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

[[Hj...]]

Hi all, still feeling better today. Now, I do keep in mind that I was not feeling well from being sick but my physical illness is still around. What I noticed from the ceftriaxone was mental clarity, calmness and no startle response ATM...I guess one could argue I'm having a window but it was the timing of the medicine in relation to relief of symptoms that promoted me to look up some info on ceftriaxone. Not a placebo effect because you're looking for physical relief, not mental, when you get a shot of antibiotics. I've done more research this morning and have found that ceftriaxone has had good success in treating psychiatric symptoms of Lyme disease and found more research on it being used to keep addicts from relapsing to cocaine abuse. I will pick some of the best research on this and post later..... Thanks for the replies.

[[sp...]]

taking cephalosporin antibiotics, or antibiotics in general, without a demonstrated bacterial infection is a bad idea. They kill off craploads of bacteria that are necessary for useful function, and recent research has demonstrated that a single course of antibiotics mucks up your body in ways that are still detectable years later.

 

http://www.wired.com/wiredscience/2011/08/killing-beneficial-bacteria/

http://www.wired.com/wiredscience/2012/08/antibiotics-obesity/

http://www.newyorker.com/reporting/2012/10/22/121022fa_fact_specter

 

[[zo...]]

I've been looking for more detail about how benzos work on the nervous system.  I came across some papers which may be of interest although they go deep into neurochemistry.

 

Ashton wrote in her 2005 paper "The diagnosis and management of benzodiazepine dependence" http://www.benzo.org.uk/amisc/ashdiag.pdf that "The pharmacological mechanisms underlying benzodiazepine tolerance and withdrawal are complex and still not clear. Present knowledge has recently been reviewed in detail".

 

To support this she gives 2 references.  It looks as if Ashton used the following two articles as her sources for her "present knowledge" rather than her own research.  (1) One is the Bateson paper from 2002 mentioned above in this thread. 

 

(2) The other is a more recent 2003 paper which I can't get hold of .... Allison & Pratt's "Neuroadaptive Processes in GABAergic and Glutamatergic Systems in Benzodiazepine Dependence".  I guess that's one to add to the "search list" in addition to the full version of Podhorna's paper "The Experimental Pharmacotherapy of Benzodiazepine Withdrawal" http://www.ncbi.nlm.nih.gov/pubmed/11812248

 

However I did manage to come across an even more recent paper from 2011 by Vinkers & Olivier which is on exactly the same topic. It's rather good even if much of it is impenetrable!  "Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use" http://downloads.hindawi.com/journals/aps/2012/416864.pdf

 

-Zoner

[[ih...]]

More good research, thanks, Zoner.

 

I had read the Vinkers article & was a little disturbed to see that they seemed to be suggesting that tolerance was less of an issue for the "newer bzs". They didn't specify which drugs they were referring to but seemed to be including receptor specific meds like the Z meds.

 

Can only hope that they only meant some chemicals still in investigation as it's hardly our experience that anything currently on the market is free from tolerance effects.

 

Still trying to get the other papers.

[[IG...]]

Thank you

[Guest [Po...]]

"(These drugs dissolve in body fats and are retained in the body for long periods (they have been detected five years after coming off)."

 

From Battle against Tranquillisers website

 

 

[[Dr...]]

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.

 

That last sentence is a brilliant acknowledgment of whats seems to be very likely the case. Very well put.

[[Pe...]]

Wow, Bart and ihope- you two have explained so many things brilliantly from excitotoxicity to IPSP- I am in awe.  Great job to both of you!

 

I have only read through the last two pages of this thread- going back to the beginning to read the whole thing.  Can't wait to read the rest.

 

[[Da...]]

Hi

 

Would you say this is the bottom line?  David

 

 

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.

[[...]]

I would say that.

[[...]]

Great insight, that does sound the bottom line, we already know that we tried supplements and diet changes but the real factor that is making a difference is how far away from the last dose we are. 

[[Ti...]]

I just wanted to say that this a great thread. There are so many intelligent people here at BB.  I hope this discussion stays active. And I hope everyone heals with that magic word "time."

 

I know an excellent MD and I always think of a quote he loves to use and really believes, "The human body has an amazing ability to heal itself."

 

It is true that our bodies have evolved over millions of years too acheive perfect homeostasis. So it makes sense to think that it will always strive for that.

 

One question I have is this: If our GABA receptors can so quickly (2-4 weeks) be down-regulated in th presence of Benzos (in order to maintain homeostasis), then why don't they up regulate just as quickly to maintain homeostasis once the benzo is removed?

 

Is it because the excitoxicity of the excessive glutamate interferes with the receptors upregulation? Or maybe because the process of downregulation is easier for the body to carry-out than upregulation?  I am just guessing here...

[[...]]

Hi Tina

I've never seen an answer to that question in the literature. I think that whatever the reasons are they are in large part genetically determined. Time seems to be the great healer here. We can probably do things to interfere with the healing process, but there seems to be little we can do to speed it up. Mostly, we just get some symptom relief. Exercise may be the exception here and actually help the healing process but not everybody can do it.

[[...]]

Tina - That's a really really good question.

Bart - Great feedback and you are right about the exercise, I used to basically be a bodybuilder and now I haven't been in the gym for a year.  I try to go once in a while now at 8 months off but I still get tightness in my throat, stomach bloating, trouble breathing normal etc... as I exert myself.  The DP/DR goes hand in hand with that too.  I know once I'm 100% I will be able to return to my routine, it's very very hard to deal with. 

[[...]]

inw

You may be able to do some working out. I couldn't do anything earlier in my taper. Eventually, I started up really minimally, basically with just the bar and moving little tiny dumbbells, like the colored plastic ones for women. After a while I learned to eyeball about 4 reps before failure and stopped there. The trick is to not rev up symptoms which is really easy to do. I also take 3grams or vitamin C, aspirin or ibuprofen before workouts and phosphatidylserine in an effort to reduce cortisol during the workout. I go for about 20-30 minutes 3-4 day per week and then do some aerobics at a reduced pace. I think with trial and you can find a balance between gaining the benefits of exercise while minimizing the extra release of adrenal hormones.

[[Da...]]

Hi

 

I find walking for about an hour is okay, nothing too strenuous. It's sad because before all this, I found that walking really did me a lot of good and helped boost my mood, now this doesn't happen. I hope that I can return to the former feel good factor after all the taper is over?  David

[[Pe...]]

Hi everyone- just popped in to ask a question about an article Zoner posted several pages back entitled "Basic Pharmacologic Mechanisms Involved in Benzodiazepine Tolerance and

Withdrawal"- (here is the link: http://nltc.files.wordpress.com/2010/03/benzprimer.pdf ) to see if anyone here can clarify one of the medical terms for me so I can make sure I am on the right track.  Here is the term in context:

 

It has been suggested recently that internalised receptors

may provide the signal for subsequent changes in GABAA

receptor gene expression [227]. Taking this model further, it

is possible that uncoupling may be a signal for changes in

receptor turnover and degradation. Thus, exposure to

benzodiazepine-site positive allosteric modulators would

result in the following chain of events. Initial potentiation of

the GABA response would be quickly followed by

desensitisation. Prolonged desensitisation could be the

signal for uncoupling to occur, which either happens as a

consequence of the internalisation of receptors or is itself the

signal for internalisation. Once internalised, preferential

degradation of certain subunits occurs which provides some

sort of signal to the nucleus for changes in GABAA receptor

gene transcription.

 

I am assuming that 'internalisation' is referring to Receptor-mediated endocytosis (RME)- just want to make sure so I though I would ask.

[[ih...]]

Well read Pers, internalization is indeed receptor mediated endocytosis.

[[Ti...]]

Once this gene transcription occurs, as described above, is it reversible once the Benzos are removed? It is frightening to think that taking this horrid med could have caused genetic changes :/ Yikes!

[[Pe...]]

Well read Pers, internalization is indeed receptor mediated endocytosis.

 

Thanks ihope- just wanted to make sure I was understanding it all correctly.

[[ih...]]

Once this gene transcription occurs, as described above, is it reversible once the Benzos are removed? It is frightening to think that taking this horrid med could have caused genetic changes :/ Yikes!

 

Don't worry, Tina, tiny genetic changes are occurring in your body every day.  I am not aware of any studies establishing that GABA receptor numbers return to pre-benzo level, but the fact that we all heal highly suggests that they do.

[[...]]

Internalization of receptors would be a logical mechanism for ligand activation leading to decreased GABA_A receptor production. I would guess possibly as far back as the mRNA level. This process should be entirely reversible. This does not constitute a genetic change, but rather a gene expression change.

(PS I want my genes to re-express faster, dammit)

 

[[Ti...]]

Bart and Ihope-

 

Thank you for the reassuring responses.

 

Tina

[[Pe...]]

Internalization of receptors would be a logical mechanism for ligand activation leading to decreased GABA_A receptor production. I would guess possibly as far back as the mRNA level. This process should be entirely reversible. This does not constitute a genetic change, but rather a gene expression change.

(PS I want my genes to re-express faster, dammit)

 

Me too.

 

Yeah, it appears that they are suggesting that this is working as a sort of negative feedback mechanism resulting in changes to the gene expression to reduce the inhibition.

[[Pe...]]

Once this gene transcription occurs, as described above, is it reversible once the Benzos are removed? It is frightening to think that taking this horrid med could have caused genetic changes :/ Yikes!

 

Don't worry, Tina, tiny genetic changes are occurring in your body every day.  I am not aware of any studies establishing that GABA receptor numbers return to pre-benzo level, but the fact that we all heal highly suggests that they do.

 

Exactly.