Gaba b agonist dont do anything?

[Dtresearch17]

i always heard GHB a gaba b agonist was a pleasant downer, so when i heard phenibut and baclofen shared pharmacology i had to see what they did. but i feel absolutely nothing but sick with even 150mg of baclofen or 5gr of phenibut. is ghb special or something? or is there just something weird about me? why would GHB be fun if these drugs are so worthless

 

[sekio]

GHB is more than a selective GABA-b agonist, it also activates the GHB receptor.

 

[Solipsis]

^ Which is what considered to be what gives it the fun, stimulating action at low-moderate dosages. At higher dosages it becomes less specific and also starts acting on GABA way more, and while some mild drunkenness can go nicely with it - the stupor at higher doses is hardly what makes it interesting.

So no, the pharmacology baclofen shares is not quite what makes GHB nice, and phenibut doesn't even primarily act that way but rather as a gabapentinoid like pregabaline or gabapentin. Although 5 gram is so much that yes you would also start to see GABAergic effects... but it is not surprising it gets disgusting - it is not how it is mostly meant to act.

 

[Limpet_Chicken]

Personally I found phenibut pretty disgusting no matter what the dose was. Granted I didn't try for example, baclofen dose ranges. But it was nasty stuff, gives me a strong mental image of a kitchen-slops waste bin, left with the lid open on a hot summers week (or two), full of rancid meat, rotting boiled cabbage, bits of creamy slime of origin indeterminate (and best not to try), covered with a swarm of fat, bloated buzzing flies busily feasting away.

Mixed with the aftereffects of a just BARELY sub-hungover morning after a binge on really cheap and nasty spirits. Methylated variety, possibly

 

[theGirlWithBlueHair]

Did you jump straight in at those dosages? Damn. You would have wanted to take like 40mg of baclofen at first and 750mg of phenibut, to test it out. That is ridiculous amounts of both...

The GABA B receptor is what gives it is "Liquid ecstasy" name - which is why baclofen, gabapentin, pregabalin, and phenibut, have all been compared to MDMA itself. It's not just the GHB receptor that gives it recreational potential.

If it was the GHB receptor... why aren't we seeing a whole bunch of GHB agonist analogues on the market as recreational drugs? but instead we are seeing GABA B agonists?

 

[theGirlWithBlueHair]

This explains that it is the GABA B and NOT the GHB receptor that is responsible for the recreational effects of these drugs:


[h=2]RGS2 modulates coupling between GABA_Breceptors and GIRK channels in dopamine neurons of the ventral tegmental area[/h]
Agonists of GABA_B receptors exert a bi-directional effect on the activity of dopamine (DA) neurons of the ventral tegmental area, which can be explained by the fact that coupling between GABA_Breceptors and G protein-gated inwardly rectifying potassium (GIRK) channels is significantly weaker in DA neurons than in GABA neurons. Thus, low concentrations of agonists preferentially inhibit GABA neurons and thereby disinhibit DA neurons. This disinhibition might confer reinforcing properties on addictive GABA_B receptor agonists such as

-hydroxybutyrate (GHB) and its derivatives. Here we show that, in DA neurons of mice, the low coupling efficiency reflects the selective expression of heteromeric GIRK2/3 channels and is dynamically modulated by a member of the regulator of G protein signaling (RGS) protein family. Moreover, repetitive exposure to GHB increases the GABA_Breceptor-GIRK channel coupling efficiency through downregulation of RGS2. Finally, oral self-administration of GHB at a concentration that is normally rewarding becomes aversive after chronic exposure. On the basis of these results, we propose a mechanism that might underlie tolerance to GHB.
http://www.nature.com/neuro/journal/v10/n12/full/nn2006.html

If you, they say it has a bi directional effect, which explains different effects at different doses as it inhibits different neurotransmitters.

 

[Limpet_Chicken]

First time I took baclofen it was prescribed for muscle spasm due to nerve damage, 10mg I forget which, either BD or TDS. I can't really compare anything with baclofen as I barely respond in any way to it, orally at least, never tried the spinal route, the problem doesn't warrant it and I don't want it in any case. But the only effect I ever get, is crappy, nausea and slight ataxia, and even then only in the dose range from several hundred mg to about 500mg. Doesn't change much, doesn't do anything else whatsoever. Goes from nothing, to almost nothing and what there is, not pleasant or rewarding and then stays at almost nothing, but slightly crap.

Switched to tizanidine, which is lovely stuff, works a treat for the muscle spasticity, combines even better than clonidine does (I take both, the other to stop me getting overloaded) with opiates, and works pretty well for getting to sleep.

 

[theGirlWithBlueHair]

^Limpet_Chicken, I was on tizanidine before baclofen, and I agree with you, tizandine is an excellent muscle relaxer! Have you ever noticed any of the psychiatric side-effects that they seem to say are quite common with this alpha agonist - even more so that with clonidine, ie hallucinations, strange thought patterns, introspection.

I've gotten some NMDA-type CEV's from them some times along with some pseudo-psyschedelic introspecitivness on a couple of other occasions at bedtime when watching tv... That's about it. But I've read that it can cause quite vivid hallucinations otherwise as well.

I've never read of this occurring with clonidine. Do you think this might be because tizanidine does induce the marked hypotension at equipotent dosages that tiazanidine does? Tizanidine is great for sleep though, as you said, and feel remarkably similar to an opioid if the dose/ROA is correct.

Have you ever taken any other GABA B agonist?

 

[Limpet_Chicken]

I have taken GHB, and phenibut. And yes phenibut is foremost an agonist at alpha2delta type VGCCs, but it does have moderate affinity for GABAb, Other than that, thats it.

I daresay after the lackluster effects from the above, hunting the lit for, and attempting design of new GABAb agonists, it has never been a priority to make a project of synthesizing and testing a series of different GABAb agonists. The incentive is just simply not there. Maybe some day I might but only if I run out of things I WANT to do, and simply have to find projects to work on for the sake of my sanity, and of sating The Hunger.

As for clonidine, I take both tizanidine and clonidine, the former being for myorelaxant effects, which conversely, seem lacking in clonidine until one gets to doses where hypotension results in my being unable to move. The clonidine I take to suppress my tendency towards overloading. Works pretty well and helps counteract the physical, central overstimulation that is one of the few downsides of being 'severely' (LMFAO!) classically autistic. Whilst the term 'severely autistic' is to me and many many others of my kinsfolk, disgusting, and the type of fucking poisonous language that sperm-gargling knobmongrel fuckwit whoreamuffins such as the despicable, repugnant and vile autism squeaks and their filthy affiliates like 'DAN' and 'CAN' (defeat/cure autism now), not to mention curebie trash in general love to vomit forth like foetid, stinking slime squirting from a rupturing pus-filled cyst buried within an oesophageal tumor, I find that it funny as hell when selfapplied in sarcastic manner, but coming from THEM it is just one more gout of putrescent slop that should be taken for what it is, derisive, loathing-filled propaganda in dire need of being stomped on with my pair of heavy steel-toed combat boots.

The tizanidine seems less hypotensive than clonidine at an equipotent dose, its shorter acting but effects more profoundly myorelaxant and sedating. And indeed it can provoke something extremely akin to an opioid nod, including the nodding in and out itself, the semiwaking dreams and hallucinations as are provoked by MOR agonists. Combined with opioids its even better, as these of course add in the euphoria to the mixture. Love tizanidine, especially plugged or snorted. Fucking great stuff. I'd LOVE to try dexmedetomidine and xylazine.

As for combination with opiates, I'm just on a combination of some tizanidine with an IV shot of prope-dope as well a little chlormethiazole.

Turning out very pleasant indeed.

 

[theGirlWithBlueHair]

chlormethiazole. sheesh. I don't see how that's still available. lucky.

Do you notice a more "psychedelic" aspect to the tizanidine, though? I always found it reminiscent of dxm when I got those effects. Like the CEVs and the introspection though effects, more than an opioid's effects. The nod, though, goes to a narcotic, of course.

I would like to try xylazine too. I forgot about that one. I hear abuse of that is pretty big in some other countries. Fogot which one...Oh here we go...

http://link.springer.com/article/10.1007/s11524-011-9662-6

 

[Limpet_Chicken]

Neither do I really.

Except for one reason and one only. Uniquely as far as I am aware, amongst GABAa agonists chlormethiazole has the additional property of inhibiting alcohol dehydrogenase. So it gets used in in-patient detox of alcoholics who need measures in their treatment which do not count fucking about with crap like Z-drugs, and most benzos. I'm not an alcoholic, so thats not the reason I use it. I take it for seizure prophylaxis, although it is not first line for seizures in the BNF, indeed I checked my copy and its..no-line, actually

But somehow I ended up taking it, at first twice a day although just persuaded my doc to give it three times daily. Its intermediate-acting, got some funky properties physically (the freebase at least, I've never tried making it in salt form, nor bromethiazole) it eats plastic like a starving concentration camp victim or war refugee with a pair of leather shoes, remarkably aggressive, welds plastic containers shut, or melts right through them. In fact even the pharmaceutical variety coming in capsules, which is the freebase, if left out on susceptible plastic surfaces will burn dents into the surface. Had an old computer keyboard, now afaik defunct and gone, but had left a pair of heminevrin caps on the top, and when I came back for them then I found that they had eaten their way into the keyboard and welded the cap outsides to the plastic. I had to stick in a syringe with a wide-bore needle, withdraw the contents and then QUICKLY dilute it with alcohol, shake it up into an suspensio then evaporate the alcohol before plugging the chlormethiazole base, emulsified with a bit of water.

Its somewhat volatile, as the intermediate thiazolethanol from the bisulfite/metabisulfite cleavage of thiamine (vitamin B1) seems to be (this seems active as well, to a degree at least. It stinks something heinous, and its of far lower potency than either chlormethiazole or bromethiazole. But, not inactive. And whilst crystalline it effloresces slowly and if stored in the open will slowly but steadily creep up and away.

Other than its use in alcoholics, almost the only indication is for elderly people for short term insomnia treatment. Its extremely clear-headed, no hangover that I have ever noted, and at least in my case, for seizures it is top notch, and not to mention I have been really quite astonished by the benign tolerance profile. Doubtless withdrawal from physical dependency would be horrific, as most GABAa agonists are. This one is a barbiturate binding site agonist at GABAa, so alcohol kinetics aside (its also very, very dangerous to drink on, especially if unused to it, and even then, small amounts only, take slowly if your going to drink at all) I am pretty amazed, in this day and age of filthy rotten Z-drugs and the weakest benzos available being first line for any benzo, that its still around. Even my GP, he commented when reminded that was what I am taking, when I needed a small dose increase (from twice to 3x a day), something like 'shit, that is a VERY old drug, almost surprised its still in use. And at that, the guy must be 70-something, certainly over 65, maybe even older. Close to retirement and afaik it was fairly antiquated when he started. And not indicated at all for seizure prophylaxis or treatment in the UK.

But, I'm on it already, however so, it works great, has a kick like an pissed off cassowary. Sod all hangover, seems like a low dependency-tolerance induction drug, and great for the seizures. Also, unlike the benzos, it actually can RELIABLY get me to sleep. Recreationally it needs only two notes of caution, bar the obvious do not mix with depressants or opioids unless already used to them. I take either a bit less than 0.5g morphine for my doses per day, plus a smaller amount of oxy, or else it is......replaced....with dipropionylmorphine, as, well its just superior for one and I like it better than almost any other opioid I've ever had. Plus it lasts a LOT longer. Nice sexy pair of legs on that girl, thats for sure. Long ones too


I'll have to reexamine tizanidine in that respect.

(actually I JUST found a full strip of 4mg zanaflex, and took a break from my work for a while lest it (plus a half bottle of DXM cough syrup) K.O me while actually working. That would not be pleasant. Can't afford to lose my project, and nor do I wish to be covered in corrosives again (in fairness those incidents happened when I was either pre- or just entering my teens, but still, the things that did it, don't take prisoners, even through leather gloves in one case).

Just had 16mg zanaflex, plus enough DXM to get my leetle grey cells booted up correctly, and a little DPM in order to keep the wolves at the door busy with pissing all over somebody else's front lawn. Lets see where this goes (tizanidine dosed orally)

Theres another commonly used adrenergic autoreceptor agonist in common medical use, lofexidine, used for assisting with the misery of opioid withdrawal/detox. Never had it though.

Guanfacine in particular is one I've really wanted to try out, as its meant to have nootropic potential. It isn't used clinically here, but when I have enough saved for my next cycle off life-giving memantine then I think I am going to look for it in the same place I'd get my memantine. I've wanted to give guanfacine a shot for ages.

The thing that puts me off DIYing these clonidine analogs is due to how insanely potent many of them are by weight.

For ex. with clonidine the dose per tablet is 25μg, and given the hypotensive effects it would take very little to drop somebody to the floor.

4-NEMD is a military-grade alpha2 adrenoreceptor agonist, developed as a nonlethal weapon. Could be interesting in carefully metered doses. I for some reason, love adrenergic autoreceptor agonsts. Could eat/plug the tizanidine for breakfast.