Euphoria from (particular) benzos...mechanism(s)?

[Riemann Zeta]

Jamshyd, you have an excellent point that a more specific and technical definition of the term "euphoria" is needed before we can attempt to define what chemical signatures cause euphoria. We obviously have an assload of structures (there are just hundreds of benzos and atypical "non-benzo" benzos), but if we don't have a predefined criteria for what constitutes 'activity,' then we're not going to ascertain any kind of SAR.
The problem is, obviously, that 'euphoria' is a vague or non-rigid designator. Like all qualia, just what exactly it is, both physically and psychically is specific to the person or entity experiencing it. So, maybe for people that really tend to like downers (e.g. opioids and benzos, but probably not NMDA antagonists like ketamine or cannabinoids, as I don't really think of those as "depressant" drugs), numbness is euphoric. For me, euphoria is an extraordinarily rare state--I guess it occurs when my perception shifts from being discrete to continuous. That is, instead of perceiving and thinking in a moment-to-moment, analytic, almost "after-the-fact" manner, I experience time, physical phenomena and my own inner psychic rumblings as flowing and I am aware not just of each little separate event but of the rate-of-change in my perception.

Whoa, that may have gotten a little too deep for a thread about which substituents make a better benzo. OK, back to the point...I had a point, didn't I? Oh yeah. So, I guess for me to really notice that I'm experiencing euphoria, I have to have a crystal clear awareness and intact memory. That's why benzos just don't seem to do it for me, I seem to get too drowsy and torpid to enjoy--or notice that I'm enjoying, if that makes any sense--the experience. I might just end up wanting to go to sleep. Of the one's I've tried (diazepam, lorazepam, alprazolam, midazolam and bromazepam), the most useful has been bromazepam by far. It has the least deleterious effects on memory and cognition (diazepam had the most, 'cause it was so long-lasting), in my experience. Alprazolam was the worst, because the rebound effect is intense, even after only a few doses. It is the only one that I've tried that really had me--I could see it becoming incredibly addictive, so I stopped taking it cold-turkey and have never taken it since. The rebound anxiety upon withdrawal was a real bitch and I had only been on it for 6-8 weeks at the time. Since I was spooked about being really addicted, since then I've only used benzos sparingly, as tools in unusual situations--I've had to reduce the number of stressors in my life so that I don't have to band-aid the anxiety with chronic benzos.

Man, I got on a rant again. Anyway, I don't think the comparative receptor sub-type affinity has been mapped out for all that many benzos. More for the recent atypicals like zolpidem and zopiclone. We do know with some confidence that the a1 subtype is associated with the most intense hypnotic effect. The a2/a3 subtypes are a little sedating and anxiolytic and the a5 might cause the most intense amnesiac effects. Maybe a2,a3 and a5, along with y2 would be the best for "recreation" because alcohol seems to hit all of those and it is certainly the most popular recreational downer out there. I mean, most people seem to like small doses of alcohol (and of course some like really large doses and unfortunately end up becoming chronic alcoholics).

Damn, Imidazenil sounds like absolute benzo perfection; imagine midazolam without the intense sedative and amnesiac effects and without the problem of strong potentiation of alcohol (causing death from resp. depression). If only imidazenil existed as a commercialized product, either prescription or grey-market. I could see it being much safer and friendlier than a lot of the current benzos.

 

[LuxEtVeritas]

again though however you wish to defione euphoria and the above definition bears merit for sure, there is a definite general consensus of certain benzos that are for the majority of users more desirable in that they produce said 'euphoria' and thus one could ithink say that this si the desirable benzo trait/euphoria of the class that is most pronounced to the general consensus

now as to that does this limited group of agents that are i believe considered by said general consensus to be the most euphoric have receptor subtype profuiles in common...that is an issue to be explored to understand the mechanism/pathways involved, which is what I am curious to and not simply just how to build the structure in a SAR manner

 

[jspun]

I decided to resurrect this thread, because I was interested in this question. There is alot of interesting discussion of SAR but I am more interested in receptor selectivity per se as it influences side effect profile.

i believe if one looks at general consensus there is definitely some benzos that are far more highly seen to have a quality of euphoria and sought after for such reason (though indeed individual variance is somewhat high perhaps here and that may even be an indicator of something.)

I think there are a few factors peripheral to neuropharm/physiology that I'd like to discuss first. Cultural factors- word on the street. In the 90s when they were handing out Temazepam like candy in the US I thought of it as shit for squares. At that time, chloral hydrate, halcion, and if I was really lucky placidyl were preferable (CH and placidyl non benzos). Even managed to score seconal once.%). Valium and clonopin were the benzos of hoice along with halcion. However, for many years "jellies" as I believe they are called in the UK and many common wealth nations are in great demand (And they come in a lower strength.) The perception among the various health ministries in these countries is that they have a higher abuse potential relative to other benzos. Rohypnol, which is schedule I in the US is desirable by some (because of its notoriety?) and shuned by some dope fiends- bad dape rape conotation. Hear in San Diego it is not exceedingly rare on the black market given our proximity to the pharm paradise TJ. However, it is a prefered benzo in EU contries among dope fiends were it is legal to prescribe .

There is also probably subject specific differences in individual neurochem as the above poster intimates. So differences in pharmacology presumably result from differences in selectivity for bzd subunits named alpha1beta1...ect for different subunits that make up the GABA A ligand gated channel (ionophore complex). They use to talk about the omega 1, 2, and then three BZD subtype but that convention may have gone into disuse (me neurochem rusty). Now different side effect profiles presumably reulted from differential selectivity with w1 causing sedation, w2 causing anxiolysis. Z compounds were supposed to have great selectivity for 1 and low affinity for 2 although this assertion has been disputed. It has also been postulated that some of the anxiolytic properties of benzos is mediated by blocking the reuptake of adenosine. Also- low and high potency benzos seem to have unique peculiarities in pharmacology. It has been suggested that this is why xanax, ativan, and clonopin are supperior at treated panic disorder possibly by influencing 5-ht neurotransmission compared to valium, oxazepam, or librium. Alot of these theories may have been disproved.

Ability to cross BBB. Valium is very lipophilic thus crosses the blood brain barrier quickly. This was often proposed as a reason for its higher abuse potential relative to other drugs. Also with anxiolytics compared to sleep aids, the fact that xanax is usually taken several times a day to treat anxiety makes it more likely that one builds tolerance to its sedative properties compared to flurazepam that typically is only taken at bedtime. I used to take clonopin for panic disorder at night and it would put me to sleep at night compared to xanax typically taken by me tid or qid which would relax me but not make me sleepy.

Personally, in my opinion it is probably a combination of all these variables (of course) but receptor pharmacology and individual variability are the most important factors. But then what do I know (not much anymore).

If you are using these drugs to potentiate opiates I prefer xanax and clonopin but euros seem to hold temazepam in higher esteem for that indication.

Is DA involved in reiforcement?- good question given similarities in pharmacology/ some degree of cross tolerance. With EtOH I've come across studies suggesting that NMDA inhibition and activity at opiod receptors as the basis of increase release of DA in the mesolimbic reward pathways. Presumably, in the case of the latter, this is the basis for naltrexone bloking reinforcement.

So whats new on this topic?

 

[onmyway]

you guys and your chemistry. goddamn it makes me feel ignorant.

 

[MyExcuse]

I know this isn't directly related to the mechanism of action of the drug itself, but it's still interesting.

I did a report a while back on how individuals with a family history of alcoholism reported a much higher incidence of euphoria from benzodiazepines. This, naturally, led to a higher incidence of addiction to benzo's.

I wish I still had the paper, it had some interesting references. Have to wonder if that works for other receptors (ie, 5-HT, NMDA, AMPA) and if so, what implications it may have.

 

[otto]

as a sidenote: lorazepam is one of the best short-term antidepressants. many patients with severe major depression react with an immediate relief and reduction of depressive symptoms when given lorazepam (especially at higher doses). In the meantime the antiderpessant drug that is being given to the patient (SSRI or whatever) has enough time to build up its own genuine thymoleptic effect (which usually lasts 2-3 weeks).

 

[TMoney11111]

I know this isn't directly related to the mechanism of action of the drug itself, but it's still interesting.

I did a report a while back on how individuals with a family history of alcoholism reported a much higher incidence of euphoria from benzodiazepines. This, naturally, led to a higher incidence of addiction to benzo's.

I wish I still had the paper, it had some interesting references. Have to wonder if that works for other receptors (ie, 5-HT, NMDA, AMPA) and if so, what implications it may have.

I have to agree from experience of my own and family members. I'm just a pharmacy tech, don't know a whole lot as far as the science behind most medications but I can tell you that is true based on the people I know. Diazepam is the one that seems to be the most euphoric or similar in feeling to alcohol when the right dose and effect are achieved so I would be interested to see that report and it's details. Also, speaking for a few dozen junkies including formerly myself I would say Diazepam seems to cause the most euphoria for those who's drug of choice is an opiate.

 

[shibireru]

Well, to make a clumsy attempt at answering LuxEtVeritas' question (I recognize that it was propounded about a year and a half ago, but it may well be that in all this time it hasn't been satisfactorily answered):

There exists a good number of GABAergic neurons within the ventral tegmental area which modulate the activity of the dopaminergic efferent projections in the same region. By binding to and, in inducing chloride anion ingress, hyperpolarizing these GABAergic neurions, benzodiazepines may permit the dopaminergic neurons to more liberally send their signals to the striatum/nucleus accumbens/ventral globus pallidus or something like that. The reason why there is so much variation from one individual to the next in terms of euphorigenesis may relate to individual differences in cerebrovasculature or what have you that conduce to one benzodiazepine reaching the appropriate region and another not doing so very efficiently. Or, perhaps more likely, it may be due to individual differences in GABAergic neuronal density with respect to dopaminergic neuronal density. (Edit: meaning, if one had relatively few GABAergic neurons in that region, that instead of preponderantly inactivating the GABAergic, a given benzodiazepine might inactivate a great deal of dopaminergic neurons, too. And if one has few GABAergic neurons in that region by nature, then the pleasure centers of his brain may be worn down a bit more so that what little increase in dopaminergia were produced by the benzodiazepine had a minimally euphoric effect.) As for why there exists differences between one benzo and another in terms of euphorigenesis, it may be due to the differences in efficacy with which a given benzo hyperpolarizes these said GABAergic neurons and the doses at which they are able to do this job adequately (thus, highly potent hyperpolarizers introduced in sufficiently low quantities such that few dopaminergic neurons were inactivated would perhaps maximize euphoria). And if the ventral tegmental area is stratified in such a way that the dopamine neuron populations are sitting atop the GABAergic, then the facility with which a given benzo diffused through brain tissue due to characteristic chemical properties may have something to do with it as well?


Edit2: I am, by the way, not the person who brought this thread back from the dead. My powers of necromancy are not nearly so astounding and august.

 

[negrogesic]

On an entirely (or virtually entirely) unrelated matter, does anyone know (from subjective experience or otherwise) which benzo is considered to be the least amnestic? Clonazepam maybe?

 

[MyExcuse]

On an entirely (or virtually entirely) unrelated matter, does anyone know (from subjective experience or otherwise) which benzo is considered to be the least amnestic? Clonazepam maybe?

I'm going to go out on a limb here and say Lorazepam.

In my experience, Lorazepam has to be the least amnesiac benzo I've tried.

I've also read that lorazepam works on a slightly different system of receptors than the classical benzo's (clonazepam/diazepam/alprazolam) and so often times during the treatment of benzo withdrawal from those three, they will give lorazepam to offset some of the effects.

 

[seep]

On an entirely (or virtually entirely) unrelated matter, does anyone know (from subjective experience or otherwise) which benzo is considered to be the least amnestic? Clonazepam maybe?

I'm also very interested in getting a non-anecdotal answer to this question. Many of the patients I deal with are spooked into thinking that benzos will cause irreparable memory loss. I tell them (though I'm not licensed to do this) that the amnestic effects of benzos are only for the duration of activity, dissipate completely when the dose has worn off and affect primarily the short-term memory. But after being on alprazolam every day for 5 continuous years, it seems to me that my short-term continues attenuated even after the dose has worn off, and I'm beginning to experience what seems like anomic aphasia (like today I told my wife to get me "the thing that makes things combust" because I couldn't remember the word "lighter").

I can find no research into chronic benzo use vis-a-vis permanent memory loss (except for subjects with early-onset AD). Are my fears justified and if so, what's the least amnestic benzo?

 

[MyExcuse]

But after being on alprazolam every day for 5 continuous years, it seems to me that my short-term continues attenuated even after the dose has worn off, and I'm beginning to experience what seems like anomic aphasia (like today I told my wife to get me "the thing that makes things combust" because I couldn't remember the word "lighter").

I suffer from this exact same thing. I used to do a lot of alprazolam and diazepam when I was in my early teen's for a period of a few years. I've found that certain aspects of my memory are irreparably altered (for the worse). I'll forget the names of common items, I'll tell the same story multiple times, and I'll ask the same questions multiple times (not on the same day but on a daily basis it would seem).

Not trying to derail the thread, just I'm glad to know I'm not alone in this perpetual amnesiac boat.

I wonder if there is something that can aid in recovery of short and long term intermediate memory (my long term seems fine).

 

[seep]

I wonder if there is something that can aid in recovery of short and long term intermediate memory (my long term seems fine).

Memantine enhances procedural memory; not sure about interactions with benzos as GABAa has a 5-HT3 BINDING SITE. grue knows more about this.

 

[shibireru]

I'm also very interested in getting a non-anecdotal answer to this question. Many of the patients I deal with are spooked into thinking that benzos will cause irreparable memory loss. I tell them (though I'm not licensed to do this) that the amnestic effects of benzos are only for the duration of activity, dissipate completely when the dose has worn off and affect primarily the short-term memory. But after being on alprazolam every day for 5 continuous years, it seems to me that my short-term continues attenuated even after the dose has worn off, and I'm beginning to experience what seems like anomic aphasia (like today I told my wife to get me "the thing that makes things combust" because I couldn't remember the word "lighter").

I can find no research into chronic benzo use vis-a-vis permanent memory loss (except for subjects with early-onset AD). Are my fears justified and if so, what's the least amnestic benzo?

I believe you asked this very question about three quarters of a year ago and I cited studies to support the notion that benzodiazepines may cause long-term, semi-reversible, and/or permanent cognitive deterioration.

It's interesting how few people seem to be aware of this. This topic comes up a lot on other fora as well.

http://www.ncbi.nlm.nih.gov/pubmed/8159265

You might take a look at IDRA-21, as I have suggested to many others. It looks very promising.

 

[seep]

I believed you asked this very question about three quarters of a year ago and I cited studies to support the notion that benzodiazepines may cause long-term, semi-reversible, and/or permanent cognitive deterioration.

You see! My memory is shot.

So it's trophic and plasticity interference that's implicated. In the recent SSRI euphoria thread I asked something about trophins that I think is relevant to this, but I forgot what exactly I asked.

Excuse me while I go learn to tie my shoes.

Thanks

 

[halfmarathon6]

I have a Ph.D and work in a lab at Purdue that is performing the research of which you speak. Feel free to ask me what you will.

 

[seep]

I have a Ph.D and work in a lab at Purdue that is performing the research of which you speak. Feel free to ask me what you will.

The initial question of this thread has yet to be answered convincingly as the thread continually veers into SAR jenga (not saying this is a bad thing).

OP asked what biochemical mechanism causes some bezodiazepines to induce euphoria, and why then is this effect absent from other benzos.

Jamshyd asked an epistemological question about what we mean when say "euphoria".

Negrogesic asked which benzodiazepine is the least amnestic.

I asked whether or not we know with certainty that chronic benzo use contributes to permanent memory loss in persons without pre-existing neurological damage.

 

[MyExcuse]

Back on the topic of why/how benzodiazepines cause euphoria, I offer another anecdote:

When I was younger and abusing benzo's (in particular alprazolam and diazepam) I suffered extreme anxiety due to family issues.

As I got older, whenever I would abuse benzo's it would happen to be around times of stress and discomfort.

Years later after I had decided to stop abusing benzo's, I decided to acquire some on a whim. What I found was that they did not have any euphoria for me. The most I got, no matter the dose, was a sense of sedation and relaxation (but nothing to write home about). I put the pills aside and decided to hold on to them in case I ever needed them.

Well time passed and eventually another very stressful event came into my life unexpectedly and I opened the stash and downed a few pills. Sure enough, I was met with the euphoria that had been missing the previous time taking it.


I am unsure of the biochemical role this would relate to. On the one hand, my brain chemistry could have been altered and now reacts differently to benzo's. Or perhaps, to truly feel some of the anxiolytic effects (and subsequent euphoria), one would have to actually be anxious or at least have an axious personality to feel the euphoria.

Just a thought, based on some personal experience.

 

[WhiteLinesNcoffee]

I agree^^^ Benzos seem to only give me euphoria when i take them in times of extreme stress. The relief is what seems to cause the euphoria for me.

 

[theWorldWithin]

^I will further confirm those observations. Even within the time span of the same week, days of high stress lead to a very rewarding experience but during otherwise happy and stress free days benzos are simply sedative and frankly kind of icky feeling many times.

Trying to explain benzo euphoria on the receptor level is a mistake and grave oversimplification. Certainly the binding of particular receptor sub-types is a necessary condition for euphoria to occur, but alone it is not enough. It is my opinion that benzo euphoria is a much higher level cognitive phenomenon. This would also help to explain the great discrepancy in personal preference for benzos. Much the same as it is foolish to explain machine elves as a result of 5ht2a agonism, there is surely some larger things going on to produce vivid hallucinations during psychedelic experiences than a simple monoamine receptor state. Benzos are very likely to be the same type of situation.