How come GABA does not return to homeostasis even with slow taper?

[[ih...]]

My university doesn't have access to the journal the Podnorma article is in. If i thought it covered more than experimental chemicals which are not generally accesible anyway, I would be more inclined to spring for the outrageous $63 they are charging for pay per view, & it's already 12 years old. Will see if I can access via another uni.

 

Hello iHope.

 

If you do manage to get hold of this article then I would be very interested to see what it says.

 

Hey Zoner, will definitely let you know.  How are you going now, still taking any supps & are they helping?

 

Maybe I would have had a good result anyway but I do believe my supp stack has helped my recovery.

 

PS: Well done to you for recently jumping from 0.5mgs!

 

-Zoner

[[Ti...]]

Very interesting.

 

Have noted that Bateson, (in the same journal), found that benzos do not appear to produce tolerance and dependence by simple downregulation of receptor number.

 

This challenges the ethos of receptor upregulation. Can't tell you more until& if I can find a way to access the full article.

 

GABAA receptors are hetero-oligomers comprised of multiple subunits encoded by a multigene family, so there are many genes involved which explains the broad range of genetic responses to bzs & wdwl. For every subunit, there is a unique biochemical pathway so we have a highly complex receptor system within a highly complex brain, no wonder we are fumbling around in the dark.

 

It kind of makes the fact that we all recover even more miraculous.

[[zo...]]

Have noted that Bateson, (in the same journal), found that benzos do not appear to produce tolerance and dependence by simple downregulation of receptor number.

 

This challenges the ethos of receptor upregulation. Can't tell you more until& if I can find a way to access the full article.

 

GABAA receptors are hetero-oligomers comprised of multiple subunits encoded by a multigene family, so there are many genes involved which explains the broad range of genetic responses to bzs & wdwl. For every subunit, there is a unique biochemical pathway so we have a highly complex receptor system within a highly complex brain, no wonder we are fumbling around in the dark.

 

It kind of makes the fact that we all recover even more miraculous.

 

 

 

Hello iHope.  I located the Bateson article you were looking for from that special issue. I haven't read it yet because it is long and detailed so I don't know if it says anything about what you were looking for.  http://nltc.files.wordpress.com/2010/03/benzprimer.pdf

 

For me to make sense of what Bateson is saying, I first need to revise a rigorous introduction to GABA receptors such as Stahl's "Essential Psychopharmacology" http://goo.gl/YWTsu.

 

-Zoner

[[os...]]

Scary s**t.

 

They have no idea really, i just read the last paragraph... they may one day have a greater understanding yadda yadda yadda.

 

 

Oscar

[[...]]

So it is probably not just the GABA receptors, it does look like the withdrawal can be caused by a bunch of other unknown changes that are trying to revert back to normal.

[[ih...]]

Zoner, you are a research hero. This is a fascinating article.

 

The bottom line is pretty much as INW put it. However, I thought it was interesting that different bzs have individual tolerance profiles for properties such as sedation & anxiety relief, due to thecomplexity of the subunit system. 

 

Valium has slow tolerance for its anxiolytic properties so those plagued by anxiety during wdwl may benefit by switching to a valium taper & the sedative effects should be reduced quite quiclkly as valium has a rapid tolerance factor for sedation.

 

It also explains why drugs like carbamazepine may help to alleviate anxiety in wdwl by binding only to the sub-units involved in this physiological response.

 

The chemistry of the subunits allows for the configuration of a potential 500 subunits, although they are far from identifying that many, we are pretty much at the neurosurgery with a ratchet stage.

 

Thanks again for finding this, Zoner.

[[...]]

Zoner- Great job on the article and text.  Here is a quote down below directly from the Ashton manual.

In a nutshell, benzos cause reduced output of the excitatatory transmitters norepinephrine, serotonin, acetyl choline and dopamine via increasing GABA's inhibitory activity she states. The other excitatory pathways we all know about are the glutamate and NMDA systems. I don't recall Ashton mentioning them but we know the body upregulates them in an effort the maintain homeostasis in the presence of benzos. These other excitatory pathways will take a while to come back down after benzos are withdrawn. You could probably find others if you dug around the literature enough and no doubt more are yet to be discovered. As I see it, GABA receptors have to upregulate during recovery, yes, but at least 6 excitatory transmitters and pathways have to downregulate. Oh, I just remembered there is something like a TORS? ligand or something like that recently described effected by benzos in the gut which may relate to all the GI symptoms.

 

"As a consequence of the enhancement of GABA's inhibitory activity caused by benzodiazepines, the brain's output of excitatory neurotransmitters, including norepinephrine (noradrenaline), serotonin, acetyl choline and dopamine, is reduced. Such excitatory neurotransmitters are necessary for normal alertness, memory, muscle tone and co-ordination, emotional responses, endocrine gland secretions, heart rate and blood pressure control and a host of other functions, all of which may be impaired by benzodiazepines. Other benzodiazepine receptors, not linked to GABA, are present in the kidney, colon, blood cells and adrenal cortex and these may also be affected by some benzodiazepines. These direct and indirect actions are responsible for the well-known adverse effects of dosage with benzodiazepines."  Ashton

 

So yeah, there is a lot more to it than just the GABA receptor but it remains the most important direct effector.

[[ih...]]

Also benzos ain't benzos.  Each may have a different effect on the other NTs depending upon the subunits involved & individual biochemistry.

 

With valium wdwl, I continue to have way too much noradrenaline without the GABA modulation & have not suffered serotonin related depression but believe my dopamine levels have definitely been affected.

[[...]]

Zoner- Great job on the article and text.  Here is a quote down below directly from the Ashton manual.

In a nutshell, benzos cause reduced output of the excitatatory transmitters norepinephrine, serotonin, acetyl choline and dopamine via increasing GABA's inhibitory activity she states. The other excitatory pathways we all know about are the glutamate and NMDA systems. I don't recall Ashton mentioning them but we know the body upregulates them in an effort the maintain homeostasis in the presence of benzos. These other excitatory pathways will take a while to come back down after benzos are withdrawn. You could probably find others if you dug around the literature enough and no doubt more are yet to be discovered. As I see it, GABA receptors have to upregulate during recovery, yes, but at least 6 excitatory transmitters and pathways have to downregulate. Oh, I just remembered there is something like a TORS? ligand or something like that recently described effected by benzos in the gut which may relate to all the GI symptoms.

 

"As a consequence of the enhancement of GABA's inhibitory activity caused by benzodiazepines, the brain's output of excitatory neurotransmitters, including norepinephrine (noradrenaline), serotonin, acetyl choline and dopamine, is reduced. Such excitatory neurotransmitters are necessary for normal alertness, memory, muscle tone and co-ordination, emotional responses, endocrine gland secretions, heart rate and blood pressure control and a host of other functions, all of which may be impaired by benzodiazepines. Other benzodiazepine receptors, not linked to GABA, are present in the kidney, colon, blood cells and adrenal cortex and these may also be affected by some benzodiazepines. These direct and indirect actions are responsible for the well-known adverse effects of dosage with benzodiazepines."  Ashton

 

So yeah, there is a lot more to it than just the GABA receptor but it remains the most important direct effector.

 

Great stuff, the fact that seratonin, dopamine,etc... were affected too would explain the depression & inability to be happy or get in a good mood.  I noticed that it took about ~6 months from the start of tolerance withdrawal for me to to be able to get in a decent mood and recently (~8 months from tolerance w/d) when I am able to walk or do physical activity, I get the euphoric endorphin rush sometimes.  I see what normal is but it is only a few hours per month.

 

 

[[ro...]]

This is a very interesting discussion and is germane to my issues with a klonopin reduction gone badly.

 

I attempted to reduce to a lower dose (from 3.5 to 3 to 3.25 to 3 to 2.75) in ~30 days. Obviously this is very fast, but my doctor wanted me lower, faster even though I had absolutely no problems with my dose (used to treat a severe anxiety-related disorder). Anyway, as you might imagine, I never recovered from those cuts and was made to hold at 2.75 for 5 months before convincing my doctor that I had gone into a state of protracted wd/my condition (which mimics wd) was not being dealt with.

 

Since then (May), we've been trying to stabilize me by going back up incrementally, to no avail. I'm actually above my initial dose by quite a bit (5mg...i know, scary, but what can I say, they never should have messed around with what had worked beautifully for over 4 years). I've decided to just stay at this dose (since end July) and see if my system can try and reach its previous homeostasis. Tbh, I never wanted to taper in the first place, but the fact that I did may have imposed a downregulation of my receptors (i.e. reducing ironically caused donwregulation, not maintaining a dose of 3.5 for 4 years).

 

To this end, my symptoms have been all over the place and while paradoxical reactions have occurred, they've been cyclical (with depression and anxiety fading since holding this dose steady). Some of my worst symptoms (which are also those that comprise my disorder) include muscle tension, dizziness and all the stuff that comes with it. These have actually started to fade, HOWEVER, they've been replaced with an extreme chronic restlessness. Because I took so long to correct the taper (5 months), I believe my updosing was not as successful as it could have been. That said, given the gradual improvement, I'm inclined to believe that there's a process of healing that can occur when still ON a benzo (which is my goal, since I need klonopin to treat my very serious disorder for which it is the #1 treatment by far).

 

I'm not sure whether this cycling of symptoms is indicative of a re-setting of not only the GABA system, but also the serotonin and dopamine-related pathways that are affected by the glutamatergic system.

I know some people who had similar experiences and when they held after an updose, it took 3-4 months for them to return to pre-cutting. Is it possible that you can still be on a benzo, a steady dose and that it just takes time to get the system back in order (upregulation, re-coupling, all systems working to inhibit excitatory signals)? Or do you have to be on a downward path (tapering) to cause this response?

 

I read earlier in the thread that "real healing" and "healing" are semantics, a concept that appeals to my logic. Does one have to be at 0mg benzo for the brain to recover from cutting or can this occur simply over time either during the tapering process or even at a stable dose of benzo (consider that I didn't have tolerance issues, just a bad reaction to cutting rapidly)?

[[...]]

rolling

 

I'm sorry to hear about your withdrawal during the cuts, I know what a hell this is.  We always hear of people on benzos for a LONG time with no issues, this also proves that the physiology is different in everyone where they can stay at the same dose for say 15 years with no problems.

 

Recovering from taper cut?

As far as recovering from a cut I have no idea and that's basically why I started this thread because the dr's don't even know!  I can say that in my experience, I went from 3mg to .25mg with no noticeable after effects of the dose reduction.  However I can say that I did notice more anxiety/fatigue setting in gradually over months then after a month of .25mg I got slammed with more intense anxiety and fatigue.  I up-dosed to .75mg which alleviated the symptoms for about a week, then they came back and after researching I KNEW it was tolerance so I continued to finish the taper. 

 

The problem with these drugs is that after you reach tolerance, you are ONLY on the drug to prevent the withdrawal that "IT" is actually causing and for the most part the dr's will not acknowledge that the drug is causing the uncomfortable symptoms. 

[Guest [my...]]

Zoner-

I've been looking for answers to this question for a long time now and it appears  nobody knows for sure. With benzo use when they say gaba receptor function is downregulated what happens is many individual gaba receptors are lost as they are no longer needed. In recovery, gene expression has to increase, mRNA  probably goes up and more gaba receptors are then manufactured. There is no known way to speed this process up with the possible exception of exercise.http://www.ncbi.nlm.nih.gov/pubmed/18801833 . Exercise also increases BDNF (brain derived neurotropic factor) which increases neurogenesis (growing new nerves in the brain). Not everyone can exercise because it also stimulates norepinephrine, cortisol and other adrenocorticotropic hormones which revs up symptoms. If you are able to exercise, by all means do it. Lucky for you. You may heal faster as long as you do not overdo it. Listen to your body.

 

Movement of chloride ions through their channel in the gaba receptor is the mechanism by which the  neuron is hyperpolarized making it less likely to fire in response to stimulatory impulses. That's the reason for the inhibitory effect. This movement of chloride ions has nothing to do with the healing process. I think that by far the most important factor in healing is time and lots of it. Healing does occur throughout the taper as healing means growing more gaba receptors. There is no real difference between "true" healing and healing; just semantics used by some. All this other stuff we do are secondary players (exercise, nutrition, supplements, rest, yoga etc.) that probably helps some and ameliorates symptoms while mother nature works her magic and grows more gaba receptors.

 

Great summary Bart. While the polarisation of chloride ions is a mechanism, there are also genetic variations that effect the rate of hyperpolarisation & other munitiae of the process. Some peeps are probably genetically short changed in the GABA receptor department from the get go so even with a slow taper, their CNS will react adversely to the absence of the artificial binding factor.

 

Ironically, people who are genetically prone to anxiety are probably the very people who should not go near benzos.

 

Can you explain what you mean by this please?  "Ironically people who are genetically prone to anziety are probably the very people who should not go near benzos"  Because that is me and I don't understand but sure would like to.  thank you. 

[[ih...]]

Hi mylilcappi, it seems that people who may have a genetic predisposition to the conditions that benzos are prescribed for, such as anxiety & depression, may also be more sensitive to the effects of benzos & more likely to develop tolerance & have difficulty withdrawing.

[Guest [my...]]

thank you Ihope,

I suppose there is no way to test if you have a genetic predisposition.  And if there were, it would probably be ALOT of money.  One of the things I worry about is what to do with the anxiety after this is all over.  A big worry. I have had a anxiety disorder since I was a little girl.  I am now 52. 

 

From all the things I read on here tonight, it just seems like when I heal, that would go away too.  I pray.

I'm going with that!

Thank you again.

[[ih...]]

Hey, mylil, I am also 52 & used to have more anxiety when I was younger but don't really suffer now.  I have found that a combination of mindfulness meditation & certain supplements have been more effective than any psych med, without the side effects.

 

I'm sure when you are healed, you will have the strength to deal with whatever life brings you.

 

Best wishes.

[Guest [my...]]

Ihope,

so by your sig you have only been off for two months?  Am I reading that correctly?

What supplements are you using if you don't mind me asking.

 

I have read your sig line.  I'm hearily sorry for your loss. You are very very strong IMHO. 

 

Thanks again.

[[ih...]]

Thanks for your kind thoughts. Yes, I have been off 2 months & am substantially healed which is a much better outcome than the first time I withdrew from a benzo, via cold turkey.

 

I have been taking inositol for several years now, since my original withdrawal as I believe it has been the most helpful in preventing anxiety. I have also continuously taken fish oil & magnesium glycinate. For this withdrawal, I have added ashwagandha & a combination of arginine & lysine, both of which I think have helped with the benzo related fatigue.

 

Of course, supplements can have individualised effects & it seems that some benzo buddies do not tolerate any supps. I am more than happy to share my experiences with you but just wanted to point out that others seem to have less positive results.

 

 

[Guest [my...]]

Ihope,

I know exactly what you are saying.  It's so very individualized.  I was just wondering.  I thought you would mention about inositol.  It seems to get good ratings on here.  I have never tried it but keep it in the back of my mind.  Supplements don't like me very much.  It's disheartning to say the least. 

 

thanks!

[[Hj...]]

I know there are some very smart people on this thread so give an opinion please!

 

I got a shot of rocephin (ceftriaxone) today for respiratory infections. Odd thing happened, I felt better mentally, like really clear, calm... Out of curiosity I came home and googled ceftriaxone and read the Wikipedia version. It was amazing. This antibiotic restores glutamate to homeostasis and had neuro protective qualities. Wow. Also google ceftriaxone and glutamate. I'm shocked. Can one of you guys that research tell me what you think?

[[ih...]]

Yes, it seems that ceftriaxone increases levels of the glial glutamate transporter GLT-1, which helps regulate glutamate levels in cells.

 

N acetyl cysteine has a similar effect via a different mechanism.

 

How great for you to get such a good side effect from an antibacterial med.  they seem to have used ceftriaxone, in trials at least,to treat glutamate dysregulation after cocaine use, so I wonder if any mds would prescribe off label to help with wdwls.

[[Hj...]]

I'm so glad you read this! Isn't it strange? Now I have no idea how long this nice effect will last because it was one shot but this is definitely something that deserves more research. I've read clinical trials that they are using it for als, treatment resistant schizophrenia and Lyme disease.

 

I guess if my symptoms flare again, I'll ask for another shot...

[[ih...]]

Sounds as though you are still feeling better, so how long now since the shot?

 

I hope the effects do hold for you.

[[...]]

Very interesting on the ceftriaxone, that's awesome you got such a good reaction.  Maybe we should look into those types of supplements regulate glutamate.

[[...]]

That's really interesting. I'd like to know how the shot effected your symptoms in detail and please let us know what happens if you get another one. There is strong evidence that rocephin (ceftriaxone) increases glutamate transporter (GLT-1) which transports glutamate out of certain cells. Glutamate is an excitatory neurotransmitter that is upregulated when we take benzos. It does not do this directly. Benzos increase the inhibitory effect of GABA by making the GABA receptor more active. The body upregulates the glutamate and other excitatory pathways in an effort to maintain homeostasis. When we stop benzos , nerve inhibition is less while the increased excitation remains. This accounts for the myriad symptoms we all have which is from too much stimulation and not enough inhibition. Her is one abstract:  http://www.ncbi.nlm.nih.gov/pubmed/22998524

 

[[Ma...]]

wow I read the article on rocephin and find it very interesting.  I wish I could show it to my pdoc.

 

the idea of glutamate toxcicity is a little scary.