Study, May/18: "Valium without dependence? Individual GABAA receptor subtype..."

The full title of this American/Canadian study is "Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects".

 

I would be very interested to hear from those who read the full study and can explain things. I noted the section below, which appears to differ from what is often explained about the downregulation of benzodiazepine receptor sites. I also noted that many of the studies referenced within this study are from the 1980s and 1990s, and I wondered if there might be more recent information available. Perhaps not. Just wondering.....

 

Also, there's quite a bit of information that's based on mice and rat studies, and I wondered if such information could be extrapolated to humans.

 

So many questions....

 

 

Excerpt from full study:

 

Mechanisms of benzodiazepine tolerance

 

Efficacy of benzodiazepine progressively reduces after long-term exposure; not only is a higher dosage of the drug required to experience the same therapeutic effects, but also discontinuation of prolonged treatment induces withdrawal.80

 

A simple way to explain tolerance to any drug is down-regulation of the receptor as the aftermath of neuroplasticity. However, it is demonstrated that even after chronic administration of benzodiazepines, the number of benzodiazepine sites is not reduced, neither is the sensitivity of the benzodiazepine site.81,82

 

Benzodiazepine site downregulation does not seem to happen unless astronomical doses are given, in many studies over 100 mg/kg in rats, which translated into human doses that are far above the therapeutic range.83,84 Not to mention, only inconclusive and inconsistent results have been presented regarding possible changes in subtype composition and their mRNA expression.85,86 So, if its not downregulation, what is the underlying mechanism?

 

While tolerance to sedative and anticonvulsant effects seems to build quickly in both humans and animal models, a lack of tolerance regarding the anxiolytic and amnesic effects of long-term benzodiazepine use has been consistently demonstrated in clinical trials.87–89

 

Excerpt from Conclusions section:

 

Benzodiazepine tolerance is complicated and appears to result from a combination of various factors. Complex mechanisms involving uncoupling, intracellular trafficking, post-translational modifications of GABAA receptors all appear to contribute toward benzodiazepine tolerance.89,119 Various studies have also suggested the involvement of other neurotransmitters, especially adenosine and glutamate, during the tolerance and withdrawal effects of benzodiazepines.92–105

 

Abstract:

 

https://www.ncbi.nlm.nih.gov/pubmed/29872302

 

Full Study:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973310/

My comments: downregulation of the alpha 1 subunit is fast and very detrimental.

 

That 'addiction' theme ! Tolerance/dependence occurs with every benzo, some studies suggest that this would not happen with benzos that only affect alpha2/3, not alpha1 /5. Those benzodiazepines are not in clinical use.

Hi Lapis

 

Thanks for posting .  I will read the whole article later this week, but I think all processes (including downregulation and desensitization) are possible.

I do agree that

Intracellular trafficking and post translational modifications of the receptor are the big common ones.  Synaptic and extrasynaptic subunit distributions are altered during chronic benzdiazaphine use and tolerance development , and this takes time to revert during wd. 

 

Since synaptic and extrasynaptic clustering is affected, tonic and phasic inhibitory signaling is altered and this contributes to tolerance symtoms.  It’s part of the “action potiential dynamics “ component in the layman’s benzdiazaphine model.

 

This all occurs in a brain region specific manner.  That’s one place where a lot of these older studies fail.  Downregulation and desensitization can be very brain region specific and very dependent not only on the drug dosage level but how the drug is administered (single dosing vs multiple dosing) over long term, which type of drug is used, half life, pharmacokinetics of the drug studied, etc.  Many studies fail to control these variables properly.

 

Thanks so much for your post, dm123. I'll be interested to hear what you think once you've read the whole thing, but I appreciate your perspective on what you've read so far. I'm a non-science layperson, so trying to wrap my mind around the detailed info here is difficult. But seeing the references to relatively old studies gives me pause when it comes to judging the relevance of such a paper.

 

In addition to the variables you mentioned, I would guess that the other important variable here is genetics.

I did a slow skim of the article, will need to go back for a second slower skim, lol, but I have some thoughts on it from one non-science layperson to another.  Will have to return.  Good find, Lap. 

Sure, abcd! Please do weigh in whenever you get a chance.

"Complex mechanisms involving uncoupling, intracellular trafficking, post-translational modifications of GABAA receptors all appear to contribute..."

 

I'll need at least one more espresso before taking this one on.

Big questions for me: Is there downregulation or not? Are there fewer receptors or not? Is the sensitivity reduced or not? The quote below says "No." But the references are from the mid-1980s. Still valid? It's a 2018 paper, so one would hope the info is current, but......

 

 

 

"A simple way to explain tolerance to any drug is down-regulation of the receptor as the aftermath of neuroplasticity. However, it is demonstrated that even after chronic administration of benzodiazepines, the number of benzodiazepine sites is not reduced, neither is the sensitivity of the benzodiazepine site."

Big questions for me: Is there downregulation or not? Are there fewer receptors or not? Is the sensitivity reduced or not? The quote below says "No." But the references are from the mid-1980s. Still valid? It's a 2018 paper, so one would hope the info is current, but......

 

 

 

"A simple way to explain tolerance to any drug is down-regulation of the receptor as the aftermath of neuroplasticity. However, it is demonstrated that even after chronic administration of benzodiazepines, the number of benzodiazepine sites is not reduced, neither is the sensitivity of the benzodiazepine site."

 

Which brings up another question whether tolerance happens due to hyper-polarization (Chloride ion channels) and hypo-polarization (is that a word) of the neurons in the brain, which causes cellular changes leading to a mechanism we call tolerance.

 

So if it is the cholride ion action that causes negative polarization (slowing down the brain activity), then the brain will fight back with hyper polarization of Calcium channels and sodium channels, etc. Heck, that is a lot of "brainstorm" activity, what William Styron called it in his book.

Big questions for me: Is there downregulation or not? Are there fewer receptors or not? Is the sensitivity reduced or not? The quote below says "No." But the references are from the mid-1980s. Still valid? It's a 2018 paper, so one would hope the info is current, but......

 

 

 

"A simple way to explain tolerance to any drug is down-regulation of the receptor as the aftermath of neuroplasticity. However, it is demonstrated that even after chronic administration of benzodiazepines, the number of benzodiazepine sites is not reduced, neither is the sensitivity of the benzodiazepine site."

 

Hi Lapis

 

I read through the paper.  I think this is an issue of semantics.  The paper clearly mentions uncoupling, receptor trafficking, internalization, phosphorylation, posttranslational modifications , etc.....so they understand.

 

To make my point please read this 2010 article with more citations and how they use the word downregulation.    Benzodiazaphines change subunit configurations.  There’s no dispute about that.  This is clear from the 2018 article as well.  It’s clear in all the research.    If there are less alpha1 subunit GABAaRs synaptically, one could say the expression of alpha1 GABAaRs has been downregulated  synaptically.  The receptors are less sensitive to alpha1 agonists, etc. as well.

 

Downregulation as you know refers to population, and if alpha1s are less expressed those receptors are lower in population and “downregulated”

I guess it boils down to “downregulation “ = “downregulation of subunit expression “.  2018 article doesn’t use the term like that, 2010 article does....

 

 

 

 

 

Here is the link, and some quotes to make the point.  There’s many such references like this

 

Let me know what you think

 

Note how the effects of downregulation are dependent on brain region and by the type of Benzodiazaphine, and temporal aspects.  I would imagine that dosing schedule and duration of drug exposure would create even more differences.  It’s all very complex

 

http://pharmrev.aspetjournals.org/content/62/1/97

See section III A.

 

Sections A 1-12 covers all the various subunits and how they are affected by benzdiazaphines

 

 

Some examples below

 

 

 

Quote alpha1

 

On the other hand, the presence of GABAA agonists in medium of cultured neurons down-regulates GABAA receptor subunits (Montpied et al., 1991a; Mehta and Ticku, 1992; Baumgartner et al., 1994).

 

Calcium is a crucial second messenger in the transduction of synaptic activity into gene expression (Carafoli et al., 2001), and it is involved in the mechanisms of GABAA receptor up- and down-regulation (Gault and Siegel, 1998; Lyons et al., 2001).

 

 

Activation of adenylate cyclase or the presence of cAMP analogs in cultured CGCs up-regulate β2 and down-regulate α6 mRNA expression but have no effect on α1 and β3 mRNA (Thompson et al., 2000).

 

The expression of the most abundant α subunit, the α1 subunit, has been studied most often. Sedative doses of the compounds have been used in most in vivo studies. In the cerebral cortex, α1 mRNA expression was significantly down-regulated by diazepam, the general agonist for α1/2/3/5βγ2 receptors in several (Heninger et al., 1990; Impagnatiello et al., 1996; Longone et al., 1996) but not all (Wu et al., 1994; Holt et al., 1996) studies (Table 2).

 

 

Long-term treatment of rats with the general agonist lorazepam and the α1-preferring agonist zolpidem down-regulated cerebral cortical α1 mRNA by 50 and 27%, respectively (Kang and Miller, 1991; Holt et al., 1997a). In contrast, long-term treatment with other full or partial agonists (e.g., abecarnil, alprazolam, flurazepam, imidazenil, and triazolam) were ineffective (Zhao et al., 1994a,b; Holt et al., 1996; Impagnatiello et al., 1996; Ramsey-Williams and Carter, 1996; Fahey et al., 1999; Tietz et al., 1999a). Long-term treatment with the inverse agonist FG 7142 slightly up-regulated α1 mRNA (Primus and Gallager, 1992). Withdrawal (2 days) from long-term flurazepam treatment reduced α1 mRNA in the cerebral cortical layers II to III and IV (Tietz et al., 1993), whereas on withdrawal day 7, α1 mRNA had returned to the control level (Tietz et al., 1999a) (Table 4)

 

 

In the cerebellum, none of the above-mentioned BZ-site compounds affected α1 mRNA expression except for a 21% up-regulation by diazepam (Holt et al., 1999). Treatment of cultured rat CGCs with diazepam reduced α1 mRNA expression slightly (Follesa et al., 2001a, 2002), but treatments with imidazenil, zaleplon, or zolpidem were ineffective (Table . Withdrawal (6 h) of CGCs from diazepam, imidazenil, zaleplon, and zolpidem decreased α1 mRNA by 20 to 37% (Table 9). Long-term treatment of CGCs with diazepam, flunitrazepam, and bretazenil reduced the level of α1 polypeptide (Brown and Bristow, 1996; Brown et al., 1998; Johnston and Bristow, 1998; Follesa et al., 2001a), whereas imidazenil had no effect on it (Johnston and Bristow, 1998) (Table 10). Withdrawal (6 h) from long-term diazepam treatment down-regulated α1 polypeptide in CGCs by 75% (Follesa et al., 2001a) (Table 11).

 

Overall, there are controversies in results of studies on long-term BZ treatments on expression of α1 subunit. Many of the studies indicate down-regulation of α1 mRNA and polypeptide after long-term treatment and especially on withdrawal in the cerebral cortex and in hippocampus. There is a tight control between α1 mRNA and α1 polypeptide expression that was particularly clearly manifested in the GABAA receptor α6 subunit knockout mice, where an alteration in the structure of α6 gene within the β2-α6-α1-γ2 gene cluster altered the expression of the other genes in the cluster (Uusi-Oukari et al., 2000). Down-regulation of α1 mRNA transcription in the forebrain of α6 knockout mice was accompanied with similar down-regulation of forebrain α1 polypeptide (Uusi-Oukari et al., 2000).

 

End quote

 

 

Quote conclusion

 

 

Studies on regulation of GABAA receptor subunit expression in vivo by long-term BZ treatment have shown that the regulation is subunit-specific, is brain region-specific, and occurs at subunit-specific time scales. In addition, the inverse agonist studied (FG 7142) often had opposite effects on the expression as compared with BZ agonists. The partial agonist imidazenil was mostly without an effect on expressions of receptor subunits (Tables 2 and 3, Impagnatiello et al., 1996; Longone et al., 1996; Pesold et al., 1997; Johnston and Bristow, 1998). In vitro studies with cultured cells treated with long-term BZs produced surprisingly controversial results compared with studies in vivo. The in vitro results from rat CGCs and hippocampal neurons are often opposite those received from hippocampus or cerebellum of rats treated in vivo. Thus, the in vitro results should be interpreted very cautiously.

 

Quantitative RT-PCR studies usually monitor the steady-state mRNA levels, not the rates of mRNA synthesis or degradation. Therefore, it has not been possible to deduce whether down-regulation of a subunit mRNA results from reduced transcription rate or increased degradation rate. However, using a nuclear run-off assay, Holt et al. (1997b) showed a 65% decrease in the γ2 mRNA synthesis rate in the cerebral cortex of rats continuously treated with diazepam, whereas in the cerebellum, the rate was increased by 42% (Holt et al., 1999). The changes in γ2 mRNA transcription rate paralleled the changes in γ2 mRNA steady-state levels indicating that diazepam predominantly regulates γ2 mRNA at the level of transcription (Holt et al., 1997a, 1999). The results suggest a brain region-specific regulation of γ2 mRNA transcription by long-term treatment with diazepam. Lorazepam-induced reduction in transcriptional activity is suggested in α1 subunit down-regulation (Kang et al., 1994). The group isolated human α1 gene promoter and showed that long-term lorazepam treatment down-regulates transcriptional activity of α1 promoter in neurons transiently transfected with a α1 promoter-firefly luciferase construct (Kang et al., 1994). Lorazepam treatment dose-dependently attenuated expression of luciferase activity in the cells (Kang et al., 1994). The signaling mechanism by which lorazepam represses α1 gene promoter activity is unknown. However, it has been shown that GABA agonist-induced reduction of cell surface GABAA receptors occurs before down-regulation of receptor subunit mRNA expression (Baumgartner et al., 1994; Miranda and Barnes, 1997). It was subsequently found that long-term BZ treatment also induces GABAA receptor internalization (Tehrani and Barnes, 1997). How this receptor internalization is signaled into cell nucleus to suppress receptor subunit gene transcription is currently not known.

 

Studies on long-term BZ treatment in vivo indicate alterations in GABAA receptor subunit expression. The clearest effects are the down-regulation of α1 and β3 in several cortical and hippocampal subregions and the down-regulation of γ2 in the cerebral cortex. In addition, α4 subunit is strongly up-regulated in BZ withdrawal. There is also an indication of up-regulation of γ3 subunit. BZ-induced alterations in GABAA receptor subunits may produce receptors with lower sensitivity or insensitivity to BZs (e.g., formation of α4βγ2 and αβγ3-containing receptors). The changes, however, are quantitatively rather small and short-lasting. Therefore, the changes cannot solely explain the development of BZ tolerance, dependence or withdrawal syndrome after the discontinuation, but they may partially contribute to mechanisms underlying these phenomena.

 

End quote

 

Dm123: the conclusion is well written.  All these changes fall short of modeling tolerance , wd and PWS fully.  That’s what the benzdiazaphine model attempts to address.  All this stuff here falls into the Action potiential dynamics component system of the laymans benzdiazaphine model.  It’s another piece of a much larger model. The stress system pillar and homeostasis ties things together..

 

 

 

 

 

 

quote.  SIDENOTE:: More recent research on Benzodiazaphine regulation of other genes

 

 

Changes in the Expression of Other Genes.

 

BZ administration induces a wide variety of other changes in neuronal gene expression that may participate to the development of tolerance and dependence. In a microarray study using wild-type and α1(H101R) knockin mouse lines, it was shown that even a single dose of diazepam significantly changed the expression of 54 transcripts (0.43% of the transcripts on the array), 34 transcripts being down-regulated and 20 transcripts being up-regulated (Huopaniemi et al., 2004). Changes in the expression of six transcripts, CaMKIIα, BDNF, MKP-1, GIF, c-fos, and NGFI-A, were mediated via action of diazepam on α1 subunit-containing GABAA receptors (Huopaniemi el al., 2004).

 

According to glutamate hypothesis of BZ tolerance and dependence, excitatory mechanisms become up-regulated to compensate for BZ-induced enhancement of inhibition (Stephens, 1995). Expression of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors has been shown to be regulated after long-term BZ treatment. Cerebral cortical GluN1 and GluN2B, but not GluN2A subunits of NMDA receptors (Tsuda et al., 1998), glutamic acid decarboxylase (GAD67), and GluA1 subunit of AMPA receptor were increased in diazepam-withdrawn rats (Izzo et al., 2001). In rats withdrawn from flurazepam, amplitudes of AMPA receptor-mediated miniature excitatory postsynaptic currents were increased in hippocampal CA1 neurons (Van Sickle et al., 2004; Xiang and Tietz, 2007). The 50% enhancement in AMPA receptor function was attributed to an increase in GluA1 polypeptide trafficking from the endoplasmic reticulum and its subsequent incorporation into membranes (Song et al., 2007; Das et al., 2008), whereas NMDA receptor-mediated currents were reduced in this brain region (Van Sickle et al., 2004; Xiang and Tietz, 2007). Mice deficient in GluA1 subunits have reduced short-term tolerance (i.e., prolonged short-term impairment to high doses of flurazepam) and develop less tolerance but show increased withdrawal signs after a 7-day flurazepam treatment and challenge with flumazenil (Aitta-Aho et al., 2009). Even a single injection of diazepam to young mice increases the AMPA receptor function over that of NMDA receptors in dopamine neurons of the ventral tegmental area, measured in vitro 24 h after the drug injection in the ventral tegmental area dopamine neurons in vitro (Heikkinen et al., 2009).

 

Long-term BZ administration up-regulates L-type high voltage-gated calcium channels in the cerebral cortex (Katsura et al., 2007) and potentiates high voltage-gated calcium channel currents in the hippocampal CA1 neurons (Xiang et al., 2008).

 

End quote

dm123 offers this quote: 

 

"Changes in the Expression of Other Genes.

 

BZ administration induces a wide variety of other changes in neuronal gene expression that may participate to the development of tolerance and dependence. In a microarray study using wild-type and α1(H101R) knockin mouse lines, it was shown that even a single dose of diazepam significantly changed the expression of 54 transcripts (0.43% of the transcripts on the array), 34 transcripts being down-regulated and 20 transcripts being up-regulated (Huopaniemi et al., 2004). Changes in the expression of six transcripts, CaMKIIα, BDNF, MKP-1, GIF, c-fos, and NGFI-A, were mediated via action of diazepam on α1 subunit-containing GABAA receptors (Huopaniemi el al., 2004)."

I've been looking for something like this that confirms benzo-driven changes to neuronal gene expression.  Thanks.  FYI, using google search term "Huopaniemi et al bz neuronal" produces a torrent of research findings on this and similar topics!  Like this excellent one, for example:

 

http://www.pnas.org/content/109/45/18595

 

 

"Complex mechanisms involving uncoupling, intracellular trafficking, post-translational modifications of GABAA receptors all appear to contribute..."

 

I'll need at least one more espresso before taking this one on.

 

     

 

Hilarious, PBug.  I know I'll never ask dm for a "layman's" explanation.  For me, it'll have to be Kindergarten class, you know, red buckets/blue buckets, that kinda thing.

dm123 offers this quote: 

 

"Changes in the Expression of Other Genes.

 

BZ administration induces a wide variety of other changes in neuronal gene expression that may participate to the development of tolerance and dependence. In a microarray study using wild-type and α1(H101R) knockin mouse lines, it was shown that even a single dose of diazepam significantly changed the expression of 54 transcripts (0.43% of the transcripts on the array), 34 transcripts being down-regulated and 20 transcripts being up-regulated (Huopaniemi et al., 2004). Changes in the expression of six transcripts, CaMKIIα, BDNF, MKP-1, GIF, c-fos, and NGFI-A, were mediated via action of diazepam on α1 subunit-containing GABAA receptors (Huopaniemi el al., 2004)."

I've been looking for something like this that confirms benzo-driven changes to neuronal gene expression.  Thanks.  FYI, using google search term "Huopaniemi et al bz neuronal" produces a torrent of research findings on this and similar topics!  Like this excellent one, for example:

 

http://www.pnas.org/content/109/45/18595

 

There’s so much research it’s mindblowing , literally.

 

The link above is co-authored by Stephen J. Moss

If you google his name and GABAa receptor you will come up with tons more very good references.

 

Why the benzdiazaphine is still on the market is beyond me.

They affect every area of our physiology, but I am still amazed at the body’s ability to recover.

"Complex mechanisms involving uncoupling, intracellular trafficking, post-translational modifications of GABAA receptors all appear to contribute..."

 

I'll need at least one more espresso before taking this one on.

 

     

 

Hilarious, PBug.  I know I'll never ask dm for a "layman's" explanation.  For me, it'll have to be Kindergarten class, you know, red buckets/blue buckets, that kinda thing.

 

Hi dm123,

Thanks very much for sharing all of that info! I can't weigh in very much, since I just don't have the science background, but I can grasp the major concepts.

 

I noticed that you don't have a signature, and I'm not acquainted with your story. What did you take and for how long? Have you already tapered? What are your major symptoms? Apparently, your cognition is NOT affected too much, which is great!

Hi dm123,

Thanks very much for sharing all of that info! I can't weigh in very much, since I just don't have the science background, but I can grasp the major concepts.

 

I noticed that you don't have a signature, and I'm not acquainted with your story. What did you take and for how long? Have you already tapered? What are your major symptoms? Apparently, your cognition is NOT affected too much, which is great!

 

Hi Lapis

 

Regarding this downregulation  thing, in real laymans terms:

 

Human=GABAaR

Color of hair=GABAAR subunits present in the humans

 

If we initially have the following in the USA

45% people in the population with brown hair

25% people with blond hair

20% people with black hair

10% people with red hair

 

After benzdiazaphines these percentages change.  For example alpha1s are no longer found in the same amounts synaptically as they were before.  So in New York, USA there are less people with brown hair.

 

So the hair color has changed and the location (brain region and synaptic vs. extrasynaptic)makes a difference as well. 

 

Subunits aren’t only the only thing that gets dysreguated  during benzdiazaphine Chronic use. Many different gene regulatory processes inside the neuron get up and down regulated.

 

To make things more complex we have all these different variables like half life, how the Benzodiazaphine is dosed, etc that all affect gene expression in the neurons in different ways.  And things become paradoxical when you compare studies of acute vs. chronic dosing vs. intermittent dosing vs. withdrawal, etc.

 

And regarding location, we have synaptic and extrasynaptic. (Extrasynaptic in rural  New York, USA, synaptic in the city) .And subunit distributions are brain region (New York vs Austin, Texas ) specific and each Benzodiazaphine affects different brain regions differently

 

Finally, genetically we are all a bit different relative to distributions, and some are more susceptible to the bad effects of certain Benzodiazaphines due to these differences, metabolic differences, and different intracellular gene resiliency.

 

To get back to the hair color analogy, perhaps the 2018 paper authors are referring to the total number of GABAaRs on the neurons in the area of brain slices that they were studying.  Perhaps the total number of receptors (people) don’t change in those studies in those regions of the brain (unless very high doses are used, as the study stated) but we know subunit compositions do change and the results are dependent on all the variables above.  And different subunit compositions do affect sensitivity of the receptor, depending  on which subunits are affected and what ligand (endogenous GABA, vs benzdiazaphine vs barbiturate, etc) we are studying.    And different subunit compositions  ultimately affect the physiological neuronal function and how we feel.

 

Back in the 1980s and 1990s Neuroplasticity was researched but they know a lot more about it today.(still we have a long way to go).  When we study the single neuron in a neural circuit (ie real life), we then discover how plastic neurons truly are.  Homeostatic plasticity and other forms of plasticity are prevalent when the Neural circut is “perturbed”or stressed.  Benzdiazaphines stress neural circuits especially when improperly doses.  Dosing high potency short half life Benzodiazaphines is a needless and pointless way to increase the stress on neural circuits.  I hold the doctors,who don’t understand the pharmacokinetics of these high potency benzdiazaphines , accountable for this needless harm and suffering.  Patients who are relying on them for their “expertise” are graced with their sheer and utter incompetence. 

 

 

 

 

 

======

 

Regarding signature I don’t have one because I would feel too much pressure.  Perhaps it’s an after effect of benzdiazaphine use.

 

Here’s what I’ve tapered off of.  I’m doing a symtom based taper to avoid PWS.  So far 18 months for the “package”listed below.

 

Crossed over from 2 mg/ day single dosing lorazepam to Librium to start the taper process.

 

Once stable:

Tapered off hydrocortisone first

Then fludrocortisone

Then dropped ambien cold turkey

Tapered lunesta over next 2 weeks

Got off most of thyroid T3 (we all have Hashimoto’s in family).  Mostly on T4

Tapered down the Librium

I’m currently at sub 4 mg Valium equivalent of Librium.  So very low dose.

 

 

You have to go slower as you get to low levels. I Experience wd after each cut, then stabilization, then once symptoms resolve cut again.

 

Overall, the lower the dose the better I feel.

 

this is a symtom based taper.  I did post the crossover and taper methodology in detail in the layman’s thread about a month ago.

 

Hope this helps.

 

 

Thanks so much, dm123! Much appreciated.

 

The variability in symptoms makes sense to me based on the vastly different experiences we've each had with benzos (dose, type, length of time taken, concurrent meds), as well as genetics. What's so hard to understand is the strange healing patterns, e.g. In my case, an every-other-day pattern of better day/worse day of disequilibrium. What could possibly be going on in my brain for me to have such a pattern? I'm on tiny boat in a turbulent ocean on bad days, and then, on better days, the ocean seems to have calmed somewhat. I just don't get it. And, of course, I don't understand what, if anything, I can/should be doing to make it better. I can hardly walk. I broke a bone in one foot and my other chronic foot issue has worsened as a result of dizziness. I'm housebound. Walking is almost impossible. I'm in severe pain.

 

Is there nothing we can do but wait for our receptors to normalize? Thank goodness for neuroplasticity! I just need it to work in the right direction.

 

With regards to balance, I understand that benzos work as "vestibular suppressants". It's in the ENT textbooks, an excerpt from which I brought to my doctor, who noted that I knew "more than most doctors" on the topic. Thanks very much, Doc! One of the studies I came across years ago said that the benzos (well, in this case, it was lorazepam) "selectively suppressed" a certain part of the vestibular system, i.e. the one responsible for the type of motion most of floaty-boaty-benzo-dizzy people feel. I also know that numerous neurotransmitters are involved in the process of balance. So, it's not just GABA, but it's also glutamate, and acetylcholine, and dopamine, and histamine, and serotonin, and norepinephrine, some of which are also affected by the benzos. Since I took more than one kind of benzo, plus an SSRI, I can only guess that the effects were multifaceted in terms of the neurotransmitters and their receptors.

 

https://www.dizziness-and-balance.com/anatomy/physiology/neurotransmitters.htm 

 

Thanks, too, for sharing your info here. I'm not following that other thread, so I missed whatever info you might have shared there. The fact that you're feeling better as you drop your doses is wonderful! Not everyone is that lucky. I'll keep my fingers crossed that that continues to be the case, so that by the time you're off, you'll be feeling much better. That would be excellent!

 

 

 

 

 

 

Thanks so much, dm123! Much appreciated.

 

The variability in symptoms makes sense to me based on the vastly different experiences we've each had with benzos (dose, type, length of time taken, concurrent meds), as well as genetics. What's so hard to understand is the strange healing patterns, e.g. In my case, an every-other-day pattern of better day/worse day of disequilibrium. What could possibly be going on in my brain for me to have such a pattern? I'm on tiny boat in a turbulent ocean on bad days, and then, on better days, the ocean seems to have calmed somewhat. I just don't get it. And, of course, I don't understand what, if anything, I can/should be doing to make it better. I can hardly walk. I broke a bone in one foot and my other chronic foot issue has worsened as a result of dizziness. I'm housebound. Walking is almost impossible. I'm in severe pain.

 

Is there nothing we can do but wait for our receptors to normalize? Thank goodness for neuroplasticity! I just need it to work in the right direction.

 

With regards to balance, I understand that benzos work as "vestibular suppressants". It's in the ENT textbooks, an excerpt from which I brought to my doctor, who noted that I knew "more than most doctors" on the topic. Thanks very much, Doc! One of the studies I came across years ago said that the benzos (well, in this case, it was lorazepam) "selectively suppressed" a certain part of the vestibular system, i.e. the one responsible for the type of motion most of floaty-boaty-benzo-dizzy people feel. I also know that numerous neurotransmitters are involved in the process of balance. So, it's not just GABA, but it's also glutamate, and acetylcholine, and dopamine, and histamine, and serotonin, and norepinephrine, some of which are also affected by the benzos. Since I took more than one kind of benzo, plus an SSRI, I can only guess that the effects were multifaceted in terms of the neurotransmitters and their receptors.

 

https://www.dizziness-and-balance.com/anatomy/physiology/neurotransmitters.htm 

 

Thanks, too, for sharing your info here. I'm not following that other thread, so I missed whatever info you might have shared there. The fact that you're feeling better as you drop your doses is wonderful! Not everyone is that lucky. I'll keep my fingers crossed that that continues to be the case, so that by the time you're off, you'll be feeling much better. That would be excellent!

 

Hi Lapis

 

I’m going to read that link, and do some research into this area (vestibular dysfunction and Benzodiazaphines) and get back to you.  I will also reread Perserverances paper on the same to get some starting point on references.

 

 

Regarding symtom based taper, it’s been terribly difficult at times.  So I don’t want to sugarcoat it.  Each time I start to forget how bad it was, I have to cut and sometimes get slammed.  It’s very much dependent on how resilient my stress system is at the time, and what negative internal and external stressors are present at the time.  I’ve read so many accounts of excessive stress throwing people back into relapse.  It’s a major player.

I think that barbiturates were safer.

 

More overdose potential, but not that false sense fo security. Docs would never prescribe insane doses because of the acute dangers. Also, I recall to have read that some GABAA receptor issues were less likely with barbs. We can all thank Leo Sternbach !

 

dm123 offers this quote: 

 

"Changes in the Expression of Other Genes.

 

BZ administration induces a wide variety of other changes in neuronal gene expression that may participate to the development of tolerance and dependence. In a microarray study using wild-type and α1(H101R) knockin mouse lines, it was shown that even a single dose of diazepam significantly changed the expression of 54 transcripts (0.43% of the transcripts on the array), 34 transcripts being down-regulated and 20 transcripts being up-regulated (Huopaniemi et al., 2004). Changes in the expression of six transcripts, CaMKIIα, BDNF, MKP-1, GIF, c-fos, and NGFI-A, were mediated via action of diazepam on α1 subunit-containing GABAA receptors (Huopaniemi el al., 2004)."

I've been looking for something like this that confirms benzo-driven changes to neuronal gene expression.  Thanks.  FYI, using google search term "Huopaniemi et al bz neuronal" produces a torrent of research findings on this and similar topics!  Like this excellent one, for example:

 

http://www.pnas.org/content/109/45/18595

 

There’s so much research it’s mindblowing , literally.

 

The link above is co-authored by Stephen J. Moss

If you google his name and GABAa receptor you will come up with tons more very good references.

 

Why the benzdiazaphine is still on the market is beyond me.

They affect every area of our physiology, but I am still amazed at the body’s ability to recover.

Thanks so much, dm123! Much appreciated.

 

The variability in symptoms makes sense to me based on the vastly different experiences we've each had with benzos (dose, type, length of time taken, concurrent meds), as well as genetics. What's so hard to understand is the strange healing patterns, e.g. In my case, an every-other-day pattern of better day/worse day of disequilibrium. What could possibly be going on in my brain for me to have such a pattern? I'm on tiny boat in a turbulent ocean on bad days, and then, on better days, the ocean seems to have calmed somewhat. I just don't get it. And, of course, I don't understand what, if anything, I can/should be doing to make it better. I can hardly walk. I broke a bone in one foot and my other chronic foot issue has worsened as a result of dizziness. I'm housebound. Walking is almost impossible. I'm in severe pain.

 

Is there nothing we can do but wait for our receptors to normalize? Thank goodness for neuroplasticity! I just need it to work in the right direction.

 

With regards to balance, I understand that benzos work as "vestibular suppressants". It's in the ENT textbooks, an excerpt from which I brought to my doctor, who noted that I knew "more than most doctors" on the topic. Thanks very much, Doc! One of the studies I came across years ago said that the benzos (well, in this case, it was lorazepam) "selectively suppressed" a certain part of the vestibular system, i.e. the one responsible for the type of motion most of floaty-boaty-benzo-dizzy people feel. I also know that numerous neurotransmitters are involved in the process of balance. So, it's not just GABA, but it's also glutamate, and acetylcholine, and dopamine, and histamine, and serotonin, and norepinephrine, some of which are also affected by the benzos. Since I took more than one kind of benzo, plus an SSRI, I can only guess that the effects were multifaceted in terms of the neurotransmitters and their receptors.

 

https://www.dizziness-and-balance.com/anatomy/physiology/neurotransmitters.htm 

 

Thanks, too, for sharing your info here. I'm not following that other thread, so I missed whatever info you might have shared there. The fact that you're feeling better as you drop your doses is wonderful! Not everyone is that lucky. I'll keep my fingers crossed that that continues to be the case, so that by the time you're off, you'll be feeling much better. That would be excellent!

 

Hi Lapis

 

I’m going to read that link, and do some research into this area (vestibular dysfunction and Benzodiazaphines) and get back to you.  I will also reread Perserverances paper on the same to get some starting point on references.

 

 

Regarding symtom based taper, it’s been terribly difficult at times.  So I don’t want to sugarcoat it.  Each time I start to forget how bad it was, I have to cut and sometimes get slammed.  It’s very much dependent on how resilient my stress system is at the time, and what negative internal and external stressors are present at the time.  I’ve read so many accounts of excessive stress throwing people back into relapse.  It’s a major player.

 

Hi Lapis

 

I read the link you sent above.  It will give me a good starting point.  I’m suspecting the serotonin receptor side of things.   

Regarding LSD, mushroom extracts etc, my sister uses a nasal spray for migraines, the active ingredients is a compound extracted from mushrooms that acts as an agonist on certain serotonin receptors.  This is ironically mentioned in the vestibular link you sent.  I’ve bolded it out in the quote below.  It works very well for her.

 

 

Regarding the link above, I found the parts below the most interesting and will start from these areas.  Soto appears to be one of the major researchers in the more recent papers

 

 

Quote

Withdrawal from serotonergic drugs, such as SSRI antidepressants, is commonly associated with vertigo, and serotonin depletion can cause severe dizziness (Soto et al, 2013). It has been speculated that this is due to loss of inhibition of glutamate -- in other words, increased vestibular responses as glutamate is excitatory (Smith PF, Darlington CL, 2010). There is some equivocal data suggesting that serotonin agonists such as sumatriptan (a 5-HT1-d and1-b agonist), used for migraine can prevent motion sickness. Serotonin is one of the numerous neurotransmitters involved with nausea, and drugs that block the 5-HT3 receptor such as ondansetron are very effective.

 

Nitric oxide is also produced in the vestibular nucleus, and may play a role in compensation (Soto, 2013).

 

Cannabinoid receptors are present in the central vestibular circuitry, but their action is presently unclear (Smith, 2006). It is well known that recreational use of substances that contain THC often reduce nausea.

 

According to Soto et al (2013), hair cells and efferent neurons release numerous other neuroactive substances including CGRP (which co-localizes with 5HT1-1F), substance-P, opiod peptides, ATP, and adenosine. In the near future, a CGRP antagonist will become commercially available for migraine treatment, and it will be interesting to see if it is useful for vestibular medicine.

 

 

End quote

 

 

If you search for adenosine in that 2018 in the original post, you will note that adenosine is affected by acute administration of benzdiazaphines.  I don’t know what happens to adenosine homeostasis during chronic benzdiazaphine use and post wd.

 

Regarding NO, as you know there’s that long thread on NO/ONOO- in the layman’s thread and in a dedicated thread.

 

 

Hi dm123,

I'd appreciate any input or info you could offer. I've been researching this topic for ages -- in particular, on PubMed -- and I continue to do so. The closest description/diagnosis we tend to get is "Mal de Debarquement Syndrome", which has similar symptoms but a different cause. Whether the two are related appears to be in question, based on a paper I just read a few days ago. Most of us go through extensive testing, and it comes back "normal". The neurologist told me that we don't have the means to test the vestibular system to the degree that we would like at the present time. He also said that the vestibular system is finely tuned, and if it's off a little bit, one can feel dizzy.

 

Taking "vestibular suppressants" (benzos, antihistamines and anticholinergics) obviously isn't a good thing to do. Once I became dizzy, no one -- not one of the many doctors I consulted -- pointed at the benzo. Yet, as I mentioned, the ENT textbooks say that benzos are "vestibular suppressants" and they interfere with the process of "vestibular compensation" (a process by which the vestibular system normalizes itself). So, I continued to take the benzos for another two years after I became dizzy, until I eventually came across BenzoBuddies and a ton of people describing the exact same symptoms I was suffering from. I printed out 100 pages worth of it and brought it to my next appointment. The diagnosis became clear at that point.

 

Obviously, the added benzo time after I'd already become dizzy was NOT a good thing. Two years, plus the time it took to taper off -- about eight months. I just followed the Ashton Manual, but I wasn't yet on BB.  I also had to taper off the SSRI, which I'd started because one of the docs thought I was in Cymbalta withdrawal. He'd had a previous patient with "swimmy head", he said. Right. The SSRIs have a similar type of dizziness associated with them. Double whammy! Or triple, in my case, since I took two different benzos and an SSRI.

 

Anyway, yes, please do share any insights you might have. We have a whole group of dizzy BBs in the Support Group section, and that's where I regularly post any relevant studies on this topic. Dizziness is one of the more brutal symptoms, because it renders people disabled. You can't walk. You can't do normal things. You can't go out. In my case, you might even break a bone from losing your balance or falling outright. It's scary as hell.

 

Regarding your situation, I will definitely be sending good wishes your way as you continue to make your way through your taper. I don't know very much about microtapers and whether one tapering style is better than another. In my case, once I understood that the benzos were suppressing my vestibular system, I wanted them out of my body, but I had to follow a controlled, appropriate taper. I don't know whether it would have changed things had I done it differently. For now, it's all about moving forward and hoping for the best. I will hope for the best for you. Take good care, dm123. Keep the stress as low as you can, and stay positive.

 

I know you're helping others around here, and that's a huge gift. Thank you for that. I'm sure others are grateful as well. For us non-science folks, it's reassuring to have some knowledgeable people around to shed a bit of light on the murky details. 

Hi dm123,

I'd appreciate any input or info you could offer. I've been researching this topic for ages -- in particular, on PubMed -- and I continue to do so. The closest description/diagnosis we tend to get is "Mal de Debarquement Syndrome", which has similar symptoms but a different cause. Whether the two are related appears to be in question, based on a paper I just read a few days ago. Most of us go through extensive testing, and it comes back "normal". The neurologist told me that we don't have the means to test the vestibular system to the degree that we would like at the present time. He also said that the vestibular system is finely tuned, and if it's off a little bit, one can feel dizzy.

 

Taking "vestibular suppressants" (benzos, antihistamines and anticholinergics) obviously isn't a good thing to do. Once I became dizzy, no one -- not one of the many doctors I consulted -- pointed at the benzo. Yet, as I mentioned, the ENT textbooks say that benzos are "vestibular suppressants" and they interfere with the process of "vestibular compensation" (a process by which the vestibular system normalizes itself). So, I continued to take the benzos for another two years after I became dizzy, until I eventually came across BenzoBuddies and a ton of people describing the exact same symptoms I was suffering from. I printed out 100 pages worth of it and brought it to my next appointment. The diagnosis became clear at that point.

 

Obviously, the added benzo time after I'd already become dizzy was NOT a good thing. Two years, plus the time it took to taper off -- about eight months. I just followed the Ashton Manual, but I wasn't yet on BB.  I also had to taper off the SSRI, which I'd started because one of the docs thought I was in Cymbalta withdrawal. He'd had a previous patient with "swimmy head", he said. Right. The SSRIs have a similar type of dizziness associated with them. Double whammy! Or triple, in my case, since I took two different benzos and an SSRI.

 

Anyway, yes, please do share any insights you might have. We have a whole group of dizzy BBs in the Support Group section, and that's where I regularly post any relevant studies on this topic. Dizziness is one of the more brutal symptoms, because it renders people disabled. You can't walk. You can't do normal things. You can't go out. In my case, you might even break a bone from losing your balance or falling outright. It's scary as hell.

 

Regarding your situation, I will definitely be sending good wishes your way as you continue to make your way through your taper. I don't know very much about microtapers and whether one tapering style is better than another. In my case, once I understood that the benzos were suppressing my vestibular system, I wanted them out of my body, but I had to follow a controlled, appropriate taper. I don't know whether it would have changed things had I done it differently. For now, it's all about moving forward and hoping for the best. I will hope for the best for you. Take good care, dm123. Keep the stress as low as you can, and stay positive.

 

I know you're helping others around here, and that's a huge gift. Thank you for that. I'm sure others are grateful as well. For us non-science folks, it's reassuring to have some knowledgeable people around to shed a bit of light on the murky details. 

 

Hi Lapis

 

Thanks for the additional info.  The more the better.  I will look at that syndrome above.  What does the french translate into in english?

 

Also could you send the link on BB for dizziness.  Im sure there’s a great deal if information there.

 

“We have a whole group of dizzy BBs in the Support Group section”

 

Best,

Dm123

´ this is a symtom based taper.  I did post the crossover and taper methodology in detail in the layman’s thread about a month ago´

 

It´s a lot harder to do a symptom based taper if you have basically 4 or 5 other issues, depending on the way you count ... symptoms of what ? I know, noone has the answer. If only local healthcare wasn´t so horrible.

Hi dm123,

Mal de Debarquement means "bad disembarkation", i.e. when you're getting off a boat, plane, car or other mode of transportation. It happens to people who have been on cruises, for instance. But again, the symptoms are similar but the mechanism by which it happens is different. There was a study in NYC not long ago, and they found that the treatment they came up with helped some of the motion-induced dizzy people but didn't help as much in those whose dizziness was not motion-induced. Of course, some of those people were taking benzos and SSRIs, so that likely affected outcomes. As far as I know, that NYC clinic continues to do the treatment -- and with variable outcomes.

 

Here's The Dizziness Group link. I started the group quite awhile ago, and you'll find a number of interesting links in the first few pages. I've continued to post vestibular studies and info ever since, and I'm about to post another Mal de Debarquement study soon. I came across it the other day, but I just didn't get a chance to share it yet.

 

http://www.benzobuddies.org/forum/index.php?topic=128947.0

Can anybody explain how this causes muscle rigidity etc?