Benzo cross tolerance/subunit adaptation in specific benzo tolerance?

[>Marquis<]

Forgive my posting in this subforum if it's not considered advanced enough. It seemed like a better subforum to post in than any of the others.

I'm wondering to what extent cross tolerance exists between the different benzos. I've tried UTSE but for reasons I won't go into I'm having problems getting an answer to my query through that method.

I know a person who heavily abused diazepam for several months to the point where euphoria was no longer attainable at any dose. My friend has recently found that even after an 8 month break post taper, he still cannot obtain euphoria or other desirable effects from diazepam; just cognitive impairment, ataxia and sedation akin to that from diphenhydramine. In fact he found the effects remarkably similar to the effects that chlordiazepoxide had on him on the two occasions he took it most recently, once during a GBL detox and once during an alcohol detox: feeling tired and quite emotionally depressed.

This came as somewhat of a surprise to him as during a GBL detox some 6 months ago he found diazepam to be just as euphoric as it had ever been even from a starting dose of 10mg. Yet now it is back to the stage he was at during his dependence; euphoria is an unattainable goal.

Anyway my question is whether or not he will experience this same heavy, long term tolerance with other benzos, particularly with respect to the goal of inducing euphoria with the likes of clonazepam or alprazolam. As I understand it, different benzos are active at different subunit combinations of the benzo allosteric site. I have also gotten the impression (I cannot recall where from, but I believe it was in this forum) that when tolerance develops to a specific benzo, adaptation occurs and the subunit combo to which the benzo for which tolerance is developing becomes downregulated, while production of other subunit combinations is increased.

Does this mean that benzos with affinity for subunit combinations that differ from that to which tolerance has developed (diazepam in this case) will be more effective than before (due to the increased amount of these subunits) or will at least not exhibit the same tolerance as has occured with the diazepam? Will benzos that bind a similar subunit combo as diazepam exhibit an equivalent tolerance?

I would appreciate an answer hugely as this is bothering me quite a bit.

If my speculations regarding different benzos to diazepam still being effective are possible, could you recommend for me any benzos that are likely to be effective based on their subunit binding affinites?

Cheers guys.

 

[seep]

It's not unlikely that I'm amnestic, but I don't remember them making it to market yet. The GABA-A receptor benzodiazepine-subunit-subtype-selective ligands*, that is.

If you know of any that are available, in whatever market, please nod your head.

With the exception of some of the Z-drugs, which I don't find euphoric at all.

Anyway, the structure of the selectives is not the classical 1,4 benzodiazepine structure. The closest in structure are the imidazos like imidazenil (and even that one deviates because of the 3-carboxamide). And anyway that's OT because I don't think it'd be euphoric.

I have also gotten the impression (I cannot recall where from, but I believe it was in this forum) that when tolerance develops to a specific benzo, adaptation occurs and the subunit combo to which the benzo for which tolerance is developing becomes downregulated, while production of other subunit combinations is increased. Does this mean that benzos with affinity for subunit combinations that differ from that to which tolerance has developed (diazepam in this case) will be more effective than before (due to the increased amount of these subunits) or will at least not exhibit the same tolerance as has occured with the diazepam? Will benzos that bind a similar subunit combo as diazepam exhibit an equivalent tolerance?

No. I thought the same thing and Bilz0r set me straight in this post:

Me: Theory: the more selective the benzo, the more efficient utilization of the receptors. Lower percentage occupancy = lower disruption of inhibitory circuits = lower physical dependence.

Bilz0r: I'm not sure if I agree with your logic. Lets just assume there are two populations of benzos for the sake of argument, lets use the oldschool BZ1 and BZ2 terminology. If a drug was 100% selective, it would have no affinity for, lets say, BZ2. Hence, it's occupancy at any given concentration would be asymptotically close to 0. However, that doesn't mean it doesn't mess with inhibitory circuits. 1) we could imagine that BZ1 is expressed preferentially on interneurons. Hence acting at either BZ1 or BZ2 would mess with the inhibitory circuits in completely different manners. 2) BZ2 could actually be expressed at vastly lower titres, or in a very restricted area, hence, acting selectively at BZ1 would not really be very different from acting non-selectively. Most importantly, the question of dependence has nothing to do with that. A drug can act at a vast array of targets, the question of whether or not you get dependence has to do with what the drug does to the receptors once it's bound. The dependence caused by benzos is poorly understood, but if we assume it is caused by some re-jigging of the subunits that make up synaptic GABAA receptors, then we just need to find a ligand that doesn't induce this change in the receptor.

The paper he links to is now available here.

*There has got to be a shorter way of saying "GABA-A receptor benzodiazepine-subunit-subtype-selective ligand".

 

[>Marquis<]

Semantics aside, what I'm asking is: given the tolerance to diazepam being such that euphoria is unattainable, would the use of another benzo such as clonazepam or alprazolam be worthwhile?

 

[seep]

2mg of alprazolam in the morning still gives me a prosocial and euphoric rush for about an hour, and I've been taking 3mg a day every day since 2005.

Diazepam does nothing for me.

 

[>Marquis<]

Just out of curiousity, is diazepam's uselessness for you one of those idiosyncratic reactions that some people have with some benzos, or did diazepam once work well for you and you have developed a tolerance to it?

 

[seep]

Diazepam never worked for me. Like, I never even noticed an effect. This has happened to me with a host of other benzos (um, oral lorazepam, chlordiazepoxide, chlorazepate and a few other weak ones I can't remember now).

I think the only benzos I've enjoyed are alprazolam, temazepam and flunitrazepam. And IM lorazepam they gave me at a hospital once at a dose that wasn't revealed to me because I was breaking furniture.

For whatever it's worth, I was formerly prescribed clonazepam, and took it every day at 2mg for about 6 months. Initially it gave me a mild calming effect, but after 6 months it was not even doing this. It was my doctor's decision to upgrade to alprazolam. The difference was immediately noticeable, though I deviated from his dosing instructions a little bit. He told me to take 1mg 3 times a day. Instead I take 2mg in the morning and 1mg 4-6 hours later. At 1mg alprazolam at a time, it was mildly calming, but I was unable to enjoy it.

The thing that gets mentioned often here is the correlation between short onset, short duration and recreational value.