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

[[li...]]

https://en.wikipedia.org/wiki/Category:GABAA_receptor_positive_allosteric_modulators

 

This is quite interesting to me. I see Fluoxetine on this list, yet I don't see either Sertraline or Venlafaxine. Out of my own reasons, due to taking Fluoxetine and Ativan together for a while, I wonder if Fluoxetine has any direct/indirect effect on GABAa receptors. There have been claims that Fluoxetine may potentiate ativan, but I have not found any study or any research done to substantiate that claim. Makes me wonder if some of the SSRI's missing on a wiki page are just that, an omission, or if there was more research done on Fluoxetine that made it go up to that list.

 

http://www.drugsdb.com/rx/ativan/ativan-drug-interactions/

 

Hi LPfree2015, I think the later.  A lack of research.  Hydrocortisone, which they had me on while on lorazepam is not on the list but is thought to be a PAM.  it's not officially a neurosteroid.

 

'Hydrocortisone, sold under a number of brand names including Cortef, is the name for the hormone cortisol when supplied as a medication'

It is chemically the same as cortisol ? So that means that that hormone directly affects GABA ?  <feeling screwed>

 

'Quote

 

An important question is how the development of tolerance of benzodiazepines could be reduced. One interesting suggestion could be—rather than intermittent use that can be defined by an individual—to develop benzodiazepine dosing schedules with varying daily doses including placebos. This could result in continued clinical efficacy (obviously depending on the indication) and utilize the placebo effect. The other possibility to reduce tolerance is the currently developing and promising body of literature on subtype-selective GABAA receptor PAMs. From the literature we reviewed, it appears that α2/α3 subtype selective compounds do not lead to tolerance or withdrawal symptoms. However, the underlying mechanism (reduced α1 efficacy or a generally reduced efficacy profile) is unknown. Also, it is presently unclear whether this lack of tolerance also applies to α1- and α5-selective GABAergic positive allosteric modulators, although a broad and unspecific tolerance resulting from selective (and often low potency) compounds seems unlikely.

End quote' I think that clonazepam is relatively selective for alpha2/3. Yet you will build up tolerance/dependence.

 

Anyway, it's all incredibly complicated.

 

'" You try to put the neuron to sleep by excessive inhibitory potentials, and the neuron responds by producing less GABAa receptors that make it to the surface,  You excite and stimulate the neuron, as painful as it is, and the neuron responds by slowing the degradation of subunits(inside the cell) thereby increasing the number of assembled receptors that make it to the surface.  This gives a whole new appreciation to the term downregulation, and gives us insight into one of the mechansims that the cell uses to achieve this.'

 

Remember the animal models, where animals where put on high doses for months, CT'd, followed by abstinence convulsions, after which the muscarinic receptors returned to normal ?

 

Btw, I respectfully disagree about short acting benzos. I'd prefer to haver been on a short acting one. Sure, the effects may be harsher but at least you can taper faster. That whole 'half life' thing can be a ****.

 

And personally, I'm dealing what you could describe as 'non benzo related action potentials'. ('body in distress', mostly having to do with iatrogenic damage not directly caused by the drug)

And for the most part, this is not a 'recognized medical condition' (if you get what I mean) so even in the USA I'd have a hard time getting treatment.

[[Be...]]

dm, I didn't micro taper.  Didn't know anything about it.  I also did everything wrong while on the pills.  I didn't take them everyday and also only took them at bedtime only.  I didn't take a pill the night before and the next day I had a seizure  event at work and had to come home and haven't worked since.  Then sitting in my backroom that day it felt like my brain melted.  Did some real damage.  My brain hasn't been the same since and I knew I'd never work again.  Couldn't think much anymore then.  I don't know what happened?  Maybe it was a mini-stroke?  I may be having micro strokes now alot.  Doc agreed with me a few months ago that it's possible I may have had a stroke.  She wanted me to get memory testing and brain scan, but I don't have insurance and can't afford it.  I had tolerance and interdose w/d for about a year and didn't even know it was from the pills.  My one foot would catch on the floor at work and I walked like I was drunk with balance problems.  Also mental issues started and I started having very bad thoughts about the people I was working with who abused me.  I never used to be like that.  Lost my physical energy and strength then too.  When I finally got off them, all hell broke loose.  Lost my appetite and it's never come back.  My mind is gone now, too.  I suffered so horribly and still am and also I'm getting worse. 

[[cs...]]

https://en.wikipedia.org/wiki/Category:GABAA_receptor_positive_allosteric_modulators

 

This is quite interesting to me. I see Fluoxetine on this list, yet I don't see either Sertraline or Venlafaxine. Out of my own reasons, due to taking Fluoxetine and Ativan together for a while, I wonder if Fluoxetine has any direct/indirect effect on GABAa receptors. There have been claims that Fluoxetine may potentiate ativan, but I have not found any study or any research done to substantiate that claim. Makes me wonder if some of the SSRI's missing on a wiki page are just that, an omission, or if there was more research done on Fluoxetine that made it go up to that list.

 

http://www.drugsdb.com/rx/ativan/ativan-drug-interactions/

 

Hi LPfree2015, I think the later.  A lack of research.  Hydrocortisone, which they had me on while on lorazepam is not on the list but is thought to be a PAM.  it's not officially a neurosteroid.

 

'Hydrocortisone, sold under a number of brand names including Cortef, is the name for the hormone cortisol when supplied as a medication'

It is chemically the same as cortisol ? So that means that that hormone directly affects GABA ?  <feeling screwed>

 

'Quote

 

An important question is how the development of tolerance of benzodiazepines could be reduced. One interesting suggestion could be—rather than intermittent use that can be defined by an individual—to develop benzodiazepine dosing schedules with varying daily doses including placebos. This could result in continued clinical efficacy (obviously depending on the indication) and utilize the placebo effect. The other possibility to reduce tolerance is the currently developing and promising body of literature on subtype-selective GABAA receptor PAMs. From the literature we reviewed, it appears that α2/α3 subtype selective compounds do not lead to tolerance or withdrawal symptoms. However, the underlying mechanism (reduced α1 efficacy or a generally reduced efficacy profile) is unknown. Also, it is presently unclear whether this lack of tolerance also applies to α1- and α5-selective GABAergic positive allosteric modulators, although a broad and unspecific tolerance resulting from selective (and often low potency) compounds seems unlikely.

End quote' I think that clonazepam is relatively selective for alpha2/3. Yet you will build up tolerance/dependence.

 

Anyway, it's all incredibly complicated.

 

'" You try to put the neuron to sleep by excessive inhibitory potentials, and the neuron responds by producing less GABAa receptors that make it to the surface,  You excite and stimulate the neuron, as painful as it is, and the neuron responds by slowing the degradation of subunits(inside the cell) thereby increasing the number of assembled receptors that make it to the surface.  This gives a whole new appreciation to the term downregulation, and gives us insight into one of the mechansims that the cell uses to achieve this.'

 

Remember the animal models, where animals where put on high doses for months, CT'd, followed by abstinence convulsions, after which the muscarinic receptors returned to normal ?

 

Btw, I respectfully disagree about short acting benzos. I'd prefer to haver been on a short acting one. Sure, the effects may be harsher but at least you can taper faster. That whole 'half life' thing can be a ****.

 

And personally, I'm dealing what you could describe as 'non benzo related action potentials'. ('body in distress', mostly having to do with iatrogenic damage not directly caused by the drug)

And for the most part, this is not a 'recognized medical condition' (if you get what I mean) so even in the USA I'd have a hard time getting treatment.

 

Hi liberty, I agree,it's  horribly complex.  I'm not sure a static model is even capable of explaining what happens in interdose wd and tolerance.  But hopefully this thread, as it continues  will shed some light on things. 

I think my damage is iatrogenic as well as directly from the toxic nature of these benzos.  I respect your stand on short life benzos, but still hold to my opinion on them.  They have to be very carefully managed and prescribed.  I was told to dose all at night, clearly a mistake.  The doctors don't know enough about these types of drugs to even correctly dose them, and even if they do, they don't seem to care, since you really can't overdose on benzos alone.....

 

Short half lives......  It's like thyroid hormones.  T4 has a tremendously long half life.  It's easy to dose.  T3 , on the other hand can wind out of control very quickly, and speaking of homeostasis again, really mess things up.  It suppresses TSH, for one thing, and this leads to a cascade of other issues.  The body does not do well with short half life medicines, but I know there are exceptions.  Shortnhalf life meds produce rapid peaks and troughs, and this means the neuron is exposed to severe hyperpolarizations, followed by sharp depolarizations as the drug wears of.  Kindling , in and of itself, like this changes phosphorylation of some subunits as described earlier.  There are lots of studies in this area.  Inhibitory (GABAa) signaling deteriorates over time.  Once tolerance sets in, the whole effect is magnified, especially if dose is not increased.    Some hormones and receptors where designed to work with short acting ligand. For example insulin, but there are not many substitutes for it...

 

I'm not sure about short half life benzos allowing you to taper quicker.  I see your logic, since it stabilizes to a new steady state much quicker, but many people can't taper and don't taper a shorter acitng benzo by single daily dosing it.  They usually split it up during the day.  If you are already in is interdose wd, it's simply too hard to taper with single dosing.  I know this from first hand experience.  All these benzos are bad, but I'm glad you are no longer on lorazepam.    It's like trying to tame a wild lion, and when it decides to roar, it's really bad.

 

Hydrocortisone is similar to cortisol, which he adrenal cortex produces.  Cortisone has to be converted to cortisol by the liver.

They are a bit different in mineral corticosteroid content.

Quote

The principal glucocorticoids are corticosterone and hydrocortisone (cortisol) and the principal mineralocorticoid is aldosterone. Cortisone, originally called compound E, is a glucocorticoid, but also has some mineralocorticoid properties. It quickly converts protein to the carbohydrate glucose (sugar), and it helps regulate salt metabolism. The adrenal cortex's production of cortisone and hydrocortisone is controlled by the hormone ACTH (adrenocorticotropic hormone), which is secreted by the pituitary gland (a small, oval gland attached to the base of the brain).

 

Read more: http://www.discoveriesinmedicine.com/Com-En/Cortisone.html#ixzz4pm092tnR

End quote

 

Yes, that study sent me is still in my paper.  It's part of the GPCR dysregulation that we see.  We know that metabotropic Glu receptors, as well as ACh systems (muscarinic or mAChRs)are effected

by benzodiazaphines.  That's my current area of research, but it's very broad.  Yes once they seized, the mAChRs returned to normal sensitivity.  I think since the mAChRs are coupled to GABAa receptors there is a feedback loop.

 

  Do you have access to the full paper?

[[cs...]]

dm, I didn't micro taper.  Didn't know anything about it.  I also did everything wrong while on the pills.  I didn't take them everyday and also only took them at bedtime only.  I didn't take a pill the night before and the next day I had a seizure  event at work and had to come home and haven't worked since.  Then sitting in my backroom that day it felt like my brain melted.  Did some real damage.  My brain hasn't been the same since and I knew I'd never work again.  Couldn't think much anymore then.  I don't know what happened?  Maybe it was a mini-stroke?  I may be having micro strokes now alot.  Doc agreed with me a few months ago that it's possible I may have had a stroke.  She wanted me to get memory testing and brain scan, but I don't have insurance and can't afford it.  I had tolerance and interdose w/d for about a year and didn't even know it was from the pills.  My one foot would catch on the floor at work and I walked like I was drunk with balance problems.  Also mental issues started and I started having very bad thoughts about the people I was working with who abused me.  I never used to be like that.  Lost my physical energy and strength then too.  When I finally got off them, all hell broke loose.  Lost my appetite and it's never come back.  My mind is gone now, too.  I suffered so horribly and still am and also I'm getting worse.

 

dm, I didn't micro taper.  Didn't know anything about it.  I also did everything wrong while on the pills.  I didn't take them everyday and also only took them at bedtime only.  I didn't take a pill the night before and the next day I had a seizure  event at work and had to come home and haven't worked since.  Then sitting in my backroom that day it felt like my brain melted.  Did some real damage.  My brain hasn't been the same since and I knew I'd never work again.  Couldn't think much anymore then.  I don't know what happened?  Maybe it was a mini-stroke?  I may be having micro strokes now alot.  Doc agreed with me a few months ago that it's possible I may have had a stroke.  She wanted me to get memory testing and brain scan, but I don't have insurance and can't afford it.  I had tolerance and interdose w/d for about a year and didn't even know it was from the pills.  My one foot would catch on the floor at work and I walked like I was drunk with balance problems.  Also mental issues started and I started having very bad thoughts about the people I was working with who abused me.  I never used to be like that.  Lost my physical energy and strength then too.  When I finally got off them, all hell broke loose.  Lost my appetite and it's never come back.  My mind is gone now, too.  I suffered so horribly and still am and also I'm getting worse.

 

Hi BecksBlue, ok.  So it looks like you were on short acting benzos with z drugs.  I only dosed at night with short acting benzos and z drugs and that is what got me in trouble, but I did not CT like you did.  I know if I had I would have seized. I know the feeling.... hyperexcitabilty is what I call it.  I had no choice but to crossover,

 

I know you understand LTP, because you mentioned it to me once.  I'm not sure if that's what is going on with you, as I'm not a doctor.  I will research dementia, since that is your main concern, in the context of a CT, and kindling, and LTP.    How long ago did you CT, i.e. How long are you in PWS.? 

[[Be...]]

dm, it's in my sig.  Nov. 2012.  All hell broke loose right after that and it's not gotten better and I'm over 4.5 years off.  I have dementia now along with high anxiety, depression, anhedonia, fear, and OCD which is very bad.  No appetite since I got off them.  While in tolerance w/d went to docs and specialists and was diagnosed with Lupus, Thrombophilia, and later on, Paroxsymal Tachycardia.  Now new doc diagnosed me with Memory Impairment and Amnesia.  I've got a pro-coagulant antibody in my system wrecking my circulatory system.  It's possible I had a stroke, the doc said, since I'm at risk for it.  It might be vascular micro or mini strokes. 

[[li...]]

dm123,

 

Two questions/remarks.

 

'Cortisone, originally called compound E, is a glucocorticoid, but also has some mineralocorticoid properties. It quickly converts protein to the carbohydrate glucose (sugar),' Buy, I was not aware of that. While I haven't been able to measure it, exercise seems to be able to produce a massive amount of glucocorticoids. Cortisone seems a likely culprit.

It's not the only reason I'm suffering from muscle catabolism, but it would seem it played a part.

 

 

'Hydrocortisone, which they had me on while on lorazepam is not on the list but is thought to be a PAM' Chemically, does it have the exact chemical formula as cortisol ? The internet says it's the same.

 

So, old regular cortisol as produced by the body is a PAM also ?

[[cs...]]

dm, it's in my sig.  Nov. 2012.  All hell broke loose right after that and it's not gotten better and I'm over 4.5 years off.  I have dementia now along with high anxiety, depression, anhedonia, fear, and OCD which is very bad.  No appetite since I got off them.  While in tolerance w/d went to docs and specialists and was diagnosed with Lupus, Thrombophilia, and later on, Paroxsymal Tachycardia.  Now new doc diagnosed me with Memory Impairment and Amnesia.  I've got a pro-coagulant antibody in my system wrecking my circulatory system.  It's possible I had a stroke, the doc said, since I'm at risk for it.  It might be vascular micro or mini strokes.

Hi, thanks for the information.  I know you told me a lot about the autoimmune issues as well.  We're your basic ANA titers high as well?  As I mentioned in an earlier post, the autoimmune factor going on with you can provoke a cascade of feedback cytokines.  I know you know about microglia, basically the immune system of the CNS.  I posted an excellent article on microglia response to inflammatory cytokines (in this case it was LPS lipopolysaccharides, in an alcohol study).  The microglia can dump Glutamate and NO into the extracellular space. That in and of itself could cause this feeling of hyperexcitability. I know how it feels.  I'm going to add a search on autoimmune and dementia to the paper I wrote on dementia and benzos.    Just a preview, drawing a cause and effect line from benzos to dementia is very difficult, as the research papers that I will post acknowledge.  There's lots of reasons for this, and I will explain them in the paper. 

 

Have you also been tested for vasculitis?  It can also be accompanied by lupus, which I know you've been diagnosed with.  It can cause strokes.

 

I'm going to add a section on vascular dementia  and do a search on benzos and that, since there seems to be vascular issues as well.  I'm not a medical doctor, so I'm not going to make any medical recommendations.  I will just provide the research.  I hope it helps once it's posted.

[[cs...]]

dm123,

 

Two questions/remarks.

 

'Cortisone, originally called compound E, is a glucocorticoid, but also has some mineralocorticoid properties. It quickly converts protein to the carbohydrate glucose (sugar),' Buy, I was not aware of that. While I haven't been able to measure it, exercise seems to be able to produce a massive amount of glucocorticoids. Cortisone seems a likely culprit.

It's not the only reason I'm suffering from muscle catabolism, but it would seem it played a part.

 

 

'Hydrocortisone, which they had me on while on lorazepam is not on the list but is thought to be a PAM' Chemically, does it have the exact chemical formula as cortisol ? The internet says it's the same.

 

So, old regular cortisol as produced by the body is a PAM also ?

 

Hi liberty, I know neurosteroid are PAMs, but I have not been able to find direct evidence that it is a PAM because I got off it and moved on.  I got the info from one of Pers' papers  and ironically she was also on it for a while, but a much much shorter time than I.   

Can you quote the refence for converting protein to glucose.  I know it raises blood sugar levels because it makes it much more difficult for insulin to do its work at the receptor level.  It's once again about homeostasis.  The body is under stress and the hypothalamus detects this and tells the pituitary to get more cortisol into the blood. So the pituitary secretes ACTH, and the adrenal ACTH receptors on cortex get hit with the ACTH and the gland pumps out cortisol.    Cortisol has hundreds of functions in the body, but a main use for it is to mobilize stress resources so you can run away from the lion

 

Raising glucose will give you the energy you muscles need. 

 

It is very catabolic.  When I was on it I had trouble adding muslce even via weightlifting.  It also does a lot of other bad things and taking it if you don't need it can lead to terrible problems.  It's extremely powerful.  I would not recommend it for anyone other than addisons patients and those who need it for life saving autoimmune inflammatory conditions like RA, etc.  it necessary for life but in excesss it lowered testosterone, lowers conversion of T4 to T3, demineralizes bone(it both reduces osteoblastogenesis bone building and increases osteoclastic bone removal, so one is left with old brittle demineralized bone).  I know all this from experience with it.

Yes HC has a bit of mineral corticosteroid in it, but it's relatively low, compared to fludrocortisone, which is a synthetic version of aldosterone, which is involved in water and fluid homeostasis and blood pressure regulation as well as sodium and potassium serum levels.

 

 

So I don't know if it is a PAM, but Pers has well researched documentation, so i would take her word on it, but I think it requires more research.  I'm thinking indirectly it could have an effect since cortisol effects every part of the body.  Sorry if too much information.  I don't think I answered your question 

[[li...]]

dm123,

 

Your post #102, quoting you.

 

'The principal glucocorticoids are corticosterone and hydrocortisone (cortisol) and the principal mineralocorticoid is aldosterone. Cortisone, originally called compound E, is a glucocorticoid, but also has some mineralocorticoid properties. It quickly converts protein to the carbohydrate glucose (sugar), and it helps regulate salt metabolism. The adrenal cortex's production of cortisone and hydrocortisone is controlled by the hormone ACTH (adrenocorticotropic hormone), which is secreted by the pituitary gland (a small, oval gland attached to the base of the brain)''

 

Looking at several sources, it looks like the literature is messing up cortisol, hydrocortisone and cortisone. I believed that cortisol had a short half life, and cortisone a longer half life. But what do I know. Hard to make sense of it without extensive study.

 

 

 

 

[[cs...]]

dm123,

 

Your post #102, quoting you.

 

'The principal glucocorticoids are corticosterone and hydrocortisone (cortisol) and the principal mineralocorticoid is aldosterone. Cortisone, originally called compound E, is a glucocorticoid, but also has some mineralocorticoid properties. It quickly converts protein to the carbohydrate glucose (sugar), and it helps regulate salt metabolism. The adrenal cortex's production of cortisone and hydrocortisone is controlled by the hormone ACTH (adrenocorticotropic hormone), which is secreted by the pituitary gland (a small, oval gland attached to the base of the brain)''

 

Looking at several sources, it looks like the literature is messing up cortisol, hydrocortisone and cortisone. I believed that cortisol had a short half life, and cortisone a longer half life. But what do I know. Hard to make sense of it without extensive study.

Liberty,

 

Cortisol and hydrocortisone are the same.  Cortisone needs conversion.  That's the way I always understood it.  I'm not sure why there's not an agreement.

 

im sticking with Wikipedia, since it has references

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

 

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

 

The last sentence here is the converting enzyme.

Quote

Cortisone is one of several end-products of a process called steroidogenesis. This process starts with the synthesis of cholesterol, which then proceeds through a series of modifications in the adrenal gland (suprarenal) to become any one of many steroid hormones. One end-product of this pathway is cortisol. For cortisol to be released from the adrenal gland, a cascade of signaling occurs. Corticotropin-releasing hormone released from the hypothalamus stimulates corticotrophs in the anterior pituitary to release ACTH, which relays the signal to the adrenal cortex. Here, the zona fasciculata and zona reticularis, in response to ACTH, secrete glucocorticoids, in particular cortisol. In the peripheral tissues, cortisol is converted to cortisone by the enzyme 11-beta-steroid dehydrogenase.

 

End quote

 

And this

 

The mineral corticosteroid content is roughly the same.  Note last sentence is not referenced. No footnote.

 

Quote

 

Cortisone has marginally reduced glucocorticoid activity compared to cortisol (80-90%[14]), and thus, cortisone can be considered an active metabolite of cortisol. However, 11-beta-steroid dehydrogenase can catalyze the reverse reaction as well, and, thus, cortisone is also a precursor molecule of cortisol. Cortisone is activated through hydrogenation of the 11-keto-group, and cortisol is, thus, sometimes referred to as hydrocortisone.[citation needed]

 

End quote

 

 

Regarding(biological)  half life I know hydrocortisone (cortisol) has an  hour and a half , half-life, because I used to dose it.  I used to have an excellent PDF on details on this and dosing , but I have no idea where I put it.

Precisely , half life varies about.  These people had CAH.  I'm not sure if that changes things, but CAH people don't produce much endogenous cortisol.

 

https://www.ncbi.nlm.nih.gov/pubmed/25369980

 

Regarding protein to sugar, it's called gluconeogenesis

 

Regarding its effect on insulin receptors, it raises glucose levels that way too.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942672/figure/F1/?report=objectonly

 

 

Quote

 

Under stressful conditions, cortisol can provide the body with protein for energy production through gluconeogenesis, the process of converting amino acids into useable carbohydrate (glucose) in the liver.

End quote

 

 

 

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

 

Quote

 

Many stressing factors may lead to increased cortisol in the bloodstream. Cortisol counteracts insulin, contributes to hyperglycemia-causing hepatic gluconeogenesis,[66] and inhibits the peripheral utilization of glucose, which eventually leads to insulin resistance.[66] It does this by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.[67][68]

 

End quote

 

EDIT add:  for anyone considering taking HC please reconsider.  It's very powerful, and if you do need to use it, don't go above 10mg / dayif you need it for longer than 6 weeks.  Equivalent prednisone 2.5 mg.  I'm not a doctor and just my personal experience of taking much higher doses in the past(up to 30 mg/day). I'm off it now, but it was a big mistake. ...

[[...]]

dm, it's in my sig.  Nov. 2012.  All hell broke loose right after that and it's not gotten better and I'm over 4.5 years off.  I have dementia now along with high anxiety, depression, anhedonia, fear, and OCD which is very bad.  No appetite since I got off them.  While in tolerance w/d went to docs and specialists and was diagnosed with Lupus, Thrombophilia, and later on, Paroxsymal Tachycardia.  Now new doc diagnosed me with Memory Impairment and Amnesia.  I've got a pro-coagulant antibody in my system wrecking my circulatory system.  It's possible I had a stroke, the doc said, since I'm at risk for it.  It might be vascular micro or mini strokes.

Hi, thanks for the information.  I know you told me a lot about the autoimmune issues as well.  We're your basic ANA titers high as well?  As I mentioned in an earlier post, the autoimmune factor going on with you can provoke a cascade of feedback cytokines.  I know you know about microglia, basically the immune system of the CNS.  I posted an excellent article on microglia response to inflammatory cytokines (in this case it was LPS lipopolysaccharides, in an alcohol study).  The microglia can dump Glutamate and NO into the extracellular space. That in and of itself could cause this feeling of hyperexcitability. I know how it feels.  I'm going to add a search on autoimmune and dementia to the paper I wrote on dementia and benzos.    Just a preview, drawing a cause and effect line from benzos to dementia is very difficult, as the research papers that I will post acknowledge.  There's lots of reasons for this, and I will explain them in the paper. 

 

Have you also been tested for vasculitis?  It can also be accompanied by lupus, which I know you've been diagnosed with.  It can cause strokes.

 

I'm going to add a section on vascular dementia  and do a search on benzos and that, since there seems to be vascular issues as well.  I'm not a medical doctor, so I'm not going to make any medical recommendations.  I will just provide the research.  I hope it helps once it's posted.

 

 

dm, you should create a stand-alone thread for your dementia and benzo paper so it doesn't get lost here.  I think this topic might be of interest to a lot of people. 

[[cs...]]

dm, it's in my sig.  Nov. 2012.  All hell broke loose right after that and it's not gotten better and I'm over 4.5 years off.  I have dementia now along with high anxiety, depression, anhedonia, fear, and OCD which is very bad.  No appetite since I got off them.  While in tolerance w/d went to docs and specialists and was diagnosed with Lupus, Thrombophilia, and later on, Paroxsymal Tachycardia.  Now new doc diagnosed me with Memory Impairment and Amnesia.  I've got a pro-coagulant antibody in my system wrecking my circulatory system.  It's possible I had a stroke, the doc said, since I'm at risk for it.  It might be vascular micro or mini strokes.

Hi, thanks for the information.  I know you told me a lot about the autoimmune issues as well.  We're your basic ANA titers high as well?  As I mentioned in an earlier post, the autoimmune factor going on with you can provoke a cascade of feedback cytokines.  I know you know about microglia, basically the immune system of the CNS.  I posted an excellent article on microglia response to inflammatory cytokines (in this case it was LPS lipopolysaccharides, in an alcohol study).  The microglia can dump Glutamate and NO into the extracellular space. That in and of itself could cause this feeling of hyperexcitability. I know how it feels.  I'm going to add a search on autoimmune and dementia to the paper I wrote on dementia and benzos.    Just a preview, drawing a cause and effect line from benzos to dementia is very difficult, as the research papers that I will post acknowledge.  There's lots of reasons for this, and I will explain them in the paper. 

 

Have you also been tested for vasculitis?  It can also be accompanied by lupus, which I know you've been diagnosed with.  It can cause strokes.

 

I'm going to add a section on vascular dementia  and do a search on benzos and that, since there seems to be vascular issues as well.  I'm not a medical doctor, so I'm not going to make any medical recommendations.  I will just provide the research.  I hope it helps once it's posted.

 

 

dm, you should create a stand-alone thread for your dementia and benzo paper so it doesn't get lost here.  I think this topic might be of interest to a lot of people.

 

Great idea.  Will do once it's ready.  Thanks

[[Be...]]

Yes, my ANA was high, so was referred to a Rheumatologist who found a procoagulant antibody in my blood, Anti-beta2 glycoprotein 1 (IGM) and low complement, so she diagnosed me with Lupus.  Also went to an Endocrinologist and my ACTH was sky high and she couldn't tell me why.  No vasculitis testing done.  I can't follow or read all you're writing since I've got dementia now and can't understand it.  I'm a mental basketcase.  If you start a thread about dementia and benzo's I'll read it.  I know they've caused my mental decline and severe anxiety.  I truly believe I have damaged nerve receptors and autoantibodies to them and other stuff going on.  I've got just about everything which causes anxiety.  I'm screwed.  Alot of external stress on me each day. 

[[li...]]

Cortisol and cortisone, it remains confusing.

 

Several cources: https://www.ncbi.nlm.nih.gov/books/NBK13300/ 'The plasma clearance of cortisol is rapid, with a half-life of 66 min at normal hormone levels16. With large steroid loads, however, the half-life increases to 120 min.'

 

http://www.globalrph.com/corticocalc.htm

 

Glucocorticoid Approximate Equivalent dose (mg) Half-life (Biologic) hours

Short-Acting

Cortisone            25 8-12

Hydrocortisone    20 8-12

 

There may be a difference between plasma half lfie and biological half life ?

[[cs...]]

Yes, my ANA was high, so was referred to a Rheumatologist who found a procoagulant antibody in my blood, Anti-beta2 glycoprotein 1 (IGM) and low complement, so she diagnosed me with Lupus.  Also went to an Endocrinologist and my ACTH was sky high and she couldn't tell me why.  No vasculitis testing done.  I can't follow or read all you're writing since I've got dementia now and can't understand it.  I'm a mental basketcase.  If you start a thread about dementia and benzo's I'll read it.  I know they've caused my mental decline and severe anxiety.  I truly believe I have damaged nerve receptors and autoantibodies to them and other stuff going on.  I've got just about everything which causes anxiety.  I'm screwed.  Alot of external stress on me each day.

 

Hi BecksBlue I branched out a separate thread on the dementia paper.  It's very long, but I'm hoping you can read the intro and get some insight into what's going on with you.

Here is the link

http://www.benzobuddies.org/forum/index.php?topic=186964.0

 

[[cs...]]

Cortisol and cortisone, it remains confusing.

 

Several cources: https://www.ncbi.nlm.nih.gov/books/NBK13300/ 'The plasma clearance of cortisol is rapid, with a half-life of 66 min at normal hormone levels16. With large steroid loads, however, the half-life increases to 120 min.'

 

http://www.globalrph.com/corticocalc.htm

 

Glucocorticoid Approximate Equivalent dose (mg) Half-life (Biologic) hours

Short-Acting

Cortisone            25 8-12

Hydrocortisone    20 8-12

 

There may be a difference between plasma half lfie and biological half life ?

 

Hi liberty, yes.  Isn't plasma half life blood for serum levels and biological referring to level of biological activity, i.e. Pharmacological and physiological activity.  Yes , they can be quite different.

 

https://en.m.wikipedia.org/wiki/Biological_half-life

 

I would focus on plasma half life for cortisol.  I had to dose the hydrocortisone 3 times a day.  Saliva testing indicated cortisol (free cortisol) levels through the roof, even by night time.  By morning my levels were normal, so the 90 minute plasma half life seems on the mark, just from my experience.

 

These short half life drugs are very difficult to manage and have the potential to suppress pituitary function if you don't have addisons or secondary adrenal failure,

 

Hydrocortisone is cortisol from what I understand.  Cortisone and cortisol just differ by one hydrogen bond and atom at C11.  The image of chemical structure won't paste.

 

They are reversibly convertible in both directions by liver

 

Quote

Cortisol is directly given to the patient - it is then called Hydrocortisone. I don't know why this is done but probably to avoid confusion because both names are too similar.

 

The difference between both forms is one hydrogen atom at the C11 position of the molecule in Cortisol (or Hydrocortison) (image from here):

 

Otherwise is Cortisol (or Hydrocortisone) the active version, while Cortisone isn't very active in the human body. Both forms can enzymatically turned into the other form (from active to inactive and vice versa). Since Cortisone needs to be activated in the liver, it can only be used for oral uptake. Most of the uses which are colloquially called Cortisone in fact contain Hydrocortisone.

 

End quote

 

I would not be to concerned with cortisone. It's an acetate version, and it's not used much here in the states.  We use hydrocortisone , i.e. Biologically active cortisol.

[[cs...]]

I'm not sure when I will post it, but the next ADDENDUM will be on phosphorylation, because understanding the basics in this area is required for the topics that will follow.

[[Te...]]

dm, what is the mechanism of action that causes benzo withdrawal to go on for a very long time in terms of waxing and waning symptoms? For instance, I've had terrible problems with my blood pressure fluctuating wildly, depending on the anxiety/adrenaline/cortisol issues I've had. At the end of March I had frightening rises, and then falls. The bp would go up to 194 in the evening, in the morning a 98 reading. Then it would rise again to 180. I kept a log of it, and without going back to that log, if I remember correctly, for a day it settled pretty steadily in the 160s, and then from there gradually started going down to lower numbers, 120s, 106, 90s, etc. I finally realized that it was the body's way of regulating blood pressure after years of benzo abuse. Unfortunately, I drank coffee for a few weeks (I was incredibly tired and foggy-headed and thought that it was okay to do such a thing) and ruined my bp again. It once again rose to 190. I stopped taking it after a second 190 reading and getting panic attacks. That was at the end of June. I'm still not ready to take my bp again. I disrupted the nerves. I've had to take bp pills for a long time, although they seem to do nothing when the adrenaline hits. Then, when I settle down again, I'm exhausted.

 

People with insomnia issues also have wild fluctuations. I know the benzos pummel the autonomic nervous system. Is it that the brain becomes ingrained to repeat the pattern over and over? 

 

I don't know if I have explained this well, but LF2015 was bringing this to my attention, and I was wondering what the scientific basis for it was. Granted, I have no scientific background, but this has been bothering me for years. It's taken me years to figure out that my bp has nothing to do with weight, exercise, what I eat, salt - all the normal things that people say you should watch out for.

 

Thank you for any answers you can give me!!

[[Te...]]

"after years of benzo abuse." I meant suffering abuse at the hands of benzos, not that I was abusive with them.

[[li...]]

Terry, I'm not dm123 but maybe I know a few things ...

 

One thing could be that GABA receptors 'never' come back quite the way they were ... , hormonal issues ('HPA axis', also influencing other hormones), and I suspect cholinergic hyper/supersensitivity.

I recall the phrase that cholinergic neurons are the last to stabilize.

[[Te...]]

liberty, can you explain cholinergic neurons? In what way would they influence the wax/wane symptoms we have? Thank you for answering, by the way. The bp has been driving me crazy because the benzo influence causes massive fluctuations and fear. I have to be very careful what I do. It's like a barometer.

[[li...]]

That's such an incredibly difficult question.

 

https://en.wikipedia.org/wiki/Cholinergic_neuron some of these issues mentioned in that article may seem familiar to those in benzodiazepine withdrawal.

 

https://link.springer.com/article/10.1007/BF01244733

 

'The aim of this review is to summarize the effects of acute and chronic treatment with barbiturates, ethanol and benzodiazepines on cholinergic mechanisms in the brains of experimental animals. A single dose of each of these substances reduces the turnover of ACh in the brain. Long-term treatment has the opposite effect; complicated interactions including decreased content of ACh are induced. Barbiturates have been shown to bind stereospecifically to muscarinic and nicotinic receptors in the brain, but this has not been observed for ethanol or the benzodiazepines. The effects on the cholinergic system are affected by the length of treatment and choice of treatment regimen. No effect on cholinergic parameters, such as muscarinic receptors, in the brain is observed on withdrawal of ethanol or barbiturate treatment when the animals are still tolerant towards the substances. The increase in the number of muscarinic receptors observed in several brain regions on withdrawal is seen as a sign of cholinergic supersensitivity. The number of receptors returns to normal when abstinence convulsions have occurred' (last part: the animals were not put on the drug for years!)

 

Cholinergic supersensitivity is also known as cholinergic hypersenstivity, I think it's about the same. ''https://pdfs.semanticscholar.org/2381/ba12938f995f7a8d1896a4ac7274118cb09e.pdf' (did I get that right?)

'Janowsky et al. (1983) proposed

that stress increases the sensitivity of central

cholinergic mechanisms and that the latter

mediates some neurobiological effects of stress'

 

http://www.sciencedirect.com/science/article/pii/001429999290127P

 

'The modifications in rat brain muscarinic acetylcholine receptors induced by acute immobilization stress lasting 10 min or 2 h were analyzed by quantitative in vitro autoradiography. [3H]N-Methylscopolamine ([3H]NMS) was used as a ligand. Immobilization stress for 10 min did not produce any significant change in the properties of [3H]NMS binding sites throughout the brain. In contrast, 2 h immobilization caused a significant increase in receptor affinity (Kd) without modification in the maximal number of receptors (Bmax) in several brain areas such as the caudate-putamen, cortical layers and CA1 field of the hippocampus, among others. These results, found even in animals killed immediately after the end of the immobilization sessions, suggest that immobilization stress induces supersensitivity of muscarinic receptors in certain cholinergic pathways in rat brain.'

 

Not the best sources, but I was just looking for something to support what I had stated. It appears there is also some evidence linking cholinergic neurons and the HPA axis.

 

Just a few items. I didn't say it wasn't complicated.

 

 

[[Te...]]

Thanks, liberty! Whew!! I'll have to read it carefully. I'd never even heard of muscarinic receptors. Thanks so much for all the research and time put into it!!

[[cs...]]

That's such an incredibly difficult question.

 

https://en.wikipedia.org/wiki/Cholinergic_neuron some of these issues mentioned in that article may seem familiar to those in benzodiazepine withdrawal.

 

https://link.springer.com/article/10.1007/BF01244733

 

'The aim of this review is to summarize the effects of acute and chronic treatment with barbiturates, ethanol and benzodiazepines on cholinergic mechanisms in the brains of experimental animals. A single dose of each of these substances reduces the turnover of ACh in the brain. Long-term treatment has the opposite effect; complicated interactions including decreased content of ACh are induced. Barbiturates have been shown to bind stereospecifically to muscarinic and nicotinic receptors in the brain, but this has not been observed for ethanol or the benzodiazepines. The effects on the cholinergic system are affected by the length of treatment and choice of treatment regimen. No effect on cholinergic parameters, such as muscarinic receptors, in the brain is observed on withdrawal of ethanol or barbiturate treatment when the animals are still tolerant towards the substances. The increase in the number of muscarinic receptors observed in several brain regions on withdrawal is seen as a sign of cholinergic supersensitivity. The number of receptors returns to normal when abstinence convulsions have occurred' (last part: the animals were not put on the drug for years!)

 

Cholinergic supersensitivity is also known as cholinergic hypersenstivity, I think it's about the same. ''https://pdfs.semanticscholar.org/2381/ba12938f995f7a8d1896a4ac7274118cb09e.pdf' (did I get that right?)

'Janowsky et al. (1983) proposed

that stress increases the sensitivity of central

cholinergic mechanisms and that the latter

mediates some neurobiological effects of stress'

 

http://www.sciencedirect.com/science/article/pii/001429999290127P

 

'The modifications in rat brain muscarinic acetylcholine receptors induced by acute immobilization stress lasting 10 min or 2 h were analyzed by quantitative in vitro autoradiography. [3H]N-Methylscopolamine ([3H]NMS) was used as a ligand. Immobilization stress for 10 min did not produce any significant change in the properties of [3H]NMS binding sites throughout the brain. In contrast, 2 h immobilization caused a significant increase in receptor affinity (Kd) without modification in the maximal number of receptors (Bmax) in several brain areas such as the caudate-putamen, cortical layers and CA1 field of the hippocampus, among others. These results, found even in animals killed immediately after the end of the immobilization sessions, suggest that immobilization stress induces supersensitivity of muscarinic receptors in certain cholinergic pathways in rat brain.'

 

Not the best sources, but I was just looking for something to support what I had stated. It appears there is also some evidence linking cholinergic neurons and the HPA axis.

 

Just a few items. I didn't say it wasn't complicated.

 

Thanks for the great info liberty.

 

Terry, in regards to the above I've noticed a consistent theme in the research on benzodiazaphines and ACh....benzos are highly paradoxical, in that tolerance , withdrawal and interdose wd have completely opposite physiological effects in almost every way, when compared to chronic non tolerant use.  This accounts for the danger of the these drugs....

 

 

In addition, another area that I'm looking at is the G protein coupled receptor nature of the muscarinic ACh receptors.  They have been found to be coupled to GABAa receptors.  I have not presented the material on GPCRs yet, but it's important to realize that ACh can affect a lot of different physiological functions.  The coupling to GABAa receptors is significant as it will affect neuronal excitability.

 

Here are some more studies on benzos and ACh.  Note that withdrawal has an opposite effect than chronic non-tolerant use.

 

 

This study is very interesting in that chronic diazepam dosing causes a decrease in ACh in the nucleus accumbens, whereas abrupt withdrawal causes ACh to spike.  Clearly benzodiazaphines and abrupt withdrawal have distinct effects on ACh dysregulation.  Part of the theory is that it is the rise in ACh that causes withdrawal symptoms in acute withdrawal.  I'm not sure if the same could be applied to PWS....

 

 

https://www.ncbi.nlm.nih.gov/pubmed/15680263

 

Quote

 

Acetylcholine in the accumbens is decreased by diazepam and increased by benzodiazepine withdrawal: a possible mechanism for dependency.

Rada P1, Hoebel BG.

Author information

Abstract

Diazepam is a benzodiazepine used in the treatment of anxiety, insomnia and seizures, but with the potential for abuse. Like the other benzodiazepine anxiolytics, diazepam does not increase dopamine in the nucleus accumbens. This raises the question as to which other neurotransmitter systems are involved in diazepam dependence. The goal was to monitor dopamine and acetylcholine simultaneously following acute and chronic diazepam treatment and after flumazenil-induced withdrawal. Rats were prepared with microdialysis probes in the nucleus accumbens and given diazepam (2, 5 and 7.5 mg/kg) acutely and again after chronic treatment. Accumbens dopamine and acetylcholine decreased, with signs of tolerance to the dopamine effect. When these animals were put into the withdrawal state with flumazenil, there was a significant rise in acetylcholine (145%, P<0.001) with a smaller significant rise in dopamine (124%, P<0.01). It is suggested that the increase in acetylcholine release, relative to dopamine, is a neural component of the withdrawal state that is aversive.

End quote

 

 

Central depletion of ACh, NA, AD, cortisol, serotonin, and dopamine in chronic administration

Need full text 1996

 

 

https://www.ncbi.nlm.nih.gov/pubmed/8843497

 

Quote

 

Aging is a physiological process that shares many behavioral, biochemical and neuroendocrine phenomena with the pathophysiological situation of unresolved stress, as well as with a pharmacologically induced syndrome resulting from chronic benzodiazepine (BZ) consumption. Behavioral findings include symptoms such as drowsiness, ataxia, fatigue, confusion, weakness, dizziness, vertigo, syncope, reversible dementia, depression, impairment of intellectual, psychomotor and sexual function, agitation, auditory and visual hallucinations, paranoid ideation, panic, delirium, depersonalization, sleepwalking, aggressivity, orthostatic hypotension, and insomnia. Neuroendocrine findings include: central depletion of noradrenaline (NA), dopamine, adrenaline (AD), and serotonin (5-HT); reduction in the ratio of circulating NA/AD as well as platelet 5-HT and increase of AD, plasma free 5-HT and cortisol. These disturbances together with the increased platelet aggregability observed in the three groups are typical of unresolved-stress situations. Immunological findings include significant reduction of peripheral T lymphocytes (CD3, CD4, CD8) and the CD4/CD8 ratio, CD16 and gamma-delta cells. On the other hand, the three groups (elderly subjects, subjects faced with unresolved stress, and BZ consumers) show increase of the CD57 lymphocyte subset as well as natural killer cytotoxicity. Alterations of several biological markers have also been found, specifically in the oral glucose tolerance test, the intramuscular clonidine test, and the supine/orthostasis/exercise test. From a clinical point of view, the three groups appear to be more susceptible to the appearance and progression of many acute and chronic diseases (infectious and malignant diseases). As a result, chronic consumption of BZs should be avoided in both the elderly and subjects in unresolved-stress situations.

End quote

 

 

 

 

 

 

[[cs...]]

dm, what is the mechanism of action that causes benzo withdrawal to go on for a very long time in terms of waxing and waning symptoms? For instance, I've had terrible problems with my blood pressure fluctuating wildly, depending on the anxiety/adrenaline/cortisol issues I've had. At the end of March I had frightening rises, and then falls. The bp would go up to 194 in the evening, in the morning a 98 reading. Then it would rise again to 180. I kept a log of it, and without going back to that log, if I remember correctly, for a day it settled pretty steadily in the 160s, and then from there gradually started going down to lower numbers, 120s, 106, 90s, etc. I finally realized that it was the body's way of regulating blood pressure after years of benzo abuse. Unfortunately, I drank coffee for a few weeks (I was incredibly tired and foggy-headed and thought that it was okay to do such a thing) and ruined my bp again. It once again rose to 190. I stopped taking it after a second 190 reading and getting panic attacks. That was at the end of June. I'm still not ready to take my bp again. I disrupted the nerves. I've had to take bp pills for a long time, although they seem to do nothing when the adrenaline hits. Then, when I settle down again, I'm exhausted.

 

People with insomnia issues also have wild fluctuations. I know the benzos pummel the autonomic nervous system. Is it that the brain becomes ingrained to repeat the pattern over and over? 

 

I don't know if I have explained this well, but LF2015 was bringing this to my attention, and I was wondering what the scientific basis for it was. Granted, I have no scientific background, but this has been bothering me for years. It's taken me years to figure out that my bp has nothing to do with weight, exercise, what I eat, salt - all the normal things that people say you should watch out for.

 

Thank you for any answers you can give me!!

 

Hi Terry, the waxing and waning are due to a complex interaction of physiological factors compounded by the fact that benzodiazaphines are paradoxical.(see my post above).  This is because the body's natural homeostatic response is to oppose what benzos do to our physiology.  Form example, we start taking the Benzo, feel great, increase Cl- in the postsynaptic neuron, everything is fine, then the neuron catches on to what's going on.  That ADDENDUM 7 is a perfect example.  Once you try to medicate a neuron to "sleep" natural hoemeststic,processes in the body like ubiquitination in ADDENDUM 7 take over, and start endocytizing (absorbing)the GABAa receptors that are letting in too much chloride.  In this way the body is trying to reduce postsynaptic GABAA receptor density of that particular subunit, to get the neuron firing like it used to, i.e. More often.....At this point we don't feel too good, because we are used to the sleepy neuron, and now it's starting to send out more Action potentials down the axon.  I know this doesn't answer your question directly for what you are going through, but if your pysiology has been compromised by Benzo use, it might not be as resilient to stresses as it once was, and therefore it can be "knocked out of balance" more easily , and is more sensitive relative to the process above.    As liberty mentioned, and as I explained in detail in ADDENDUM 6 part II, we know why the cluster subunit configuration of extra synaptic and synaptic neurons can change when using these drugs.  Since you are PWS, we don't know what your receptors are like.  Most likely they will recover in time, but long term studies in these areas are lacking.

 

For your BP issue, I'm not a medical doctor, so please ask your doc if he can explore these areas

- since caffeine started this BP issue, it could be related to the hypothalamus or pituitary, and sympathetic nervous system.  Once you get caught up it feeds on itself in a loop, anxiety feeding adrenaline, adrenaline feeding anxiety and lack of sleep, lack of sleep deregulating cortisol, leads to worse sleep, etc. 

-the most important correlates to classical Benzo wd are diastolic reading (lower one) and pulse.  Do you have those in your log?  These are the most important .

- you mentioned stroke.  Can your doc insure that you don't have and POTS or orthostatic hypotension or any type of autonomic dysfunction due to the stroke.  Since your doc knows your history can you ask him about autonomic  dysfunction.....If your resting pulse is high when sitting, you need to check this out with your doc.  anything over 100 sitting is too high.

-how is your sleep?

-what did you mean by you are not ready to measure your BP.  Please try to measure that and your pulse every day

-since BP is low in morning and high at night, your cortisol may be in stage 2, i.e. Backwards, high at night and low in morning.  Can you get a serum morning cortisol done.?

-you can measure your temperature with a digital thermometer.  No drinking 15 minutes before, and sitting 15 min before measuring under tongue.  Take 3 times a day if you can. Same time each day.  If variance between same time each day greater than 0.2 to 0.3 F, you can ask for bloodwork from your doc.    For example, Monday 9am 97.7, tues 9am 97.2, something's not right.  Also if you can do 3 times a day, variance between all 3 times should not be greater than 1 degree F, for example morning 98.2 and evening 97.1, ask your doc for some bloodwork.    Anything below 97.7 is low.

Blood work is thyroid FT3, FT4 and TSH

 

I hope these items can help you work with your doctor.  I know how dysregulated cortisol feels. 

 

EDIT add: I forgot to mention, have them draw serum aldosterone as well.