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A less dependence-forming benzo

C

clubcard

Bluelighter
Joined
Apr 12, 2013
Messages
1,483
I've been on 20mg clobazam [BID] which, according to benzos.org.uk equates to 20mg of diazepam daily. I've been on them for a year and was left, due to a clerical error, with none for 48 hours. I suffered no kind of withdrawal at all. I doubt you will see any of the potent analogues like the 2'F derivatives or nitro analogues because there is no neat precursor freely available.

I mention this in passing. They have no cross-tolerance so anyone swapping from clonazepam to clobazam needs to go down on the clonazepam over a couple of weeks.

I predict that the 7-nitro-'2-fluoro will be the most potent although 3-ring derivatives have been made and tested because THAT is a LOT of work.

Of course, the QSAR of etifoxine hasn't been established. I would expect the nitro analogue to be more potent but '2 substitution (with chlorine at least) has no advantage and higher toxicity. Who knows, as soon as diazepam hit the market, all research stopped.
 
So you're saying that clobazam doesn't produce withdrawal syndrome!? Need to get it then.. it's even available in my country here. But is it really different than the other BZDs? I've been using lorazepam on and off over many years, and never hit serious tolerance (I don't become tired any more from it, this is a plus and a minus at the same time) but once when they had me on at least 2mg/day for 2 months or so and then a stupid doc decided to do cold turkey, I rushed into a hell of anxiety and sleeplessness. Probably only 1/10 of what real BZD withdrawal must be like, but it was more than enough to be very wary of anything messing with GABA...

The cross-tolerance is interesting indeed, as is etifoxine, but the latter has unfortunately been associated with acute liver injury ... there seems to be (almost) always some catch. But we definitely have yet much to learn about the GABA complex, I believe that anxiolytics with much less or no tolerance / withdrawal will be possible. We already have some, but strangely they aren't used ... tiagabine, and the not even marketed deramciclane.
 
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Yes - it won't stop withdrawal of 1,4-benzos but it doesn't, at medical doses, cause dependence. I E-mailed the lady behind all the work on benzo dependence to let her know about clobazam not being a replacement from diazepam (and it has a long enough T1/2 to detox on it. She had NO IDEA. NEITHER DID MY NEUROLOGIST! I can always spot the GREAT doctors - the ones who aren't put off by someone more qualified in the meds than them; they are happy to learn... if not, change doc (they have the common 'god complex').

You should checkout the overlay of (S)etifoxine and, say, chlorodiazepoxide.

After the worst air-disaster in history, it was no longer captain<<copilot<engineer. It's called 'cockpit management' where any member of the crew can question an action and both or all 3 of the people on the flightdeck have to 'buy in' to the best solution. It's saved countless thousands of lives. So Specialist<<doctor<nurse IS killing people. If 'integrated patient management' were introduced, all would agree on best treatment. Of course, the BMA doesn't WANT the nurses (who see you 24/7) to have a say.
Food for thought.
 
I don't think it is saying much that you survived 2 days, it took 8 weeks of tapering when I got off diazepam. Even clobazam has a halflife of about 40 hours and then that of an I suppose active metabolite N-desmethylclobazam of 80 hours.

Unless there is some special pharmacological action of reuptake inhibition instead of agonism etc, you should expect a rebound effect that is the opposite of the indication for which you are treating it / the opposite of the normal effect of that benzo. So clobazam being especially anti-convulsant would be more likely to cause seizures. This really does depend on how high your normal doses are and if you quit cold turkey.. if you take it easy a lot of people don't get super serious acute withdrawal effects, but never underestimate the chronic withdrawal effects which can be hell for benzos.

The lack of cross-tolerance probably has to do with different selectivity for GABA receptor subunits?
 
Is this lack of withdrawal explained by half life? I have a hard time believing that your receptors (whatever receptors this drug has affinity for) aren't down regulated, I mean it would be the holy grail if there is any drug that doesn't down regulate receptors and gets around receptor homeostasis :eek:

The only thing I can think of close to this scenario is a drug that binds to tons of different receptors very mildly rather than something like ambien that has high affinity for just one receptor. I think the Ambien type scenario would induce receptor downregulation a lot faster than something that was binding a little bit to a lot of different receptors.

Along the lines of something that doesn't induce tolerance as much because it binds to a lot of different receptors is modulating the GABA synthesis itself, it would increase GABA binding globally across all receptors but maybe there are other problems with this. There are also the aforementioned GABA reuptake inhibitors, I suppose these would work globally as well and might have less tolerance building effects/withdrawal to them, but then again look at SSRIs.
 
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I should throw into this discussion that apparently there isn't tolerance to the anticonvulsant effects of some GABA neurosteroids but they are cross tolerant with benzos. Wonder where their anticonvulsant effects are from. Ganaxolone is interesting.
 
I think reuptake inhibition of GABA. That pharmacology apparently doesn't induce tolerance like actual receptor ligands do - this is also seen with e.g. methylphenidate I think. Or at least relatively a lot less, since the action comes from elevated levels of synaptic neurotransmitter.
There is some cross tolerance, or at least desensitization if you have used releasers or agonists that downregulate the receptors and then take a reuptake inhibitor. There is then probably less effect with a less dense receptor population.

Oh shit sorry ganaxolone is not a reuptake inhibitor, confused it with tiagabin.

Isn't the action of valerian also similar to the allosteric modulation of ganaxolone? (Indeed >> look up valerenic acid)
Perhaps unsurprisingly valerian also does not seem to cause tolerance effects, it is rather mild as anxiolytic but some compounds in there can make you drowsy - not always such clean effects but it does depend on the extract in question.

Can there be potent and strongly effective GABA-A positive allosteric modulators that still don't cause tolerance? Or is the limited / attenuated effect a logical turnside i.e. that you can't have your cake and eat it,too ?
 
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I think with such long half-lives of the drugs in your system 48 hours is not really enough to say whether you would have experienced withdrawal or not.

It is an interesting question whether receptor down-regulation is an inevitable result of increased action at that receptor. It would be nice if it wasn't.
 
Somehow I think it isn't per se, because we already have too many compounds that don't fit in the traditional tolerance scheme. With most the differences are too subtle to being easy spot, but there are things like the opioid peptide DAMGO or the said GABA reuptake inhibitors, tiagabine and deramciclane. My current theorizing is that there are both reactions to excess receptor activation but that the major part is some sort of immune response to a xenobiotic molecule. And metabolic changes of course, that the body becomes more efficient in inactivating the agent as well as the involved transmitters (because I've experienced with many drugs that the duration tends to become shorter after repeated usage, and this lasts for a long time).

What lead me to think about this was my research about NMDA antagonists. It seems like the NMDAR's don't readily (or not at all) upregulate with antagonism but we still see heavy tolerance to things like ketamine. Curiously, I have been able to sustain a 'therapeutic' regimen of MXE for weeks or even months with tolerance staying at a plateau, 3x 10mg/d or so still being effective, but with ketamine after just 1-2 weeks it goes through the roof. So I really suspect involvement of the immune system (or whatever you'd like to name it), and/or changes in gene expression - is this the same? SSRIs I think have been shown to change the activation of some genes when used chronically. And things like psilocybin are just ineffective for several days after dosing and I think this is not due to receptor down-regulation.

Another point might be that agonists or allosteric modulators (which are agonists at their site too) cause much worse and more rapid tolerance and especially PAWS than reuptake inhibitors or releasers because of constant vs firing-dependent activation. See dopamine agonists vs. methylphenidate. BZDs vs. tiagabine.

Genetics play a big role too of course, some people can do a specific drug repeatedly over an extended period of time and get away with it while somebody else gets horrible withdrawal just after a very short time.

There's still so much to research and discover ... but I'm positive that we'll have non-dependency forming drugs some day. And/or ones which reset tolerances - we already have this with opioids & NMDA antagonists, but there are too many pieces missing. With more new, specific drugs maybe this concept can be expanded to other systems in a way that we have a compound for every tolerance to reverse it... :)
 
Don't forget - the T1/2 is IN THE BLOOD. What's lesson 1 of medicinal chemistry? Absorption Distribution Metabolism Excretion so as it's drifting between brain and blood, the fraction in the blood becomes plasma-bound. High LogP means it's MOSTLY in the brain but there is always a fraction in the blood. That part is excreted. That's why, even with HUGE T1/2, you need to take them twice a day and double-dosing doesn't last for 24 hours.
 
Not really an understandable argument for me.. what you seem to be saying is that not only is there a long half-life for the blood fraction (in which plasma protein binding is accounted for?) but the drug also lingers in brain / fatty tissue, which delays excretion even more.
You need to take what twice a day, even with very long T½ ? If you taper benzos they give you diazepam, even then stable decline in concentrations helps to avoid the more acute, dangerous and hard to keep up withdrawal symptoms. With what you are dosing you are driving levels up, excretion drives them down. After reaching a steady state you steadily go down. Double dosing doesn't necessarily last long at that point since this is not a single dose in an otherwise clean individual, here it is part of that larger equation of blood concentrations that are considerably raised after chronic use.
 
As it drifts between brain and blood - your losing some to protein binding so a T1/2 on the BLOOD concentrations yields little to no information on brain concentration. Like I said, the LONG T1/2 of, say, diclazepam (detectable at 11 days) only lasts 12 hours... Just check out Lipinski's rule of 5, use free software to check LogP and then plasma binding - then you can calculate duration.... very roughly.
 
clubcard said:
Don't forget - the T1/2 is IN THE BLOOD. What's lesson 1 of medicinal chemistry? Absorption Distribution Metabolism Excretion so as it's drifting between brain and blood, the fraction in the blood becomes plasma-bound. High LogP means it's MOSTLY in the brain but there is always a fraction in the blood. That part is excreted. That's why, even with HUGE T1/2, you need to take them twice a day and double-dosing doesn't last for 24 hours.
Click to expand...

T1/2 is correlated with logP however. A huge T1/2 implies a huge logP. A compound with an high logP is going to stay in the brain longer, as well as the blood longer. When it reaches the collecting duct in the kidney, if it is lipophilic enough then it will diffuse across the membrane back into bloodstream, just like when it diffuses across the BBB into the brain.

The only case where this is not valid is when liver metabolism, along with making the drug more polar, actually changes the binding interactions of the drug with the target itself. For example if drug X which binded to target Y was metabolised to drug Z (which no longer binds to target Y), but drug Z is still too lipophilic to be excreted, and any more metabolic reactions on Z are hard to accomplish by the liver, then that is the only case where I see your logic applying. I don't think it applies in this particular case though.
 
Phase 0 study? Well me, too.. They didnt teach pharmacology there. But obviously you learned it elsewhere. Still I'd appreciate "peer review" of what you were getting at.
 
There are plenty of drugs with long half-lives that only have to be dosed once per day. Just to name a few examples of CNS drugs: buprenorphine, methadone, fluoxetine. Half-life isn't the only factor that determines dosing frequency; it also matters how much of a concentration drop is tolerated before the effects become sub-therapeutic. There can also be individual variations in drug metabolism and in the intensity of the withdrawal syndrome. I've heard examples of people who can tolerate dosing buprenorphine once every two days, but that isn't frequent enough for most patients.

It is conceivable that a long-acting benzo, with active metabolites, could have a delayed withdrawal syndrome. The only way to know for sure would be to discontinue the drug for an extended washout period. Going 48 h isn't long enough. But in any event, even if clubcard never experiences withdrawal from clobazam, that doesn't mean that clobazam does not produce a withdrawal syndrome in most people.
 
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clubcard said:
I've been on 20mg clobazam [BID] which, according to benzos.org.uk equates to 20mg of diazepam daily. I've been on them for a year and was left, due to a clerical error, with none for 48 hours. I suffered no kind of withdrawal at all. I doubt you will see any of the potent analogues like the 2'F derivatives or nitro analogues because there is no neat precursor freely available.

I mention this in passing. They have no cross-tolerance so anyone swapping from clonazepam to clobazam needs to go down on the clonazepam over a couple of weeks.

I predict that the 7-nitro-'2-fluoro will be the most potent although 3-ring derivatives have been made and tested because THAT is a LOT of work.

Of course, the QSAR of etifoxine hasn't been established. I would expect the nitro analogue to be more potent but '2 substitution (with chlorine at least) has no advantage and higher toxicity. Who knows, as soon as diazepam hit the market, all research stopped.
Click to expand...

Some people can get away with up to 1 year on benzos without withdrawals. For many this is not the case. Also, it's only the 18th now so the drug might have accumulated and you might gradually feel some withdrawal on days 5-7. Keep an eye out for it. Sensitivity to light, noise, mild anxiety or even a panic attack out of the blue.
 
Also, and this is just thinking out loud: when different benzo's have different effect profiles as: anxiolytic, skeletal muscle relaxant, anti-convulsant and hypnotic, and carry a withdrawal potential that is the inverse of that... perhaps these effects have different thresholds of action, maybe it is quite easy to get anxiety withdrawals but the threshold for getting a seizure is quite a bit higher - though when you do get one it may be quite the event. Or alternatively some seizures may not even be noticed such as absence seizures.
 
Affinity to each of the 4 'valium sensitive' subtypes explains the differences.
 
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