neonatal&f=false

 

https://onlinelibrary.wiley.com/doi/abs/10.1002/cne.23815

 

Maybe a bit much. But repeated stress ...

 

And its rather unfortunate, but benzodiazaphines should be added to the list below.  Benzodiazaphines neurochemically alter both our perception of stress and our physiological response to stress, and this aberrant response and perception becomes profound once the nervous system is kindled.

 

Quote

Based on the work of Le Doux in the ‘90s (5), Gupta suggested that an infectious, chemical

or psychological stressor could create a “cell assembly” within the unconscious amygdala

and that these cell populations are particularly resistant to extinction. As with Goddard and Gellhorn, this again implied that people could become “hard-wired” to respond more easily response established by Selye’s classic model of stress.(3-5)

End quote

And this from a chronically overactive stress system.....

 

Quote

 

This includes:

immune system activation and movement from TH1 to TH2 dominance;;

up-regulation of the hypothalamic-pituitary- adrenal axis initially, which over time leads

to reduction of cortisol output and glandular depletion;;

disruption in ion channel transport;;

reduction of grey matter in the brain;;

reduction of GABA;;

depletion of neurotransmitter acetylcholine;; depletion of antioxidants;;

and eventually the oxidative stress,

End quote

 

And finally this...coming back to adaptive homeostasis. This occurs at the cellular level and at the system level.

 

 

Quote

The fact that limbic kindling

can both cause and be caused by relationship between the brain and the body, and the fact that the human body is a complex adaptive system where essentially everything affects everything else.

End quote

[[cs...]]

Also came across this study on another forum regarding the influence of BH4 at supra-optimal levels, which may be an issue in certain circumstances.

 

http://biopku.org/pdf/choi58.pdf

 

-RST

 

I did not read the pdf yet, but it is known that BH4 can itself can become  peri oxidized

 

I did list two precursors in my original post.  I hope you can find them in this thread.  I would use precursors.

 

I will take a look at the pdf as well....

 

 

I just read the abstract.

 

Looks pretty scary.  I’m hoping one has to be predisposed to PD for this to occur.  It’s hard to conceive that BH4 in and of itself would cause PD.    For myself, i dont have NO/ONOO- dysfunction and would not take BH4.  Please look into those precursors.

 

Quote

Together with our previous observation that BH4 leads to generation of oxidative stress and selective dopaminergic neurodegeneration both in vitro and in vivo via inducing apoptosis, the mitochondrial involvement in BH4 toxicity further suggests possible relevance of this endogenous molecule to pathogenesis of PD.

End quote

[[li...]]

dm123,

 

I know you read about clonazepam. So did I, quite some time ago ... Did you encountered anything about clonazepam lowering GABA in some sort of fashion ? I recall statements about the GAD enzyme, I'm just not sure if that goes everywhere in the brain in the same direction ...

Another issue is the thalamus and the thalamic reticular nucleus. I think it's in some way part of the 'motor cortex'. Anything clear about the effect on GABA ?

 

I'm just wondering if -when I just get the clonazepam out of the body- certain issues that could be due to 'low GABA' like HPA axis hyperreactivity (which started after the lorazepam, just like someone else here had issues after going from lorazepam to clonazepam) would be gone. Whithout relying on Librium or diazepam 'boosting' GABA.

 

[[Re...]]

dm123,

 

I know you read about clonazepam. So did I, quite some time ago ... Did you encountered anything about clonazepam lowering GABA in some sort of fashion ? I recall statements about the GAD enzyme, I'm just not sure if that goes everywhere in the brain in the same direction ...

Another issue is the thalamus and the thalamic reticular nucleus. I think it's in some way part of the 'motor cortex'. Anything clear about the effect on GABA ?

 

I'm just wondering if -when I just get the clonazepam out of the body- certain issues that could be due to 'low GABA' like HPA axis hyperreactivity (which started after the lorazepam, just like someone else here had issues after going from lorazepam to clonazepam) would be gone. Whithout relying on Librium or diazepam 'boosting' GABA.

 

Interesting, Liberty.  I'm guessing the lorazepam did a number on my HPA axis too.  Therafter I went to diazepam for my taper.  But I haven't touched a benzo in 16 months (although I'm on effexor and gabapentin) and suffering mightily these days.  As I mentioned earlier, exercise is impossible and leads to intense symptom increase.  Everytime I had physical stress culminating in a significant increase in withdrawal symptoms I initially correlated these to my gabapentin taper or lingering ativan withdrawal.  However, when the symptoms subsided and I resumed my taper, I discovered I could not taper at the same pace as before.  Now, I wonder if in fact my gabba receptors were further damaged in each withdrawal 'episode' and the gabbapentin is interrupting the ability of gabba A receptors to successfully neurogenerate (as some recent studies suggest and was explained by dm123 in part of the model)? 

 

If so, I must get off the gabapentin or I will be stuck in a progressively worsening situation which is what I feel is happening.  I have only reduced my gabapentin by 6 miligrams since March  (150 to 144 per day)  and it has been very difficult. 

 

Much to think about and I'm not so good with thinking these days.

 

Finally, does gabbapentin down regulate gabba b receptors at these doses?  It doesn't matter if it is a 'low' dose or not, it's what the dose does to me (us) that matters.

 

-RST

[[cs...]]

dm123,

 

I know you read about clonazepam. So did I, quite some time ago ... Did you encountered anything about clonazepam lowering GABA in some sort of fashion ? I recall statements about the GAD enzyme, I'm just not sure if that goes everywhere in the brain in the same direction ...

Another issue is the thalamus and the thalamic reticular nucleus. I think it's in some way part of the 'motor cortex'. Anything clear about the effect on GABA ?

 

I'm just wondering if -when I just get the clonazepam out of the body- certain issues that could be due to 'low GABA' like HPA axis hyperreactivity (which started after the lorazepam, just like someone else here had issues after going from lorazepam to clonazepam) would be gone. Whithout relying on Librium or diazepam 'boosting' GABA.

 

Hi liberty,

 

I’m not sure about the endogenous GABA levels and clonazepam.  There’s lots of research pointing to changes in dopamine, ACh and serotonin levels (as well as other neurotransmitters and neuromodulators), but I haven’t really researched endogenous GABA levels and how they are affected by Benzodiazaphines and/or clonazepam

 

You can start the research in these areas

Google:

clonazepam and gaba autoreceptors

Here’s one that i see from 1988

https://www.ncbi.nlm.nih.gov/pubmed/2853310

Quote

Small concentrations (less than 1 microM) of the benzodiazepine full agonist clonazepam did not significantly alter K+-evoked release of [3H]GABA but shifted the concentration-effect curve for muscimol to the left.

....

The results suggest that the GABA autoreceptor in cortical slices from the rat is modulated by a benzodiazepine receptor.

End quote

 

Muscimol is a potent direct agonist of the GABAaR, unlike Benzodiazaphines which are PAMs.

 

 

 

Wiki has a good description on what an autoreceptor is.  It would modulate presynaptic release of neurotransmitters, and if an autoreceptor on the GABA axon terminal it would modulate the release of GABA.  Since the GABA autoreceptor is affected by the Benzodiazaphine receptor (in cortical slices), it would affect presynaptic GABA release.  However, other literature states that Benzodiazaphines and clonazepam do not.  So perhaps its by brain region??

 

Also other google topics

“Retrograde signaling and benzodiazaphines”

“NO retrograde signaling and clonazepam “

Etc.   

 

I haven’t looked much in this area, but if Benzodiazaphines affect retrograde signaling from the post synapse to the presynaptic terminal, then they would affect neurotransmitter release.  Next would be to research this topic in the context of the GABA neurotransmitter release and how retrograde signaling might be affected by Benzodiazaphines

 

There’s probably tons of other research......

 

Regarding thalamus , its part of a greater cortical motor circuit but to my knowledge is not included in the “motor cortex” regions of the brain.

 

Lots to think about......

 

 

[[cs...]]

hi RST,

 

I will let liberty address your other questions regarding lorazepam, etc.

 

Regarding the GABAbR, i know it will be difficult to find, but i wrote a lot about it on this thread..... there was one paper on Neurogenesis that might have the info and i think i put the info in the Summary paper on page 40.    It has the links as well. The GABAbR is much more resilient than the GABAaR.  (It recovers much more “easily” than GABAaRs and is less apt to the same type of profound conformational subunit changes that the GABAaR undergoes when assaulted by these various drugs).

 

If you cannot find the section and links let me know and i will get them for you by searching through that paper.  I hope this reassures you a bit.  This is why , even though GABAb agonist drug withdrawal can be bad, it is usually not as protracted as GABAa agonist and PAM withdrawal.

 

i understand what you are saying about the taper.  We all have obligations in life, and its very very difficult to wait for a slow moving train to arrive, so to speak. Obligations build up over time make it very difficult and trying for our patience. But I’ve read enough stories to know that you have to listen to your body. Pushing through pain works for some but not for all.......

 

Best,

Dm123

[[cs...]]

Lapis just posted this on the dizziness support thread.  I’m posting it here as it is on exercise induced Neuroplasticity, one of my favorite areas of research.  This one pertains to plasticity in the vestibular cortical regions of the brain.

 

https://www.sciencedirect.com/science/article/pii/S105381191830572X?via%3Dihub

[[li...]]

dm123,

 

Thank you, some good things to look into.

 

'he inhibitory and excitatory systems when in balance enable the body to handle an enormous amount of stress.  Once these pillars are destabilized, we become vulnerable to all sorts of stressors that would we may not have even noticed prior to getting sick.  The exercise tolerance is a good example of this.  I had a very similar experience, and its very very difficult to reestablish resiliency, when one cannot even exercise.    Resiliency is built up via challenge, and when we cannot challenge the systems, it is a double edged sword because not challenging the system in and of itself, weakens resiliency further.

 

...And challenging the system by overexerting throws one into further disarray because the systems cannot recover from the challenge stressor the way a normal person can.  Exercise is a positive stressor, but in this scenario, it can become very negative if resiliency is severely compromised.

 

The compromised HPA axis is first and foremost the center of the stress system.  If that is dysregulated, resiliency will be poor. ' Well, not that good for me ... basically, my body is in a constant state of stress. Both CNS and other health problems. Building up resiliency ? ... I guess there is not a 'trick' ... ? A rapid taper after which I would be fine is a mirage. Lorazepam did a lot of harm.

 

'Regarding thalamus , its part of a greater cortical motor circuit but to my knowledge is not included in the “motor cortex” regions of the brain.'

I guess that technically it's not a part of the motor cortex but it's connected ...

[[li...]]

Possibly I am repeating myself.

About lorazepam (and my own experience by switching from clonazepam to lorazepam and back):

 

One of the properties of clonazepam is its antimyoclonic action, that appears to be mediated by serotonin rather than gaba. https://www.sciencedirect.com/science/article/pii/0014299979900499 A serotonin antagonist blocks that effect.

 

Ever since I went back to clonazepam it hasn't been the same. Taking a dose of a certain  relatively mild opiate compensates for that, up to a point. It enhances muscle relaxation, stimulates melatonin secretion (as clonazepam used to do in the past), it can stimulate appetite (suppressed all the time), temporarily lower HPA axis activity (with a likely rebound).

 

By what mechanism lorazepam causes exercise intolerance (objective, subjectively I don't feel it), HPA axis hyperreactivity is not clear. But lower serotonin could cause less melatonin, HPA axis hyperreactivity (mechanism analogous to SSRI withdrawal ?). Caused by GABA downregulation ? I feel like I'm rambling, but it's not good.

 

I'm such an idiot for ever having accepted lorazepam. And no, I'm by no means 'fine'.

[[cs...]]

Possibly I am repeating myself.

About lorazepam (and my own experience by switching from clonazepam to lorazepam and back):

 

One of the properties of clonazepam is its antimyoclonic action, that appears to be mediated by serotonin rather than gaba. https://www.sciencedirect.com/science/article/pii/0014299979900499 A serotonin antagonist blocks that effect.

 

Ever since I went back to clonazepam it hasn't been the same. Taking a dose of a certain  relatively mild opiate compensates for that, up to a point. It enhances muscle relaxation, stimulates melatonin secretion (as clonazepam used to do in the past), it can stimulate appetite (suppressed all the time), temporarily lower HPA axis activity (with a likely rebound).

 

By what mechanism lorazepam causes exercise intolerance (objective, subjectively I don't feel it), HPA axis hyperreactivity is not clear. But lower serotonin could cause less melatonin, HPA axis hyperreactivity (mechanism analogous to SSRI withdrawal ?). Caused by GABA downregulation ? I feel like I'm rambling, but it's not good.

 

I'm such an idiot for ever having accepted lorazepam. And no, I'm by no means 'fine'.

 

Hi liberty,

 

I wish I had more answers to those questions.  The HPA axis does get out of kilter during benzdiazaphine chronic usage.  Opiates do as well.

[[li...]]

dm123,

 

'Small concentrations (less than 1 microM) of the benzodiazepine full agonist clonazepam did not significantly alter K+-evoked release of [3H]GABA but shifted the concentration-effect curve for muscimol to the left.' (your post)

 

That pretty much means that muscimol becomes less effective, right ? Isn't that a lot like the statement that GABA becomes less effective after downregulation of the 'benzodiazepine receptor' ?

I'm not quite sure if this relates to the one time effects of a dose. Is that it, downregulation of the 'benzodiazepine receptor' ?

 

[[li...]]

And I thought of something else. In 2013 I was prescribed solifenacin, basically off label.  Antimuscarinic drug.

It did have certain effects, just not those it had in the past two years.

 

Last year when I took one tiny dose I experienced major muscle rigidity. I had very little muscle mass, but I noticed it nonetheless. Hormonal effects too, likely a dampening effects on the HPA axis (temporarily). Also, up to a point it would block some of diazepam´s or an opiate´s effects

 

These days I'm much worse off, and some infrequent use of diazepam can help ... but when that wears off, I can get that muscle rigidity between doses or at other times. Recently even a burning feeling ... most likely that affects the CNS, not sure how. (´action potential´ ?) The theory is complicated.

 

I get that GABAergic withdrawal can cause excessive acetylcholine release. Perhaps a bit the same as blocking those muscarinic receptors. Increasing the availability of acetylcholine.

 

All sorts of issues ... in theory dopamine (dopamine agonists, levodopa, dopamine reuptake inhibitors (amantadine!)) could help. But there is a lot of crosstalk between these neurotransmitters, not even counting others.

 

I recall that lorazepam had profound muscle relaxing effects at the full 4 mg dose, likely even causing minor ataxia. So some GABA receptors have been 'clipped', shifting the balance.  I just wonder if that would be over if I were off clonazepam. It has been a long time (3 years) since my lorazepam 'taper'. Not quite sure about the point of this post ...

 

I need a new body.

[[cs...]]

dm123,

 

'Small concentrations (less than 1 microM) of the benzodiazepine full agonist clonazepam did not significantly alter K+-evoked release of [3H]GABA but shifted the concentration-effect curve for muscimol to the left.' (your post)

 

That pretty much means that muscimol becomes less effective, right ? Isn't that a lot like the statement that GABA becomes less effective after downregulation of the 'benzodiazepine receptor' ?

I'm not quite sure if this relates to the one time effects of a dose. Is that it, downregulation of the 'benzodiazepine receptor' ?

 

Wouldn’t  a shift to the left make the muscimol more effective for each given concentration level? 

 

They indicated it was through the autoreceptor.

[[Re...]]

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

 

[[li...]]

dm123,

 

A question about Librium. I sort of know your own point of view, and the view of your doc ... And while I know your doc´s view, well all have our own perspective ... what would work for one person dependent and even sensitized on a high dose of clonazepam doesn´t mean it would work for someone else ...

 

My idea is that clonazepam has a strong effect on both the brain stem, spinal cord and other areas of the CNS.

 

https://www.benzo.org.uk/librium.htm

 

'Benzodiazepines affect the GABA receptors, but unlike barbiturates, which take effect primarily at the level of the brain stem, they affect the subcortical nuclei. This implies that they have a tranquillising function with only minor influence on the cognitive functions and level of consciousness. They do not work primarily as sedatives, but they reduce the strength of incoming sensory stimuli: the effect is that the world around you seems to become more tranquil. The area of prescription is thus primarily as an anxiolytic.'

 

https://link.springer.com/chapter/10.1007/978-1-4899-6746-6_97

 

'Librium is from the class of benzodiazepine antianxiety drugs. It has sedative, appetite-stimulating, and weak analgesic action. The precise mechanism is not known. In common with barbiturates, chlordiazepoxide blocks EEG arousal from stimulation of the brainstem reticular formation.'

 

There are some other sources. I know there are few benzodiazepine receptors in the brain stem (sources, example : https://books.google.nl/books?id=bOo8AAAAIAAJ&pg=PA21&lpg=PA21&dq=benzodiazepine+receptors+brain+stem&source=bl&ots=zT3Zry96JY&sig=adUv2Lfpf2fAUOPn3kADl8sgk3Y&hl=nl&sa=X&ved=2ahUKEwjEo92kyszcAhXG2aQKHYrkAw4Q6AEwCHoECAQQAQ#v=onepage&q=benzodiazepine%20receptors%20brain%20stem&f=false ) which would mean that only high potency benzodiazepines would have any significant effect there. Do you believe Librium does have any significant effect there, and if so could you say why ? It doesn´t seem ´logical´.

[[cs...]]

dm123,

 

A question about Librium. I sort of know your own point of view, and the view of your doc ... And while I know your doc´s view, well all have our own perspective ... what would work for one person dependent and even sensitized on a high dose of clonazepam doesn´t mean it would work for someone else ...

 

My idea is that clonazepam has a strong effect on both the brain stem, spinal cord and other areas of the CNS.

 

https://www.benzo.org.uk/librium.htm

 

'Benzodiazepines affect the GABA receptors, but unlike barbiturates, which take effect primarily at the level of the brain stem, they affect the subcortical nuclei. This implies that they have a tranquillising function with only minor influence on the cognitive functions and level of consciousness. They do not work primarily as sedatives, but they reduce the strength of incoming sensory stimuli: the effect is that the world around you seems to become more tranquil. The area of prescription is thus primarily as an anxiolytic.'

 

https://link.springer.com/chapter/10.1007/978-1-4899-6746-6_97

 

'Librium is from the class of benzodiazepine antianxiety drugs. It has sedative, appetite-stimulating, and weak analgesic action. The precise mechanism is not known. In common with barbiturates, chlordiazepoxide blocks EEG arousal from stimulation of the brainstem reticular formation.'

 

There are some other sources. I know there are few benzodiazepine receptors in the brain stem (sources, example : https://books.google.nl/books?id=bOo8AAAAIAAJ&pg=PA21&lpg=PA21&dq=benzodiazepine+receptors+brain+stem&source=bl&ots=zT3Zry96JY&sig=adUv2Lfpf2fAUOPn3kADl8sgk3Y&hl=nl&sa=X&ved=2ahUKEwjEo92kyszcAhXG2aQKHYrkAw4Q6AEwCHoECAQQAQ#v=onepage&q=benzodiazepine%20receptors%20brain%20stem&f=false ) which would mean that only high potency benzodiazepines would have any significant effect there. Do you believe Librium does have any significant effect there, and if so could you say why ? It doesn´t seem ´logical´.

 

 

Liberty,

 

I think all benzdiazaphines, in general, act on that part of the brainstem.  Nothing specific about Librium, but I’m no expert on Librium and pharmacology and could be wrong on that.

 

https://books.google.com/books?id=X3cCZQCrrjcC&pg=PA283&lpg=PA283&dq=chlordiazepoxide+blocks+EEG+arousal+from+stimulation+of+the+brainstem+reticular+formation.&source=bl&ots=SyOs1FMxAJ&sig=nRKZhfyB-_ObMv0gMSQxrA1YQ04&hl=en&sa=X&ved=2ahUKEwjmyYGSi83cAhWxKH0KHZkyBwYQ6AEwCXoECAMQAQ#v=onepage&q=chlordiazepoxide%20blocks%20EEG%20arousal%20from%20stimulation%20of%20the%20brainstem%20reticular%20formation.&f=false

 

 

IntendtobeOff (and many others) is tapering direct from clonazepam with a split dose AM PM schedule, liquid microtaper.  That provides the steady state that one needs.(as an alternative to Librium, which is different from clonazepam )

 

One would initiallly equally titrate up on AM and PM doses until out of tolerance (1-2 months to titrate up and stabilize), and then start the slow microtaper on both AM and PM doses by similar amount every 2-4 weeks, or longer if required.

 

 

Please note that I am not a medical doctor.

 

Best,

Dm123