>200 Ren? jesus fucking christ. Thats exploding head and skull-derived bone shrapnel hand grenade sort of territory. Damn!. I'm glad she was alright hun. And all the more given you say, she was a teenager? meaning presumably the first hint of tiny little pink Renster baby-toes were long hence due to make their first wriggle?
You don't need to be bipolar or have unnatural or unstable brain chemistry for barbs to make you feel all relaxed, trippy, disinhibited and sort of...well....sedated, yes, but at the same full of relaxed, bubbly energetic...not exactly get up and go, but 'bang into the walls repeatedly and go nowhere, but feel pretty fucking bubbly and good doing it; but not very much else at that particular point in time'
Thats exactly what barbs are like, good ol' wallbanger type downers, most of that sort of GABAergic depressants have been shitcanned, partly due to the fact that benzos went and got invented. Still physically addictive if misused (or rather if misused in the wrong way and for too long), but benzos won't kill you if you OD on benzos and benzos alone, not unless you REALLY push it, and even then, only some benzos have much liability to do so.
Barbs? they will not bat an eyelid about wiping someone out if they overdose. Partly due to differences in the way they gate the GABAa receptor chloride channel.
GABAa being the principle CNS receptor mediating inhibitory neurotransmission and maintaining overall inhibitory tone (glutamate being counter to GABA in being the primary excitatory neurotransmitter within our brains), the two, GABA and glutamate work both to oppose each other, counter to each other and in tandem, to allow the functions of either to play out as they should (although there is a lot more to either, they don't just regulate each other and nothing else, in fact there are very very few CNS neurotransmission flavoured pies that GABA and glutamate don't both have their sticky fingers in big time)
With the GABAa receptor, our main CNS inhibitory receptor, its structurally a heteropentameric receptor, formed of varying ratios of GABAa receptor protein subunits, of varying different subtypes, the whole receptor consists of an arrangement of five out of a selection grab bag of these subunits, making up the different subtypes of GABAa receptor. There are always five subunits no matter what overall subtype of GABAa receptor it is, and only certain combinations come together naturally to form functional GABAa receptors.
These subunits form a pentagonal structure overall, with a gap in the center, which with the receptor's overall structure is able to serve as an ion channel, in this case selective for passing chloride ion currrents, which, upon opening of the central ion channel in response to GABA binding to it's binding site, depending on the electrochemical potential of the cell at the time (I.e whether it is depolarized, or hyperpolarized with respect to the resting potential of the neuron), chloride ions flow through until the channel closes again, and cause the cell to be less responsive to further depolarization (E.g due to stimulation events of an excitatory nature, translated into sodium currents transmitted via voltage-gated sodium channels which depolarize the cell), when the cell is depolarized, an action potential, fires once the cell's potential rises past a certain threshold, repetitive stimuli over a short time being additive, and their being an overall minimum threshold which must be overcome, and subthreshold stimuli being summable to form, when repeated within a given time window, a large enough stimulus takes place when the subthreshold stimuli, if in total they are sufficient, take place, then the action potential fires.
GABA receptors are inhibitory, the influx of chloride ions affecting the potential of the cell in such a way that it is less likely to fire an action potential, by making the overall cell potential more negative, and thus requiring an overall greater magnitude of stimulus in order to permit the neuron to depolarize and fire an action potential. In short, activation of GABA receptors causes the cell voltage to become more negatively hyperpolarized, and thus a greater positive ion current is required to depolarize the cell and thus the cell is less likely to fire an action potential.
And this is why GABAa agonists have depressant properties, sedative, and also anticonvulsant effects, their helping to counter the raging out of control synchronous storm of useless, sustained and repetitive neuronal firing which characterizes an epileptiform seizure. As well as being one of the many mechanisms by which anxiolytic effects, by calming down excessive, overstimulated states, can be manifested.
Benzodiazepines and barbiturates recognize different binding sites at the GABAa receptor complex. When a benzodiazepine binds to it's binding site, it causes the 3D conformation of the GABAa receptor protein complex surrounding the ion channel to change shape, altering the conformation in such a way as to cause the result to have a higher affinity for GABA. Thus there more binding events of GABA binding to the GABAa receptor which also has a benzodiazepine bound to the benzodiazepine recognition allosteric binding site (an allosteric site, from the greek 'allos' 'other', is a site other than the orthosteric site, the orthosteric binding site being the primary recognition site for the native neurotransmitter, in this case, GABA itself, binds the orthosteric site, whilst all manner of things bind to different allosteric sites, benzos, barbs, neurosteroids bind to a neurosteroid regulatory site and have anaesthetic, depressant properties, as well as the Z-drugs like zolpidem/ambien, zopiclone (lunesta IIRC) and zaleplon (I forget the brand, its fucking useless shit anyway so not worth remembering for any other reason than to know what to tell your doctor to shove up his arse if they offer it to you.
So, with causing more frequent binding of GABA due to the increased affinity benzos induce, that means more ion channel openings per given time period, and also, the reason benzos are less dangerous and less likely to kill in overdose (MUCH less likely, to the point its difficult to die from a benzo OD without complicating factors), is that the increase in GABAergic stimulation is due to more FREQUENT opening of ion channels, the body can respond to this adaptively by opting to release less GABA, and thus decrease GABAergic stimulation. The benzos themselves don't actually activate GABAa receptors, they just increase the likelihood of GABA binding to them and activating the receptor.
Barbs on the other hand, bind to a different allosteric recognition site, and when one does bind to it's site, they cause an increase in the EFFICACY of GABA, that is, each GABA binding stimulus becomes more potent, by extending the duration the chloride channel opens, allowing more chloride ion flux to pass)
Can't remember if they increase the AFFINITY for GABA as benzos do (affinity being how tightly the ligand, in this case GABA, binds to the receptor, you could picture it as how much 'hunger' a given ligand has for it's receptor, and once it bites (I.e binds) how forcefully one would have to pry it's mouth apart before it'll give up and bugger off (I.e dissociate from the receptor-ligand complex.
Whilst efficacy, being, as it might indeed seem, being how effective the ligand is in producing it's stimulus once it binds to the receptor. An agonist or inverse agonist by definition, having a positive efficacy, and negative efficacy respectively, whilst an antagonist (more specifically, a silent, or neutral antagonist) simply blocks the receptor, like chewing gum in a lock, and prevents other ligands binding, and by definition has is a ligand with affinity but zero efficacy.)
Anyhow, that explained, with barbs, they cause, on their binding to their allosteric recognition site at GABAa, a much greater channel opening time, and correspondingly larger chloride flux. This, the body cannot compensate for, by decreasing GABA release to cause fewer openings, or if it does then nowhere near as effectively as when decreasing GABAergic tone by releasing less GABA to cause fewer channel openings, due to with barbs, the channel open time being greater, and thus ion flux larger overall.
In addition, barbiturates have a second, non-GABAergic mode of exercising a depressant effect on the body, they do this by acting as AMPA receptor antagonists (a type of ionotropic glutamate receptor (ionotropic receptors being those which work via direct coupling to an ion channel of some nature; the counterpart being a metabotropic receptor, glutamate, the main excitatory neurotransmitter, has both ionotropic and metabotropic types. Metabotropic receptors on the other hand are coupled to intracellular metabolic chemical cascades that do things like act on intracellular second-messenger chemical pathways eventually leading to alterations in gene transcription etc.] AMPA type ionotropic glutamate receptors [named for AMPA, the first powerful selective agonist of AMPA receptors] are perhaps THE main population of the glutamate-sensitive excitatory receptors in the brain. Sine qua non, the big set'o'cohones, so to speak.
Barbiturates also block this subtype of ionotropic glutamate receptor (the other two subsets being NMDA type (stands for N-methyl-D-aspartate, which recognize glutamate, or more weakly, aspartic acid, although NMDA receptors also require a co-agonist, the aminoacid glycine, to bind to an allosteric glycine recognition site (glutamate or aspartate both bind the orthosteric site, aspartate activates NMDA glutamate receptors more weakly than does glutamate). And lastly, the much less well understood KA receptors (short for kainate, a selective agonist for this population of ionotropic glutamate receptors, and again ionotropic receptors)
So with barbs, one has a set of GABAa agonist drugs that is not only more difficult, on a cellular and receptor level for the body to compensate for excess or overdose, AND, in addition to their exerting the inhibititory, GABAergic agonist effect, they block excitatory, AMPA receptor-type glutamatergic activity. Sort of like likening the part of the nervous system that is the brain and spinal cord likened to an amplifier, with a 'GABA' setting, increasing it to a higher GABAergic (agonism) value damps down overall activity, system-wide and one marked 'glutamate' which does the opposite (an agonist is excitatory), the more one turns up the glutamate dial, the more activity there is.
So by turning the glutamate dial right down and the GABA dial right up, one is doing as much as one possibly can to mute the eventual note when the string of a plugged in guitar is plucked, turning up the 'more quiet' signal and turning down the 'more loud' signal. If that makes sense. Its a bit of a crude analogy that only shows the basic overall effect on CNS tone, but it fits. Could just as easily have likened it, I suppose to both whispering, and having the listener put ear-defenders on at the same time.
So the barbs have a real one-two punch of an effect, across both inhibitory and excitatory competing systems.
And just because they are real beefy heavyweight sonsofbitches like that, at higher end doses, barbiturates can also directly open the GABAa receptor chloride channel, in the absence of GABA binding.
Added all together, stuck in the oven and baked for half an hour and all you need do is serve with two scoops of chocolate ice cream for 'fucking staggering, bouncing off the walls shitfaced of a depressant sedative-hypnotic, anxiolytic and anticonvulsant'
Part of the reason they got pulled from the market for the vast majority of use indications, is the danger of overdose, they are as good at killing people in OD as they are at doing what it says on the tin, so to speak, in either clinical or recreational doses.
But not all, their recreational potential had a lot to do with their demise, or almost-demise too. Essentially governments going 'we can't let people have these, they will enjoy them too much'. I shit you not.
In the UK, aside from the crappy (in recreational terms, really, really crappy, really really long acting too) phenobarbital (same as phenobarbitone,depending whether you are in the US or UK, some suffix the names with -XYZbarbital and with the other region its -XYZbarbitone, I forget which way round it is), and for surgical use by anaesthesiologists in hospital, IIRC the only one available is seconal, secobarbital, and that is on a named-patient basis, you'd have to be specially approved as a patient to receive it, and no pharmacy would stock it, they'd have to order it specially on that basis.
Plus the chance of actually GETTING that to happen, from any doctor, for insomnia or anxiety, forget it. About as much chance of that happening, as there is of father bloody christmas bringing me my own transnational borders-sized suite of proton/antiproton accelerator and heavy ion accelerator suite and dedicated nuclear power plant just for me personally, and the government to just offer me as much plutonium or uranium fuel as I feel like asking for, when I feel like asking for it. Plus the lead pigs for the fuel rods to come lined with gift-wrap and tied off with a little red satin bow.
Only reason I ever managed to try other than phenobarbital (shitty, shitty, as in actively shitty not just lackluster shitty), was that barbital itself, (as is phenobarb IIRC but I lucked out selection wise in that respect) is used as a PH buffer in genetics/microbiology labs, and I had a contact who could easily and safely grab about 30g with it not being missed, and offer him something he couldn't get in return. Something I thought, honestly, really shitty, phenergan, OTC here, not where he is, although its a dopamine receptor antagonist, strong sedating antihistamine as well, but essentially an antipsychotic (phenothiazine typical antipsychotic with very very very weak potency), but, he knew what it was, and I in no way deceived him, but when he asked for that in particular I didn't refuse him either. He knew what he was getting and how much, and seemed happy to get just that, despite my pretty much feeling like he was being massively short-changed. Almost to the point I didn't like the trade in principle because it was so heavily weighted in my favour.
But, you can't really say its ripping somebody off if someone offers you gold bars in return for a handful of dirt, just because they happen to collect dirt samples from around the world, and they KNOW exactly what the thing they are asking for, and getting, is, can you?
Never look a gift horse in the mouth as they say, so I didn't. I sure as shit wouldn't ACCEPT the trade he did, let alone ask for it, in reverse, fuck no, not in a thousand years of sundays would I fuck! but hey, someone offers me gold in return for yesterday's newspaper soaked in piss and spit? they can have all the piss and loogie-soaked out of date tabloid second-rate-bog-roll newspapers they want. Not my problem if some people just have strange desires. If its what they want, why not let them have it
Weird as hell, but people are entitled to be weird. Just as well for me they are too, what with the whole being a spazz and all.
Otherwise, I'd never have gotten to try any of the barbs, unless I were to do the work myself and make them for myself. Although I never have done it personally, I gather the synthesis isn't difficult. Wouldn't mind trying sometime, try some of the short-intermediate duration ones with a real reputation for being recreational as hell.
Its one of those things that is pretty appealing, and that I could certainly manage, but that for whatever the reason, I haven't actually gotten round to it before. And I don't know why, either. Nothing specific I can pin down as an active reason NOT to run up a batch of seconal, or amytal, only 'haven't got round to it because there are other things that want me to get round to them as well, and I only have one pair of hands'
Kinda odd really, because even long-duration barbital was fucking nice stuff (I do mean barbital itself here, not phenobarbital, which is fucking shit unless you need it for seizure control), and barbital is more or less the cheap cider next to the bum-wine and prison inmate-export pruno special brew in the local off-license, were they yet at the stage of fucking prohibition off sufficiently to serve the mind-altering things people want in stores suited for the purpose. But relative to other barbiturates, that is. sedative-hypnotic-wise, it is quite outstanding, same as a recreational. Certainly far better than any benzo I've ever had or that anyone is ever likely to invent.
