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

[[...]]

Feedback loops in cell biology serve the purpose of temporarily adjusting for change. They are specifically not permanent.

[[Pe...]]

Feedback loops in cell biology serve the purpose of temporarily adjusting for change. They are specifically not permanent.

 

Probably would have been better if I called it a homeostatic response?  I know what you are saying- it is not like for e.g. the Cortisol negative feedback loop.

 

My background is in electronics- which makes things like electrical potentials, thresholds, summation, etc... easier to understand-but still learning and trying to grasp the biological stuff.  Hoping I can learn a lot from you and ihope.

 

Since this reverses after benzo cessation (as shown by people who have recovered) this would suggest that it is not permanent - (just wanted to add that so no one misunderstands what we are saying and gets scared. )

 

 

 

Modified to add a sentence to help clarify things.

[[...]]

Great confirmation on the gene changes, I know it's scary but we highly doubt any change is permanent.  I always go back for reassurance by looking at the rock stars and other alcoholics or people who have used a cocktail of drugs and substances for an extended time period.  Once they kick the habit, they're fine.  The only people who are usually messed up for a while or permanently are football players, MMA fighters, or boxers due to the direct impact to the brain. 

[[...]]

Feedback loops in cell biology serve the purpose of temporarily adjusting for change. They are specifically not permanent.

 

Probably would have been better if I called it a homeostatic response?  I know what you are saying- it is not like for e.g. the Cortisol negative feedback loop.

 

My background is in electronics- which makes things like electrical potentials, thresholds, summation, etc... easier to understand-but still learning and trying to grasp the biological stuff.  Hoping I can learn a lot from you and ihope.

 

Since this reverses after benzo cessation (as shown by people who have recovered) this would suggest that it is not permanent - (just wanted to add that so no one misunderstands what we are saying and gets scared. )

 

 

 

Modified to add a sentence to help clarify things.

 

Electronics. Good for you. My grad schools were in cell biology and then pharmacology. I still didn't know jack squat about benzodiazepines and their withdrawal until I got caught up in it, read the Ashton manual and joined BB.

[[Bi...]]

bart that's because benzo's are Allosteric modulator's

 

http://en.wikipedia.org/wiki/Allosteric_modulator

 

Lab rat #2

 

[[Bi...]]

Cure?? SEE -  http://en.wikipedia.org/wiki/Inverse_agonist

[[Bi...]]

Two-state receptor theory

 

The two-state model is a simple linear model to describe the interaction between a ligand and its receptor, but also the active receptor (R*).[15] The model uses an equilibrium dissociation constant to describe the interaction between ligand and receptor. It proposes that ligand binding results in a change in receptor state from an inactive to an active state based on the receptor's conformation. A receptor in its active state (UP-REGULATION) will ultimately elicit its biological response. It was first described by Black and Leff in 1983 as an alternative model of receptor activation.[16] Similar to the receptor occupancy model the theory originated from earlier work by del Castillo & Katz on observations relating to ligand-gated ion channels.[3] In this model agonists and inverse agonists are thought to have selective binding affinity for the pre-existing resting and active states[3][17] or can induce a conformational change to a different receptor state. Whereas antagonists have no preference in their affinity for a receptor state.[18][19] The fact that receptor conformation (state) would affect binding affinity of a ligand was used to explain a mechanism of partial agonism of receptors by del Castillo & Katz in 1957 was based on their work on the action of acetylcholine at the motor endplate[3] build on similar work by Wyman & Allen in 1951 on conformational-induced changes in hemoglobin's oxygen binding affinity occurring as a result of oxygen binding.[20] The del Castillo-Katz mechanism divorces the binding step (that can be made by agonists as well as antagonists) from the receptor activation step (that can be only exerted by agonists), describing them as two independent events.[20]

 

 

FROM  http://en.wikipedia.org/wiki/Receptor_theory

 

YOU do not want to here how PAWS could be cured,, ANY ONE?

[[...]]

I wonder how flumazenil works. It apparently binds to the benzo receptor and has some basal activity yet blocks benzo bending. My guess is it opens the chloride channel somewhat less than benzos do while at the same time competitively inhibits benzo binding. Maybe this is the basis for the relief of PAWS. It seems a longer acting version of the molecule could be synthesized.

[[Bi...]]

Hi bart,

 

You would be shocked at how simple it is to WAKE UP billions of sleeping receptors?

 

First question: WHAT IS THE OPPOSITE OF A TRANQUILLIZER??

 

http://en.wikipedia.org/wiki/Methylphenidate

 

Question #2: Do people on diet pills EVER complain of ANXIETY?  Why not? This is very odd in itself yes? So how can people get hooked on an ANXIETY CAUSING MEDICATION Think about it very carefully now?? 

 

sub-performance of the dopamine, norepinephrine, and glutamate processes in the brain responsible for self-regulation functions

http://en.wikipedia.org/wiki/Methylphenidate

 

 

So about a month after jumping and your still NOT feeling right this is what you may wish to explore this with your Dr. in small doses.

 

Low dose - Anti-tranquillizer therapy

 

[[...]]

That's very interesting and the mechanism of Methylphenidate seems to 'regulate' things that are out of whack so it's more of a solution and not a mask.  I know the same can be done with food, supplements, and exercise, but the drugs are way more powerful and concentrated. 

 

We also understand that the dopamine, seratonin and other chemicals are all affected by benzos, it's not just the Gaba receptors so this explains the depression, lack of motivation, extreme fatigue, intrusive thoughts,etc...

[[Bi...]]

Hi inw,

 

This is really a forgotten secret. Any Hippie that lived in the 1960's will tell you that when they fooled with uppers and downers / Valium and coke,  since one would counteract the long term symptoms of the other and they would YOYO back and forth month after month and year after year until they were totally burned out. The trick is learn what worked and just QUIT.

 

I do find it interesting that people complain of ANXIETY can THEN get hooked on uppers and LOVE anxiety all of a sudden? Weird yes?  That's a BIG WHOPPING clue to what's going on in the brain.  I have never heard a "METH HEAD" say "wow man this anxiety really sucks", they just want more and more of the drug. Think about this very carefully

 

Fixes do exist, the brain can be fixed, the chemistry however is delicate, very delicate.

 

Methylphenidate is legal and you could relearn to LOVE anxiety with light doses.

(please someone say that Methylphenidate lowers anxiety,,, yes it does, it calms in small doses, how does that work and you will answer your own question :) )

[[Ma...]]

Bird I wish I could hang out with you.  You seem to have amazing insights.  I graduated college Cum Laude with a science degree, but I have to say I'm having a hard time really comphrehending this.

 

This morning I've been reading a lot, Parker's stuff and yours.

 

What I am thinking about is the fact that I was put on a very high dose of Klonopin, and then taken off that suddenly and put on ativan.  Or put back on ativan.  It wasn't a crossover it was just a sudden switch.  It seemed to take me 5 months to stabelize from that, and I was even cutting during that time.  I really wonder, how did my body and brain stabelize from that?

 

There must be healing even on benzos because after that switch I was quite a mess mentally and physically for many months.  But it got better.  I wish I had the clear insights that you do.

 

So do you think this M substance can reverse benzo withdrawal, is that what you're saying?

[[Bi...]]

Hi Mairin,

Cum Laude with a science degree, very cool 

I'd say that only a taper can ease withdrawal but many people have PAWS after they quit so for THESE people "M" may be very useful to KICK START their brain's natural processes again.  Some people get stuck after a taper and healing is too slow.  This is risky since they may reinstate and that's a dead end road.  Sometimes the opposite approach is needed,  A STIMULANT.  Yes that's sounds nerve racking to people afraid of anxiety but THAT'S the key, people like stimulants too. In other words anxiety is also an addictive state-of-being for many people. Short term stimulant therapy could help many people who have PAWS from long term benzo use. Of coarse tapering the "M" would be important to avoid any more shocks to an already delicate nervous system.

 

This is  not my idea. This is common knowledge in 'DRUGGY' circles.  They are the real experts but they use their know how to perpetuate their own "Keith Richards" syndrome. We could learn much from them about how drugs work minus their habitual nature of coarse

[[Pe...]]

ihope and Bart- I have a question for you guys-

 

There is a member here who is at 2 yrs and 7 months.  She tested high for Glutamate levels and is wondering if anyone knows how to get these levels down.

 

I saw you guys posted this on page 5 of this thread with regards to rocephin:

 

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

 

quote from Bart "There is strong evidence that rocephin (ceftriaxone) increases glutamate transporter (GLT-1) which transports glutamate out of certain cells."

 

My question is whether you think this medication might help bring her levels down.

 

Thanks.

[[ih...]]

Hi Pers, i have reservations about recommending off label use of an antibiotic when there is no infection present.

 

Maybe the BBcould ask her MD about memantine which is also a glutamate antagonist which some studies have found may help regulate glutamate back to normal levels.

[[...]]

I reviewed the literature on this and there is real evidence for the phenomena. I suspect the medication may bring her glutamate levels down but the effect would be temporary. Unfortunately, Rocephin is an IV or IM drug only and has big downsides as it is a powerful broad-spectrum antibiotic. It would be an interesting project to try and develop a pharmacological agent that would retain the anti glutamate effect without the antibiotic properties. I suppose if I were desperate enough I might try some short course of an oral cephalosporin for relief. This would be risky and may not work as Rocephin is a third-generation cephalosporin and most oral cephalosporins are first-generation. Also, I doubt a doctor would prescribe it.

[[Pe...]]

Hi Pers, i have reservations about recommending off label use of an antibiotic when there is no infection present.

 

Maybe the BBcould ask her MD about memantine which is also a glutamate antagonist which some studies have found may help regulate glutamate back to normal levels.

 

I completely understand and agree with your reservations about off label use for medications.  However she has also been dx'd with Lyme Disease- do you know if this antibiotic has ever been used in that treatment protocol?  I am not familiar with the bacterialcidal profile for this one- just wondering if you knew.

 

I will inform her about the memantine so she can ask her doctor about it.

 

Thanks for getting back to me so fast.

[[Pe...]]

I reviewed the literature on this and there is real evidence for the phenomena. I suspect the medication may bring her glutamate levels down but the effect would be temporary. Unfortunately, Rocephin is an IV or IM drug only and has big downsides as it is a powerful broad-spectrum antibiotic. It would be an interesting project to try and develop a pharmacological agent that would retain the anti glutamate effect without the antibiotic properties. I suppose if I were desperate enough I might try some short course of an oral cephalosporin for relief. This would be risky and may not work as Rocephin is a third-generation cephalosporin and most oral cephalosporins are first-generation. Also, I doubt a doctor would prescribe it.

 

She also has been dx'd with Lyme disease- I am not familiar with the specific antibiotics used in Lyme Disease treatment- do you know if cephalosporins have been used as part of the IV antibiotic protocol in the past for Lyme?  I know this may be a stretch -- I am not familiar with the bacterialcidal profile for this family of antibiotics.  It would be great if there were a possibility of knocking out two birds with one stone.

[[Pe...]]

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.

 

I have one more for you- in addition to neuroadaptations such as increased Glutamate levels, down-regulation, and the changes in levels of other neurotransmitters there is also a potential negative affect on the HPA Axis due to benzos inhibitory affect on CRH- thus affecting steroid hormone production.  Here is an excellent article demonstrating this affect:

 

http://jcem.endojournals.org/content/87/10/4616.long

 

If there is some polymorphism which has made us all genetically prone to these affects and it could be identified- perhaps people could be genetically tested prior to prescription of benzos so all this could be prevented.

[[Hj...]]

Perseverance, I have read that rocephin is very helpful to people with Lyme...

[[...]]

Rocephin has been used for acute lyme disease and does kill the organism. In post lyme disease syndrome it gives some people temporary relief of symptoms but it is not from killing the organism. It may be from some type of modulation of the immune system.

There are significant side effects with Rocephin so this would be a gamble even if she could find a doctor to prescribe it.

[[Pe...]]

Thank you Hjc2899 and Bart.  I will let her know.  I am sure she will really appreciate your inputs- she has been fighting multiple dxs in addition to BW- which has really complicated things.

[[Pe...]]

Here is an article which I thought was very appropriate for this thread and I think many here will find interesting.  (Note: This article also discusses effects of Flumazenil -I think someone was asking about that a while back).

 

http://bjp.rcpsych.org/content/179/5/390.full

 

Just wanted to add that they used gene manipulation to identify the functions of the sub-units and to observe the binding characteristics of different drugs.  I think this article points to a possible direction things may go regarding prescription of benzos in the future.  If they can identify the genes involved they can avoid prescribing this medication to vulnearable people.  They obvioulsy want to figure this out so that they can continue to use benzos to treat anxiety conditions.

 

 

 

 

[[zo...]]

Here is an article which I thought was very appropriate for this thread and I think many here will find interesting.  (Note: This article also discusses effects of Flumazenil -I think someone was asking about that a while back).

 

http://bjp.rcpsych.org/content/179/5/390.full

 

Just wanted to add that they used gene manipulation to identify the functions of the sub-units and to observe the binding characteristics of different drugs.  I think this article points to a possible direction things may go regarding prescription of benzos in the future.  If they can identify the genes involved they can avoid prescribing this medication to vulnearable people.  They obvioulsy want to figure this out so that they can continue to use benzos to treat anxiety conditions.

 

I've always liked this article by David Nutt even though it seems at complete variance with his public reputation for drug liberalisation and poor showing on Channel 4's Live Ecstasy Trial last year. It's almost as if there are two very different sides to him.

 

I recall this interesting chart originally came from a paper by Nutt.  http://upload.wikimedia.org/wikipedia/commons/9/9c/Rational_scale_to_assess_the_harm_of_drugs_(mean_physical_harm_and_mean_dependence).svg

 

-Zoner

[[Pe...]]

Wow Zoner- that was interesting.  I had never heard of him before reading this article.