# People Who Don't Respond to Benzos



## TheoBobTing (Jul 8, 2010)

Most people here seem to at least initially find that benzodiazepines are quite potent. There are a small number of us here though that can take relatively large doses of benzos and feel absolutely no effects (without building up a tolerance beforehand). I've thought about why this might be the case for me personally, and I'm starting to believe that this abnormal reaction (or non-reaction) represents the biological root of my anxiety. Basically, if one's benzodiazepine receptors are in some way screwed up, not only would benzos not work, but anything else that relies upon these receptors to function wouldn't work either.

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

"WHY DOES THE BENZODIAZEPINE SITE EXIST?

The benzodiazepine site is the most evolutionary recent part of the GABAA complex discovered (Nielsen et al, 1978 ). So what evolutionary pressures have led to the emergence of benzodiazepine receptors and their widespread presence in neurons? One theory is that they are necessary to regulate anxiety, and that the brain itself produces an anxiety-reducing compound (an 'endogenous agonist')."

"Abnormalities of these benzodiazepine receptors may underlie some anxiety disorders."


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## Mr Bacon (Mar 10, 2012)

That could be a theory.

However, maybe your social anxiety is linked to other neurotransmitters. Maybe you're the type to lack serotonin. Or perhaps dopamine/norepinephrine.

For instance:

I don't react at all to benzos. They just make me sleepy. The reason why I have social anxiety, is because I am depressed and have anehdonia, which makes me feel disconnected from other people, thus, uncomfortable in social settings. The stuff I need is most likely the stimulating meds, not benzos or antipsychotics...


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## TheoBobTing (Jul 8, 2010)

Mr Bacon said:


> That could be a theory.
> 
> However, maybe your social anxiety is linked to other neurotransmitters. Maybe you're the type to lack serotonin. Or perhaps dopamine/norepinephrine.
> 
> ...


I'm talking about people like myself who literally feel *nothing* from taking large benzo doses. No effects and no side effects. If they make you sleepy then you don't fall into this category.


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## TheoBobTing (Jul 8, 2010)

I only know of one other person on these forums who shares my complete non-response to benzos.


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## mark555666 (May 1, 2008)

The next step: Barbiturates

Have you already tried any stimulant?


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## istayhome (Apr 4, 2012)

I have pretty much the same theory as for my anxiety. I do respond to benzos but I require much higher doses than most people do. I think that a lot of the anxiety I experience stems from Biological abnormalities of the Gaba receptors.

Obviously I do respond so it is not to the degree that you experience. But it seems reasonable that if my GABA receptors require a lot of stimulation from high doses of benzos to relieve anxiety then the receptors themselves likely are not very sensitive; making the GABA my body naturally produces unable to get the job done in the first place which started the anxiety to begin with.


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## istayhome (Apr 4, 2012)

Freesix88 said:


> The next step: Barbiturates
> 
> Have you already tried any stimulant?


Being prescribed Bariturates for an anxiety disorder nowadays would be as likely as going to the moon. Stimulants are the complete opposite of BZD's and Barb.'s


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## chiaza (Aug 9, 2012)

istayhome said:


> Being prescribed Bariturates for an anxiety disorder nowadays would be as likely as going to the moon. Stimulants are the complete opposite of BZD's and Barb.'s


They don't work as well as benzos anyway, I took some Phenobarbital and just fell asleep for like 2 days.


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## mark555666 (May 1, 2008)

chiaza said:


> They don't work as well as benzos anyway, I took some Phenobarbital and just fell asleep for like 2 days.


Really? How many mg you took? 300 mg had aN decent effect for me.


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## chiaza (Aug 9, 2012)

Freesix88 said:


> Really? How many mg you took?


I took 6x 100mg pills. They were generic phenobarbital(fenobarbital) by Zentiva Pharmaceuticals.


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## metamorphosis (Dec 18, 2008)

TheoBobTing said:


> Most people here seem to at least initially find that benzodiazepines are quite potent. There are a small number of us here though that can take relatively large doses of benzos and feel absolutely no effects (without building up a tolerance beforehand). I've thought about why this might be the case for me personally, and I'm starting to believe that this abnormal reaction (or non-reaction) represents the biological root of my anxiety. Basically, if one's benzodiazepine receptors are in some way screwed up, not only would benzos not work, but anything else that relies upon these receptors to function wouldn't work either.
> 
> http://bjp.rcpsych.org/content/179/5/390.full
> 
> ...


There can be many reasons. GABA receptor sites may be severely down-regulated for various reasons. Genetics, toxins, and often the use of benzos or other drugs/medications that will eventually kill off many of the GABAa receptors. Which will cause a huge issue with all of the other NT's associated with mental illness. One of those being the most influential is the excitatory NT glutamate, a CNS stimulant. Often times the lack of GABA production in the brain is in direct correlation to an influx or up regulation NMDA receptors producing excess glutamate. NMDA antagonists can help control the release of the glutamate.

Of course that is just one of many different scenarios.


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## istayhome (Apr 4, 2012)

metamorphosis said:


> There can be many reasons. GABA receptor sites may be severely down-regulated for various reasons. Genetics, toxins, and often the use of benzos or other drugs/medications that will eventually kill off many of the GABAa receptors. Which will cause a huge issue with all of the other NT's associated with mental illness. One of those being the most influential is the excitatory NT glutamate, a CNS stimulant. Often times the lack of GABA production in the brain is in direct correlation to an influx or up regulation NMDA receptors producing excess glutamate. NMDA antagonists can help control the release of the glutamate.
> 
> Of course that is just one of many different scenarios.


Yeah, I think we're more discussing the idea of GABA receptors sites being severely down-regulated from genetics, toxins, brain damage or what have you right off the bat leading to anxiety disorders as opposed to the down-regulation that is a result of prolonged GABA agonist use.

In which case it seems like any GABA agonist would be ineffective, Benzo's, Barb's, ETOH, GHB, GBL, etc. depending on whether on which exact GABA receptor sites are down-regulated, damaged, non-existent, etc.

Such a scenario would certainly lead to a variety of disorders including anxiety.


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## riptide991 (Feb 1, 2012)

TheoBobTing said:


> I'm talking about people like myself who literally feel *nothing* from taking large benzo doses. No effects and no side effects. If they make you sleepy then you don't fall into this category.


Do you respond to opioids? What about synthetic opioids (Although harder to find)? I've read that moclobemide seems to help users who respond to synthetic opioids on their depression. Now keep in mind stuff like oxycodone, codeine, etc are not synthetic opioids. I wouldn't know where to get my hands on em just to try.


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## ricca91 (Mar 11, 2012)

kehcorpz said:


> Do you respond to opioids? What about synthetic opioids (Although harder to find)? I've read that moclobemide seems to help users who respond to synthetic opioids on their depression. Now keep in mind stuff like oxycodone, codeine, etc are not synthetic opioids. I wouldn't know where to get my hands on em just to try.


I think the synthetic opioid which are easiest to get are diphenoxylate (an antidiarrheal, related to fentanyl, but of very weak potency) and dextropropoxyphene (I don't know if it's banned in canada, it is in the US because they said it's cardiotoxic. In reality a metabolite of it is cardiotoxic, but only in overdose, it's also quite weak but very good for pain. It's related to methadone).

Just say that you have really bad diarrhea and don't respond to imodium to try to get diphenoxylate or that you have bad back pain which doesn't respond to NSAIDs or Tylenol and that a friend of yours gave you propoxyphene and it worked (obviously it's not so easy to get, considering how doctors operate nowadays, but you can try).

Or you could try to get meperidine or buprenorphine, but that would be much more difficult...


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## istayhome (Apr 4, 2012)

kehcorpz said:


> Do you respond to opioids? What about synthetic opioids (Although harder to find)? I've read that moclobemide seems to help users who respond to synthetic opioids on their depression. Now keep in mind stuff like oxycodone, codeine, etc are not synthetic opioids. I wouldn't know where to get my hands on em just to try.


A list of synthetic opioids:

http://en.wikipedia.org/wiki/Category:Synthetic_opioids

Methadone, Mederidine, Desmethyltramadol, Fentanyl readily come to mind

I've never heard of anyone NOT responding to synthetic opioids. It seems like Tramadol helps a lot of people. Tramadol itself being an SNDRI and metabolizing into Desmethyltramadol: a Mu opioid agonist.


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## chiaza (Aug 9, 2012)

I would try to avoid Tramadol maybe, it made me feel very sick. Don't know if it was just me though.


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## istayhome (Apr 4, 2012)

chiaza said:


> I would try to avoid Tramadol maybe, it made me feel very sick. Don't know if it was just me though.


I'm not a tramadol fan either. I just see a lot of posts on this forum about it and many people really find it beneficial.


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## riptide991 (Feb 1, 2012)

istayhome said:


> A list of synthetic opioids:
> 
> http://en.wikipedia.org/wiki/Category:Synthetic_opioids
> 
> ...


Well not just "euphoria" or pain relief. Apparently if you become energetic and anhedonia lifts, etc. I mean I've taken some nice opiates and while it feels good it doesn't really lift my anhedonia. If anything it makes me lazier as if I just had some pot.


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## istayhome (Apr 4, 2012)

kehcorpz said:


> Well not just "euphoria" or pain relief. Apparently if you become energetic and anhedonia lifts, etc. I mean I've taken some nice opiates and while it feels good it doesn't really lift my anhedonia. If anything it makes me lazier as if I just had some pot.


Yeah I figured out what you were saying. The synthetic opioids that I have tried do tend to make me feel very energetic and active; make anxiety, depression and anhedonia disappear. Although Opiates and Semi-synthetic opioids cause the same response for me as well. A little euphoria but mostly just activity, motivation, confidence, etc. It's weird; when I take the CNS depressants I find myself unbelievably active and sleeping as little as possible/


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## TheoBobTing (Jul 8, 2010)

Bear in mind that in the UK doctors are not at all keen on handing out strong mind-altering medications. I personally think barbiturates would be effective for me, because I believe that they don't use the specific receptor sites that benzos use. 

Alcohol numbs me like it would anyone, so I tend to point the finger at my benzodiazepine receptors rather than at a wider GABA issue, as if it was a wider GABA issue then presumably alcohol's effects would also be compromised.

I don't think I could get a stimulant. In the UK most doctors would probably be afraid of prescribing caffeine.


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## chiaza (Aug 9, 2012)

TheoBobTing said:


> I don't think I could get a stimulant. In the UK most doctors would probably be afraid of prescribing caffeine.


Can't you just say that you have ADHD ? I have a friend in USA who went to see his doctor, listed the symptoms of ADHD that he found on the internet, and walked out with a prescription for 30mg/d Adderall.


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## TheoBobTing (Jul 8, 2010)

chiaza said:


> Can't you just say that you have ADHD ? I have a friend in USA who went to see his doctor, listed the symptoms of ADHD that he found on the internet, and walked out with a prescription for 30mg/d Adderall.


As far as I know, even the genuine ADHDers in the UK sometimes struggle to get stimulants. That's how it is here.


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## riptide991 (Feb 1, 2012)

TheoBobTing said:


> Bear in mind that in the UK doctors are not at all keen on handing out strong mind-altering medications. I personally think barbiturates would be effective for me, because I believe that they don't use the specific receptor sites that benzos use.
> 
> Alcohol numbs me like it would anyone, so I tend to point the finger at my benzodiazepine receptors rather than at a wider GABA issue, as if it was a wider GABA issue then presumably alcohol's effects would also be compromised.
> 
> I don't think I could get a stimulant. In the UK most doctors would probably be afraid of prescribing caffeine.


Try baclofen or even Nardil.


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## istayhome (Apr 4, 2012)

TheoBobTing said:


> Bear in mind that in the UK doctors are not at all keen on handing out strong mind-altering medications. I personally think barbiturates would be effective for me, because I believe that they don't use the specific receptor sites that benzos use.
> 
> Alcohol numbs me like it would anyone, so I tend to point the finger at my benzodiazepine receptors rather than at a wider GABA issue, as if it was a wider GABA issue then presumably alcohol's effects would also be compromised.
> 
> I don't think I could get a stimulant. In the UK most doctors would probably be afraid of prescribing caffeine.


Are there "Benzodiazapine Receptor sites?" I am only aware of benzo's crossing the BBB and acting as agonists at various GABA-A receptor sites. I have never heard of particular receptor sites in the brain that are only activated specifically by BZD's. That seems really unlikely.


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## riptide991 (Feb 1, 2012)

istayhome said:


> Are there "Benzodiazapine Receptor sites?" I am only aware of benzo's crossing the BBB and acting as agonists at various GABA-A receptor sites. I have never heard of particular receptor sites in the brain that are only activated specifically by BZD's. That seems really unlikely.


I think it has something to do with some receptors the benzos bind to in the peripheral system that are not GABAa. It's nothing to do with the CNS. But since these specific drugs that were made that bind only to GABA a receptors this lead to confusion because these receptors were not Gaba A or Gaba B but these drugs were binding to them. So they started giving them different names.


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## istayhome (Apr 4, 2012)

kehcorpz said:


> I think it has something to do with some receptors the benzos bind to in the peripheral system that are not GABAa. It's nothing to do with the CNS. But since these specific drugs that were made that bind only to GABA a receptors this lead to confusion because these receptors were not Gaba A or Gaba B but these drugs were binding to them. So they started giving them different names.


So you're saying that Benzos also have an affinity for some receptor sites in the PNS that no other drug or Neurotransmitter uses? Making essentially a "Benzodiazapine receptor site." That is, a receptor site which is specific to BZD's?

Also As far as the CNS is concerned there is no such thing as a "Benzodiazapine receptor site," Benzodiazapines just pass the BBB and have certain affinities as agonists at the various GABA A receptor sites?


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## TheoBobTing (Jul 8, 2010)

istayhome said:


> So you're saying that Benzos also have an affinity for some receptor sites in the PNS that no other drug or Neurotransmitter uses? Making essentially a "Benzodiazapine receptor site." That is, a receptor site which is specific to BZD's?
> 
> Also As far as the CNS is concerned there is no such thing as a "Benzodiazapine receptor site," Benzodiazapines just pass the BBB and have certain affinities as agonists at the various GABA A receptor sites?


I was under the impression that GABA A receptor complexes contain numerous different specific receptors, and that different drugs/neurotransmitters bind to different specific receptors within the GABA A receptor complex. The link I posted has a lot of interesting info in it. It talks of 'benzodiazepine receptors'. I might have to read through it again because there's a lot to remember.


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## istayhome (Apr 4, 2012)

TheoBobTing said:


> *I was under the impression that GABA A receptor complexes contain numerous different specific receptors, and that different drugs/neurotransmitters bind to different specific receptors within the GABA A receptor complex.* The link I posted has a lot of interesting info in it. It talks of 'benzodiazepine receptors'. I might have to read through it again because there's a lot to remember.


This Is true. But from what you posted and hours of my own research I can not find any specific 'benzodiazapine receptors.'

I find such things highly unlikely because BZD's are a modern synthetic drug created by accident. It would be odd if the body just happened to already have pre-existing, never-before used BZD specific receptors.

The BZD receptors that that article discusses seem to just be a way of discussing the various GABA A receptor complexes.

After re-reading the article, they just refer to the GABA A Complex as "the Benzodiazapine receptor."

The article acknowledges that the GABA A complex is not specific to BZD's but is activated by all anxiolytics, hypnotics, etc.


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## riptide991 (Feb 1, 2012)

istayhome said:


> So you're saying that Benzos also have an affinity for some receptor sites in the PNS that no other drug or Neurotransmitter uses? Making essentially a "Benzodiazapine receptor site." That is, a receptor site which is specific to BZD's?
> 
> Also As far as the CNS is concerned there is no such thing as a "Benzodiazapine receptor site," Benzodiazapines just pass the BBB and have certain affinities as agonists at the various GABA A receptor sites?


Ahh so that's what is going on:



> *Translocator protein* (*TSPO*) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It interacts with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria. It was first described as *peripheral benzodiazepine receptor* (*PBR*), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain.[


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## istayhome (Apr 4, 2012)

kehcorpz said:


> Ahh so that's what is going on:
> 
> Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It interacts with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain.


I get it completely. What I've been asking which this quotation seems to answer is that there are no receptors in the body, CNS or PNS, that are Benzodiazapine specific. Though BZD's do act as agonists at a variety of sites it is not because these receptor sites are specifically for BZD's, it's because BZD's just happen to be the right shape to have an effect there.

It makes sense that Valium in particular (as well as other BZD's) would having binding sites in the PNS due to their muscle relaxant effects.

So it seems that these receptor binding sites that are referred to as "BZD receptor binding sites," are called that due to convenience, not because that is their only action.


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## riptide991 (Feb 1, 2012)

istayhome said:


> I get it completely. What I've been asking which this quotation seems to answer is that there are no receptors in the body, CNS or PNS, that are Benzodiazapine specific. Though BZD's do act as agonists at a variety of sites it is not because these receptor sites are specifically for BZD's, it's because BZD's just happen to be the right shape to have an effect there.
> 
> It makes sense that Valium in particular (as well as other BZD's) would having binding sites in the PNS due to their muscle relaxant effects.
> 
> So it seems that these receptor binding sites that are referred to as "BZD receptor binding sites," are called that due to convenience, not because that is their only action.


Yah that wouldn't make sense because our receptors would only develop for endogenous substances for communication purpose. Unless of course we started evolving at an alarming rate from all the benzos people abuse.


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## istayhome (Apr 4, 2012)

kehcorpz said:


> Yah that wouldn't make sense because *our receptors would only develop for endogenous substances for communication purpose.* Unless of course we started evolving at an alarming rate from all the benzos people abuse.


Exactly.

And such an evolution would not only be unlikely to happen but would also take tens of thousands of years.


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## riptide991 (Feb 1, 2012)

istayhome said:


> Exactly.
> 
> And such an evolution would not only be unlikely to happen but would also take tens of thousands of years.


One day we won't even have any hormones/neurotransmitters we will fully depend on prescription drugs. I think that's the goal of the companies. Think about the money they would make.


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## TheoBobTing (Jul 8, 2010)

I could be wrong here, because I have an amateur interest in these matters at the end of the day, but here goes.



istayhome said:


> I find such things highly unlikely because BZD's are a modern synthetic drug created by accident. It would be odd if the body just happened to already have pre-existing, never-before used BZD specific receptors.


"So what evolutionary pressures have led to the emergence of benzodiazepine receptors and their widespread presence in neurons? *One theory is that they are necessary to regulate anxiety, and that the brain itself produces an anxiety-reducing compound (an 'endogenous agonist')*."

It's basically suggesting that that there could be endogenous compounds that essentially behave just like benzos.



> The BZD receptors that that article discusses seem to just be a way of discussing the various GABA A receptor complexes.
> 
> After re-reading the article, they just refer to the GABA A Complex as "the Benzodiazapine receptor."


"The benzodiazepine site is the most evolutionary recent *part* of the GABAA complex discovered (Nielsen et al, 1978 ). "



> The article acknowledges that the GABA A complex is not specific to BZD's but is activated by all anxiolytics, hypnotics, etc.


Yes, but that's precisely because it's a _complex_ composed of numerous distinct receptors.


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## riptide991 (Feb 1, 2012)

TheoBobTing said:


> "The benzodiazepine site is the most evolutionary recent *part* of the GABAA complex discovered (Nielsen et al, 1978 ). "
> .


Any receptor a benzo binds to is considered a benzodiazepine site.


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## TheoBobTing (Jul 8, 2010)




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## riptide991 (Feb 1, 2012)

Right but I think Gaba still binds to these benzodiazepine sites. The difference is that the primary GABA site is unique only to GABA because it has an exact snug fit for that particular molecular structure. The sites that also accept benzodiazepines are able to bind both gaba and benzos as they are more generalized. All those sites accept endogenous substances, no doubt about it they aren't there specifically for drugs we created. Benzos were discovered by accident too as they realized these drugs were binding to these sites.


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## istayhome (Apr 4, 2012)

@ TheoBobTing. I believe GABA is the primary endogenous NT that activates all of those various sites in order to have certain effects depending on which particular binding site it attaches to and how much is present. Benzos are basically a synthetic GABA that is bound to specific GABA receptors (different Benzo's have a different affinity for different receptors.

The above diagram is showing where exactly on the GABA complex the different receptors that the given drugs bind to.

So your theory is that because benzos have no effect for you, you are missing the BZD specific GABA receptors? That would certainly cause anxiety in the first place. Because if those receptors were not present GABA itself, the endogenous calming NT, would be unable to have an effect at all wherever the GABA receptor sites are missing.

Edit - I do like that diagram.


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## istayhome (Apr 4, 2012)

kehcorpz said:


> Right but I think Gaba still binds to these benzodiazepine sites. The difference is that the primary GABA site is unique only to GABA because it has an exact snug fit for that particular molecular structure. The sites that also accept benzodiazepines are able to bind both gaba and benzos as they are more generalized. All those sites accept endogenous substances, no doubt about it they aren't there specifically for drugs we created. Benzos were discovered by accident too as they realized these drugs were binding to these sites.


I "like" this post but for some reason the option of simply pushing "like" did not appear.


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## riptide991 (Feb 1, 2012)

See they are still GABA receptors 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1188559/



> Benzodiazepine receptors are allosteric modulatory sites on GABAA receptors. GABAA receptors are probably composed of five protein subunits, at least some of which belong to different subunit classes. So far six alpha-, four beta-, three gamma-, and delta- and two rho = p subunits of GABAA receptors have been identified. A large number of different subunit combinations, each of which will result in a GABAA receptor with distinct electrophysiological and pharmacological properties, are therefore possible


Yah wonder why you can't cheat and like your own posts


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## istayhome (Apr 4, 2012)

kehcorpz said:


> See they are still GABA receptors
> 
> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1188559/
> 
> *Yah wonder why you can't cheat and like your own posts*


I was trying to like *your* post dude!


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## istayhome (Apr 4, 2012)

kehcorpz said:


> See they are still GABA receptors
> 
> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1188559/


That Abstract I believe explains why I respond to most benzos But I do NOT respond to Klonopin at all. When I had no benzo tolerance I took over 20 mg of Clonazepam many times and had absolutely no effect whatsoever. Similarly Lorazepam has very minimal effects for me.

I think that is a direct argument against what the popular theory is; which is "that every benzo is exactly the same." No - not for everyone. If they were all exactly the same there would probably be much fewer benzodiazapines on the market.


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## Canadian4Life (Sep 27, 2010)

If benzos don't work for you then there are a couple of other things that may. Nardil is one that is said to be very effective (I've never tried it so I cant tell you) but studies show it works wonders. I personally find benzos help me but only when mixed with a stimulant (and it HAS to be dexedrine). Dexedrine and a benzo together battle social phobia bigtime and work well. But there's the tolerance thingy that made this combo not work for me. There are a few ways you can battle tolerance though look it up. I quit the dexedrine and was on a benzo (clonazepam) and I was functionable for a few years. I read that Zoloft and Paxil were indicated for social phobia and me not being able to get Nardil decided to try zoloft with my clonazepam. It did help me but I needed my clonazepam everyday and the zoloft made me dysphoric (sad) but it did help with anxiety becauase I cared about noone or nothing. I already had tried effexor, celexa, lexapro and mirtazapine and none worked except mirtazapine (very weakly). So off the zoloft I went and gave up on ssri's/ Once again I was solo of the clonazepam but after 2 years I felt myself going downhill fast. So I tried paxil. I can tell you since Day 1 it has changed my social life bigtime!! everyone says that the old me is back and I don't fear or even think twice of having to go into public situations. So for me all the ssris were like candy and didnt work Except for paxil. It combined with my clonazepam helps my social anxiety like 90-95% no joke! and I am treatment-resistant! Just my two cents worth


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## ricca91 (Mar 11, 2012)

istayhome said:


> That Abstract I believe explains why I respond to most benzos But I do NOT respond to Klonopin at all. When I had no benzo tolerance I took over 20 mg of Clonazepam many times and had absolutely no effect whatsoever. Similarly Lorazepam has very minimal effects for me.
> 
> I think that is a direct argument against what the popular theory is; which is "that every benzo is exactly the same." No - not for everyone. If they were all exactly the same there would probably be much fewer benzodiazapines on the market.


Exactly. I dare anyone to take Rohypnol for anxiety!

Saying that benzos are all the same is like saying that antibiotics are all the same or NSAIDs are all the same. Just because the are in the same class, doesn't mean their pharmacodynamics and kinetics are the same.


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## TheoBobTing (Jul 8, 2010)

kehcorpz said:


> Right but I think Gaba still binds to these benzodiazepine sites. The difference is that the primary GABA site is unique only to GABA because it has an exact snug fit for that particular molecular structure. The sites that also accept benzodiazepines are able to bind both gaba and benzos as they are more generalized. All those sites accept endogenous substances, no doubt about it they aren't there specifically for drugs we created. Benzos were discovered by accident too as they realized these drugs were binding to these sites.


Are you guys 100% sure that GABA binds to the specific receptors that benzos bind to? I know that they all bind to the same receptor complex, and that GABA is that main neurotransmitter that uses the complex, but I can't find anything about GABA binding to the exact sites that benzos bind to.
The mighty wikipedia says:

"The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor"

"*The endogenous ligand that binds to the benzodiazepine site is inosine.*"

EDIT: Though having just read a little about 'Inosine' that assertion seems questionable. But still, I can't find anything stating that GABA is the endogenous ligand that binds to the _exact_ same receptors as benzos (just the same receptor _complex_). People discuss that a different endogenous ligand could exist for the benzo site (as they said in the link in the first post).


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## istayhome (Apr 4, 2012)

TheoBobTing said:


> Are you guys 100% sure that GABA binds to the specific receptors that benzos bind to? I know that they all bind to the same receptor complex, and that GABA is that main neurotransmitter that uses the complex, but I can't find anything about GABA binding to the exact sites that benzos bind to.
> The mighty wikipedia says:
> 
> "The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor"
> ...


Are you asking if there is a receptor site in the GABA-A Complex which only BZD's bind to and nothing else?

No one can be 100% sure of anything in the body, That is what Anatomy and physiology taught me.

However it is extremely unlikely that some receptor site specific to BZD's and BZD's only exists in the body. The odds of such a genetic mutation is statistically insignificant. You're talking about a receptor site that would have existed in our brain which was completely useless and remained as a part of our genetic makeup for tens of thousands of years. Because BZD's are not endogenous, a BZD only receptor would not make sense.

BZD's are a class of drugs which cross the BBB easier than GABA then bind to various GABA-A receptor sites because the body is flooed into "thinking" that the BZD molecule is GABA.

It's not that GABA binds to the BZD receptor sites; It's that BZD's bind to the GABA receptor sites.

Your original reference merely uses the term "BZD Receptor sites," as opposed to saying, "The various GABA-A receptor sites that BZD's also bind to."

You're not going to find anything that states that there are receptor sites in our brain which are specifically designed for BZD's; because no such thing exists. BZD's trick certain GABA-A receptor sites into believing that the drug is endogenous GABA.

I hope that clears it up, you dig?


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## TheoBobTing (Jul 8, 2010)

istayhome said:


> Are you asking if there is a receptor site in the GABA-A Complex which only BZD's bind to and nothing else?


No, that's the opposite of what I'm saying. Put simply, I'm saying that I think there is an alternative, endogenous benzo-like substance that binds to the _exact_ same sites as actual benzodiazepines, and that it isn't GABA. Of course, it's just a theory (consistent with the literature I posted).


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## TheoBobTing (Jul 8, 2010)

istayhome said:


> BZD's are a class of drugs which cross the BBB easier than GABA then bind to various GABA-A receptor sites because the body is flooed into "thinking" that the BZD molecule is GABA.


So what you believe is that benzodiazepines interact with the brain in the exact same ways as GABA? And that GABA binds to all of the receptor types on the GABA A complex? This is not so.










You should look at this image again. GABA binds to the GABA site, Benzos bind to the Benzo site, et cetera.


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## istayhome (Apr 4, 2012)

TheoBobTing said:


> No, that's the opposite of what I'm saying. Put simply, I'm saying that I think there is an alternative, endogenous benzo-like substance that binds to the _exact_ same sites as actual benzodiazepines, and that it isn't GABA. Of course, it's just a theory (consistent with the literature I posted).


I read the literature you posted again. The part you are referring to is where it poses the question, Are there endogenous BZD similar compounds which act on the same GABA sites that Benzo's do?

The literature poses three hypotheses to answer that question, one of the possibilities being no, there is not. It is a subject that clearly is in it's infancy The literature you posted poses exactly the question you are asking.

"I'm saying that I think there is an alternative, endogenous benzo-like substance that binds to the _exact_ same sites as actual benzodiazepines, and that it isn't GABA."

Science doesn't know and it sounds like there aren't any active studies yet trying to definitively answer that. So we don't know. Maybe, maybe not.

The sole purpose of GABA is to act as an agonist in those GABA receptors and act as the "calming" NT if you will. I personally do not think that there is a BZD like endogenous compound that is yet to be discovered. Why? Because GABA already does that job sufficiently in normal physiology and no such NT has been discovered despite how closely this subject has been studied for the past 50 years.



TheoBobTing said:


> So what you believe is that benzodiazepines interact with the brain in the exact same ways as GABA?...
> 
> No not in the exact same way. Obviously each BZD has it's own specific effects on various GABA receptor sites. The literature you posted does explain that BZD's do act very similarly to GABA by how they effect the the GABA receptor sites and by not opening the calcium channel in the GABA receptor site complex.
> 
> ...


I studied it fully. It's not cut and dry as you make it out to be. ALL of those sites are GABA receptor sites. GABA can and does act as an agonist on all the receptor sites on the GABA receptor complex. That chart merely illustrates which exact GABA receptor sites act as BZD receptor sites, Barb. receptor sites etc. etc. But they ALL are GABA receptor sites, part of the GABA receptor site complex.

Think of SSRI's. All SSRI's act on 5-ht receptors. 5-ht receptors which all exist as Serotonin receptor sites. So Serotonin acts as an agonist on all the 5-ht receptor sites. But a variety of drugs can act on exactly the same sites in one way or another.

The comparison is that in the case of GABA receptors they all primarily exist for GABA. but a variety of drugs act on individual receptors in different ways.

In the case of 5-ht receptors they all primarily exist for Serotonin but again, a variety of drugs can act on the same receptors in one way or another.

So the Gaba receptors obviously exist for GABA but other drugs/chemicals are able to effect them as well. ya dig?


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## TheoBobTing (Jul 8, 2010)

istayhome said:


> Science doesn't know and it sounds like there aren't any active studies yet trying to definitively answer that. So we don't know. Maybe, maybe not.


Well, I did say it's a theory. Maybe one day we'll find out.



> I studied it fully. It's not cut and dry as you make it out to be. ALL of those sites are GABA receptor sites.


Well, is there any evidence of this? None of the stuff I've read talks about GABA binding to benzo sites or vice versa. All the information I've read talks about quite distinct receptor sites.


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## istayhome (Apr 4, 2012)

TheoBobTing said:


> Well, I did say it's a theory. Maybe one day we'll find out.
> 
> Well, is there any evidence of this? None of the stuff I've read talks about GABA binding to benzo sites or vice versa. All the information I've read talks about quite distinct receptor sites.


There's no such thing as a "benzo site." The accepted medical theory is that GABA is an endogenous NT, Benzos are a drug. There are not "Benzo specific binding sites." Until science can prove otherwise that is completely false thinking. Benzos bind to GABA receptor sites.

Why would there be a Benzo specific receptor site in the brain when Benzo's are not an endogenous NT? Not only are they not endogenous but they have only existed for 50 years so there's no possible way in which the brain would have evolved to have a BZD receptor site. It is illogical.

It's such a simple matter I'm not sure what the error in communication is. The literature you referenced clearly expresses this as well. Different BZD's bind to certain GABA receptor sites. There is no such thing as a BZD receptor site. That term is only used in the literature out of convenience as I previously explained. They are GABA receptors which BZD's act as GABA agonist's upon.


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## TheoBobTing (Jul 8, 2010)

istayhome said:


> There's no such thing as a "benzo site." The accepted medical theory is that GABA is an endogenous NT, Benzos are a drug. There are not "Benzo specific binding sites." Until science can prove otherwise that is completely false thinking. Benzos bind to GABA receptor sites.
> 
> Why would there be a Benzo specific receptor site in the brain when Benzo's are not an endogenous NT? Not only are they not endogenous but they have only existed for 50 years so there's no possible way in which the brain would have evolved to have a BZD receptor site. It is illogical.
> 
> It's such a simple matter I'm not sure what the error in communication is. The literature you referenced clearly expresses this as well. Different BZD's bind to certain GABA receptor sites. There is no such thing as a BZD receptor site. That term is only used in the literature out of convenience as I previously explained. They are GABA receptors which BZD's act as GABA agonist's upon.


No evidence then?


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## riptide991 (Feb 1, 2012)

Interesting, apparently it has been proven these endogenous substances to exist, they aren't benzos but they do bind to those same receptors so naturally they gave them the name endozepines.

http://thebrain.mcgill.ca/flash/a/a_04/a_04_m/a_04_m_peu/a_04_m_peu.html

Always learning new stuff.


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## TheoBobTing (Jul 8, 2010)

kehcorpz said:


> Interesting, apparently it has been proven these endogenous substances to exist, they aren't benzos but they do bind to those same receptors so naturally they gave them the name endozepines.
> 
> http://thebrain.mcgill.ca/flash/a/a_04/a_04_m/a_04_m_peu/a_04_m_peu.html
> 
> Always learning new stuff.


Yup, hence why one would have such receptors.


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## istayhome (Apr 4, 2012)

TheoBobTing said:


> No evidence then?


Man, I'm sorry that BZD's don't help you but denying what is accepted by the medical and scientific community won't change reality. The evidence you demand is in the very same article you presented in the first post. It's what is known as "common knowledge." Meaning that those facts are encyclopedic. You'll find that idea presented in every medical text on the planet. There is no such thing as a BZD specific receptor site. The suggestion you are making is akin to saying that Aliens control the world and demanding evidence that it is untrue. If you're going to deny medical science go ahead but I don't understand why you are stubbornly refusing to acknowledge what is accepted by all. Especially regarding such an insignificant matter,

From your signature I can see that you are very frustrated with the ineffectiveness that medication has shown you. But you will get much further in your recovery if you acknowledge that these drugs didn't work (which you have), Obviously we won't know why exactly they did not work which is unfortunate. So your next step should be to accept your whole situation and move forward by looking for alternatives that do help you.

Best of luck and I genuinely hope you find what works for you. Over the internet I can not say if there is a miscommunication (which I doubt because I have repeated myself ad infitum) or if you are stubbornly hanging onto an idea you have for no logical reason whatsoever. If you wan't to pursue this unlikely theory then I encourage you to pursue a career in perhaps neurophysiology or biopsychiatry, neuropharmacology, etc. some position that will land you in a place of research. I am very willing to accept any new knowledge that helps us better understand anxiety. So for your own benefit I hope you can look forward instead of insisting on a fallacy. Of course everyone has the freedom to believe what they want to. Hang onto those beliefs if you want to but I think you're making a big mistake.

Out of curiosity do you have any experience in neurophysiology or biopsychiatry, neuropharmacology or any related fields which helped to give you at least preliminary understanding of basic Neuro anatomy and physiology?

Either way agian, best of luck to you. Benzo's have been a big help for me and I can feel how frustrated you may be with no way to relieve severe anxiety.


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## istayhome (Apr 4, 2012)

kehcorpz said:


> Interesting, apparently it has been proven these endogenous substances to exist, they aren't benzos but they do bind to those same receptors so naturally they gave them the name endozepines.
> 
> http://thebrain.mcgill.ca/flash/a/a_04/a_04_m/a_04_m_peu/a_04_m_peu.html
> 
> Always learning new stuff.


That's cool and not unsurprising when you think of Endogenous Morphines

@TheoBobTing

I encourage you to read the following sentence.

"researchers have now identified molecules produced by the body that bind to exactly the same site on the GABAa receptor as synthetic benzodiazepines."

Again, GABAa receptor sites that also act as receptor sites for synthetic benzodiazepines.

Many drugs, same receptors


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## riptide991 (Feb 1, 2012)

There's no argument that the receptors are Gaba receptors. It's just these areas that modulate gaba within the same receptors are the only ones benzos bind to, they don't bind to the primary gaba receptor. So I guess he wanted to know if there is something else that does the same thing in the body. And that would be Endozipines. Maybe I'm wrong. I just don't think he thought it was a benzo receptor hehe.

I think there's some miscommunication happening due to the wording he used.


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## istayhome (Apr 4, 2012)

kehcorpz said:


> There's no argument that the receptors are Gaba receptors. It's just these areas that modulate gaba within the same receptors are the only ones benzos bind to, they don't bind to the primary gaba receptor. So I guess he wanted to know if there is something else that does the same thing in the body. And that would be Endozipines. Maybe I'm wrong. I just don't think he thought it was a benzo receptor hehe.
> 
> I think there's some miscommunication happening due to the wording he used.


I hope that is the case. He has said things like this numerous times

"Well, is there any evidence of this? None of the stuff I've read talks about GABA binding to benzo sites or vice versa. All the information I've read talks about quite distinct receptor sites."

I understand various substances both endogenous and exogenous having a variety of binding affinities for the various Gaba receptors. But it is undeniable that they are all GABA receptors. Not Gaba receptors, Barbiturate receptors,, General Anaesthetic receptors, Benzodiazapine receptors, Endozipine receptors, etc. They're all GABA receptors that merely have different affinities for different substances. Like I said different substances; same receptor.

This is how every NT I can think of works.


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## TheoBobTing (Jul 8, 2010)

kehcorpz said:


> There's no argument that the receptors are Gaba receptors. It's just these areas that modulate gaba within the same receptors are the only ones benzos bind to, they don't bind to the primary gaba receptor. So I guess he wanted to know if there is something else that does the same thing in the body. And that would be Endozipines. Maybe I'm wrong. I just don't think he thought it was a benzo receptor hehe.
> 
> I think there's some miscommunication happening due to the wording he used.


Yeah, you seem to have a much better understanding of what I'm saying.


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## yourfavestoner (Jan 14, 2010)

TheoBobTing said:


> I only know of one other person on these forums who shares my complete non-response to benzos.


I have no reaction to them now, but I think that's more due to tolerance. I noticed initial effects on Lorazepam, but it's faded as I've built up tolerance.

PS - your drug names are amusing.


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## TheoBobTing (Jul 8, 2010)

yourfavestoner said:


> PS - your drug names are amusing.


Thanks.

*istayathome* I think we've just managed to have a lengthy heated debate even though we hold the same opinion, simply because we have different ways of describing the same phenomena... Bear in mind I'm not exactly a trained neurologist so perhaps my ways of describing these matters are not the formal norm. For the record, I do know that GABA, benzos, barbiturates and the rest do indeed all bind to the the same... _thing_ :sus


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## istayhome (Apr 4, 2012)

Glad you're satisfied. For the record, no heat here. Real life has it's own anxieties to deal with so when it comes to online discussions I keep it cool.

Well again, good luck.


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