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Why is zolpidem so different cmared to other benzo's?

Memantine

Bluelighter
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May 16, 2015
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I've been on benzo's for years. None of them make me high anymore except zolpidem.

When I take 60mg rectally it hits me within 3 minutes and in 15 minutes I'm in a full blown delirium with serious delusions and shit. I start talking to objects and it feels like there are people around me even if i'm alone. It's not like mushrooms but more like a deliriant/dissociative I guess.

The only thing I experience from an OD on regular benzo's is amnesia. So what makes zolpidem so much more powerfull and different?
 
zolpidem isn't a benzo. Its a GABAergic positive allosteric modulator that works in many ways similarly.

Subtype selectivity is likely the reason.

Anyone know if it has any affinity/efficacy at the loreclezole binding site? From my experience with zolpidem, again, weird shit, amnestic as hell and dissociative in an odd kind of way, not like an NMDA antagonist, more akin to fly agaric (muscimol) in my opinion, muscimol being a GABAa orthosteric agonist primarily (that is to say, it binds at the GABA binding site itself), does zolpidem do so at all? because Amanita muscaria is the drug that zolpidem most reminds me of. Or valerian, after falling asleep, whence it induces the most astonishingly vivid, intense and often lucid dreaming in me, although this effect is subject to a most profound tachyphylaxis, being very much diminished the second night in a row of high-dose valerian extract, and AFAIK the GABAa modulatory active compounds in valerian and its extracts are agonists at the loreclezole binding site.

Never had loreclezole, but its one of the drugs I'd most like to try, to see if it does anything similar to valerian as an oneirogen. Have inquired on BL as to this drug, but nobody at all has ever provided any feedback to this potentially most interesting drug. Certainly, an intriguing and alluring drug, I've wanted to try it for years.
 
Zolpidem is a full agonist at gaba a a1 and a5 receptor subunits benzo positivèly allosterically modulate gaba a a1a2a3a4a5 via the benzodiaz receptor
 
Not true, it is potent at alpha1 (alpha1-gamma interface specifically) which is considered responsible for the hypnotic effects but much less at alpha2 and alpha3 and the others even less (or pretty much not at all) so no not alpha5. Because of this selectivity it doesn't really have much of the other effects benzos can have. Benzos however can on occasion produce hallucinations of the kind, but usually the balance between effects would not favor this at all. I guess sedation and other kinds of depression prevent it.

Alpha2,3,4,5 don't even occur on the same sort of GABA A receptor as alpha1 so it means that zolpidem lacks quite a bit of the effects of benzos, how much depends on the benzo you compare with but hardly any are selective like this. Pyrazolam seems relatively selective but differently, I believe for alpha2.
 
^This, because of it's high selectivity for the alpha 1 subunit of the BZD complex on the GABA A receptor.

Benzodiazepines are dirty in regard to their binding affinity because they tend to bind to every BZD subunit without much selectivity (they do - but not to the extent the z-drugs do) except the hypnotic benzodiazepines like temazepam which are relatively alpha 1 selective as well, but nowhere near as much as the z-drugs, such as zolpidem, zolpiclone, and zaleplon.
 
I agree with solipsis after rereading. Zolpidem doesnt bind to gaba a a5
 
I bet not as selective as pyrazolam? Otherwise I don't understand why pyrazolam is zero recreative while alprazolam is nice stuff. Haven't checked the numbers.
 
´Alpha2,3,4,5 don't even occur on the same sort of GABA A receptor as alpha1´ Seriously ?

Not just different subunits, but different receptors ?
 
https://en.wikipedia.org/wiki/GABAA_receptor#Subunits

Five subunits can combine in different ways to form GABAA channels. The minimal requirement to produce a GABA-gated ion channel is the inclusion of both α and β subunits,[24] but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α1β2γ2)

I'm not sure if they call it different omega types anymore - there is something outdated about the nomenclature, but yes. The alpha1 containing type is considered a different omega type (i think omega 1?) and exists mostly in the brain while another type (omega 2?) with alpha2,3,4,5 mostly in the spine.

Obviously with many isoforms with different behaviors, roles, subunit makeup with the benzoids affinity it is a complex matter, but I just meant that it seems especially different (zolpidems selectivity) if the type in question has a significantly different distribution in the CNS...
 
^Apparently they renamed that peripheral benzo receptor "translocater protein/TPSO" or something, I think it's a neurosteroid site as well but still a target of benzos.

IIRC, a1 is largely expressed at the axon-hillock
 
I bet not as selective as pyrazolam? Otherwise I don't understand why pyrazolam is zero recreative while alprazolam is nice stuff. Haven't checked the numbers.

I'm not aware of literature finding pyrazolam as non-abusable, or near non-abusable. No time to research.

If wikipedia is to be believed, it appears that xanax may induce antidepressant effects due to strutural similarity with the tricyclics, and that it's a DA releaser. That it has antidepressant effects, I believe is substantiated.

^This, because of it's high selectivity for the alpha 1 subunit of the BZD complex on the GABA A receptor.

Benzodiazepines are dirty in regard to their binding affinity because they tend to bind to every BZD subunit without much selectivity (they do - but not to the extent the z-drugs do) except the hypnotic benzodiazepines like temazepam which are relatively alpha 1 selective as well, but nowhere near as much as the z-drugs, such as zolpidem, zolpiclone, and zaleplon.

I don't think differential binding to the benzo subunits explains how zolpidem can induce bizarre activity while asleep. For instance, one patient ate a whole tub of butter in their sleep, another drove their car for hundreds of miles...in their sleep.
 
I bet not as selective as pyrazolam? Otherwise I don't understand why pyrazolam is zero recreative while alprazolam is nice stuff. Haven't checked the numbers.

Pyrazolam is definitely abusable. 1.5mg (without tolerance) made me feel extremely intense euphoria.
 
if i take zopiclone for the first time - is there a possibility I will have a "hang over" effect tomorrow?
 
I don't think differential binding to the benzo subunits explains how zolpidem can induce bizarre activity while asleep. For instance, one patient ate a whole tub of butter in their sleep, another drove their car for hundreds of miles...in their sleep.

Why couldn't differences in selectivity be responsible? Given the effects of muscimol, there is obviously a population of GABA-A receptors that can seriously disturb consciousness when activated.
 
I did think that the selectivity would be responsible (I mentioned thinking at least that absence of the common sedative or amnestic benzo effect to be necessary as not to suppress dream-like experience - I mean you do tend to dream less on them don't you?), but the mention of muscimol complicates things: it is selective for GABA A but not allosterically and it doesn't seem like it has selectivity beyond that? Obviously it is atypical for a 'depressant' but if the non-selective muscimol has high hallucinogenic potential then how is selectivity a good explanation?

@john Zopiclone does last longer than zolpidem, unlike zolpidem which can be just about gone in the morning zopiclone can still be a little bit active but that is not the same as a hangover. In my experience there isn't much of a hangover with z-drugs with limited experience. Zopiclone tastes like robocop took a shit in your mouth though for a lot of people (perhaps not purely due to taste but dysgeusia or the drug passing through the tongue like DMSO, not sure, but it doesn't depend on the drug actually having been on your tongue).

Maybe finding pyrazolam uninteresting for abuse is just relative and from my own findings, I don't claim anything beyond that. People abuse phenazepam too which is beyond me because it mostly makes me feel like a zombie but nothing pleasant otherwise. Pyrazolam literally only relaxes me and not even physically like forced skeletal muscle relaxation.
 
but the mention of muscimol complicates things: it is selective for GABA A but not allosterically and it doesn't seem like it has selectivity beyond that? Obviously it is atypical for a 'depressant' but if the non-selective muscimol has high hallucinogenic potential then how is selectivity a good explanation?

Because of the nonselectivity of benzodiazepines, there is probably a ceiling on the range of benzodiazepine doses that people will tolerate. Alternatively, non-alpha1 subtype-mediated effects could suppress alpha-1 mediated effects.
 
Perhaps atypically, whilst I am not a huge benzo fan, I find the nitrobenzodiazepines and nitro-substituted triazolos can make me do weird shit whilst semi-conscious. I've even done things like (albeit less competently than sober) involuntarily, without making a conscious decision, found myself many hours after taking nitrazepam, having donned a gas mask, fitted fresh filter canisters to it, put on goggles, elbow-length gloves and strapped on a blast shield to my face, finished a synthetic project of the time, although damned if I can remember exactly what it was. General idea but could be one of around three things. I woke up with my work done for me, nothing but a couple of flashes of memory of being in the room, everything cleaned up, and me having flopped down on the sofa, still wearing my shoes, still wearing the gas mask, face shield goggles and gloves, the gloves having been washed, face shield wiped down, and dried off. I could tell because a few streaks of tarry shite were gone from the clear part one looks out from.

I'd obviously finished the project, done the workup, cleaned everything up and put the nastier reagents (acylating, alkylating agents, SOCl2) out of the way where they couldn't get knocked over and the bottles broken, and set the finished article out to dry with a cold airstream from a hairdrier aimed at the solution of product in solvent, with the fans on, from a distance, with the product in a mortar and pestle, sans the pestle, left, and gone to grab a quilt, snuggled up on the couch using a cushion for a pillow with the quilt and a coat over my face, still wearing the safety gear and before going to sleep stuck 'kerrang' channel on the TV, obviously taken an opioid of some kind before hitting the deck as I didn't wake up in withdrawal.

Then woke up to find my work done for me as if the bloody benzo-fairy had paid a visit and had all the work do itself by magic.

Not the first time thats happened either. I remember a birch type dissolving metal reduction, or rather, remember one done, without any intent to do it or remembering doing it, but being the only one around capable of its being done, again, nitrazepam (10mg) after also taking my usual chlormethiazole dose. I woke up that time after finishing and walking into the corner post of a closed door:p


Perhaps some resistance to the sedative effects courtesy of my using (assuming nothing unpleasant actually getting past the daily prophylactic dose) chlormethiazole, for seizure control, since I take it every day (its a barb site allosteric GABAa modulator, that lacks the glutamatergic antagonism of barbiturates, its like a very very clear-headed, much shorter acting version of veronal. Only thing like it closer I've had is bromethiazole, which is pretty much the same drug, with the chloroethyl group of chlormethiazole swapped for a bromoethyl. Not used clinically, but pretty much the same. Apparently slightly or somewhat less stable than chlormethiazole, according to the one reference I've ever seen to it, dating back from the 1930s or thereabouts, but I've never tried storing bromethiazole, its always been used on the same day or within a couple of days of its being available as the freshly made compound.

But if the theory of a 'ceiling effect' due to the sedative effects of benzos counteracting what otherwise might be fairly similar to zolpidem, if that is the case, then maybe the benzo fairy had me tripping in a manner of speaking those times.

I've heard of having a midnight snack...but a midnight birch reduction or midnight acylation/alkylation/halogenation................that is a new one on me, and then some. Or at least, any of the above when not 100% awake and motivated by conscious decision and waking up to find a wand waved over the equipment and the whole thing done by an unfelt, unseen and unremembered hand, it was a fair mite disconcerting, needless to say, a bit of a double-take moment of, well, shock. It'd have been one thing to have dreamed the entire thing, and it not ever happened, but to find such a multi-step relatively speaking complex task performed whilst not behind the steering wheel was a headfuck to say the least.

I've taken nitrazepam before plenty of times before getting on the chlormethiazole, and its only ever happened since I've been taking the latter.

I should add, that I have a long and fairly extensively experienced history of using muscimol, in the form of cured A.muscaria, and I've never, ever done anything like that. I've tripped my arse off in a zolpidem-esque kind of way, although different from that drug, both with and without using chlormethiazole at the same time. Its always been, when taken at a sedating/psychotropic dose, rather than at medicinal levels (I use it to inure myself to the discomfort of cold, in the form of tea, made from the very gently heat-dried mushroom caps, simmered in hot water until golden-amber in color, and the room smells like the taste of meat strong as hell (really..its odd..fly tea will when prepared, make the entire room smell like what really good steak or beef stew tastes like) or when just added, as I often do, at sub-sedative levels to a cooking meat-based meal. (I use it especially in chili con carne, stews, casseroles, and in combination with peppery boletus, a cardamom or two, cubeb (Piper cubeba, the dried seeds, a relative of black pepper but that tastes cooling and camphoraceous without heat), just a few, too much overpowers the rest of the spices, dried birds-eye chilli peppers, black pepper, pink peppercorns and szechuan pepper (a weird ass spice if ever there was one, camphoraceous-like, not hot, but with a numbing, or in concentrated form, almost paralytic-feeling effect upon the mouth), dried powdered onion and dried powdered garlic flakes, all whizzed up together in a spice grinder, because the peppery boletus (Chalciporus piperatus) especially is not a mushroom that is willing to crumble, even when dessicated thoroughly over NaOH in the dessicator its still resistant to powdering with a pestle and mortar. And the pink peppercorns are very oily.

And when/if I can get any, water pepper, that bistort relative, I forget the binomial name, but a relative of bistort, grows in marshy areas or more often close to riverbanks, spear-shaped light green leaves and pink flowers that grow in tight, long clusters, has a fiery biting sharp heat to it when a portion of leaf is chewed and the juice allowed to contact tongue or lips. That is somewhat of an uncommonly available spice though, but if I'm lucky enough to find it, for I don't think it can be bought, then that too, is added, and the powdered mixture added a couple of dessert-spoons full per cook-pot of stew, chilli etc. when making enough for perhaps two people and three days of eating.

And mixed to a paste with H.P sauce or Daddie's sauce, devil's brown sauce or whatever kind of brown sauce is available, some of the habanero pepper variant of tabasco sauce (about a teaspoon per side of a slab of steak, don't be shy, its meant to have a kick to it:)) some dark soy, worcestershire sauce and perhaps a splash of teriyaki marinade, and some EtOH extract of freshly crushed onions (I want the flavour but despise the texture, autie sensory nightmare. That slimy and crunchyness at the same time...bugger me, that is way beyond disgusting. The thought makes my skin crawl typing of it, having the thought brought into my mind. Foul doesn't even come into it. Ew.EW. *shudders*

Thats how I use it as steak spice, sprinkled into the sauce mixture/onion extract and rubbed into a steak with slashes cut into the surface cross-hatched in order to absorb as much sauce and spice-paste as possible, after marinading in soy, worcestershire and more tabasco sauce for a while, then given a light brush of oil to seal in the flavour, both sides rapidly seared then the heat turned right down and slow-cooked until well done but nevertheless tender and well-done, full of juice and impossible to not have seconds or thirds. The fly agaric really makes it something special, turns a good steak into the crack cocaine of meat, assuming one were to recrystallize and purify the coke, before basing with NH3/EtOEt. In other words, you WILL go back for more. The first time. Any time after that you'll make more to begin with so you can go and have second or third helpings without any fuckabout cooking, and just dive straight into another plateful of steak ala limpet chicken=D
 
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Styx bloody well take it, I want a steak ala me now.

I think I'm about to try a bit of that spice blend on a cheeseburger now. The thought of that is making me really REALLY hungry. Try it folk, I don't think many people who will eat any food with spicy heat at all will be disappointed. Although it does pack quite a roaster of a punch. The fly agaric I believe, due to traces of ibotenic acid left behind after the curing, is acting as an agonist of the 'umami' taste receptors, that sense glutamate naturally, and contribute the savoury taste sensation. I might be wrong, but thats my theory at least. Mycological MSG. Right, or wrong, what I do know is it works damned well, and I'm about to go chow that burger, but add some of my steak spice to the cheese slices while I nuke it.
 
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