Has it ever been scientifically proven that benzos cause downregulation?

Has it ever been scientifically proven that benzos cause downregulation of the gaba receptors?

Good question.  Downregulation is something that Ashton discussed in her manual.  I don't think it's been proven.  I'm not sure if it even can be proven. 

It might be that its one thing proving that it happens to varying degrees, but another thing proving that its what is causing such an array of problems...??

I suspect that the further one gets away from the “standard Ashton experience”, in a problematic sense, the less the singular Gabba receptor theory applies..??

I would “guess” the “average” Dr probably works on the “receptors up-regulate in a few weeks” theory..!!

 

But no, I cant say I personally have seen anything that convinces me of much of anything... Working this stuff out is like attempting to count stars, -for me at least...

Thats not to say the journey of discovery isnt both distracting, providing ongoing hope, and productive from a more general health awareness perspective...

 

...one day hopefully.. -perhaps even the next post..!!??

There is no such thing as "scientifically proven". Science isn't about proofs. Proofs exist only in logic and disciplines that use logic, such as mathematics, philosophy, etc. In science there are only hypotheses and theories.

 

Downregulation has been observed in rats treated with high doses of benzos. Mechanism of damage to GABAA receptors in humans is thought to be mostly from uncoupling of receptor sites, not downregulation, though some downregulation probably does occur as well.

There is no such thing as "scientifically proven". Science isn't about proofs. Proofs exist only in logic and disciplines that use logic, such as mathematics, philosophy, etc. In science there are only hypotheses and theories.

 

Downregulation has been observed in rats treated with high doses of benzos. Mechanism of damage to GABAA receptors in humans is thought to be mostly from uncoupling of receptor sites, not downregulation, though some downregulation probably does occur as well.

 

Citations?

There is no such thing as "scientifically proven". Science isn't about proofs. Proofs exist only in logic and disciplines that use logic, such as mathematics, philosophy, etc. In science there are only hypotheses and theories.

 

Downregulation has been observed in rats treated with high doses of benzos. Mechanism of damage to GABAA receptors in humans is thought to be mostly from uncoupling of receptor sites, not downregulation, though some downregulation probably does occur as well.

 

True, there are no proofs in science. Nevertheless, the scientific method allows us to have an ever better understanding of the world we live in. There is some evidence supporting down-regulation of GABA receptors by benzos. Here is a review:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

 

"This way, the GABAA receptor may become less responsive to the continuing acute effects of benzodiazepines, either as a result of adaptations in the GABAA receptor itself, intracellular mechanisms, or changes in other neurotransmitter systems, such as the glutamatergic system."

 

In addition, it is well known that many agonists down-regulate their receptors or down-stream intracellular signaling pathways.

 

Nonetheless, it is irrelevant what the mechanism of benzo tolerance is. What is clear is that the only thing we can do at this point is to taper the benzo and do this slowly, preferably based on symptoms. 

There is no such thing as "scientifically proven". Science isn't about proofs. Proofs exist only in logic and disciplines that use logic, such as mathematics, philosophy, etc. In science there are only hypotheses and theories.

 

Downregulation has been observed in rats treated with high doses of benzos. Mechanism of damage to GABAA receptors in humans is thought to be mostly from uncoupling of receptor sites, not downregulation, though some downregulation probably does occur as well.

 

True, there are no proofs in science. Nevertheless, the scientific method allows us to have an ever better understanding of the world we live in. There is some evidence supporting down-regulation of GABA receptors by benzos. Here is a review:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

 

"This way, the GABAA receptor may become less responsive to the continuing acute effects of benzodiazepines, either as a result of adaptations in the GABAA receptor itself, intracellular mechanisms, or changes in other neurotransmitter systems, such as the glutamatergic system."

 

In addition, it is well known that many agonists down-regulate their receptors or down-stream intracellular signaling pathways.

 

Nonetheless, it is irrelevant what the mechanism of benzo tolerance is. What is clear is that the only thing we can do at this point is to taper the benzo and do this slowly, preferably based on symptoms.

 

The bolded text is your opinion. I have taken benzos my entire adult life, decades. IMO, it is clear that everyone should decide for themselves what is best for them, based upon symptoms. best wishes

Thank you for the citation, Maugham1!

There is no such thing as "scientifically proven". Science isn't about proofs. Proofs exist only in logic and disciplines that use logic, such as mathematics, philosophy, etc. In science there are only hypotheses and theories.

 

Downregulation has been observed in rats treated with high doses of benzos. Mechanism of damage to GABAA receptors in humans is thought to be mostly from uncoupling of receptor sites, not downregulation, though some downregulation probably does occur as well.

 

True, there are no proofs in science. Nevertheless, the scientific method allows us to have an ever better understanding of the world we live in. There is some evidence supporting down-regulation of GABA receptors by benzos. Here is a review:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

 

"This way, the GABAA receptor may become less responsive to the continuing acute effects of benzodiazepines, either as a result of adaptations in the GABAA receptor itself, intracellular mechanisms, or changes in other neurotransmitter systems, such as the glutamatergic system."

 

In addition, it is well known that many agonists down-regulate their receptors or down-stream intracellular signaling pathways.

 

Nonetheless, it is irrelevant what the mechanism of benzo tolerance is. What is clear is that the only thing we can do at this point is to taper the benzo and do this slowly, preferably based on symptoms.

 

The bolded text is your opinion. I have taken benzos my entire adult life, decades. IMO, it is clear that everyone should decide for themselves what is best for them, based upon symptoms. best wishes

 

You are absolutely right that everyone should decide what's best for them. This board is about the following:

 

Members of the BenzoBuddies community are encouraged to exchange ideas, information and support during the process of withdrawal and recovery.

I never experienced any probs on the for 20 years.

 

Peru’s ally I think it is more damage from glutamate when stopped or of ppl get tolerence that causes the problems.

There is no such thing as "scientifically proven". Science isn't about proofs. Proofs exist only in logic and disciplines that use logic, such as mathematics, philosophy, etc. In science there are only hypotheses and theories.

 

Downregulation has been observed in rats treated with high doses of benzos. Mechanism of damage to GABAA receptors in humans is thought to be mostly from uncoupling of receptor sites, not downregulation, though some downregulation probably does occur as well.

Do you know of any way to upregulate benzodiazepine receptors besides time? Like while we are tapering?

 

True, there are no proofs in science. Nevertheless, the scientific method allows us to have an ever better understanding of the world we live in. There is some evidence supporting down-regulation of GABA receptors by benzos. Here is a review:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

 

"This way, the GABAA receptor may become less responsive to the continuing acute effects of benzodiazepines, either as a result of adaptations in the GABAA receptor itself, intracellular mechanisms, or changes in other neurotransmitter systems, such as the glutamatergic system."

 

In addition, it is well known that many agonists down-regulate their receptors or down-stream intracellular signaling pathways.

 

Nonetheless, it is irrelevant what the mechanism of benzo tolerance is. What is clear is that the only thing we can do at this point is to taper the benzo and do this slowly, preferably based on symptoms.

Has it ever been scientifically proven that benzos cause downregulation of the gaba receptors?

it doesn't really matter if it's down regulation of GABA receptors or down regulation of benzodiazepine receptors or up regulation of glutamate receptors. In the end benzos behave like narcotics eventually you get used to them and you need a higher dose and then a higher dose and then a higher dose and so on. The other option is to stay on the same dose which causes tolerance and millions of people these days remain intolerance and live happy lives including 800,000 veterans who came back from Iraq and Afghanistan and are on some kind of benzo for life without problems,,,,,, until they quit and Commit a mass shooting / suicide event which I believe comes mainly from quitting these drugs and underestimating their power, few people talk about it, few people in the news media blame benzos as the primary factor in these horrifying events of violence but if you dig deep enough you'll find these people were on benzos 90% of the time. It's a shame the news media and the police department does not put 2 and 2 together.

Many people experience health problems and blame it on the benzos and then go on a taper. Sometimes the benzos do create health problems like depression which is absolutely a common side effect of long-term benzo use. Benzo suppress serotonin release, that's a known fact of science. Whatever the case long term use of anything is going to create a situation where you become immune to the drug, the real question is what  to do about?

Has it ever been scientifically proven that benzos cause downregulation of the gaba receptors?

it doesn't really matter if it's down regulation of GABA receptors or down regulation of benzodiazepine receptors or up regulation of glutamate receptors. In the end benzos behave like narcotics eventually you get used to them and you need a higher dose and then a higher dose and then a higher dose and so on. The other option is to stay on the same dose which causes tolerance and millions of people these days remain intolerance and live happy lives including 800,000 veterans who came back from Iraq and Afghanistan and are on some kind of benzo for life without problems,,,,,, until they quit and Commit a mass shooting / suicide event which I believe comes mainly from quitting these drugs and underestimating their power, few people talk about it, few people in the news media blame benzos as the primary factor in these horrifying events of violence but if you dig deep enough you'll find these people were on benzos 90% of the time. It's a shame the news media and the police department does not put 2 and 2 together.

Many people experience health problems and blame it on the benzos and then go on a taper. Sometimes the benzos do create health problems like depression which is absolutely a common side effect of long-term benzo use. Benzo suppress serotonin release, that's a known fact of science. Whatever the case long term use of anything is going to create a situation where you become immune to the drug, the real question is what  to do about?

 

Thank you for pointing out the option of staying on the same dose which, as you correctly stated, millions of people do. It is an option that imo should be considered as carefully as the options of up-dosing or tapering.

Hi All,

There's a recent study that may be of interest to people here:

 

"Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology"

 

https://sci-hub.tw/https://www.researchgate.net/publication/341688809_Understanding_the_effects_of_chronic_benzodiazepine_use_in_depression_a_focus_on_neuropharmacology

 

It includes a section on the "Neurobiological effects of chronic benzodiazepines". The whole paper is well worth reading, and there are many references, should you want more info. Figure 1 provides "a summary of acute and chronic effects of benzodiazepines on amino acids, monoamines, HPA-axis function, and neurotrophins."

 

 

Dear All,

 

OMG.  Of COURSE things can be scientifically proven by experimentation and measurement techniques as well as math.  Everyone who has a degree or any experience in any science or engineering knows this to be true.

Oxford: "Proven - demonstrated by evidence or argument to be true or exisiting"

 

For example, gravity.  We can calculate gravitational force between two objects very accurately using a mathematical formula, and it contains a constant (G) that was determined entirely by experimentation.

 

On topic: We do not know everything that benzos do, that is for sure. But we sure as hell know that they decrease the number of and anion (-ion) current thru GABA receptors and increase the number of and cation (+ion) current thru glutamate receptors.  There are dozens of papers where they addict rats to benzos, killed them, and measured these things precisely in their poor neurologically ruined corpses.  When you do something over and over again, measure it accurately, and get the same result, that is proof.

 

What we do not know, is why some people reach tolerance quickly, and some seem to never reach tolerance which simply means the rate of change in GABA and glutamate receptors is very individual.  This is why some for some people staying ion the same dose of benzo in an option, while for others it is not.

 

I am not myself buddies.  I have been real sick for several months.  I am not bringing you my A++ game, which is why I have not posted much recently.  I do recall much of what I learned before I took a downward turn.  I learned that things can be proven when I was 5 years old, so you can take that one to the bank.  I learned that benzos decrease the number of and anion current thru GABA receptors and increase the number of and cation current thru glutamate receptors 4 years ago, so you can take that one to the bank too.

 

Ramcon1

Dear All,

 

OMG.  Of COURSE things can be scientifically proven by experimentation and measurement techniques as well as math.  Everyone who has a degree or any experience in any science or engineering knows this to be true.

Oxford: "Proven - demonstrated by evidence or argument to be true or exisiting"

 

For example, gravity.  We can calculate gravitational force between two objects very accurately using a mathematical formula, and it contains a constant (G) that was determined entirely by experimentation.

 

On topic: We do not know everything that benzos do, that is for sure. But we sure as hell know that they decrease the number of and anion (-ion) current thru GABA receptors and increase the number of and cation (+ion) current thru glutamate receptors.  There are dozens of papers where they addict rats to benzos, killed them, and measured these things precisely in their poor neurologically ruined corpses.  When you do something over and over again, measure it accurately, and get the same result, that is proof.

 

What we do not know, is why some people reach tolerance quickly, and some seem to never reach tolerance which simply means the rate of change in GABA and glutamate receptors is very individual.  This is why some for some people staying ion the same dose of benzo in an option, while for others it is not.

 

I am not myself buddies.  I have been real sick for several months.  I am not bringing you my A++ game, which is why I have not posted much recently.  I do recall much of what I learned before I took a downward turn.  I learned that things can be proven when I was 5 years old, so you can take that one to the bank.  I learned that benzos decrease the number of and anion current thru GABA receptors and increase the number of and cation current thru glutamate receptors 4 years ago, so you can take that one to the bank too.

 

Ramcon1

 

GABA receptor signaling is likely to be compromised in individuals who develop tolerance. However, this hasn't been demonstrated in humans. More importantly, and this is my view, there probably are various neural pathways that are deregulated. I believe that is the reason why it takes so long to recover from benzos. Also, that is the reason why no pharmacological treatment has proven to be effective. It is unlikely that any type of "silver bullet" will be discovered to cure this condition. People who think that this is all about GABA and glutamate don't understand how simplistic that view is even though all evidence points to the fact that no matter how many approaches have tried to manipulate GABA or glutamate none of them worked.

 

 

Please read what I posted.  I specifically said it is our pain is NOT all glutamate and GABA. "We do not know everything that benzos do, that is for sure." I simply addressed the direct question asked by this thread; benzos effects on GABA and glutamate are proven, which they have been.

 

It is not easy to piss me off, but man you do your best.  Why don't you just stick to the other areas of the board that talk about tapering and the 7 years of hell that follow.  This is place where we discuss possibilities of reducing those 7 years.

 

Ramcon1

This is a good citation.  Molecular and genomic changes (subunit expression, etc) in the framework of adaptive plasticity(2020)

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352578/

 

Chapter 2 are basics of transcription and translation

Chapter 3 intro on adaptive plasticity

Chapter 4 and 4.1 are on benzos.

This is a good citation.  Molecular and genomic changes (subunit expression, etc) in the framework of adaptive plasticity(2020)

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352578/

 

Chapter 2 are basics of transcription and translation

Chapter 3 intro on adaptive plasticity

Chapter 4 and 4.1 are on benzos.

 

What's it mean in layman's terms, CS?

This is a good citation.  Molecular and genomic changes (subunit expression, etc) in the framework of adaptive plasticity(2020)

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352578/

 

Chapter 2 are basics of transcription and translation

Chapter 3 intro on adaptive plasticity

Chapter 4 and 4.1 are on benzos.

 

What's it mean in layman's terms, CS?

 

Hi tooktolong

 

Please see below, directly from the citation

The references are in [brackets] and can be found at the end of the citation

The author’s contact info is in the citation as well

 

1. There is altered GABAAR subunit gene expression. This occurs at the genomic (molecular) level (at transcription and translation) [references: pages 22-24] [figures 1-2 as well]

This is another recent citation

https://www.sciencedirect.com/science/article/abs/pii/S0304394020300719

 

2. There is uncoupling of the BZ site and the GABA binding sites making these receptors less responsive(less sensitive) to endogenous GABA even if the benzo binds to BZ site with the same affinity and BZ binding site density remains the same    “….allosteric enhancement is reduced without changes in binding affinity [see references: 113,131,132,133].”

There are many additional references on this topic, starting with this one:

 

See also:D. W. Gallager, J. M. Lakoski, and S. F. S. L. Gonsalves Rauch, “Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity,” Nature, vol. 308, no. 5954, pp. 74–77, 1984.

 

3. There is increased degradation of the GABAaRs from the neuronal cell surface membrane, most notably alpha2 containing GABAaRs with short term exposure. (Population downregulation)**

 

**See Table 1: ↑ GABAAR internalization [113][endocytosis]

↓ GABAAR α2 surface expression with 24 h exposure [113]

 

** quoted: “BZ treatment did not alter the insertion and endocytosis rates of α2-containing GABAARs, but did promote degradation, which was reversed by blocking lysosomal degradation [see reference 113]. This loss in total GABAAR levels may begin the series of adaptations that contribute to tolerance, as degradation occurs over the first 24 h of treatment.”

 

Notes:

1. From this citation: “Differences in agonist affinity, gating and pharmacological properties have been repeatedly shown by altering subunits of recombinant GABAARs [see references: 13,14,15,16].”

 

2. See also:

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

“There are numerous subunit isoforms for the GABAA receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.[see reference: 28]”

 

 

 

This is a good citation.  Molecular and genomic changes (subunit expression, etc) in the framework of adaptive plasticity(2020)

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352578/

 

Chapter 2 are basics of transcription and translation

Chapter 3 intro on adaptive plasticity

Chapter 4 and 4.1 are on benzos.

 

What's it mean in layman's terms, CS?

 

Hi tooktolong

 

Please see below, directly from the citation

The references are in [brackets] and can be found at the end of the citation

The author’s contact info is in the citation as well

 

1. There is altered GABAAR subunit gene expression. This occurs at the genomic (molecular) level (at transcription and translation) [references: pages 22-24] [figures 1-2 as well]

This is another recent citation

https://www.sciencedirect.com/science/article/abs/pii/S0304394020300719

 

2. There is uncoupling of the BZ site and the GABA binding sites making these receptors less responsive(less sensitive) to endogenous GABA even if the benzo binds to BZ site with the same affinity and BZ binding site density remains the same    “….allosteric enhancement is reduced without changes in binding affinity [see references: 113,131,132,133].”

There are many additional references on this topic, starting with this one:

 

See also:D. W. Gallager, J. M. Lakoski, and S. F. S. L. Gonsalves Rauch, “Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity,” Nature, vol. 308, no. 5954, pp. 74–77, 1984.

 

3. There is increased degradation of the GABAaRs from the neuronal cell surface membrane, most notably alpha2 containing GABAaRs with short term exposure. (Population downregulation)**

 

**See Table 1: ↑ GABAAR internalization [113][endocytosis]

↓ GABAAR α2 surface expression with 24 h exposure [113]

 

** quoted: “BZ treatment did not alter the insertion and endocytosis rates of α2-containing GABAARs, but did promote degradation, which was reversed by blocking lysosomal degradation [see reference 113]. This loss in total GABAAR levels may begin the series of adaptations that contribute to tolerance, as degradation occurs over the first 24 h of treatment.”

 

Notes:

1. From this citation: “Differences in agonist affinity, gating and pharmacological properties have been repeatedly shown by altering subunits of recombinant GABAARs [see references: 13,14,15,16].”

 

2. See also:

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

“There are numerous subunit isoforms for the GABAA receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.[see reference: 28]”

 

Thank you for this

 

It is not easy to piss me off, but man you do your best.  Why don't you just stick to the other areas of the board that talk about tapering and the 7 years of hell that follow.  This is place where we discuss possibilities of reducing those 7 years.

 

Ramcon1

 

Now you're pissing me off. You don't get to tell people where they can and can't post.

 

 

Does anyone have any information on how quickly new receptors can grow under ideal conditions?

If receptors are down regulated or uncoupled do whole new synapses have to be replaced in order for receptor to be replaced?

 

Would increasing ATP increase this process?

 

Can anyone link any papers on any of this?

 

I have been researching Frequency Specific Microcurrent. It is very interesting and can treat everything from autism, to muscle spasticity, fibromyalgia, burns, strokes, concussion, arthritis etc etc.

 

The mechanism might be via increased ATP production among other things.

 

What I can’t work out is of it would work if the receptors simply aren’t there.

 

When receptors uncouple what does that actually mean?

 

I hope someone can answer some of this or help as need to discuss it with an expert who is helping me with this.

 

Another article on ISRIB (Integrated Stress Response InhiBitor)

 

https://wjla.com/news/nation-world/researchers-discover-drug-that-reverses-mental-decline-aging

 

It’s licensed now by Calico, which was started by Google monies

 

 

 

 

(SBG) — Researchers studying cognitive deficits following traumatic brain injuries have discovered what they say is a revolutionary drug that could provide the cure for aging.

 

The study by the University of California San Francisco has shown promising results among mice, essentially reversing age-related declines in memory.

 

“We went on with this crazy experiment...and were able to return their cognitive function to as if they were never injured,” said Dr. Suzanna Rosi, UCSF professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science. “Since traumatic brain injury is really a form of accelerated aging, because your brain ages faster and develops those deficits, is it possible to even reverse aging?”

 

Researchers are using a drug called ISRIB (Integrated Stress Response InhiBitor). It works by rebooting a cell’s protein production after it’s been stunted by a stress response.

 

 

Susanna Rosi, PhD, associate professor.in the department of Physical Therapy & Rehabilitation Science, and Austin Chou, a graduate student, work on treating cognitive decline after traumatic brain injury, in the department of Neurological Surgery at ZSFGH.

 

“Basically, we need protein production for everything. All our cells need protein. Our brain cells need protein to form connections,” said Dr. Rosi. “What happens, is during stress—it can be initiated by viral infection, it can be initiated by injury, or aging—this protein machinery gets stopped. This stop is used as a defense mechanism. There is a halt so the cell can heal. The problem is that this process, if it's doesn't turn off, can be deleterious.”

 

Dr. Rosi’s team conducted tests on older mice, about the equivalent of a human 55 to 65 years old.

 

“We could reset the protein switch in their brain which resulted in amelioration of their memory function, to the level of young animals,” said Dr. Rosi.

 

Three weeks later, with no additional treatment, her team conducted another test on those mice to see if the results were long-lasting. They discovered the mice were able to perform and excel at harder tasks.

 

“That tells us that whatever we did three weeks before is translated to other cognitive levels,” said Dr. Rosi. “We believe that we've really found the switch on the cognitive ability that once we can move it on and off, we don't need to treat animals and hopefully eventually humans, for a long period of time. We just need to reset the response in the brain. I think it's exciting and kind of revolutionary.”

 

Researchers say this could have significant impacts for ailments across the board, including Dementia, Alzheimer’s Disease, Multiple Sclerosis, Parkinson’s Disease, and Down Syndrome.

 

“While it is fascinating that we can affect a broad range of disease and disorders, it's not surprising that they all converge on a specific path to controlling cognition,” said Dr. Rosi. “That's what's fascinating. Aging is something none of us can escape. You can escape traumatic injuries. In terms of importance, it touches each and every one of us.”

 

Dr. Rosi says other studies have shown there is usually a long treatment process for these issues, but their findings are “pretty dramatic” involving a single injection.

 

ISRIB has been licensed by Google’s Calico.

 

Dr. Rosi is hopeful the many resources of the big company will help move up the timeline for human trials. She says efficacy and toxicity trials could be done within two years. In many cases, it takes upward of ten years, but she doesn’t think that will be the case.

 

So far, the study hasn’t found any negative side effects to the drug.

 

The study is a collaboration with Dr. Peter Walter, the UCSF professor who initially discovered ISRIB could make normal mice smarter. Together they expanded the scope of the study to see if the drug could reverse cognitive deficits after trauma.