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

[[Te...]]

Thanks so much, dm123!!

 

My history is very complicated. I sleep well at night. I can't even discuss my blood pressure (it falling, being steady for awhile, and then going very high because of coffee). In the first place, at this medical group they don't even believe that symptoms last this long. I will read the rest of what you said. There is so much to think about here. My bp wasn't high at night, maybe 135 at the most, going to 120 later on in the evening. The reason I didn't mention my diastolic except when my bp was high is because it is usually quite low, in the 60s.

 

I'm going to have to look this over and read very closely. I'm kind of afraid to see the truth about how I've wrecked things through the stupid mistakes I've made. No one on BB has anything similar to this this far out.

 

All I know is I am healing, but at a snail's pace.

 

This is very good research. Thank you, dm123!!

 

P.S. I certainly wish doctors would read this. Their eyes would be, for once, opened wide regarding benzos.

[[Te...]]

Thanks, dm123, for all your research. I think I have to work with what I have now instead of constantly going backwards and regretting and trying to put the puzzle pieces together. It makes me too sad. I cannot even begin to say what a nightmare this has been, but I'm hoping that in some way doctors will finally understand that it's not as simple as a GAD diagnosis or that we have "anxiety" and that's that. Case closed. No further questions. It goes far, far beyond that, seeing and reading the information that you, liberty, and Perseverance have brought up. Many thanks!!

[[cs...]]

Thanks, dm123, for all your research. I think I have to work with what I have now instead of constantly going backwards and regretting and trying to put the puzzle pieces together. It makes me too sad. I cannot even begin to say what a nightmare this has been, but I'm hoping that in some way doctors will finally understand that it's not as simple as a GAD diagnosis or that we have "anxiety" and that's that. Case closed. No further questions. It goes far, far beyond that, seeing and reading the information that you, liberty, and Perseverance have brought up. Many thanks!!

Yes Terry, I agree.  I have much of the research already.  There's much more to present at least as far as interdose wd is concerned.  I haven't focused much on PWS yet, but do have a piece written on LTP derived from Perseverance's paper on the same, that I have not posted.  Unfortunately, LTP might be a good model for abrupt withdrawal, but it does not account for what we see in interdose wd and tolerance and by extension what we see during tapering.    I'm hoping to present the rest of the findings at some point in a clear and concise format. 

 

One of the main results that we have from all the disruptions benzos cause is a very dysregulated action potential curve.  The dynamics of the curve get very distorted as one continues to kindle and build tolerance, and one is ultimately left with very hyperexcitable CNS neurons that fire multiple action potientials at a high rate, with very little stimulus.  At its most extreme form there are seizures.  There's a continuum as one becomes more dependent over time on the drugs and tolerance sets in.  I don't know if all of this will be applicable to you, even if you have a PWS manifestation, but hopefully you might learn some new insights into determining why you are still experiencing symptoms.  But I do agree with you, in looking forward and doing the best you can with what you have.   

[[li...]]

I could pose the question if 'cholinergic hypersensitivity' could be treated as such/directly. Normally, one would think of drugs like antidepressants and antipsychotics ... but with benzos, that's tricky at best. Especially if this 'stress' also comes from other issues than the benzo ... but I don't want to derail dm123, he has enough on his plate ...

[[Te...]]

Thanks!! Very good work!! I know it takes a lot of time getting all the research together, and I appreciate your efforts!!

[[cs...]]

I could pose the question if 'cholinergic hypersensitivity' could be treated as such/directly. Normally, one would think of drugs like antidepressants and antipsychotics ... but with benzos, that's tricky at best. Especially if this 'stress' also comes from other issues than the benzo ... but I don't want to derail dm123, he has enough on his plate ...

Hi liberty, yes i still have those stress ACh links on my list.  I'm going to deal with those in the GPCR topic.  I think phosphorylation has to be introduced prior to that.  Much of the GPCR terminology and literature involves phosphorylation.  We've already seen how important phosphorylation is in terms of receptor trafficking, lifecycle, endocytosis,etc.....  It's also important in understand how GPCRs affect GABAa receptors via ACh, dopamine and serotonin imbalances induced by benzos.

 

I'm going to post ADDENDUM 8 on some high level areas as well as a brief intro to LTP based on a question I got from a BB.

[[cs...]]

ADDENDUM 8: Scope and  A very brief introduction to LTP and why it’s not part of the model

 

 

Scope

 

 

Pers wrote an excellent paper on LTP, as well as another one on Nuclear Mechanisms of PWS.

I want to post the introduction to my LTP paper that I had written a while back while doing independent research on benzodiazaphines. I am posting it to justify why I am not relying on its mechanism for modeling benzodiazaphine interdose withdrawal and interdose wd with tolerance.  I probably should have posted this earlier, as it gives the reader the direction and areas of focus for this particular thread, but when Terry posted the original thread, we had no idea that this thread would thrive like it has.

 

 

  I’m also posting this in response to a fellow BB who asked me a question about something that I think is very closely related to the mechanisms underlying LTP. LTP intimately involves Glutamate  sodium ionic channels, voltage gated Calcium channels, and NMDA channels (which are both voltage gated and ligand gated, but beyond the scope of this section ). 

 

 

My introduction to LTP draws heavily on Pers’ excellent research. In that research, if you recall, she acknowledges that LTP typically requires a massive chloride depletion in the postsynaptic neuron, and that would typically only occur with an abrupt or rapid withdrawal, and with receptor tolerance (i.e., compromised GABAa receptor density and/or sensitivity as indicated in ADDENDUM 6).  I agree with her.  At the end of the paper she did state that although there is no research on it, there might be more moderate or subtle LTPs during a taper that might account for the symptoms that we see during our slow tapers.  This would be in contrast to full LTP, i.e. those severe protracted symptoms seen after a cold turkey.(quote will be included below)  I agree with her on this, but we simply don’t have the data and studies on LTP as it relates to interdose wd and tapering…..  Studies in this area are lacking, in part, due to time constraints of these clinical lab studies.

 

 

I wanted to first give a very high level overview of what I hope will be the direction of this thread.

 

 

There are 5 very high level areas that one should keep in mind when researching benzodiazaphines.  Benzodiazaphines are truly a devil in disguise.  As I alluded to in an earlier post, benzodiazaphines are highly paradoxical.  Everyone reading this knows what I mean.  When one first starts taking benzodiazaphines, things are really good.  The drug is working in the way that it  was pathetically and simplistically designed to do.  I use these derogatory terms, because benzodiazaphines have no regard for the body’s natural homeostatic response. They are blunt and crude “tools” for dealing with symptoms that practitioners don’t want to root cause.  I truly doubt that many of us had innately dysfunctional levels of Extracellular GABA or  innately dysfunctional GABAa receptors. There are real diseases and pathologies that involve dysfunction in these areas, and benzodiazaphines can be therapeutic and even life saving in these areas . 

 

 

However, Many of us are given this blunt instrument for sleep, for example,  which is often very complex in its etiology.  Practitioners don’t want to devote the time to figure out the hormone or neurotransmitter imbalances to effectively treat such complex issues.  The quick and dirty fix is benzodiazaphines.  They are prescribed out of context and with no regard to potential consequences that can arise from long term chronic use.

 

 

There are other drugs like this, of course, but GABAa receptors are particularly sensitive to exogenous ligands that create imbalances in the neuronal membrane potential. They are THE main receptors that are used to maintain inhibitory balance, they are pervasive throughout the CNS, and most importantly, these receptors are very hard to upregulate and normalize once they have been downregulated and  once their cluster arrangement has been distorted.

 

 

Furthermore , once their subunit distribution has been so horribly undermined and mangled (see ADDENDUM 6 part II for one example of this; there are other examples), action potentials are disrupted.  Other neurotransmitter receptor  systems (acetylcholine, serotonin, dopamine, Glutamate )are affected by benzodiazaphines, and this further dysregulates action potential dynamics.  These will be explored in detail in the future.  These are referred to as “other systems” below.

Subunit changes are very profound and change the synaptic and extrasynaptic subunit GABAaR distribution on the surface of the neuron  Extrasynaptic GABAa receptors modulate what is called tonic or longer term inhibition in the neuron, whereas  synaptic GABAa receptors modulate phasic inhibition.  Phasic inhibition is the inhibition we’ve been focused on in regards to the action potential……both types of inhibition are required for neuronal membrane potential stability.

 

 

Most clinical studies formally establish the conditions under which the study is performed and the drug half life used,  because benzodiazaphines can be so paradoxical. Results of a study can be the exact opposite, depending on these conditions. These clinical studies usually fall into one of these 5 areas, although benzodiazaphine research in areas 4 and 5 is desperately lacking.  As a result classic kindling studies and alcohol studies can sometimes be cautiously studied in lieu of the lack of research in benzodiazaphines.

 

 

I have not included single dose in the list below, because with single dose many of the physiological changes that have occurred do revert quickly as the body immediately reestablishes  homeostasis.  Of course, this isn’t always true . With benzodiazaphines, we know that anything is possible.

 

 

We know from alcohol studies, that once the dosing becomes chronic, the changes that occur take much longer to normalize, even after withdrawal.  In addition,  changes in  gene expression that occur in LTP, for example, often take a very long time to reverse…..Individual physiology and genetics do play a role, but are cnot the sole determinant. The benzodiazaphine type, half life, duration of use, frequency of use, total daily dosage, withdrawal method,  and other factors like negative stress, all play a role. This explains, in part, why there is such a wide variety of symptoms, of symptom duration,  of symptom intensity, and of symptom recovery…..

 

 

 

A formal definition of drug tolerance

 

 

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

 

 

Quote

Drug tolerance is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects, however this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction.[5] The process of tolerance development is reversible (e.g., through a drug holiday[6]) and can involve both physiological factors and psychological factors.[7]

End quote

 

 

Quote

Pharmacodynamic tolerance begins when the cellular response to a substance is reduced with repeated use. A common cause of pharmacodynamic tolerance is high concentrations of a substance constantly binding with the receptor, desensitizing it through constant interaction.[12] Other possibilities include a reduction in receptor density (usually associated with receptor agonists), or other mechanisms leading to changes in action potential firing rate.[13] Pharmacodynamic tolerance to a receptor antagonist involves the reverse, i.e., increased receptor firing rate, an increase in receptor density, or other mechanisms.

End quote

 

 

Reference 13 cited above

Klaassen, Curtis D. (2001-07-27). Casarett & Doull's Toxicology: The Basic Science of Poisons (6th ed.). McGraw-Hill Professional. p. 17. ISBN 0-07-134721-6.

 

 

Note changes in sensitization, and/or changes in receptor density(downregulation with agonists or PAMs), and/or mechanisms leading to changes in the Action potential firing rate. This last point, the action potential firing rate,  is very important. It’s not just GABAa receptors that can cause tolerance, or for that matter,  symptoms associated with benzodiazaphine withdrawal. Systems that cause dysfunctional action potential dynamics, referred to as “other systems” above and/or dysfunctional GABAa receptors can both cause tolerance to benzodiazaphines.  The dysfunctional action potential firing rate, ironically, is where the majority of my research has been ultimately pointing to.

 

 

Five Main areas of scope

 

 

1. Cold turkey or abrupt withdrawal from a benzodiazaphine after chronic use (depending on the person’s physiology, we don’t know how dysfunctional the GABAa receptors  or the other systems are.  If the GABAa receptors are tolerant, this can predispose the person to LTP, as explained below)

 

2. Chronic use without tolerance (we don’t know how dysfunctional the GABAa receptors are, but in these cases there seems to be a steady state, and the receptors do not continue to become more dysfunctional.  However, in the absence of the drug, the receptor’s conductance and permeability are most likely compromised, as benzodiazaphines are PAMs of the receptor, and uncoupling is possible. We don’t know how compromised the other systems are, but the drug is still able to compensate such that the person has no symptoms of tolerance.  Individual physiology comes into play here)

 

3. Chronic use with tolerance (changes to the GABAa receptor have occurred, and there is no steady state; the receptor conductance and permeability continue to deteriorate with use, and total daily dosage has to increase.    Other systems mentioned above are dysfunctional and these also affect the action potential firing rate and dynamics.  As noted above, this in and of itself can also cause tolerance to the drug.  I think a lot of very long term Valium users  fall into this bucket.)

 

4. Chronic use with Interdose withdrawal (typically seen with shorter half life benzodiazaphines like lorazepam and alprazolam.  Kindling becomes a factor here, causing changes in the phosphorylation at particular GABAa receptor subunits, increased endocytosis, decreased population density, and decreased inhibitory current.  Thus, the tolerance to the drug has started through kindling; furthermore other systems can be dysfunctional, and this contributes to dysfunctional action potential dynamics)

 

5. Chronic use with Interdose withdrawal with tolerance (same as number 4, but the receptor is not at steady state , and dosage needs to be increased to compensate as the receptors conductance and permeability deteriorate. The other systems that affect the action potential dynamics  also contribute to drug tolerance and withdrawal symptoms)

 

 

There are many other physiological systems affected  as one progresses from 2 through 5, and one often does not progress through all of these stages.  In fact some can stay in the same bucket for life due to their unique physiology.

 

 

I personally progressed from 2 , and then directly to 4.  I never had to increase my total daily dosage, but had to split up the short acting benzodiazaphine into 2 separate doses to help dealing with worsening withdrawal symptoms.  Had I not crossed over, I would  have had to increase the  total daily dose.  I was severely kindled at the time of crossover…..

 

 

There’s no doubt that 4 and 5 are a continuum of the same process.  Kindling, in and of itself has been shown to cause a downregulation of GABAa receptors, thus tolerance to the drug  has already started in 4, according to the strict definition of tolerance .  The action potential dynamics can already be dysfunctional at this stage due to dysregulation of those other systems.

 

 

Kindling is a separate topic to be explored at a later time.

 

I will try to narrow the focus of this thread to areas 3,4, and 5 because many of the people tapering fall into one of these buckets.  Hopefully,  we can learn about additional safe and effective tapering strategies in the process.  We will also learn what not to do, like erratically dose with short acting benzodiazaphines .  Since LTP, for the most part, falls into bucket 1, it’s not part of the model for 4 and 5.

 

A very very brief introduction to LTP.

 

Please note, normal extracellular Glutamate is assumed to be hitting the Glutamate ionic channels below(Na influx channels).  We are not making any assumption on changes in extracellular Glutamate.

 

 

Input stimuli: A benzodiazaphine or PAM, tolerance to the PAM, and abrupt discontinuation of the benzodiazaphine, i.e. Complete withdrawal or cold turkey

 

This is a very complex area of continuing research.  Please refer to Pers’s papers on Nuclear Mechansims of PWS,  and  also Glutamate, LTP, and Withdrawal.  Also she has a paper on How GABAa receptors are created, that explains a lot about gene regulation, transcription, and gene expression, which is helpful in understanding this topic.

 

Many of the studies in the above references are withdrawal studies, i.e. the drug is completely withdrawn from the lab subjects, and they are not exposed to  truly long term Benzo usage.  I don’t know if these studies are directly applicable to one who is tapering and still on the benzodiazaphine.  The quotes below my summary explain this clearly.

 

I am reposting the links from the introduction to this paper , so that this module can also be a standalone module.  An understanding in these areas will help the reader to better understand the concepts in this section.

 

 

Excerpt

 

Some additional general references in the links below might help in understanding the various  parts of this paper  (Dynamic regulation of receptors, LTP, etc)

 

Excellent sections on DNA, RNA, mRNA, transcription,translation. Protein synthesis, etc.  Pers has an excellent paper on this as well

 

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

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

https://en.m.wikipedia.org/wiki/Translation_(biology)

https://en.m.wikipedia.org/wiki/Transcription_(biology)

 

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

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

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

 

End excerpt

 

My summary:

 

LTP upregulation and sensitization of the AMPA receptors is very significant in that it is not a homeostatic change like the majority of the changes to the GABAa receptor issues above.  This is because gene expression, activation of protein kinases (like CaMKII), and a predisposition to depolarization (due to tolerance in the GABAa receptors, explained above, and a tendency toward chloride depletion) form the basis of the upregulation and sensitization. There is no exogenous ligand binding to the Glutamate ionic channels.

 

The predisposition to chloride depletion is a major premise in the model when discussing it in the context of benzodiazaphines and their withdrawal. This is because it could instigate rapid depolarization of the post synaptic neuron during complete withdrawal of the drug, assuming glutamate is still hitting the glutamate receptors on the post synaptic neuron. The rapid depolarization activates what are called NMDA and voltage gated Ca2+ channels in the post synaptic  neuron, leading to a massive influx of Ca2+ into the neuron.  This massive influx of Ca2+ activates protein kinases like CaMKII that enhance channel conductance of the AMPA receptors via phosphorylation.  CaMKII also promotes the movement of AMPA receptors into the synapse.(i.e., a population density change or upregulation).

 

We don’t know if this can occur during Benzo drug administration, during tolerance or during a taper. We hope that LTP AMPA changes do not occur during these phases, because E-LTP of the glutamate receptors can lead to L-LTP changes to the receptor.  This L-LTP involves a maintenance kinase protein that will cause the changes to persist.

 

 

In short,  the E-LTP phase involves both enhanced channel conduction of the AMPA Glutamate receptor on the ion channel, as well as the movement of AMPA receptors from intracellular stores into the synapse via lateral diffusion.  This means increased sensitivity(changes to the receptor conductance and permeability ) + increased density(increased density means receptor upregulation)    The L-LTP phase  also involves the continued massive influx of Ca2+ ions into the post synaptic neuron, activating enzymes which  activate transcription factors that alter gene expression leading to further synthesis of new AMPA receptors (continued increase in density) and the synthesis of a maintenance protein.  This would be significant for PWS, as the quotes below clearly articulate.

 

 

Quote

Success stories offer anecdotal evidence that reversal of neuroadaptive changes can and do happen anywhere from months to years after benzodiazepine discontinuation.  When studying benzodiazepines, what most research studies consider ‘long term’ benzodiazepine treatment only tends to be anywhere from 7-32 days, and, the effects in neurons after withdrawal are typically examined anywhere from 6 hours to 7 days after withdrawal has been induced. (9)  To my knowledge there have not been any long term studies examining reversals of neuroadaptations after withdrawal associated with long term benzo usage.  Some researchers have made assumptions as to the reversibility of these changes based on short term studies.  Without long term studies, any claims regarding reversibility of long term changes in gene expression or LTP like occurrences would be unsubstantiated, and perhaps, reckless.  In a 2013 review of a paper compiled by representatives from the Royal College of Psychiatrists and the British Association for Psychopharmacology Ashton stated the following:

 

“The effects on the brain of long-term benzodiazepine use have never been adequately researched despite the reports of many patients of enduring, perhaps irreversible, adverse effects.” (17)

End quote

 

 

And this regarding E-LTP and L-LTP changes to the AMPA receptor:

 

 

Quote

LTP like changes that were observed with BZ withdrawal in the previous studies happened under conditions where the drug was abruptly discontinued.  However, it has not been ruled out that these same type of changes may happen to varying degrees after different types of tapering methods.  Researchers have only investigated abrupt discontinuation thus far.  Abrupt discontinuation might initiate the LTP by causing a rapid decease in the influx of chloride thereby depolarizing the neurons.

 

Perhaps if LTPs happen during or after a taper they may not be as numerous, especially if the taper is slow- as tapering allows neurons time to make reversals to neuroadaptations and would therefore ‘soften the blow.’  Thus the decrease in chloride levels entering the neuron would not be as drastic after a taper as it will be with a rapid or abrupt discontinuation.  This may be the underlying reason why withdrawal symptoms after tapering may fewer or less intense that Cold Turkey (CT) and rapid detox methods, and why CTs and rapid detox methods are more closely associated with protracted symptoms.  This is not to imply that symptoms cannot be numerous or intense after a taper, rather it simply offers a plausible explanation for the differences between the two scenarios

 

End quote

 

 

 

[[li...]]

'Quote

Success stories offer anecdotal evidence that reversal of neuroadaptive changes can and do happen anywhere from months to years after benzodiazepine discontinuation.  When studying benzodiazepines, what most research studies consider ‘long term’ benzodiazepine treatment only tends to be anywhere from 7-32 days, and, the effects in neurons after withdrawal are typically examined anywhere from 6 hours to 7 days after withdrawal has been induced. (9)  To my knowledge there have not been any long term studies examining reversals of neuroadaptations after withdrawal associated with long term benzo usage.  Some researchers have made assumptions as to the reversibility of these changes based on short term studies.  Without long term studies, any claims regarding reversibility of long term changes in gene expression or LTP like occurrences would be unsubstantiated, and perhaps, reckless.  In a 2013 review of a paper compiled by representatives from the Royal College of Psychiatrists and the British Association for Psychopharmacology Ashton stated the following:

 

“The effects on the brain of long-term benzodiazepine use have never been adequately researched despite the reports of many patients of enduring, perhaps irreversible, adverse effects.” (17)

End quote'

 

Bold (1) I think that's pretty much a key phrase, although it may not encompass all.

Bold (2) That's sad. Also irresponsible. It wouldn't cost that much money. I vaguely seem to recall (unreliably!) from many years ago, someone was granted access to soem documentation in the vaults of Roche, under a non-disclosure agreement. Possibly related to clonazepam ? It would not be surprise me if Roche did a little more legwork that they want to keep buried.

Long term cognitive effects suggest affected cholinergic neurons, although this interpretation may be incorrect.

 

As far as avoiding LPT goes, would the following procedure not have a high probably of success in the unkindled brain: stopping the benzo, putting the patient on an anticonvulsant like carbamazepine ? Obviously, key is if it would work for the patient. There are anecdotal success stories.

 

 

[[cs...]]

'Quote

Success stories offer anecdotal evidence that reversal of neuroadaptive changes can and do happen anywhere from months to years after benzodiazepine discontinuation.  When studying benzodiazepines, what most research studies consider ‘long term’ benzodiazepine treatment only tends to be anywhere from 7-32 days, and, the effects in neurons after withdrawal are typically examined anywhere from 6 hours to 7 days after withdrawal has been induced. (9)  To my knowledge there have not been any long term studies examining reversals of neuroadaptations after withdrawal associated with long term benzo usage.  Some researchers have made assumptions as to the reversibility of these changes based on short term studies.  Without long term studies, any claims regarding reversibility of long term changes in gene expression or LTP like occurrences would be unsubstantiated, and perhaps, reckless.  In a 2013 review of a paper compiled by representatives from the Royal College of Psychiatrists and the British Association for Psychopharmacology Ashton stated the following:

 

“The effects on the brain of long-term benzodiazepine use have never been adequately researched despite the reports of many patients of enduring, perhaps irreversible, adverse effects.” (17)

End quote'

 

Bold (1) I think that's pretty much a key phrase, although it may not encompass all.

Bold (2) That's sad. Also irresponsible. It wouldn't cost that much money. I vaguely seem to recall (unreliably!) from many years ago, someone was granted access to soem documentation in the vaults of Roche, under a non-disclosure agreement. Possibly related to clonazepam ? It would not be surprise me if Roche did a little more legwork that they want to keep buried.

Long term cognitive effects suggest affected cholinergic neurons, although this interpretation may be incorrect.

 

As far as avoiding LPT goes, would the following procedure not have a high probably of success in the unkindled brain: stopping the benzo, putting the patient on an anticonvulsant like carbamazepine ? Obviously, key is if it would work for the patient. There are anecdotal success stories.

 

Hi liberty, I agree it's sad about the studies in long term benzodiazaphine use with abrupt withdrawal.  The interdose wd/kindling research with benzodiazaphines is also a bit sparse, but not as lacking as cold turkey after long term use.  For interdose wd we can also draw on chronic alcohol studies , classic kindling studies, epileptogenesis research , and binge drinking alcohol studies to supplement the lack of research.

 

I'm not a medical doctor, and I understand your question, and from what I have seen on BB, abrupt withdrawal even with anitseizure meds is a risky endeavor.  It seems that some people do ok with rapid detox,,and others don't.  I personally don't think it's worth the risk.    I think there might be other veterans that would know more about the success rate from an anecdotal perspective than I do......  We know that even with seizure prevention some rapid detoxes still result in PWS, and possibly some form of LTP.    It's a great question......

[[Su...]]

thanks for all this invaluable information.

I would be very interested in what you know about kindling as i her so many conflicting things about it, as to what it is or even if it exists at all.

I know you mentioned that would come at a later date, just putting in a hope that the date is soon, simply out of my interest in the topic.

Many thanks for all that you do!

SS

[[...]]

Thanks for this thread .... I've no idea if this is at all of interest or relevant ,

but I'd like to add a little something that I've thought about relative to the brain and healing. I feel there's possibly a trauma factor in cold turkeys and rapid withdrawals that maybe causes brain lesions and ongoing symptoms.

 

There's a German man called dr . Hamer ( passed away recently) who spent a lot of his life researching cancer and trauma , and how shock effects the brain , he was able to image parts of the brain and make connections to other parts of the body where specifically,  cancers would manifest.

In his work ( he was an oncologist) , he found that he had over 90% cure  success rate with cancer patients simply by dealing with the traumas / shocks.

He had his license taken away in Germany for this research ! And lived abroad to continue his research .

Anyway , relative to benzos , it's not the whole picture , but I wonder how , if the brain is shocked, perhaps it causes lesions that then cause symptoms ongoing ....in the case of abrupt discontinuation this would  not neccesarily be a conscious shock, ( also can very much be) but  then not are shocks in those that develop cancers always... They are repressed in the subconscious.

I also wonder if this plays some roll in kindling ? Repeated feelings / symptoms of WD that the brain then patterns subconsciously,and physically in both the brain and thus the body ..... I'm not a scientist so I don't if any of this makes sense .

 

If you want to check out his work you can google Dr. Hamer ,German  new medicine .

He was against antianxiety meds , antidepressants , also steroids , as he felt they also suppressed the emotional roots of disease . Remarkable man ....he did go on to explore all kinds of other body illnesses related to trauma and shock . He found always that if the original shock was brought to consciousness , and a different meaning found in present time , the body would start to "reverse" the imbalance / illness.

 

MiYu

( both he and his wife developed cancer after their son died in a tragic accident , this initiated his research . He survived his cancer, his wife did not. He had access to many patients as he was an oncologist . So began his work )

[[Su...]]

Interesting stuff Miyu!

There is lots of research about how trauma effects humans in other areas, especially when it comes to depression, anxiety and psychotic conditions.  And the working definition of trauma for mental health professionals is any experience that overwhelms the person, nervous system.....

I worked in the trauma field doing counselling for many years and this w/d is definitely traumatic for me.

SS

[[Be...]]

Circumstances that are negative and out of our control produce trauma.  I've got it badly.  I've got PTSD very badly.  Cancer doesn't run in my family, so I don't expect I'll get it.  Heart disease and strokes does run in the family, so I believe trauma can bring out those genetic problems and make someone very sick.  I've already been diagnosed with Thrombophilia--at risk of stroke and heart attack, based on some lab tests. 

[[Su...]]

Circumstances that are negative and out of our control produce trauma. 

Yes! circumstances that are negative and out of our control overwhelm the nervous system!  We can't self-regulate in that kind of environment, and often are given no mirroring in how to self-regulate, that is traumatic for any organism.... I'm so sorry that you were living in an environment like that...

There are often physical manifestations of this in people...cancer, heart disease, lots of conditions can be linked to stress and trauma.

And I think this thread addresses some of the cellular manifestations of that kind of trauma, brought on by meds... as prescribed..

 

[[Be...]]

I'm still living in an environment that is extremely stressful for me.  I collapse on the floor alot because my CNS is damaged and so overwhelmed. 

[[Le...]]

dm123, thank you so much for all the time and effort you've put into researching this topic and trying to provide answers as to why the suffering. I'm trying to digest what you have presented in small pieces, but it is still a struggle for me. I don't understand Area of Scope #3. Will you expand on this in future posts? If not I understand....you've got a lot on your research plate as it is! I am long term user, was CT'd and metabolize the drug too fast, which worries me.

 

Again, thank you for all the wonderful research. Wishing you well, Left

 

"Areas of Scope

 

....3.  Chronic use with tolerance (changes to the GABAa receptor have occurred, and there is no steady state; the receptor conductance and permeability continue to deteriorate with use, and total daily dosage has to increase.  Other systems mentioned above are dysfunctional and these also affect the action potential firing rate and dynamics.  As noted above, this in and of itself can also cause tolerance to the drug.  I think a lot of very long term Valium users  fall into this bucket.)"

[[cs...]]

thanks for all this invaluable information.

I would be very interested in what you know about kindling as i her so many conflicting things about it, as to what it is or even if it exists at all.

I know you mentioned that would come at a later date, just putting in a hope that the date is soon, simply out of my interest in the topic.

Many thanks for all that you do!

SS

Hi SS,

 

Yes , I feel the same way about kindling.  There are definitive studies on its effects relative to GABAa inhibitory dyregulation.  There are lots of studies in the areas of alcohol chronic and binge drinking and epileptogenesis (development of epilepsy) and how kindling compromises the inhibitory conductance.  There are less such studies in the area of benzodiazaphines.

.

  Some of the reasons for the compromise in inhibitory signaling are clear.  For example, repeated induced seizures lowers seizure threshold, and if continued leads to status epilepticus or SE, where seizures occur spontaneously and unabated.  In these clinical studies it's clear that there is a decrease in the phosphorylation of β GABAa subunits (synaptic) by PKC.  Phosphorylation of the β subunit prevents a protein called AP2 from binding to a particular motif(protein area) of the β subunit, preventing absorption of the receptor.  Since repeated seizures causes a decrease in this phosphorylation, there is an increased absorption of β subunit receptors, meaning a downregulation of these synaptic receptors, and less inhibitory conductance.(less overall Cl- influx from the receptors).  This is an intracellular response. Progressively lower seizure threshold.....

 

  I have to present a piece on phosphorylation prior to kindling, because phosphorylation is critical to understanding these topics, and others. Otherwise it will be hard for people to understand. Note the quote below.  The benzodiazaphine sensitive receptors are downregulated in this seizure study, and we extrapolate these references to what we think goes on with exogenous benzodiazaphine kindling. 

 

 

Quote

(A) Repetitive, non-abating seizures that lead to status epilepticus result in a decrease in the phosphorylation of GABAA receptor β subunits by PKC. This leads to an increased associated with the clathrin adaptor AP2, followed by increased internalization via clathrin-mediated endocytosis. Decreased numbers of synaptic GABAA receptors lead to reduced synaptic inhibition (ie. increased excitatory drive and a lower seizure threshold) as well as decreased benzodiazepine sensitivity.

End quote

 

Extrapolating to benzodiazaphines is the difficult part.  We know in kindling epileptogenesis that there is an imbalance of excitatory vs. inhibitory signaling

 

Quote

Hyperexcitability, a characteristic feature of epileptogenesis in which the likelihood that neural networks will be activated is increased, may be due to loss of inhibitory neurons, such as GABAergic interneurons, that would normally balance out the excitability of other neurons.[2] Neuronal circuits that are epileptic are known for being hyperexcitable and for lacking the normal balance of glutamatergic neurons (those that usually increase excitation) and GABAergic ones (those that decrease it).[5] In addition, the levels of GABA and the sensitivity of GABAA receptors to the neurotransmitter may decrease, resulting in less inhibition.[2]

End quote

 

But is it just GABA?

There are lots of references in this area that still need to be reviewed to sort this out, expecially on the Glutamate side and kindling and tolerance development.  I think that kindling starts with this downregulation of GABAa receptors,above,  i.e. Tolerance especially to benzodiazaphine  sensitive GABAa receptors .  But we know that tolerance involves much more than just GABAa receptors.

 

We know that NMDA antagonists help with tolerance.  See the other thread in the Chewing the Fat section.  Does this mean that upregulated or sensitized NMDA or Glutamate channels are responsible for tolerance?  It could,  but the exact cause of why the receptors are unregulated in the first place is still very elusive.  Or, NMDA receptors might not be directly related to tolerance development, and antagonizing the excitatory path is just helping calm the overly excited neuron.

 

consider this:

 

This hyperexcitability that's present in kindling..... I believe it accounts for most of the tolerance symptoms that we have in chronic and interdose wd . At first glance the cause  would implicate Glutamate channels. However,  a hyperexcitable neuron, which is one that fires rapid action potentials with very little input stimulus, i.e.tends toward depolarization, can have many factors that are making it Hyperexcitable.  For example, there are intracellular processes that can change the dynamics of the action potential and make it more prone to depolarization.  GPCRs, for example. We have not gotten to these, but muscarinic receptors are a type of GPCR.  We know that in studies, stimulation of muscarinic  receptors cause a DECREASE in inhibitory signaling of GABAa receptors.

 

  (Reference :Receptor for Activated C Kinase-1 Facilitates Protein Kinase C- Dependent Phosphorylation and Functional Modulation of GABAA Receptors with the Activation of G-Protein-Coupled Receptors

Nicholas J. Brandon,1 Jasmina N. Jovanovic,1 Trevor G. Smart,2 and Stephen J. Moss1)

 

 

 

We know that ACh levels drop with chronic Benzo use, but can tonically rise with withdrawal. 

 

This is just one example of why its so complicated to determine how we end up with a hyperexcitable neuron during kindling. 

 

Here is a reference from an alcohol study implicating NMDA sensitization during chronic use .

Quote

In vitro studies have demonstrated that ethanol acutely inhibits NMDA functions (16,67,85), but chronic administration of ethanol may result in increased activity of this system (16,23,31).

.....

since  the NMDA receptor system is involved in processes underlying learning and memory, and since both rapid tolerance and chronic tolerance have been shown to be in- fluenced by, or to be related to, processes linked to learning and memory (40,94), we hy- pothesized that the acquisition of ethanol tolerance should similarly be subject to inter- ference by NMDA antagonists

End quote

 

Tolerance plays a part in all three items I mentioned in ADDENDUM 8.  Items 3,4, and 5.  But it appears to be caused by many different systems. ACh, serotonin, Glutamate, GABA, neurosteroids, nitric oxide,etc...

 

Another example. Note most of the serotonin receptors are GPCRs, and they are coupled to GABAa receptors , and from reading below perhaps NMDA channels.  The increased tolerance from l-tryptophan might be due to either one or both of these.....

Quote

For example, treatment with L-tryptophan, that results in increased serotonergic activity stimulated ethanol rapid tolerance as was shown previously for chronic tolerance (62,63). The increased tolerance caused by pretreatment with 5-hy- droxytryptophan was blocked by pretreatment with MK-801 in a dose-response fashion (47) suggesting that the NMDA system is involved in some way in the serotonergic modu- lation of the acquisition of ethanol tolerance.

End quote

 

Since tolerance plays such a critical role in areas 3,4, and 5 in ADDENDUM 8, I think we need to take a closer look at benzodiazaphines tolerance development before we try to figure out why kindling causes a hyperexcitable neuron. 

[[cs...]]

dm123, thank you so much for all the time and effort you've put into researching this topic and trying to provide answers as to why the suffering. I'm trying to digest what you have presented in small pieces, but it is still a struggle for me. I don't understand Area of Scope #3. Will you expand on this in future posts? If not I understand....you've got a lot on your research plate as it is! I am long term user, was CT'd and metabolize the drug too fast, which worries me.

 

Again, thank you for all the wonderful research. Wishing you well, Left

 

"Areas of Scope

 

....3.  Chronic use with tolerance (changes to the GABAa receptor have occurred, and there is no steady state; the receptor conductance and permeability continue to deteriorate with use, and total daily dosage has to increase.  Other systems mentioned above are dysfunctional and these also affect the action potential firing rate and dynamics.  As noted above, this in and of itself can also cause tolerance to the drug.  I think a lot of very long term Valium users  fall into this bucket.)"

 

Hi left, if you were cold turkeyed you would fall into area 1, which I have not researched much.    Pers' papers on LTP might give us a clue as to what happens in cold turkey.  It's very different from the other items.

 

In item 3', we see people developing tolerance to the drug, i.e., they have to escalate dosage, but they never experienced interdose wd, because of the drug's very long half life.  I may not be right, but I don't think these people are kindled.  I say this from very personal experience.  I started to experience interdose wd with lorazepam after 2 yrs of all at once dosing.  Then I started to get very sick, and it took me a long time to figure out it was the drug. I became hyperexcitable.  I was kindled.  It was a different feeling from anything before.  I never had to increase the dose during this time.  Things in hindsight are always easy to figure out.  There is agreement that short acting benzos kindle the nervous system.  I split the drug and was a bit better, but I was getting to the point where I needed to increase total daily dose.  Once I crossed over, things were much better, but it took a few weeks.

 

There seems to be a lot of different things that affect tolerance of benzodiazaphines. That is what I meant above.  It doesn't have to be all GABAa receptors, even though they play a large part..... Endogenous neurosteroids, serotonin, dopamine and acetylcholine changes, etc....all play a part

 

For example endogenous neurosteroid are PAMs.  These studies are interesting

 

Quote

In support, ovariectomy attenuated the development of tolerance to the anticonvulsant actions of diazepam [153]. Moreover, co-administration of the neurosteroids allopregnanolone or pregnenolone (but not dehydroepiandrosterone) prevented the development of tolerance after chronic treatment with either triazolam and diazepam [154].

End quote

 

References

 

N. Usami, T. Yamamoto, S. Shintani et al., “Substrate specificity of human 3(20)α-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines,” Biological and Pharmaceutical Bulletin, vol. 25, no. 4, pp. 441–445, 2002.

M. A. Wilson and R. Biscardi, “Effects of gender and gonadectomy on responses to chronic benzodiazepine receptor agonist exposure in rats,” European Journal of Pharmacology, vol. 215, no. 1, pp. 99–107, 1992.

 

End quote

 

 

If you don't mind me asking:

Why did you CT?

[[Le...]]

Hi dm123, I didn't choose to CT, it was a medical boo boo. I was hospitalized for acute back pain and low sodium. Didn't know I was dependent on benzos at the time but looking back it makes sense. The hospital doctor didn't approve or order most of my meds - valium 40 mg was taken away, depakote was taken away, and trileptal was drastically reduced. By day 2 all heck broke loose...all the really bad stuff. Ended up in psych ward for 9 days. Psych ward reinstated me to 20 mgs, but it wasn't enough after all the damage. I fully reinstated once released. My former psych doctor didn't let me stabilize after the CT, and started tapering me within a month of full reinstatement. To further complicate things, I am an ultrarapid metabolizer of V and now dose 4xs a day. I was dealing with inter-dose WD for years but didn't know that's why I always felt so so sick. Sorry for the rambling response, my brain is not working too well these days.

 

Thank you again for the invaluable research you are doing.

[[cs...]]

Circumstances that are negative and out of our control produce trauma. 

Yes! circumstances that are negative and out of our control overwhelm the nervous system!  We can't self-regulate in that kind of environment, and often are given no mirroring in how to self-regulate, that is traumatic for any organism.... I'm so sorry that you were living in an environment like that...

There are often physical manifestations of this in people...cancer, heart disease, lots of conditions can be linked to stress and trauma.

And I think this thread addresses some of the cellular manifestations of that kind of trauma, brought on by meds... as prescribed..

 

I agree.  If the tone of this thread is implicating benzodiazaphines as an inducer of trauma, then I am very glad about that.  The derogatory terms I use to describe what it does to our physiology or has done to our physiology is something everyone of us has felt.    If someone asks me how to describe hyperexcitability, I can do it, but I think if one has not lived it, it is very very difficult for them to fully understand it....

[[cs...]]

Thanks for this thread .... I've no idea if this is at all of interest or relevant ,

but I'd like to add a little something that I've thought about relative to the brain and healing. I feel there's possibly a trauma factor in cold turkeys and rapid withdrawals that maybe causes brain lesions and ongoing symptoms.

 

There's a German man called dr . Hamer ( passed away recently) who spent a lot of his life researching cancer and trauma , and how shock effects the brain , he was able to image parts of the brain and make connections to other parts of the body where specifically,  cancers would manifest.

In his work ( he was an oncologist) , he found that he had over 90% cure  success rate with cancer patients simply by dealing with the traumas / shocks.

He had his license taken away in Germany for this research ! And lived abroad to continue his research .

Anyway , relative to benzos , it's not the whole picture , but I wonder how , if the brain is shocked, perhaps it causes lesions that then cause symptoms ongoing ....in the case of abrupt discontinuation this would  not neccesarily be a conscious shock, ( also can very much be) but  then not are shocks in those that develop cancers always... They are repressed in the subconscious.

I also wonder if this plays some roll in kindling ? Repeated feelings / symptoms of WD that the brain then patterns subconsciously,and physically in both the brain and thus the body ..... I'm not a scientist so I don't if any of this makes sense .

 

If you want to check out his work you can google Dr. Hamer ,German  new medicine .

He was against antianxiety meds , antidepressants , also steroids , as he felt they also suppressed the emotional roots of disease . Remarkable man ....he did go on to explore all kinds of other body illnesses related to trauma and shock . He found always that if the original shock was brought to consciousness , and a different meaning found in present time , the body would start to "reverse" the imbalance / illness.

 

MiYu

( both he and his wife developed cancer after their son died in a tragic accident , this initiated his research . He survived his cancer, his wife did not. He had access to many patients as he was an oncologist . So began his work )

 

Hi, thanks for this very interesting post.  I'm going to look into his work.  Speaking of trauma, the field of long term potentiation is huge, and very interesting.  This might interest you in the context of repeated traumas and fear processing,,,,,

 

 

 

LTP in fear processing

Quote

 

 

While the long-term potentiation of synapses in cell culture seems to provide an elegant substrate for learning and memory, the contribution of LTP to behavioral learning — that is, learning at the level of the whole organism — cannot simply be extrapolated from in vitro studies. For this reason, considerable effort has been dedicated to establishing whether LTP is a requirement for learning and memory in living animals. Because of this, LTP also plays a crucial role in fear processing.

 

End quote

 

 

 

Quote

 

In 2006, Jonathan Whitlock and colleagues reported on a series of experiments that provided perhaps the strongest evidence of LTP's role in behavioral memory, arguing that to conclude that LTP underlies behavioral learning, the two processes must both mimic and occlude one another.[50] Employing an inhibitory avoidance learning paradigm, researchers trained rats in a two-chambered apparatus with light and dark chambers, the latter being fitted with a device that delivered a foot shock to the rat upon entry. An analysis of CA1 hippocampal synapses revealed that inhibitory avoidance training induced in vivo AMPA receptor phosphorylation of the same type as that seen in LTP in vitro; that is, inhibitory avoidance training mimicked LTP. In addition, synapses potentiated during training could not be further potentiated by experimental manipulations that would have otherwise induced LTP; that is, inhibitory avoidance training occluded LTP. In a response to the article, Timothy Bliss and colleagues remarked that these and related experiments "substantially advance the case for LTP as a neural mechanism for memory."[51]

End quote

 

 

LTP in contextual cues to instigate anxiety(fear)

 

From Pers’ paper on LTP

 

In this study, rats were administered diazepam (DZ) for 18 days then abruptly taken off the drug.  The rats exhibited symptoms of withdrawal anxiety for 4 days after the drug was withdrawn.  On the 15th day the rats were re-exposed to the same environment (a plus maze, or PM) where they had originally experienced the withdrawal symptoms.  The contextual cues in the environment of the PM triggered a recurrence of the withdrawal symptoms. If the contextual cues were changed in the environment of the PM, the rats did not experience a recurrence of the withdrawal symptoms on re-exposure. 

 

“In the present investigation we demonstrated that changes in the environmental cues associated with DZ withdrawal prevented the expression of the anxiety-like behavior observed during PM test re-exposure.” (19)

 

 

The researchers attributed the recurrence of symptoms in conjunction with contextual cues to a lowered threshold to generate LTP.  Next they repeated the experiment, but this time they administered the PKMζ inhibitor ZIP two hours prior to re-exposure and observed the following:

 

“In the present study we found that inhibition of PKMζ prior to re-exposure to the withdrawal environment with preserved contextual cues not only prevented the anxiety expression but also reversed the facilitated LTP in all DZ-dependent animals, suggesting that plasticity in the hippocampus has a crucial role in maintenance of these memories that were vulnerable to the amnesic effects of ZIP.” (19)

 

It was interesting that this study showed environmental cues could trigger withdrawal symptoms in conjunction with LTPs, which may demonstrate an overlap in functional characteristics between memory LTPs and BZ withdrawal LTPs.  This poses a question as to whether LTPs which occur during withdrawal could share other commonalities with memories.  Other LTPs, such as LTPs involved in chronic pain conditions, have been shown to share characteristics with memory LTPs:

 

 

“…these findings point to a spinally encoded mechanism for the persistence of nociceptive sensitization with molecular underpinnings that closely resemble those involved in L-LTP and the maintenance of long-term memory traces.” (24)

 

 

Functional similarities between withdrawal LTPs and memory LTPs might include such things as distraction and time, which are two concepts discussed frequently with regards to benzo withdrawal.  Distraction appears help reduce withdrawal symptoms, and ironically is also a factor in both avoidance and fading of memories.  Time has been suggested to be the only known cure for withdrawal, similarly it is also the cure for painful memories as ‘time heals all wounds.’  Just as withdrawal symptoms can seemingly pop up again out of the blue, so can memories.  As demonstrated in the previous study, this may be due to contextual cues in the environment, either consciously or subconsciously, triggering the ‘biological memory’ stored in the Central Nervous system (CNS).  Contextual cues may be varied and might result from single or multiple environmental perceptions involving visual, tactile, olfactory, or gustatory senses.  Formation of LTPs may be the reason why withdrawal symptoms can persist for such a long time.

 

 

End quote

 

 

 

 

 

[[cs...]]

Hi dm123, I didn't choose to CT, it was a medical boo boo. I was hospitalized for acute back pain and low sodium. Didn't know I was dependent on benzos at the time but looking back it makes sense. The hospital doctor didn't approve or order most of my meds - valium 40 mg was taken away, depakote was taken away, and trileptal was drastically reduced. By day 2 all heck broke loose...all the really bad stuff. Ended up in psych ward for 9 days. Psych ward reinstated me to 20 mgs, but it wasn't enough after all the damage. I fully reinstated once released. My former psych doctor didn't let me stabilize after the CT, and started tapering me within a month of full reinstatement. To further complicate things, I am an ultrarapid metabolizer of V and now dose 4xs a day. I was dealing with inter-dose WD for years but didn't know that's why I always felt so so sick. Sorry for the rambling response, my brain is not working too well these days.

 

Thank you again for the invaluable research you are doing.

 

This is horrible.  40 mgs of Valium.  I'm so sorry you had to go through this.  Now I understand the context of your question.  When I wrote item 3, i was hoping to hear from a long time valium user who might have experienced interdose wd.  Benzos never cease to amaze me.  It goes to show us how complex everything is.  I did not experience interdose wd on lorazepam for years, and you developed interdose wd on Valium .  We are all so different....

[[Le...]]

Thanks dm123, it was horrific to say the least. That being said, it appears I tick off the boxes for items 1, 3, 4, and 5 under Areas of Scope. Needless to say, I will be reading your posts with great interest and enthusiasm even if I don't fully understand everything.

[[Su...]]

Hi DM123,

thanks so much for this information, and I'm glad that the references to psychotherapeutic terms of trauma fit in with your thread.

 

The info on kindling is fascinating.....as with everything about this process it's really not understood is it? (pr perhaps it's my unscientific mind)

 

I have never had a seizure, and even though used short acting and pernicious Xanax really didn't even have any interdose w/d until about 17 years of use.  Then it lasted about 9 months before I committed to the taper.  What I'm reading from your posts leads me to think that the kindling phenomena may not be a significant factor in my w/d.  (although length of usage is) and possibly the ridiculously large cuts I made in the beginning -- where glutamate was running the show and I felt so very very unwell will factor into my w/d.  If for nothing else than the learned behaviour state specific learning that occurred.

(I may need to get a new couch!  The old one is where I was living my life...  )

 

Again I want to thank you for putting all of this here on BB.  Every time I read your posts -- although over my head -- I think I learn a wee bit more about the processes happening in my CNS and HPA axis. The science starts to make some sense and the physiology that is impacted becomes a bit more clear.  That helps me with the idea that I really need to get out of the way and let my body heal -- somehow a hard lesson to put into practice!

 

I hope that your presentation of your papers go very well!

All the best to everyone here (and on BB)

SS

[[Te...]]

dm123, are you able to find any research on benzos and platelets? I've read of people being low in platelets, but mine were as wonky as my blood pressure. Usually, while I was taking Ativan, my platelets were in the 900,000 range. They remained that high throughout the duration of Ativan and into Klonopin. My hematologist had no answers. He kept giving me test after test. He gave me iron infusions, which didn't change a thing. I didn't want a bone marrow biopsy. Then after my TIA in 2015, the platelets bounced up to 1.8 million. I had to get off almost all the pills I was put on in the hospital for them to go down to 700,000. The last time I was tested they were down to 550,000. All my doctor could say was that I had "highly reactive blood."

 

Thank you for all your research so much!! And if you can answer this, I would be grateful!!