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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 19 of 19. This is the beginning of the thread.
Posted by Extreme on October 23, 2008, at 9:13:09
I posted this in the neurotransmittor-section:
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Some weeks ago I was trying to relieve some anxiety with oxazepam. Since some years back I have been unable to get bensos to work when I need them. My thought is that it is due to overuse from some years on benso on and off. But this thing that happened did not make sense at all.
I was on quite a high level of oxazepam, nothing really did happen, just made me feel worse (probably partly CNS-depression from oxazepam)... I got this crazy idea that I would mix it with another benso that I also use sometimes. Usually I am not into mixing bensos... I take them one at the time. I mixed oxazepam with nitrazepam and guess what happened? Total success! And I mean TOTAL LOL! Yea... enough of the "happy-benso-talk" :P
So now to the mystery... if my system was pretty fed up with benzo how in the world could a combination of two of them make the situation better? In my own thoughts AND actually expectations at the time there was the risk of it becoming worse. But hey... it gets even more complex... in the past weekend I tried nitrazepam alone (same dose)... almost nothing happened!
I cant make sense of this... how come a combination of two bensos worked but neither of them work alone? My theory again is that it is due to my overuse of them since some years... and that a combo nowdays is required to "kickstart" the process.
Anyone else in here have the same experience?
-----------------------------------------------Got no response and in the meantime I came up with the bright idea of really looking into why benso work (for the 14th time or something)! From Wiki on benso:
"Benzodiazepine binding also requires that alpha subunits (in the GABA-complex that is - my remark) contain a histidine amino acid residue"
Histidine! The most simple thought came up... what if my non-response nowdays to benso is partly overuse AND that leading to smaller amounts of histidine in the brain... because SOMETHING weird was going on in the part I wrote about... would a supplement of histidine "kick-start" the benso-binding as the fact states? I will find out... because this guinea pig just ordered L-histidine (500 mg capsules)! It SHOULD be able to cross the blood brain barrier as far as I have read about it... some substanses as you know does not, like GABA for example.
So... I will report back in a few weeks!
Posted by Extreme on October 23, 2008, at 9:23:52
In reply to Benso-mystery PLUS experiment!, posted by Extreme on October 23, 2008, at 9:13:09
Almost forgot the most interesting part... stupid me! This histidine-stuff that benso apparantly depends on COULD explain why benso DO NOT work and never has during allergy-season for me... and this might be the explanation... histidine is the precursor to histamine... histamine is released in huge loads when you get allergy. There is some connection and truth in all this... how I wish for that computer-program showing a clear map of the brain and its current state of chemicals :)
Posted by Extreme on October 23, 2008, at 9:44:16
In reply to Re: Benso-mystery PLUS experiment!, posted by Extreme on October 23, 2008, at 9:23:52
Really a long monolouge here LOL.. one more thing... there actually was ONE time on a quite a huge dose of, can you believe it, nitrazepam that broke the "allergy-barrier"... and when reading about nitrazepam on wiki I found:
"At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex in mouse brain"
Histamine turnover... what a strange word without further explanation... but it did have something to do with histamine on high dosage... I cant remember exactly what dose it might have been I took that slapped the allergy in the face but I can imagine it was like 15-20 mg (probably more). That must be considered pretty high on what was probably zero tolerance towards benso at that time.
Posted by Phillipa on October 23, 2008, at 11:03:02
In reply to Re: Benso-mystery PLUS experiment!, posted by Extreme on October 23, 2008, at 9:44:16
To be honest I don't understand the theory but I combine two benzos and they don't work have had pdocs give me two lots of times. never thought about it. Phillipa
Posted by Extreme on October 23, 2008, at 12:32:54
In reply to Re: Benso-mystery PLUS experiment! » Extreme, posted by Phillipa on October 23, 2008, at 11:03:02
To explain the theory in simpler form... benso binds in the nervous system at the so called GABA-A receptors on a nervecell to make its effect (enhancing the cells "GABA-potential"/"calming-effect")... but to bind there it NEEDS some small portion of the amino-acid histidine. If there is no histidine=no binding=no effect. What I am gonna test is if a small supplement of histidine with benso will trigger a specific benso-effect on me OR will change the effect somehow. I actually dont have so much hope for such an effect because the brain and the nervous-system are so extremely complex and there is no telling exactly WHAT is going on in there. I know you have eaten benso for a looong time Philipa and I have eaten it in some large doses over the years.. who knows what actually has happened inside our brains... could be interesting to see what happens with this little experiment.. only cost me a few bucks so did not loose a fortune :)
Posted by linkadge on October 23, 2008, at 16:27:17
In reply to Re: Benso-mystery PLUS experiment!, posted by Extreme on October 23, 2008, at 12:32:54
Um, cause you're taking more benzo?
Linkadge
Posted by Extreme on October 23, 2008, at 16:58:41
In reply to Re: Benso-mystery PLUS experiment!, posted by linkadge on October 23, 2008, at 16:27:17
> Um, cause you're taking more benzo?
>
> LinkadgeUps...Havnt described the situation well enough. This was over some days where I increased the oxazepam-dosage finding out that it did not matter how large the dose was, nothing would happen with my anxiety.. only when I combined with a fairly small dose nitrazepam it did work. And the weekend after nitrazepam alone would not do anything. So something was going on beyond my direct control. Sure... tolerance to oxazepam could explain partly what happened but I did not build up a particual strong tolerance to nitrazepam and it should have worked the weekend after.
And this is not a single strange incident... sometimes on zero tolerance there is simply no effect whatsoever on benso. And sometimes it just fires away like it actually WAS dependent on something beyond anxiety-level and dosage.
Posted by Extreme on October 23, 2008, at 17:07:02
In reply to Re: Benso-mystery PLUS experiment!, posted by Extreme on October 23, 2008, at 16:58:41
Adding... Just in case nitrazepam + oxazepam has some "magic" skills I will try that combo more times... if there is a specific effect from that combo I should be able to notice it easily in future attempts. But as I said.. there are some strange things going on sometimes when benso "decides" to work in me or not that seems to relate to something beyond dosage and substance.
Posted by linkadge on October 23, 2008, at 19:30:22
In reply to Re: Benso-mystery PLUS experiment!, posted by Extreme on October 23, 2008, at 17:07:02
Not sure.
Linkadge
Posted by lucie lu on October 23, 2008, at 23:07:25
In reply to Benso-mystery PLUS experiment!, posted by Extreme on October 23, 2008, at 9:13:09
Hi Extreme,
That really is an interesting effect and I have no idea what the pharmacology is - the important thing is that it works for you!
I want to clarify a few of the confusing terms you mention. The first is that when they say that the receptors contain histidine, that is different from the form of histidine that is "free" i.e. an amino acid that is bioactive on its own (e.g. like glutamate, which acts as a neurotransmitter). The histidine in the receptors is part of a long polypeptide chain that makes up the protein receptor. (Histidine, like glutamate, lysine, arginine, are a few of the 20 essential amino acids that make such chains). When we say that one drug receptor has histidine and another receptor has arginine instead, it just refers to differences in the drug binding sites - so the receptors may each prefer slightly different drugs. If you consider the receptor as the "lock" and the drug as the "key" it means that the locks are slightly different so they may each fit a different key. Anyway, the relevant point is that histidine as part of a polypeptide chain is not in the form that can be used for any other purpose - it is not free to cross the blood-brain barrier, be used nutritionally or for making other substances, etc.
As for turnover, it reflects how quickly (well not exactly, but close enough) something like a drug or neurotransmitter gets broken down and therefore inactivated, can no longer have the same biological activity. Like a Kleenex, it gets used, wadded up and thrown away :) A higher turnover number means more tissues get used.
Hope this helps!
Lucie
Posted by Extreme on October 24, 2008, at 5:36:36
In reply to confusing nomenclature » Extreme, posted by lucie lu on October 23, 2008, at 23:07:25
Thank you so much Lucie for bringing some clarity to this. So histidine and other amino-acids that sits on the "lock"/receptor is part and attached in a bigger chemical system so to say... suspected something like that.
WELL... then this leads me to thinking, as before.. how come benso "decides" when to work or not for me and what in the world is going on under extreme pressure from histamine (allergy) in my brain that seems to inactivate benso completely! You seem to have a pretty good view on this... so I ask you Lucie, if you know.. are there any (known) conditions under which the whole polypeptide chain that "runs" the GABA-A bindingsite can change "parameter" or composition? DOES it change ever or is it attributed to a "static" DNA-sequenze?
It should be very interesting if histidine actually destoys the benso-effect completly as it is the precursor to histamine.
Posted by Extreme on October 24, 2008, at 5:55:42
In reply to Re: confusing nomenclature, posted by Extreme on October 24, 2008, at 5:36:36
Another question Lucie ;)
Does the "histamine-turnover-effect" caused by large doses of nitrazepam in rats brain (as stated on wiki on nitra) imply that histamine is a standard part and active part of the same polypetide-chain in the gaba-a receptor as histidine? Or is it simply taken out of context and refers to histamine in another part of the systems...
Posted by lucie lu on October 24, 2008, at 18:30:14
In reply to Re: confusing nomenclature, posted by Extreme on October 24, 2008, at 5:36:36
> Thank you so much Lucie for bringing some clarity to this. So histidine and other amino-acids that sits on the "lock"/receptor is part and attached in a bigger chemical system so to say... suspected something like that.
> WELL... then this leads me to thinking, as before.. how come benso "decides" when to work or not for me and what in the world is going on under extreme pressure from histamine (allergy) in my brain that seems to inactivate benso completely!
Histamine has a few different roles in the body. As you say, it can be involved in allergy but not in the brain since the antibodies (which help produce the true allergic response) are too big to cross the blood-brain barrier. But histidine (the free form, not the form making up proteins) can be made into histamine which is small enough to pass freely across the blood brain barrier. The action of histamine in this context is as a neurotransmitter, and could still (I guess) be involved in your particular reaction to certain drugs. Have you tried posting this on the neurotransmitter board?
are there any (known) conditions under which the whole polypeptide chain that "runs" the GABA-A bindingsite can change "parameter" or composition? DOES it change ever or is it attributed to a "static" DNA-sequenze?
Proteins are made up of amino acid sequences, just as genes are made up of DNA sequences. In proteins, these sequences fold up in certain ways that make a specific shape for a given protein molecule. These folded molecules can sometimes change the way they are folded but not their amino acid sequence, at least not in the way you mean. Did you have something particular in mind?
> It should be very interesting if histidine actually destoys the benso-effect completly as it is the precursor to histamine.
You should go into research, you have a healthy curiosity and a questioning mind :)
Lucie
Posted by lucie lu on October 24, 2008, at 18:40:03
In reply to Re: confusing nomenclature, posted by Extreme on October 24, 2008, at 5:55:42
> Another question Lucie ;)
>
> Does the "histamine-turnover-effect" caused by large doses of nitrazepam in rats brain (as stated on wiki on nitra) imply that histamine is a standard part and active part of the same polypetide-chain in the gaba-a receptor as histidine? Or is it simply taken out of context and refers to histamine in another part of the systems...I looked at the Wikipedia article you cited. I think what they are referring to is something called "down-regulation" which is the body's way of decreasing sensitivity to a substance (e.g. drug or hormone) when dosages are high. So I think you are right in that it is a different context. Histamine, although it is an amino acid, is not one of the 20 that makes up protein sequences.
Hope this isn't too confusing. These topics certainly can be fascinating to explore!
Lucie
Posted by Phillipa on October 24, 2008, at 19:39:37
In reply to Re: confusing nomenclature » Extreme, posted by lucie lu on October 24, 2008, at 18:40:03
Lucie wow you are very intelligent. Are you in reasearch or is this private info. I'm truly impressed. Phillipa
Posted by lucie lu on October 24, 2008, at 20:04:22
In reply to Re: confusing nomenclature » lucie lu, posted by Phillipa on October 24, 2008, at 19:39:37
Phillipa, don't be too impressed... There's a difference between intelligence and knowledge ;-)
Extreme's questions are related to a field in which I've been trained. But thank you - you are so sweet.Lucie
Posted by Phillipa on October 24, 2008, at 20:29:52
In reply to Re: confusing nomenclature » Phillipa, posted by lucie lu on October 24, 2008, at 20:04:22
Each day seems I read so many extremely intelligent people frequent this site I might have to start listening and quit being so darn stuborn!!!! Love Phillipa
Posted by Extreme on October 25, 2008, at 7:16:06
In reply to Re: confusing nomenclature » Extreme, posted by lucie lu on October 24, 2008, at 18:30:14
> Histamine has a few different roles in the body. As you say, it can be involved in allergy but not in the brain since the antibodies (which help produce the true allergic response) are too big to cross the blood-brain barrier. But histidine (the free form, not the form making up proteins) can be made into histamine which is small enough to pass freely across the blood brain barrier. The action of histamine in this context is as a neurotransmitter, and could still (I guess) be involved in your particular reaction to certain drugs. Have you tried posting this on the neurotransmitter board?
My original post was there. This is intersting... I think I have even read about histamines role as a neurotransmitter somewhere before... supposed to be part of regulating sleepiness or something like that? I too figured that histamine in the context of allergy would be somewhat different to the histamine in the brain... but then I never knew that the antibodies responsible for allergy cannot pass the blood brain barrier. I think I looked into these things many years back considering if my blood brain barrier actually was failing and letting things up there that should not be there. But then maybe a "simple" overproduction of histidine would explain increased histamine-levels in the brain somehow during allergy.
>These folded molecules can sometimes change the way they are folded but not their amino acid sequence, at least not in the way you mean. Did you have something particular in mind?
Just wondered if they show some "creative" properties but I can see now that it is more likely that whatever happens in my brain has something to do with a substance attaching/being added to the gaba-receptor making it difficult for benso to attach to it. I have never looked into to it but during allergy season when benso was inactive indeed one more substance with links to gaba-systems was also completly inactive... kava kava. I can only come to the conclusion that kava like benso had trouble attaching to the gaba-system because some other substance was already in place blocking them from it.
I'll round up here so I dont get caught in "verbal overshadowing".
> You should go into research, you have a healthy curiosity and a questioning mind :)
Well, thank you Lucie!!! Something has to be healthy in me I suppose :P
I really appreciate that you share your knowledge!!
Posted by Extreme on October 26, 2008, at 9:49:45
In reply to Re: confusing nomenclature, posted by Extreme on October 25, 2008, at 7:16:06
I just tried nitrazepam + oxazepam on very small dose (30 mg oxa - 5 mg nitra on what is probably medium tolerance to both for the moment). I timed the onset of both perfect, oxazepam takes longer to get into the system so I took it half an hour earlier than nitrazepam... so they both kicked in at the same time. Indeed there is something "magic" for me in this combo even at this small dose. Very intersting... I had this day no hope in getting anything special of benso so my expectations were not very high at all. Medium anxiety and medium-strong depression today.
Coming up in the future... test on small dose histidine in combination with nitra or oxaz alone and later combined to see if there is some obvious "factor-x" involved in all of this.
This is the end of the thread.
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