The science of benzo dependence/tolerance

[[xe...]]

So I was wondering if anyone wanted to bounce back some scientific conjecture with me just for fun?

 

So let's get started

 

Benzo brain is a little bad today, so this won't be as great as it could be, but getting a discussion started.

 

The common lingo on the grape-vine is that benzos cause down-regulation of the receptors and time is needed to up-regulate them back to normal. While true (and a fine clinical viewpoint to explain the issue), this is woefully inadequate scientifically to explain benzo withdrawal. When receptors are out-of-balance, your body very quickly fixes this (days). Up-regulation taking 6-18 months or more simply has no scientific basis whatsoever.

 

There are other influences at the GABAa receptor itself. It is one COMPLICATED receptor. Decoupling of the benzodiazepine site from the GABA receptor as a mechanism of tolerance surely exists as well, and may be a more persistent issue than simple down-regulation of GABA receptors. But this also seems insufficient to explain benzo withdrawal.

 

For example: why is it when we withdraw, often reinstatement fails to produce relief of symptoms? This points to a very unique mechanism at work here. Also note that one could go on a steady diet of flumazenil after becoming 100% benzo-free and it will cause complete reversal of both down-regulation and decoupling in a matter of a week or two. Yet that often fails to produce a complete cure of w/d, the w/d often comes back. Why flumazenil helps, I don't know. Also note that flumazenil is clinically neutral -- in benzo-naive people, it produces no clinically adverse effects -- which seems to indicate the normal functioning of the benzodiazepine system in the GABA system is not that big a deal to normal CNS activity. The theory postulated by one study as to why flumazenil causes relief of protracted w/d symptoms is that the benzo site on the GABA receptor forms into an INVERSE agonist position -- meaning that the body's natural benzodiazepines (endozepines) would cause the GABA system to be dysfunctional. This is possible, and would explain why protracted benzo w/d can sometimes not appear for several months AFTER jumping, the time-frame probably required for the body to start producing healthy amounts of endozepines again after jumping off benzos, which it almost certainly stops producing while on them.

 

But what I find just as fascinating if not more so is the concept of kindling, and what withdrawal does to OTHER systems in the brain entirely -- NMDA and AMPA. See this wikipedia article: http://en.wikipedia.org/wiki/Kindling_%28substance_withdrawal%29 .. alas you have to pay to read the entire journal article it cites here: http://linkinghub.elsevier.com/retrieve/pii/S0163725803000299 but the abstract is a good read by itself.

 

I could re-write a lot of what they both say, but you might as well just read them yourself.

 

It seems likely that benzodiazepine withdrawal, especially after a period of tolerance withdrawal, or in heavy cold-turkey situations, causes several things to break rather badly in the CNS, entire critical excitatory-inhibitory neurotransmitter balance systems, and these are the things that take so long to heal.

 

Your thoughts?

[[De...]]

My feeling based on what I have read so far is this:

 

Kindling is essentially a scientific theory and even on wikipedia, another article states that one study shows no evidence that binge drinking causes any more impairments than chronic drinking. However, I think that to an extent it is possible. I believe that either

 

A) People begin drinking/using the drug before their body has a chance to heal from the previous detoxification, or

 

B) the body gets used to a drug being present periodically that healing becomes slowed in anticipation for the next time a drug/alcohol is induced

 

C) That detoxifaction, like the wiki article says, causes neuro-excitoxicity and leads to neuronal death, and this causes impairments.

 

However, like you said, kindling refers more to seizures and seizure risk along with brain damage. It means withdrawl to mean actual physical withdrawls, not withdrawl as in removal of the drug. I think most of us have never drank heavily enough to experience actual withdrawls from alcohol (a hangover is not withdrawl, is due to other chemicals that cause inflammation in the body.)

 

I say all this because the theory of kindling can scare the hell out of someone new to benzo withdrawl, and they, along with the rest of us, don't need anything else to be worried about. Also alcohol affects almost every other system in the body, serotonin, dopamine, acytlecholine, Nicotonic Receptors, ect, along with  NMDA receptors, AMPA receptors, and gaba receptors. Also alcohol is more often than not commorbid with smoking use and possibly other drugs. Not sure what the parameters of the studies were, but I bet they didnt distinguish between smokers and non smokers.

 

Often you see that benzodiazapines and alcohol are similar because their effects on gaba, but alcohol does so much more in the body.

 

As you stated, I believe that in response to benzo withdrawl GABA becomes down-regulated AND glutamate becomes up-regulated, and this in turn throws other systems out of balance. Also I believe that this experience causes most of us to experience a bout of PTSD, which in turn can cause the anxiety to get worse which leads to slowed healing/regulation of other systems, causing a more prolonged experience.

 

IF, withdrawl does cause neuronal death and brain damage, the brain is extremely plastic and has the ability to form new connections and to change. I saw a good example once, someone said "Take for example people who are color blind all their lives. When these people have cones placed into their eyes, eventually they are able to see color, even though their brains had never seen it before."

 

THE KEY is: keeping the body healthy and obstaining from drugs that effect the brain so that the brain can adapt on its own, without outside interference.

 

These are just my thoughts, I am not an expert so don't take what I say as cold hard facts...it is merely based on what I have read thus far and piecing it together, along with my own personal experience

[[xe...]]

This is all thoughts/opinion/conjecture, not cold hard facts, thanks for sharing! Nice post.

 

I think the main point I was getting at is not really about kindling really, but how the things it is based on apply to benzo tolerance/addiction - up-regulation of glutamate (NMDA and AMPA) being the main one. The journal article I linked only talks about kindling as a side-note.

 

The reason healing takes so long is that so many systems are thrown for a loop.

 

Also, about excitotoxicity, I'm pretty sure this is fact that it occurs during benzodiazepine withdrawal? That doesn't mean it causes permanent damage, however.

[[De...]]

Yea, I think I clicked on Kindling on wikipedia and read it all then got it in my head you were talking about that lol, sorry. I was also just saying for anyone who did the same thing I did and reads about kindling..didnt want them to be scared. Also, benzo withdrawl can cause excitotoxicity, but it does not always happen. From my understanding, excitotoxicity causes neuronal death, whereas glutamate sensitivity is just that.. sensitivity, or, put more accurately glutamate disinhibition (which includes underfunctioning gaba). I think theres a fine line, and the more severe cases can be caused by excitotoxicity. However, it could be that theres a small degree of excitotoxicity in every case, with increasing toxicity in more severe withdrawl cases.

The definition is

 

Definition: Excitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated.

 

http://www.google.com/search?hl=en&defl=en&q=define:Glutamate+excitotoxicity&sa=X&ei=9VWOTdWWPMPB0QHQpLCcCw&ved=0CBQQkAE

 

I think this is a great thread to start, I've been wanting to hear others thoughts without having to read it here and there and search for it. Having it in one place is definitely a plus 

[[Da...]]

I was reading all this, I can't really understand it. But I have been in tolerance w/d for about 13 years and finally cutting real slow off Klonopin. Will my brain heal or does science say that when in w/d ot t/wd too long it's not possible?

[[xe...]]

I was reading all this, I can't really understand it. But I have been in tolerance w/d for about 13 years and finally cutting real slow off Klonopin. Will my brain heal or does science say that when in w/d ot t/wd too long it's not possible?

 

While this topic is not for people who want advice to come to or try to incorporate into their getting better, I do feel I should make it clear: science really has no idea. It certainly shows that everyone heals from w/d, if that's what you are asking, yes absolutely, you will recover from benzos if you taper and get off them. If you are asking whether cognitive deficits and some other things caused by long-term use of benzodiazepines and/or benzodiazepine w/d itself heal, the jury is still out. It would seem mostly yes but some cognitive deficits remain. Also it seems that anxiety may remain heightened for a long time to forever than pre-benzo, but recover to a level that it is far better than in tolerance w/d while on them.

[[Pr...]]

I like this thread a lot. I used to like biology and chemistry in high school but I'm still out of my league here. I didn't, and couldn't read everything ^_^

 

The essence of what is being said is that the GABA receptor downregulation sets off a cascade of other changes in downstream systems, including but not limited to the system that regulates glutamate. Different systems heal at different rates and at different times. In fact, one system might achieve homeostasis, which triggers the next to start trying to revert to its original state too, which triggers the next, and the next.

 

Is that right? It would make sense for me. I am 4 months off, and haven't had bad physical sxs in three months. This week, whammo.

 

 

[Guest [Si...]]

@[ D...]

 

"These are just my thoughts, I am not an expert so don't take what I say as cold hard facts...it is merely based on what I have read thus far and piecing it together, along with my own personal experience"

 

They're good thoughts at that!

 

You say "with my own personal experience"...

 

Actually that's the way it is for everyone.

 

There is no "Scientific Explanation" for withdrawal IMO.

Everyone is "Different" and "Distinguished"... Someone can try to explain it all they want in many ways, terms, expressions, theories & so on...

BUT no one is going to get that that "Magical Answer" of how it all works... many things can be solved, but this "Particular Enigma of how it works" is unknown to many degrees!

Ashton is whom I go by, but still... there's allot of revision there... that needs to be worked with... if that's "Possible"... very unlikely, but whatever.

 

There is no "Compute"/ "Rhythm"/ "Cypher"/ "Tally"/ "Reckon" or any of that to withdrawal, and if anyone is out to find that, they're in for a big let down, as they will not succeed.. because everyone is different.

Some of us are allergic to certain foods... some of us are not... go figure.

 

Everyone's story is different, and no one is the same, as we all know.. in withdrawal.

 

I've read one story to another, and they're all different, toss Science aside.

For example-

"I recovered with no problem.." (Someone may have a totally different outlook)

"I just tossed it down, and didn't have any withdrawal.." And again- (Someone may have a totally different outlook)

"I took Klonopin for 3 years, and when I stopped.. it was hell on earth.." so on..

"I took Klonopin for a few years, and I stopped c/t... I just felt more aware.." so on..

"I healed in 6 months" so on..

"I healed in 12 months" so on..

"It took me 3 years to heal" so on..

"I switched to Valium, and came off with no problem.." so on..

You get the point.. as everyone is different, so it cannot be conclusive..

 

I have a friend, who was on Klonopin 3 years.. she threw it down, and had no withdrawal.. she said, "I just felt more aware and active."

I know she took it.. I seen her, and NO she was not on anything else but an AB.. and insulin for diabetes.. she started a job at the Nursing Home  a few days later.. someone explain that?

They can't.

 

Basically what happens IMO, your senses wake up! I know mine has in many ways.. this is all explained in the Ashton Manual &c..

 

BUT everyone is so different and there's just no Scientific way of explaining that..

If anyone says there is, or has an explanation to that "Magical Answer" .. I would like to see it, and then I can show them.. my unicorn and dragon I have.  

 

The common lingo on the grape-vine is that benzos cause down-regulation of the receptors and time is needed to up-regulate them back to normal. While true (and a fine clinical viewpoint to explain the issue), this is woefully inadequate scientifically to explain benzo withdrawal. When receptors are out-of-balance, your body very quickly fixes this (days). Up-regulation taking 6-18 months or more simply has no scientific basis whatsoever.

 

BINGO!

 

 

S#

 

Mod# We all heal... and that's the bottom line really.

 

 

 

 

 

[[Pr...]]

There is some talk of there being a genetic component to it. I don't know what the answer is for this particular conundrum. But there *is* an answer out there for all of this, though it may seem like randomness and nonsense to us here and now. It's fun to speculate on it at least.

[Guest [Si...]]

It's fun to speculate on it at least.

 

I agree, speculation *is* ok... but as far as an answer out there?

 

Yes, but the probability is highly *Unlikely* as we all "Differ"...

 

 

S#

 

Mod- Hold up a second... a "Scientific" answer or an answer when we are healed?

 

[[De...]]

I think its fun to speculate as well, however I think this is also a good thread to post information that we come across as opposed to having and individual thread for each link or study. Will we ever find an answer, not right now...but if someone found out something interesting, I'd like to know just for my own satisfaction.

 

I think everyone is different not just because of genetics but past experiences with drugs. For instance I sadly did a lot of cold medicine to get buzzed, 60 pills a day..i got off that finally and afterwards I had insulin resistance and could no longer drink coffee for getting too jittery. I came to find out dextromethorphan is a serotonin and NE inhibitor along with a mild glutamate antagonist. I think this caused big changes to my systems, then on top of drinking and the benzos, I think it may take me longer to heal. But it may not..but I take comfort in knowing the general situation then have no clue. As I find more stuff ill post links here, typing on my phone and taking forever to type this lol

[[De...]]

Just want to add an idea that I think rate limiting steps in neurotransmitter creation is a big reason why it takes time to recover. I read that if one takes just one pill of exctasy, it can take a month to replace that serotonin.

 

Also read a study on diazapam and rats..no link to provide but it said that rats were treated with valium for 4 days. Upon cessation, 50% of gaba recovered within 4 hrs..it took 32 hrs for all to recover. This can help possibly explain why the first few weeks are so bad, and then some symptoms like anxiety last so much longer. If say 3 weeks the worst symptoms go away, times that by 8 (since 4 hrs 50% recovered, but it took 8x as long for the rest) your looking at 6 months. If this is how it works in practice, I doubt it, but it Atleast shows that gaba can take a long time to recover.

 

I think people who are fine coming off benzos just happen to have enough receptors left  to inhibit glutamate so they don't feel the overexcitation of the body

[[Pr...]]

I wouldn't feel too bad about that, Defaulted. The hardest drug I've ever done in my life is daily Claritin for my allergies. I've had one alcoholic drink -  a coco mojito back in 2006. Coffee? What's that?

 

Yet I'm still sick as a dog going into my fifth month. So don't beat yourself up. I do agree there are things we can do to make ourselves more sensitive though. The whole kindling thing speaks to that. And just let me forget a dose of my a/d. HA!

 

S#, I meant an explanation for the exact mechanism(s) of benzo withdrawal. As you mention there's SOMETHING that causes the messed up meandering nature of this illness that varies from person to person.

 

It's like...take three average people out of the population. They're all undernourished. They drink too much soda. Eat white bread. One of them develops diabetes. The other develops hypertension. The third develops depression and anxiety. Okay, but the underlying issue is the same. Just that different metabolic pathways became involved for whatever reason and different diseases result. That's how I look at benzo w/d

 

Here's something interesting. Not sure if you guys believe in neurotransmitter testing or not. Not sure if I do. But I did have one done at 1 week off. My GABA levels were through the roof. Like quadruple normal levels. Ashton does say that it's not the level of GABA, but the change in structure of the receptor that's the problem. It makes sense that the body only knows that the action of the GABA has been reduced, so one of the things it tries to do is to increase levels. But what if even that increase also sets off another cascade of changes in other systems?

[Guest [Si...]]

I find the thread interesting, but when I see "Scientific"... I need Proof, as in "PROOF".

LOL.. I'm not trying to be hateful, and I hope I didn't come across that way, but I need proof... as in reasoning.. deductive..

Yes.. we can come up with theories, which is interesting. I have my own theories, but I doubt they could be understood... I would have to break it down, as words can't express it all...

 

It's like...take three average people out of the population. They're all undernourished. They drink too much soda. Eat white bread. One of them develops diabetes. The other develops hypertension. The third develops depression and anxiety. Okay, but the underlying issue is the same. Just that different metabolic pathways became involved for whatever reason and different diseases result. That's how I look at benzo w/d

 

I hear you...

 

 

S#

[[Pr...]]

Theories theories! I want to hear them! Pretty please???

[Guest [Si...]]

delete

 

 

[[Pr...]]

holding you to that, S#

[[De...]]

Lol let's call the book "contemplations of a benzo brain" . Hopefully some other people take some time to comment..looking forward to hearing your theories s#.

 

Princezz- yea this whole experience had taught me that if you don't have your health, what do you have? My future children will benefit as well as me from a sober life. As far as neurotransmitter testing, I don't believe because they measure the metabolites of the transmitters, and blood levels don't correspond to CNS levels..it is interesting that your gaba was through the roof though lol..I've always thought about doing it just for curiosity sake

[[Pr...]]

Yea I had similar doubts about the process but hey, I had $200 to burn (NOT!) and w/d makes us desperate right?

 

As a computer scientist, I personally find all this measuring of blood and urine to be woefully inadequate. I'm very much into the idea of nanomedicine. Eventually we'll be able to inject people with tiny computers that will travel through the body without harming it, performing the perfect reconnaissance!

[[De...]]

Nano medicine is interesting..I heard they are using stuff like that for cancer now. What if they could attach mechanical  GABA receptors to neurons..thatd be crazy lol

[Guest [Si...]]

As a computer scientist, I personally find all this measuring of blood and urine to be woefully inadequate. I'm very much into the idea of nanomedicine. Eventually we'll be able to inject people with tiny computers that will travel through the body without harming it, performing the perfect reconnaissance!

 

You are a computer scientist?

 

I take it then.. you are good at algorithms?

 

I will indeed post my theories, give me a day or two.. they are Mathematical.. and I will need to break it down, and also will provide the theorems I used to express my theories..

My field is Math, and as a Mathematician.. I express things I know.. mostly through numbers. I'm not too good with words.. just me I guess.. 

 

S#

[[Pr...]]

They're *kind of* using nanomedicine for cancer. They do attach the chemo drugs to certain particles, like gold. But what I'm envisioning is a time when entire computers, complete with self-propulsion etc, are the size of a nanoparticle and can safely be injected into the body. The outside would be made out of something that doesn't trigger the immune system. Etc. If I find a lab working on something like that, I am so there.

 

S#, I'm a developer, not a theorist 

 

I've seen your math thread but I haven't had the will power to really dig into it yet. 

[Guest [Si...]]

delete

 

 

[[De...]]

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2004.02760.x/abstract

 

Apparently the body increases gaba production in response to chronic raised cortisol, which is some good news. Just wish I knew how fast receptors recover, this early morning cortisol rush is killing me..my heart beats out if chest from just rolling over in bed wtf...

[Guest [Si...]]

delete