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Dr. Bob is Robert Hsiung, MD,
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Posted by titleistguy on January 26, 2003, at 23:37:14
I was just wondering exactly HOW benzodiazepines work (specifically on GABA). Do they just affect GABA-A sites, or both A & B???
Why is "light sensitivity" such a common symptom of BZD-withdrawal?
Does the RATE at which you come off your Benzo determine the severity/length of your withdrawal symptoms (I quit both of mine "cold turkey", and have been in HELL ever since!!!)
Also, which one of these anticonvulsants would be the best "substitution" (in terms of effect on GABA) for a benzodiazepine:
-Neurontin (Gabapentin)
-Gabatril (Tiagabine)
-Depakote (Valproic Acid)
-Topamax (Topiramate)
-Tegretol (Carbamazepine)
???Finally, are there any drugs that specifically affect the "BZD receptors", aside from Benzo's themselves and antipsychotics (like Zyprexa)???
Thanks ALOT!!!
-Sean
Posted by Caleb462 on January 27, 2003, at 0:33:18
In reply to Questions about Benzo's/GABA, and AED's!!!, posted by titleistguy on January 26, 2003, at 23:37:14
Benzos bind to omega-1, omega-2 and omega-3 receptors on the GABA-A complex ONLY.
Posted by Ame Sans Vie on January 27, 2003, at 3:29:40
In reply to Questions about Benzo's/GABA, and AED's!!!, posted by titleistguy on January 26, 2003, at 23:37:14
I'm kind of unclear on this myself... I know they bind to BZD receptors, but do they bind to GABA-A receptors? I had read in a few different sources that the benzodiazepine receptor, as well as the barbiturate/convulsion-promoting drug receptor, was just a way to 'fire up' the BZD receptors so that they would in turn activate GABA channels, causing g-aminobutyrate's 'gates' to open more frequently... I don't know, it's all just a bit confusing when you've only read all that technical jargon in about 15 minutes...
The extent of my knowledge on the photosensitivity that often accompanies withdrawal is only that it's caused by melatonin suppression. Can anyone else expand on this? I find it rather interesting.
Quitting a benzo cold is quite often uncomfortable at the least, and sometimes life-threating (i.e., in the event of a seizure). However, quitting cold usually will reduce the length of withdrawal. By the way, and this plays a big role in this, which benzos were you taking?
As implied above, discontuing a benzo by tapering the dose gradually is usually less troublesome. Often they'll switch you from the benzo you're on to an equivalent dose of Valium (diazepam), which has the longest half-life of all the benzodiazepines (yet it's also the shortest-acting). The slower rate of elimination from the body as you're tapering down can be a great help. Finally, one more rather unorthodox suggestion is to use dextromethorphan to ease withdrawal. It's the active ingredient in Robitussin Maximum Strength Cough and Vicks 44 Cough (definitely don't buy a cough syrup that contains other active ingredients, with the possible exception of guaifenesin-- acetaminophen, pseudoephredine, and especially phenylpropanolamine [sp?... you know, PPA-- that stuff they're saying is causing people to have strokes] can wreak some serious havoc on your body if you take them regularly. Not to mention the horrible addiction potential for DXM itself; it is a stereo-isomer of levomethorphan, a narcotic many times more potent than morphine. Though it doesn't bind to any opiate receptors, the drug has a tendency to make you feel 'happy' as it builds up in your body. And I've been through dextromethorphan abuse- not a place you wanna be. I guzzled two 8oz bottles of Robitussin every night for several months straight; DXM is classified as a dissociative anesthetic, just like PCP and ketamine. Just take the doses as directed on the bottle-- DXM has been shown time and time again to be quite helpful in withdrawal of everything from tobacco to alcohol to cocaine. But once you feel the withdrawal symptoms are subsiding, lower the dose.
I'll respond to each of the drugs you listed individually:
Neurontin: Probably the best of the anticonvulsants for anxiety, statistically speaking. I still don't think anyone's quite sure how it works, though it is structurally related to GABA.
Gabitril: Essentially worthless-- it acts solely on the GABA-B receptors. A very few people have claimed to have been helped by this med (though from what I've heard, always for depression; not anxiety). FWIW, not long after starting this medication, I ended up going into a catatonic state followed by three hours in status epilepticus... they told me I definitely beat the odds by far when I came out of it. They'd already told my parents that the chance of my survival was, "at this juncture... minimal"!
Depakote: I'd give this a pretty close second, after Neurontin, for anxiolysis. I mean, it works very well, but the weight gain... the cognitive dulling... the possible hair loss... those are things you've got to consider. It works (but only at pretty high doses) to increase the action of GABA within the brain. It achieves this by inhibiting GABA amino-transferase, the enzyme that breaks down GABA in the brain.
Topamax: I don't know what to say about this one... it worked all right for me. I can't say for sure whether the GABA receptors are at work here, but topiramate is a carbamate derivative: so are Equanil (meprobamate, a powerful anxiolytic) and Soma (carisoprodol, a muscle-relaxant. My experience with Equanil and Soma has been very positive-- Equanil I'd describe as mixing a couple bars of Xanax along with 300mg phenobarbital. Soma feels practically the same (its active metabolite is meprobamate) except you also get those great tension-relieving, euphoric muscle relaxant properties.
Tegretol: One of very few psychiatric drugs I've yet to try, though I *have* tried Trileptal (same thing as Tegretol, just altered a bit to alleviate many of the bothersome side effects). It had no effect on me whatsoever, good or bad. It seems that it works (at least partially) like lithium-- limiting the influx of sodium ions across cell membrane in the motor cortex. This inhibits nerve impulses. I believe Tegretol/Trileptal is involved in the GABA 'cycle', as (if I remember correctly) sodium ions are a key component in the g-aminobutyrate system, and many drugs useful in treatment of anxiety (I believe Depakote may be one of them...?) also act on this sodium ion transport system.
A couple others worth mentioning: Lamictal (lamotrigine; which acts by inhibiting glutamate release) and Dilantin (phenytoin). All I know about Dilantin is that it alters ion transport.
The only other drug I can recommend that's available in the States is Rilutek (riluzole), typically prescribed for amyotrophic lateral sclerosis (ALS). It potentiates GABA at sites A and B (possibly also C), inhibits glutamate (an excitatory neurotransmitter-- MSG, monosodium glutamate, is nothing but a salt form of glutamate), interferes with binding of amino acid receptors, and inactivates voltage-dependent sodium channels. This is one drug I'm going to try next (also Parnate and a few TCAs... the only things I haven't tried yet).
Drugs that solely act on the BZD receptors... hmm... well, there's flumazenil, but I doubt you want a BZD-antagonist, lol. Other than that, all I can think of is muscimol, a psychoactive chemical found in the Fly Agaris mushroom (you've probably seen these; they're red with white scales... just like on Super Mario Bros., lol). These mushrooms are often taken in large amounts, both by spiritualists and recreational drug users, to induce a type of 'vision quest'. Nothing like LSD-- while on LSD, very rarely does one believe the hallucinations they are having are real (which, technically, forces you to refer to these as 'visuals', since these are not *true* hallucinations). The same goes for your run-of-the-mill psilocybe mushrooms. But the Fly Agaris (or amanita, as it's often called) induces true states of psychosis. *Muscimol*, however, can be extracted and can easily be ordered through the net. The mushroom and all chemicals contained within are 100% legal by federal law. If you decide to try this route, make sure to read up on muscimol and what doses are therapeutic and which ones are fatal.
Lastly, I'm just curious-- why did you go off the benzos in the first place? Any drug that acts on the BZD receptors/GABA system and has an immediate effect (such as Ambien, muscimol, g-hydroxybutyrate [GHB] and its derivatives/precursors like 1,4-butanediol and g-butyrolactone [GBL]) is most likely going to be every bit as addictive as the benzos. So, just wondering what your motivation(s) for getting off the benzos was. Anyway, hope this helped!
--Michael
Posted by mattdds on January 27, 2003, at 7:16:38
In reply to Questions about Benzo's/GABA, and AED's!!!, posted by titleistguy on January 26, 2003, at 23:37:14
Sean,
I'm sorry to read you're having a tough time. I read your previous post as well. Your symptoms sound just like mine did, including the photosensitivity and severe anxiety. The photosensitivity could probably fall under the "depersonalization" umbrella.
I just wanted to point out a few things about your experience with benzodiazepines. You mentioned that you took Klonopin for only 3.5 weeks. Now, anything is possible, but it is extremely unlikely that this would be enough time to elicit a withdrawal syndrome as severe as what you describe. I had exactly the same symptoms, although not related to Klonopin withdrawal, and I know you are going through hell! But I have to wonder if you might have gotten those symptoms anyway, even without the Klonopin. Or perhaps withdrawing so abruptly *triggered* your symptoms, but did not *cause* them.
I know when the peak of my symptoms hit, I was looking for anything to explain them, because they were so intense. At first I thought it was the Serzone, since I happened to be taking that at the same time I got really ill.
Also, your dose (I think you said 2.5 mg qd) seemed very high for just starting out! You mentioned that after taking Klonopin (Rivotril in Canada?), you would fall asleep all day. 2.5 mg would floor even me, a seasoned Klonopin user! The normal starting dose is 0.5 or 1.0 mg daily. When I first started taking Klonopin for anxiety, I could take 0.25 mg and feel a lot of relief. Now, over a year later, I take 0.5 or 1.0 mg as needed. Did you ever try Klonopin at lower doses? I think where your doctor screwed up is not titrating you up to your correct dose.
It takes some skill, but most psychiatrists can find a dose for you where your anxiety is gone, but you are not at all sedated, i.e. titrate you up to the correct dose.Also, "protracted benzodiazepine withdrawal syndrome" is a quacky diagnosis, in my opinion. None of the responsible research on benzodiazepines show any evidence for this. I believe the folks who came up with this ever-so scientific sounding term are afiliated with our beloved anti-benzo groups. Most withdrawal symptoms may be avoided by appropriate tapering, which may involve 3-6 months of gradually scaling back your dose. This is similar to most psychiatric drugs, like antidepressants.
Most doctors will say that if benzo withdrawal lasts for more than 3-4 weeks, then it is almost definitely not "protracted benzodiazepine withdrawal", but rather the pre-existing condition resurfacing.
Now I may be way off base here, and if I am, I apologize. I just don't want you to write off a drug that could potentially help, provided it was prescribed and used correctly (i.e. correct titration, dosing and taper). I'm not saying benzos are without their drawbacks, and I definitely don't think they are for everyone. But I had the same fears you did about taking them, and I regret it, because I could have been getting some much deserved relief, and possibly preventing my anxiety from spiraling into depression! For anxiety and panic, they really are the gold standard treatment, at this point. I think your dose was WAY too high to begin, so you might have gotten the wrong impression about how it "feels", as you were too sedated. You also probably quit WAY too fast, although I seriously doubt what you are experiencing now (6 months later??) is a withdrawal syndrome.
Best of luck!
Matt
Posted by mattdds on January 27, 2003, at 8:35:53
In reply to Questions about Benzo's/GABA, and AED's!!!, posted by titleistguy on January 26, 2003, at 23:37:14
Sean,
Also, to answer your question about mechanism of action of BZD's:
The benzos actually act indirectly on GABA, through the benzodiazepine receptor, or BZD receptor. The BZD receptor is part of a receptor complex surrounding a chloride channel. Basically, when benzos bind BZD receptors, it makes it easier for GABA to exert its action, which is opening chloride channels on neurons. Opening chloride channels on CNS neurons hyperpolarizes (stabilizes) their membranes, so they can't fire as easily. You can see why this would be helpful for anxiety: it calms hyperactive neurons that are sending messages for you to panic!
As for the BZD-1 / BZD-2 thing. BZD-1 and 2 are both associated with GABA-A, which is the GABA subtype associated with anxiety. BZD-1 receptors are thought to be involved in sleep and sedation, while BZD-2's involve anti-anxiety, and anti-convulsant effects. The GABA-B receptors aren't important in anxiety. Interestingly, however, baclofen, which is a centrally acting muscle relaxant, binds GABA-B. Also, GABA-B might be involved in blood pressure regulation.
You asked about different drugs that effect GABA/BZD receptors. Actually, alcohol, barbiturates, chloral hydrate (a favorite of my dental colleagues :), I prefer the benzos) also increase GABA activity, but in a much "dirtier" fashion, i.e. they affect a whole slew of other things in the process. These other agents do not work via the BZD receptor, but *directly* on the GABA receptor. Ambien (zolpidem tartrate) is a selective BZD-1 receptor agonist. Remember BZD-1 is involved in sleep, BZD-2 is anxiety and muscle relaxation. So this explains why Ambien is good for sleep, but not so much for anxiety or muscle relaxation. Interestingly, Klonopin and Xanax, both of which are thought to be less sedating and very specific for anxiety and panic, are both more selective for BZD-2 receptors.
One interesting animal study of benzodiazepines looked at macaque monkeys with damage to the septal area of the brain, making them extremely irritable and anxious. The experimenters used either barbiturates or benzodiazepines to tame these crazy monkeys. Both BZD's and barbs calmed them, but with the barbs, the amount required for anxiolysis also heavily sedated the monkeys; while the benzodiazepines caused no sedation, but got rid of all the irritability and anxiety. This suggests that benzos have selective antianxiety effects. They can calm without sedation, at the right doses (although your 2.5 mg of Klonopin was probably way too much to start with...into the sedation dosage range!!).
So benzos are quite remarkable drugs. Sure there are others that enhance GABA-ergic transmission (alcohol, barbiturates, chloral hydrate, valproate, etc.) but *none* is as specific for anxiety (not to mention as safe) as the good ol' benzos.
I hope this helps a little.
Matt
Posted by titleistguy on January 27, 2003, at 19:37:01
In reply to Re: Questions about Benzo's/GABA, and AED's!!! » titleistguy, posted by mattdds on January 27, 2003, at 7:16:38
For the record, I was on Imovane (a Canadian hypnotic; similar to your Ambien) for 10 months, and inbetween there I was put on Rivotril (Clonazepam) for 3.5 weeks (my Doctor thought I was "manic". . . what a BONEHEAD!!!).
I got my first "dissociative" symtoms after I "cold-turkeyed" the Rivotril (actually about 2 days later, which is when you'd expect withdrawal to turn up, once the drug is cleared), but when I took the Imovane at night (not a Benzo, technically, but functions in the same manner: GABA-A, BZD-receptors), ALL my symptoms DISAPPEARED!!!
Finally, I "cold turkeyed" the Imovane (beleive it or not, my Psychiatrist TOLD ME TO DO THIS!!!), and subsequently went through 3.5 weeks of SHEER HELL!!!
(Many "residual" symptoms still "linger", which is what is known as "Protracted withdrawal", it only affects about 30% of long-term Benzo users but is a REAL phenomenon!!!)
Just to clarify, I've now seen 3 Psychiatrists and they ALL say that I have NO pathology for ANY "endogenous mental illness", yet I have 3 pages worth of symptoms!!!
I spoke to a Psychiatrist/Pharmacologist who is now "Medical Director" of a Chemical Dependency Recovery Program in Oakland, California, named Dr. David Cohn, and he says it definately sounds like a "Protracted withdrawal", and was quoted in an article saying, "Most Psychiatrists won't admit to a "Protracted withdrawal syndrome" because they are hung-up on the nomenclature" (ie. they don't want to admit that it was the pills that THEY prescribed that actually did all the damage!!!).
Also, for further proof: depersonalization, photophobia, tinnitus, and muscle-twitching, as well as heightened anxiety are the MOST common symptoms of Benzo-withdrawal. . . I just happen to have all 5 (as well as a few others!).
Dr. Cohn recommended that I try an anticonvulsant (such as Tegretol or Depakote) for the physical symptoms, to go with the Effexor (for anxiety).
Finally, I came off the Benzos because I never origanally even wanted to be on them!!!!!!!!!!!
(Read my story, under the heading "Please help me!!!", it explains everything!!!)
To conclude, I think Benzodiazepines are absolute CRAP, and should NEVER be prescribed for more than 2 weeks. . . MAX!!!!!!!!!!!!!!!!!
-Sean
P.S. I don't mean to offend anyone, by bashing Benzos, but when you've gone through the type of withdrawals that I have. . . you'll feel EXACTLY the same way!!! (That is, if you haven't already killed yourself!). I'm NOT kidding: it's HELL!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Posted by titleistguy on January 27, 2003, at 19:57:42
In reply to Re: Questions about Benzo's/GABA, and AED's!!!, posted by titleistguy on January 27, 2003, at 19:37:01
Just a helpful (and INFORMED!) tip: I've read reports (by Clinical Psychiatrists/Psychopharmacologists) which state that Clonazepam (ie. Rivotril/Klonopin) actually REDUCES synaptic availability of serotonin (which is why it's such an effective anti-manic device, I suppose!).
So, someone with mental depression who is taking this drug is ACTUALLY doing themselves an injustice! While it may help with any accompanying anxiety (I'm sure it does), it is actually making your MAIN PROBLEM WORSE!!!!
Just thought I'd give a little "heads up"
-Sean
Posted by Phil on January 27, 2003, at 22:32:32
In reply to Depressed people should NOT take Clonazepam!!!, posted by titleistguy on January 27, 2003, at 19:57:42
Klonopin has saved more depressed people's butts than you can shake a stick at. Mine included. There are plenty of reports saying it works incredibly well, usually as part of a cocktail.
A psychopharmacologist started me on Klonopin and a second psychopharmacolgist/neurologist agrees that it works quite well.
I'm pretty informed myself after 4 years here, seven running a pharmacy, and 20 years on psych meds.
It's probably one of the best drugs I've ever taken.
Posted by viridis on January 28, 2003, at 1:53:51
In reply to Re: Depressed people should NOT take Clonazepam!!!, posted by Phil on January 27, 2003, at 22:32:32
I agree -- Klonopin was the first med that consistently and dramatically reduced my anxiety, and the severe depression that resulted. I've been on it over a year and a half at the same dose (with some other meds subsequently added in at low doses) and it continues to work extremely well with no side effects. I haven't experienced a panic attack or serious bout of depression since I started it, despite a lot of stress and pressure during that time. Maybe it's not for everyone, but then no med is.
Posted by Phil on January 28, 2003, at 6:57:43
In reply to Re: Depressed people should NOT take Clonazepam!!! » Phil, posted by viridis on January 28, 2003, at 1:53:51
viridis, Good point about it not being for everyone but for those of us that need it, it's a life saver.
My anxiety before meds was wicked-I never felt calm. I was in fight or flight mode for many years.Phil
Posted by Creaky_Neurons on January 28, 2003, at 12:57:27
In reply to Re: Depressed people should NOT take Clonazepam!!!, posted by Phil on January 28, 2003, at 6:57:43
and one must be mindful of the neurotoxicity of ongoing hyper-cortisol levels and anxiety on the brain itself. in this light, klonopin is actually *saving* brain tissue from damage.
mental illness is not only painful and socially debilitating, but harms the freakin' brain.
creaky.
Posted by judy1 on January 28, 2003, at 17:40:58
In reply to Re: Depressed people should NOT take Clonazepam!!!, posted by Phil on January 27, 2003, at 22:32:32
I couldn't agree more with Phil's assessment of klonopin- especially when depression is a result of anxiety/panic disorders. I've taken it for over 3 years with excellent results. I just wanted to add that xanax seems to have more of an AD effect, especially with people who don't respond well to klonopin. take care, judy
Posted by titleistguy on January 28, 2003, at 18:34:35
In reply to Re: Depressed people should NOT take Clonazepam!!!, posted by judy1 on January 28, 2003, at 17:40:58
. . . I was just stating a scientific-fact about the pharmacology of Clonazepam. Perhaps all of you "loyal" Klonopin advocates (who have co-morbid Anxiety & Depression) would be better served with a different Benzodiazapine (like Xanax, or Valium) which would at least leave your already "frail" serotonergenic system ALONE!!!
Just my $0.02. . .
PLEASE don't take this (or my other post) as meant to personally attack or OFFEND anyone, I'm just trying to give (and recieve!) some advice here, as we all are!!!
Peace!
-Sean
Posted by stjames on January 28, 2003, at 19:40:00
In reply to Re: Depressed people should NOT take Clonazepam!!!, posted by judy1 on January 28, 2003, at 17:40:58
I have to agree with the others. This way too a general statement. The one thing that will cause my depression to break through, despite 20 + years of being stable (mostly) is excessive stress. Benzo's
are my treatment of choice to stop this breakthrough
depression. Atavin if the stress is short term and Clonazepam is the stress proves longer lasting and I need 24/7 control.This is not to say that benzo's, in some people,
make depression worse or can cause it. But an absolute statement the X will always yield Y is flawed when dealing with the diverse contitions and each persons specific condition.
Posted by stjames on January 28, 2003, at 19:42:08
In reply to I was NOT trying to offend Clonazepam users!!!, posted by titleistguy on January 28, 2003, at 18:34:35
> PLEASE don't take this (or my other post) as meant to personally attack or OFFEND anyone, I'm just trying to give (and recieve!) some advice here, as we all are!!!
>
> Peace!
Keep in mind that what is written vs. treating 1,000's of real live patients leaves a big gap.
Posted by viridis on January 28, 2003, at 23:48:43
In reply to I was NOT trying to offend Clonazepam users!!!, posted by titleistguy on January 28, 2003, at 18:34:35
Xanax is great for me as an occasional add-on for Klonopin (and quick anxiety reliever), but I find that Klonopin provides more consistent results that are longer lasting. Valium makes me feel awful -- drugged and "drunk", in a negative way.
There was a thread here recently that cited several studies which indicated that among benzos, clonazepam in particular can actually increase availability of serotonin at key synapses, perhaps explaining (in part) the antidepressant effect it has for me and some others.
Posted by Peter S. on January 29, 2003, at 14:34:25
In reply to I was NOT trying to offend Clonazepam users!!!, posted by titleistguy on January 28, 2003, at 18:34:35
"Scientific facts" are very iffy in the business of psychopharmacology. Even if klonopin decreases serotonin in the brain there is still no real verification that lack of serotonin "causes" depression. So I would be very careful about drawing conclusions from any study or research claim about how the brain works.
> . . . I was just stating a scientific-fact about the pharmacology of Clonazepam. Perhaps all of you "loyal" Klonopin advocates (who have co-morbid Anxiety & Depression) would be better served with a different Benzodiazapine (like Xanax, or Valium) which would at least leave your already "frail" serotonergenic system ALONE!!!
>
> Just my $0.02. . .
>
> PLEASE don't take this (or my other post) as meant to personally attack or OFFEND anyone, I'm just trying to give (and recieve!) some advice here, as we all are!!!
>
> Peace!
>
>
> -Sean
This is the end of the thread.
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