The translocator protein (TSPO) which was first identified as PBR, peripheral benzodiazepine recepto

Listened to most of the session, then stopped at the Q and A...it was a bit demoralizing how horribly protracted these patients still are after so so many years...

 

And unless I missed something, there doesn't seem to be any ongoing research into the syndrome and what the basis is for all the damage.  Why aren't PhD candidates in neuroscience working on this???  It would be such a benefit to so many, and would make an awesome contribution to science!

 

Edit: This thread was split from this thread so the discussion could continue without detracting from the OP's message.  Here is the original thread location for context. http://www.benzobuddies.org/forum/index.php?topic=261375.0

 

 

And unless I missed something, there doesn't seem to be any ongoing research into the syndrome and what the basis is for all the damage.  Why aren't PhD candidates in neuroscience working on this???  It would be such a benefit to so many, and would make an awesome contribution to science!

 

I don't know if there have been follow on symposiums but this one explored this subject.

 

 

0:32        Dr. Irving Kron, Dean Emeritus

 

1:53        Dr. Robert Raffa – Introduction to the program

 

10:28      Carrie Silvernail, RN – A patient’s story

 

31:34      Dr. Robert Raffa – Benzodiazepine neuropharmacology

 

46:28      Dr. Joseph Pergolizzi Jr. – Benzodiazepine epidemiology

 

1:02:39  Dr. Steven Wright – Benzodiazepines:  Boon or Blunder?  Emphasis on clinical practice.

 

2:07:12  Dr. Robert Raffa – Summary

 

2:28:22  Dr.Todd Vanderah – Ongoing benzodiazepine research project at the University of Arizona

 

2:48:50  Questions and answers

 

Thanks Pam, I just watched the talk given by Dr. Todd VanDerah.  I was intrigued by one slide he had re; the translocator protein (TSPO) which was first identified as PBR, peripheral benzodiazepine receptor which is expressed in many tissues outside the brain.

 

https://en.wikipedia.org/wiki/Translocator_protein

 

Everyone always talks about GABA receptors being down regulated as the main issue with our withdrawal syndrome, but couldn't the dysregulation of the expression of this protein be another root cause of all our symptoms, especially since it is highly expressed in the adrenals where our stress intolerance stems from?

 

IDK, I am not a biochemist, just a suffering ex-scientist with little knowledge of contemporary molecular biology and just looking for answers like everyone else.

 

I didn't see any other recent publications by Dr V on the topic.

This topic goes way over my head I'm afraid but I'd love to see it discussed further, you might want to start a thread on the Chewing the Fat board, hopefully others with knowledge will join in the conversation.

 

Also according to Ritvo, only 2.1% of U.S. adults misuse benzodiazepines. Ritvo did not fully explain what she meant by “misusing” a benzodiazepine

 

 

I think she means abuse, or taking for recreational and/or self-medicating purposes, though your thought about what it means is interesting. I don’t think she meant mis-prescribed.

There's also this book -- The Benzodiazepines Crisis -- which includes chapters written by many of the doctors and researchers who participated in that symposium in 2019. I requested in writing that my library procure the book, and they actually got three copies.

 

https://oxfordmedicine.com/view/10.1093/med/9780197517277.001.0001/med-9780197517277

 

Here's the description from the link above:

 

Abstract

 

When properly prescribed, benzodiazepines and related “Z” drugs, are usually safe and effective. However, some patients experience lack of efficacy, severe adverse effects, and/or protracted withdrawal symptoms. Unfortunately, there is no reliable way to predict outcome prior to treatment. Use has dramatically expanded, to the point where some experts suggest a disconnect with actual medical need. With increased and longer prescribing there has been a corresponding increase in the “down-side” of these drugs. Benzodiazepines, as all drugs, produce some degree of normal physiologic tolerance and physical dependence. But for some patients withdrawal can result in a bewildering array of symptoms, that can persist for protracted time periods, difficult to understand and live with. Although there is currently no clear mechanistic explanation, some potentials include alterations of receptor number, promoters of receptor protein synthesis or degradation, absorption, distribution, metabolism, and elimination, GABAA-receptor function or subtype-distribution, or involvement of peripheral benzodiazepine binding/receptor sites. This book attempts to bring benzodiazepine use under a more rational paradigm and reduce the incidence of side-effects and drug–drug interactions (DDI). It is the first devoted to take on this responsibility. Use, overuse/misuse, side-effects, DDI, physiology, and withdrawal are reviewed by expert clinicians and basic scientists in-depth. The book challenges the medical community to take seriously the use of this class of drug and to ameliorate prescribing behavior. The case is made for limiting initiation and duration (2–4 weeks) of use, and careful, supported discontinuation. We laud and suggest increased research into this class of drug and it’s “down-side.”

Thanks Lapis! Wow an entire book devoted to the problem, I'll try and find it.... 

 

 

There's also this book -- The Benzodiazepines Crisis -- which includes chapters written by many of the doctors and researchers who participated in that symposium in 2019. I requested in writing that my library procure the book, and they actually got three copies.

 

https://oxfordmedicine.com/view/10.1093/med/9780197517277.001.0001/med-9780197517277

 

Here's the description from the link above:

 

Abstract

 

When properly prescribed, benzodiazepines and related “Z” drugs, are usually safe and effective. However, some patients experience lack of efficacy, severe adverse effects, and/or protracted withdrawal symptoms. Unfortunately, there is no reliable way to predict outcome prior to treatment. Use has dramatically expanded, to the point where some experts suggest a disconnect with actual medical need. With increased and longer prescribing there has been a corresponding increase in the “down-side” of these drugs. Benzodiazepines, as all drugs, produce some degree of normal physiologic tolerance and physical dependence. But for some patients withdrawal can result in a bewildering array of symptoms, that can persist for protracted time periods, difficult to understand and live with. Although there is currently no clear mechanistic explanation, some potentials include alterations of receptor number, promoters of receptor protein synthesis or degradation, absorption, distribution, metabolism, and elimination, GABAA-receptor function or subtype-distribution, or involvement of peripheral benzodiazepine binding/receptor sites. This book attempts to bring benzodiazepine use under a more rational paradigm and reduce the incidence of side-effects and drug–drug interactions (DDI). It is the first devoted to take on this responsibility. Use, overuse/misuse, side-effects, DDI, physiology, and withdrawal are reviewed by expert clinicians and basic scientists in-depth. The book challenges the medical community to take seriously the use of this class of drug and to ameliorate prescribing behavior. The case is made for limiting initiation and duration (2–4 weeks) of use, and careful, supported discontinuation. We laud and suggest increased research into this class of drug and it’s “down-side.”

 

There are a few points that I believe should be made about the above post:

 

a) That post diverts readers' attention away from the OP and onto some other tangent subject matter.

 

b) If I remember correctly Lapis, when you previously brought readers' attention to this book in another post(s), I believe you indicated that you have not read it. I'm wondering if you have since read the book now that your library has purchased 3 copies of it, apparently based upon your self described written request?

 

c) I reviewed the biographical information of the author of this book, John Peppin, D.O. and find it a bit odd that his main source of income is/was in the areas of Osteopathic Medicine https://www.nhs.uk/conditions/osteopathy/  Pain Management, Palliative Care and Hospice/End of Life Care, and related speaking and publication fees for presentations and articles written on those subjects. I find it disconcerting that he would write a book with an emphasis on deprescribing benzodiazepines which are used extensively and are considered essential by Allopathic Medical Providers (Medical Doctors) who specialize in those areas. It also troubles me that John Peppin would encourage the deprescribing of medicines that are likely to be used later by Allopathic Medical Doctors in the treatment for symptoms of anxiety and pain related to the palliative care and hospice/end of life care of patients.

 

d) While reviewing John Peppin's biography, I noticed he is a clinical adjunct faculty member for Marian University (a private Roman Catholic medical school). Marian University opened its College of Osteopathic Medicine in 2010, with funding by a $48 million donation from Michael Evans, the CEO of Indianapolis-based AIT Laboratories. I then found this article about AIT Laboratories: https://oig.hhs.gov/fraud/enforcement/ait-laboratories-agreed-to-pay-15-million-for-allegedly-violating-the-civil-monetary-penalties-law-by-paying-remuneration-to-sober-homes-in-the-form-of-free-specimen-collection-personnel-and-forging-contracts-and-orders-for-laboratory-services/

 

I will leave it to others to draw their own conclusions and suggest that if this thread is to be continued, it should continue in the direction of the OP.

 

Edit: "About John F. Peppin, DO, FACP - Center for Bioethics" https://www.practicalpainmanagement.com/author/2478/peppin

Edit:"U.S. Labor Department settles lawsuit with AIT's Michael Evans

Suit accused toxicology lab founder Michael Evans of inflating $90 million sale of the Indy company to employees." https://www.indystar.com/story/money/2016/01/08/us-labor-department-settles-lawsuit-aits-michael-evans/78519138/

There's also this book -- The Benzodiazepines Crisis -- which includes chapters written by many of the doctors and researchers who participated in that symposium in 2019. I requested in writing that my library procure the book, and they actually got three copies.

 

https://oxfordmedicine.com/view/10.1093/med/9780197517277.001.0001/med-9780197517277

 

Here's the description from the link above:

 

Abstract

 

When properly prescribed, benzodiazepines and related “Z” drugs, are usually safe and effective. However, some patients experience lack of efficacy, severe adverse effects, and/or protracted withdrawal symptoms. Unfortunately, there is no reliable way to predict outcome prior to treatment. Use has dramatically expanded, to the point where some experts suggest a disconnect with actual medical need. With increased and longer prescribing there has been a corresponding increase in the “down-side” of these drugs. Benzodiazepines, as all drugs, produce some degree of normal physiologic tolerance and physical dependence. But for some patients withdrawal can result in a bewildering array of symptoms, that can persist for protracted time periods, difficult to understand and live with. Although there is currently no clear mechanistic explanation, some potentials include alterations of receptor number, promoters of receptor protein synthesis or degradation, absorption, distribution, metabolism, and elimination, GABAA-receptor function or subtype-distribution, or involvement of peripheral benzodiazepine binding/receptor sites. This book attempts to bring benzodiazepine use under a more rational paradigm and reduce the incidence of side-effects and drug–drug interactions (DDI). It is the first devoted to take on this responsibility. Use, overuse/misuse, side-effects, DDI, physiology, and withdrawal are reviewed by expert clinicians and basic scientists in-depth. The book challenges the medical community to take seriously the use of this class of drug and to ameliorate prescribing behavior. The case is made for limiting initiation and duration (2–4 weeks) of use, and careful, supported discontinuation. We laud and suggest increased research into this class of drug and it’s “down-side.”

 

Lapis2:  Thank you for reminding members about this resource.  As you know, it’s the first major publication about benzodiazepines since the Ashton Manual and was published by Oxford University Press, one of the largest and oldest university presses in the world.  I know you’ve already read it, but for members who haven’t, I’ve included the table of contents below.

 

Deanna2020: Note that Chapter 6 addresses Benzodiazepine Receptors in the Periphery.

 

The Benzodiazepines Crisis (2020) - Table of Contents

 

Chapter 1 Introduction: The Origins and Rise of Benzodiazepines

Chapter 2 The Evolution of Benzodiazepine Receptor Agonists: Developments in Pharmacology and Toxicology

Chapter 3 Benzodiazepine Therapy: The Good, the Bad, and the Ugly

Chapter 4 Use of Benzodiazepines and Z-Drugs in the Geriatric Population

Chapter 5 The Central Benzodiazepine Receptor

Chapter 6 Benzodiazepine Receptors in the Periphery

Chapter 7 Drug Withdrawal: A Modern Motivational View and Neurobiological Substrates

Chapter 8 Benzodiazepine Withdrawal: Clinical Aspects

Chapter 9 Benzodiazepines and Pain Management

Chapter 10 The Regulatory History of Benzodiazepines in the Age of the Dark Web and Other Threats

Chapter 11 Benzodiazepines Today and Tomorrow: What We Know and Don’t Know About Them

Chapter 12 In Search of Benzodiazepine Guidelines

 

Edit: member name for redaction

 

Yes, thanks so much for sharing the table of contents, Libertas, and for highlighting that chapter on "Benzodiazepines in the Periphery". I was going to point out to others who are interested in the book that the link above includes the table of contents. And if you click on each chapter, you get a description of that chapter. Just a note: The chapters are written by different authors, and each chapter includes the references (i.e. studies, scholarly papers) at the end.

 

Obviously, once my library made the book available, I read (and renewed!) the book, and I would definitely recommend it to anyone who is interested in delving deeper into the topics we discuss here on BenzoBuddies. I'll likely take it out of the library again, since there was a lot to get through, and it was not "light" reading. The font size was rather small as well, so that made it slightly harder to read, I found.

 

One of the reasons I brought it up here was because some people here were wondering about the possible reasons for protracted withdrawal. This part of the book description, in particular, references that topic:

 

But for some patients withdrawal can result in a bewildering array of symptoms, that can persist for protracted time periods, difficult to understand and live with. Although there is currently no clear mechanistic explanation, some potentials include alterations of receptor number, promoters of receptor protein synthesis or degradation, absorption, distribution, metabolism, and elimination, GABAA-receptor function or subtype-distribution, or involvement of peripheral benzodiazepine binding/receptor sites.

 

 

Thanks Everyone, yes I noticed the mention in that paragraph of the potential involvement of peripheral binding sites....was just wondering if any deeper research had been done.  I suspect not. 

 

 

Thanks Everyone, yes I noticed the mention in that paragraph of the potential involvement of peripheral binding sites....was just wondering if any deeper research had been done.  I suspect not.

 

Hi Deanna,

Here's the description of that particular chapter in the book:

 

https://oxfordmedicine.com/view/10.1093/med/9780197517277.001.0001/med-9780197517277-chapter-6 

 

Benzodiazepine Receptors in the Periphery

 

Chapter:

    Benzodiazepine Receptors in the Periphery

 

Author(s):

    Robert B. Raffa

 

DOI:

    10.1093/med/9780197517277.003.0006

 

The benzodiazepines are almost universally thought to produce one and only one pharmacologic effect: positive allosteric modulation of GABAA receptors located in the brain. This results in an increased Cl−ion influx, greater negative transmembrane potential difference, and neurons that are less likely to fire in response to anxiety-producing stimulation. Unfortunately, the simplicity and success of this mono-target belief has distracted researchers and clinicians from studying and appreciating their other pharmacology. A glaring example is the general lack of awareness of the peripheral benzodiazepine receptor. The peripheral benzodiazepine receptor alters mitochondrial function (energy supply), cholesterol transport, and immune function. A patient who is on long-term benzodiazepine therapy (or withdrawing from them) will have these sites affected, just as are the sites located in the brain. One can easily imagine that the adverse effects associated with the peripheral sites would be fundamental, varied, and potentially profound—involving lack of energy, altered cholesterol metabolism, and aberrant immune function.

 

 

For other chapter descriptions from the book, just click on the chapter title from this link:

 

https://oxfordmedicine.com/view/10.1093/med/9780197517277.001.0001/med-9780197517277

I very much appreciate this Lapis! The description of that chapter is exactly what I suspected...that these peripheral receptors cause much of the protracted physical effects we see in withdrawal.  I once asked the community if GABAA receptors were located in the periphery, and it appears that many think they are, but this sounds much more likely as the potential cause of these peripheral effects.

 

The question of course is what can we do about it.  I've been searching for a copy of the book, and will ask my library for an inter-library loan.  I just can't see paying $60 on Amazon, but I guess I've spent so much already in the search for an answer why am I quibbling now LOL

 

Again, many thanks!

You're welcome, Deanna! Yes, I found the price a tad high for me, which is why I requested that our libraries here carry the book. They never told me that they were actually going to go ahead and purchase it, so I just had to keep checking back. I was quite pleased to see that they had, indeed, added a few copies to the collection. We have a huge library service here (100 branches!), so there will likely be others who can benefit from its availability.

 

When I had it here in my room, a couple of the health professionals that I deal with regularly noticed the title, so it led to some important conversations. Very few health professionals are aware of the effects of long-term benzo use. But because benzos are so widely prescribed, it's an important thing for them to know about.

For what it's worth, there is a drug currently available that operates on TSPO.

 

Etifoxine:  https://en.wikipedia.org/wiki/Etifoxine

 

It is obtainable from overseas, it's not a controlled substance and at least in the US people are allowed to import non controlled drugs for personal use so it's not illegal.

 

Whether or not it would be useful for benzo withdrawal I have no idea.

 

It's side effects tend to be mild but there is a very small percentage chance of hepatic damage, so periodic liver labs might be a good idea while taking it.

 

Not advocating it's use, just noting it's existence.

 

 

Lapis2, our intrepid resident researcher, has posted several studies about Etifoxine in Benzos in the News:

 

http://www.benzobuddies.org/forum/index.php?topic=247740.msg3153140#msg3153140

 

http://www.benzobuddies.org/forum/index.php?topic=210322.msg2713054#msg2713054

 

http://www.benzobuddies.org/forum/index.php?topic=125351.msg1657082#msg1657082

"Neurosteroids: Endogenous Role in the Human Brian and Therapeutic Potentials"

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139029/

 

"PPAR and functional foods: Rationale for natural neurosteroid-based interventions for postpartum depression"

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226878/

"Neurosteroids: Endogenous Role in the Human Brian and Therapeutic Potentials"

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139029/

 

"PPAR and functional foods: Rationale for natural neurosteroid-based interventions for postpartum depression"

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226878/

 

That last reference is very intriguing and supports why I indeed feel better when I eat very very healthy!

Hey @[Na...] There is an etifoxine analogue currently in phase 3 i guess, which Isnt hepatotoxic, also, an analogue on pgl chem

 

https://academic-accelerator.com/encyclopedia/deuterated-etifoxine

Edited December 2, 2023 by [De...]

On 02/12/2023 at 13:07, [[D...] said:

Hey @[Na...] There is an etifoxine analogue currently in phase 3 i guess, which Isnt hepatotoxic, also, an analogue on pgl chem

https://academic-accelerator.com/encyclopedia/deuterated-etifoxine

That's not an analog. It's deuterated etifoxine. Meaning, it's etifoxine except one or more of the hydrogens have been replaced by it's isotope deuterium.

The official reason to do this is that it alters the pharmacokinetics, usually somewhat slowing down the metabolism of the drug and increasing it's half life.

The real reason to deuterate a drug (for the most part) is that it becomes a new and therefore newly patentable drug.

For whatever reason, etifoxine was never approved in the US. That ship has now sailed years ago because the patent is long since expired and no one is going to pay a billion USD and spend a decade to get FDA approval on a drug they don't have exclusive rights to.

But, swap a few Hs with Ds and you've got yourself a new compound that you have exclusive rights to.

Now, I'm not saying there are no benefits to deuteration. There can be. Usually you get a somewhat extended released drug out of the process. But there are plenty of other ways to get an extended release drug but what the drug companies really want is a drug they can get a new patent on.

I can only image that it must significantly drive up the cost of drug production since one of your precursor compounds literally becomes heavy water, which ain't cheap.

I doubt the hepatoxic issue is vastly different. It maybe be somewhat mitigated by the fact that it is more slowly metabolized.

@[Na...]

 

The analogue i mean, the pgl chem compound, which is a tpso ligand

 

i saw that this tweaked compound has no hepatotoxicity, and as you said, longer half life and stronger effects, might bê good for nerve damage, as i was reading

 

etifoxine itself seems to be a good additon nerve damage, spinal cord, i saw some vídeos of people from arab countries speaking about etifoxine, most reported no issues, i saw some reports of dress, but that can happen with several drugs, as fluoxetine, and many others

Edited December 8, 2023 by [De...]