Opioids and GABA-B agonists

[Jaw Clenching]

Does anyone have any info (official or anecdotal) with regard to opioids and GABA-B agonists such as Phenibut and Baclofen.

It pretty much always seemed to me that all drugs with some kind of sedative action potentiate opioids. Alcohol, sedative antihistamines, benzodiazepines, barbiturates, GHB, etc.

If I can find and organize the info I'll post it but it seems like drugs like Phenibut and Baclofen may not be the best things to be taking, especially if euphoric effects are being sought. I saw some info showing the pathway from the mu opioid receptor -> GABA -> dopamine as responsible for the primary pleasurable effects of opioids. It seems like GABA-B agonists would interfere with this pathway and negate a lot of the feel-good effects.

Now this is not to say GABA-B agonists don't potentiate other effects of opioids. I saw separate info talking about possible increase in pain killing effects and reduction in nausea / vomiting.

The possible interference with the rewarding effects of dopamine would make sense as to why some GABA-B agonists are being looked in to as treatments for various drug addictions (which dopamine usually plays some sort of role).

Thoughts or info?

 

[P A]

Baclofen Inhibits Heroin Self-Administration Behavior and Mesolimbic Dopamine Release

1. Zheng-Xiong Xi1 and
2. Elliot A. Stein1,2,3,4

+ Author Affiliations

1.
Departments of 1Cellular Biology, Neurobiology, and Anatomy (Z.-X.X., E.A.S.), 2Psychiatry and Behavioral Medicine (E.A.S.),3Pharmacology (E.A.S.), and 4The Biophysics Research Institute (E.A.S.), Medical College of Wisconsin, Milwaukee, Wisconsin

Abstract

An emerging hypothesis to explain the mechanism of heroin-induced positive reinforcement states that opiates inhibit γ-aminobutyric acid (GABA)-ergic interneurons within the mesocorticolimbic dopamine (DA) system to disinhibit DA neurons. In support of this hypothesis, we report that the development of heroin self-administration (SA) behavior in drug-naive rats and the maintenance of SA behavior in heroin-trained rats were both suppressed when the GABAB receptor agonist baclofen was coadministered with heroin. Microinjections of baclofen into the ventral tegmental area (VTA), but not the nucleus accumbens, decreased heroin reinforcement as indicated by a compensatory increase in SA behavior. Additionally, baclofen administered alone or along with heroin dose-dependently reduced heroin-induced DA release. This effect was blocked partially by intra-VTA infusion of the GABABantagonist 2-hydroxysaclofen, suggesting an additional, perhaps GABAA receptor-mediated, disinhibitory effect. Taken together, these experiments, for the first time, demonstrate that heroin-reinforced SA behavior and nucleus accumbens DA release are mediated predominantly by GABAB receptors in the VTA and suggest that baclofen may be an effective agent in the treatment of opiate abuse.

Pretty disappointing.

 

[someguy200]

Eur J Pharmacol. 1996 Jun 13;306(1-3):33-9.
The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism.

Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K.

Institute of Pharmacology, University of Ferrara, Italy.
Abstract

The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30-300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (beta-p-chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 microM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 microM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 microM), whereas it was increased by the GABAB receptor agonist (-)-baclofen [beta-(p-chlorophenyl-gamma-aminobutyric acid)] (10 microM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.

PMID: 8813612 [PubMed - indexed for MEDLINE]

Strange that modafinil and opiods would have similar inhibitory effects on the GABA system, but opposite responses regarding dopamine when GABA-B agonists are introduced.

 

[/navarone/]

I would simply go with benzodiazepines, Z-drugs or gabapentin/pregabalin.
IMO they mix pretty well however they can increase the chances of severe respiratory depression in high doses. Careful.

 

[P A]

Strange that modafinil and opiods would have similar inhibitory effects on the GABA system, but opposite responses regarding dopamine when GABA-B agonists are introduced.

Interesting, but I don't know about strange. The upstream mechanisms are entirely different and more-or-less unrelated, besides the eventual GABA-A involvement, one being an issue of regionally localized, direct presynaptic disinhibition, the other involving a poorly understood, roundabout process of electrotonic reduction and possibly some peptides.

gabapentin

Opioid potentiation? Respiratory depression?

I had no idea....how? The calcium channel blockade?

 

[Howard B Huge]

Be very careful with Phenibut.

It'll put you out, but it will leave you with a terrible hung over feeling the next day and even the day after as well as nauseous and disorientated.

I didn't get any euphoria from it or any "benzo" type of effect.
It did put me out for about 12 hours and left me feeling like crap for the next 48 hours though, so be very careful with this supplement.

 

[Mycotheologist]

I find it to be a good combo but phenibut is horrific in terms of tolerance buildup so I steer clear of it from now on.

 

[keeponkeepnon]

I had my first and only mental break while experimenting with Phenibut creepy stuff.

 

[Poodles!]

Polymath posted this in the GABA Receptor Antagonists thread...

The GABAB receptor as a target for antidepressant drug action

Preclinical and clinical data suggest that a modification in GABAB receptor expression and function may contribute to the
symptoms of major depression and the response to antidepressants. This includes laboratory animal experiments
demonstrating that antidepressants modify brain GABAB receptor expression and function and that GABAB receptor
antagonists display antidepressant potential in animal models of this condition. Clinical and post-mortem studies reveal
changes in GABAergic transmission associated with depression as well as depression-related changes in GABAB subunit
expression that are localized to the cortical depression network. Detailed in this review are the preclinical and clinical data
implicating a role for the GABAB receptor system in mediating symptoms of this disorder and its possible involvement in the
response to antidepressants. Particular emphasis is placed on clinical and post-mortem studies, including previously
unpublished work demonstrating regionally-selective modifications in GABAB receptor subunit expression in brain samples
obtained from depressed subjects. Together with the earlier preclinical studies, these new data point to a role for the GABAB
system in major depression and support the antidepressant potential of GABAB receptor antagonists.

Could this mean that GABA-B antagonists can be used to potentiate? At first I was thinking that it could be the answer to the debate about using opioids as antidepressants like in this thread... but there's probably a lot more to the AD action of opioids and traditional AD's that affect the opioid system than just this.

 

[AlphaOdure]

Pretty disappointing.

..I wouldn't say "disappointing"- sure; in mice this study implies that baclofen's interaction with DA causes less reinforcement & thus may not potentiate someone's dope (a little off course from harm reduction, though.. eh?).. but this could be a potent aide in addiction medicine. As i know YOU know by a certain post I read a while back--in which you chimed in on; you made some remarks on the pharmacodynamics of baclofen & its relation to addiction & GABAergics.

Anyway, my experience w/ this is as follows: I am on 4 mg of buprenorphine (suboxone formula) & ~1500 butalbital (an intermediate-to-short acting barbiturate) per day. I started baclofen therapy to originally assist in reducing butalbital intake. It helped moderately: at doses of 30mg-40mg per day of baclofen I was able to reduce down to 1100-1400mg of butalbital. (Side note: this is all in the past, due to baclofen's side effects & family members thinking I was using.. I have been manipulated into stopping all together. Although, I still take around 10 mg of baclofen for sleep).

Although, in regards to buprenorphine, I unknowingly dropped down my daily intake to 2mg-3mg within roughly 7 days! (it took me 1-2 years to drop from 7mg-8mg to 4mg w/o baclofen! ...Which is a similar percentage reduction, 25%-50% ) I just didn't "need" the suboxone & thus unwittingly started spacing out my intake of my daily doses of it (I divide my daily four milligrams into four or five separate doses to take throughout the day. One dose per day just doesn't cut it for me; the feelings of opioidergic w/d in between doses just reminded me too much of using). Now, I don't get a high off of buprenorphine, nor do i use it for this purpose; so there was no intention or need to potentiate. But it certainly did not reduce buprenorphine's effects, at least in my experience.

 

[hollywood_cole]

here's one very anecdotal data point (and sorry in advance if this is off-base, my pharmacology knowledge is limited, and i'm assuming that ethanol and benzos each have at least some GABA-B activity):

anyway i haven't played with them all that much (though maybe more than i should), but i tend to enjoy mild low dose opiates (as so many people do). ~5 mg hydrocodone, ~3-6 g kratom (as tea), that sort of thing. the first couple times i mixed hydrocodone with a bit of GABA agonist (a couple drinks or 0.5 mg xanax), there was definite potentiation of the pleasant opiate effects.

however, doing the same on subsequent occasions was pretty much always slightly counterproductive: the alcohol or the xanax would end up dulling part of what i like about the opiate experience (a certain brightness and clarity was lost, for lack of a better description, though the warm fuzzy part of things was the same or enhanced).

strangely enough, though, i can have a drink or two (generally a couple beers or a little whiskey) with friends while we're on kratom, and i don't notice the loss. i can only guess that the gain in enjoyment from the social interaction in some way distracts from or makes up for what would be the usual loss of opiate effects due to benzo/alcohol consumption. so maybe it's better to think of that situation as (opiate) + (drinks with friends) instead of (opiate) + (alcohol). though i still wouldn't waste an opiate if i was planning on having more than a couple drinks, friends or no. and i can be a little asocial, so this has only been tried on a couple of occasions with pretty close friends, not sure what the verdict would be at a random party or something (though i can't imagine it'd be straight-up unpleasant).

MJ is pretty much always a welcome opiate potentiator for me, though these days i'll often wait until the first noticeable extended wave of effects has receded a bit before smoking. a cannabis edible and 4 g or so of kratom (or 5 mg hydrocodone) consumed simultaneously is always a very enjoyable combo. though i guess that's getting a bit off-topic for this thread.

 

[AlphaOdure]

i'm assuming that ethanol and benzos each have at least some GABA-B activity)

Ethanol & benzodiazepines do not have appreciable activity at GABA-b receptors.

& ethanol, barbiturates, & benzodiazepines all agonize GABA-a utilizing different mechanics, although they have the same and/or very similar end-all psychological effects, except for maybe ethanol/alcohol. For example, benzodiazepines bind at their own "type" of GABA-a receptor (BZP receptor).

If anything there may be indirect or secondary affect on GABA-a from GABA-b receptor agonists (albeit at a very low level). The pharmacology is complex to explain it.... I could reference a thread, where negrogesic references this pharmacodynamical action of GABA-b agonists; if you're interested, that is. (i've been a BL member for close to 10 years, & i've come to see negrogesic's posts are very reliable & informative, btw)

 

[hollywood_cole]

Ethanol & benzodiazepines do not have appreciable activity at GABA-b receptors.
...
I could reference a thread, where negrogesic references this pharmacodynamical action of GABA-b agonists; if you're interested, that is. (i've been a BL member for close to 10 years, & i've come to see negrogesic's posts are very reliable & informative, btw)

i stand corrected then, apologies for going a bit OT. any insight into the interaction i'm experiencing would be appreciated, though i don't want to derail the thread too much for the OP, so i could start a new thread or something.

and yeah, a reference to that thread would be much appreciated, i've lurked on and off here (esp in ADD) for the last few years, and i totally agree on your assessment of negrogesic's posts.

 

[AlphaOdure]

The thread has been archived, but here:
http://www.bluelight.ru/vb/archive/index.php/t-507251.html

& ok here is the quote from him (it is a long thread), referencing how GABA-b agonists may have minor effects on GABA-a... but still, GABA-a agonists don't have *any* (or negligible) cross-tolerance w/ GABA-b receptors. & remember, the GABA-complex is very, well, complicated... Even I don't understand all the nuances, functions, & mechanics of it (after 2 years of pre-pharm major, of course w/ a huge heroin habit at the time, i didn't quite prioritize understanding most of the material, heh)

Another layer of complexity comes from the interaction with both GABA-A and GABA-B modulators and their inhibition of endogenous neurosteroids (the 3-alpha-hydroxylated ones being the most potent modulators of GABA-A, like AP). From what I remember (don't remember where) benzos that are N1 substituted on the diazepine ring, or those that hare halogenated at R7 on the benzene ring (like some of the triazolo variants like alprazolam, estazolam etc) are supposed to be the most inhibitory in respect to these endogenous neurosteroids.

The interesting thing with drugs acting on GABA-B, like baclofen, GHB and presumably phenibut, is that they have been shown (like ethanol) to INCREASE levels of these neuroactive steroids like allopregnanolone and THDOC, which are primarily GABA-A specific. So even though drugs like baclofen don't directly modulate GABA-A, they cause increases in endogenous neurosteroids which are potent modulators of these sites. Perhaps long term use of baclofen could result in both GABA-A and GABA-B related withdrawal symptoms. NMDA and sigma receptors are probably somehow involved, not sure what the role. The point is, these actions are complex and not especially well understood.

 

[Hammilton]

Gabapentin will seriously reduce the effects of opioids. It prevents them from being absorbed, dropping the BA like 30%

 

[AlphaOdure]

Gabapentin will seriously reduce the effects of opioids. It prevents them from being absorbed, dropping the BA like 30%

...gabapentin isn't a GABA-b agonist. It isn't a GABA-a agonist either... Although, admittedly, from my own subjective experience, gabapentin's effects are ominously similar to higher doses of baclofen. Again, at least for me. But gabapentin had much less adverse effects for me. The first time I was Rx'd baclofen, i made the mistake of taking the prescribed dose, 20mg 3x a day- fine the day of, euphoria; decreased intake of butalbital; odd combination of stimulation & anxiolysis--the part very similar to 1200-2000mg of gabapentin (again, in my own subjective experience.. I think I have a sensitivity to both GABA-b agonists AND channel blockers like gabapentin). But the next 48 hours? Almost a psychedelic like feeling (after sleeping for about 16 hours) w/ odd & severe ataxia.. slowly giving way to vomiting every 2-3 hours; & put me into barbiturate withdrawal--from butalbital, which I am dependent upon--b/c I couldn't take it w/o puking it up immediately. (after I was 'stabilized' on butalbital, i reintroduced baclofen at 10mg doses.. slowly titrating up to 40mg/day.. before having to wean back down for personal reasons)

With that said, I did noticed decreased efficacy of buprenorphine (although taken sublingually, obviously) & butalbital. But in a good way, as in, I didn't "need" it... it didn't seem to literally antagonize it on the neurological level; but act on addiction via some unknown pathway (something baclofen shares... I think there is some unknown mechanism there; or at least, some unknown mechanism mediating addiction w/ GABA-b agonism). B/c I never experienced opioid w/d from suboxone or from butalbital, despite decreased efficacy.

As far as BA affecting opioids? I've never heard this? Do you have any abstracts/studies to reference?? It wouldn't surprise me though.

 

[Hammilton]

That was a reply to PA.

It's in the PI sheet. "The AUC of gabapentin may be increased by 14% while the hydrocodone C max and AUC are decreased by gabapentin in a dose-dependent manner. Observe the clinical response of the patient when starting, stopping, or changing the gabapentin dose. If an interaction is suspected, adjust the hydrocodone dose as needed."

 

[AlphaOdure]

That was a reply to PA.

It's in the PI sheet.

the PI sheet? Parke-Davis--gabapentin's manufacturer & the author of the PI-sheet--also got their ass-sued to shit over peddling the shit for conditions it was never approved for nor shown to have efficacy in treating. So yea, at least in regards to a 'disclaimer-type' sheet by a shady pharm company like Parke-Davis (well, I guess they all operate this way; here in the US at least.. some just haven't been caught), in this case, they don't strike me as a very reliable & factually-dedicated source (aside from reporting FDA mandated studies....).

So, I certainly wouldn't *solely* refer to gabapentin's PI sheet to prove reduced bioavailability is the reason why efficacy of opiates/opioids is afflicted. & mind you, even the generic formulas, of course, are based on the studies performed by the original patent-holder, i.e., Parke-Davis (why would pharmaceutical company X go out & spend millions of dollars on in vitro studies or double-blind studies, when they can just refer to the original ones?)

 

[AlphaOdure]

Not to mention- It was also originally claimed that gabapentin modulated GABA receptors; which we now know it doesn't, at least directly. Since I don't have the PI sheet, could you explain how they deduced gabapentin "decreased" the effects of opioids via affecting BA? From In Vivo or In Vitro research? Or just a clinical observation from double-blind studies? If the latter is true, how does this mean it is a function of bioavailability? ..And not a function of pharmacological interaction? Call me naive, but I don't know much on the pharmacokinetics of gabapentin.

Since I found similar effects & impacts on dependency/self-administration of drugs w/ gabapentin as i did w/ baclofen; I suspect its a neurological interaction, not a BA issue. In my experience gabapentin definitively reduced the effects of both barbiturates (& i'd assume other GABA-a agonists) & opioids... particularly butalbital & buprenorphine, respectively, in my case. But: First- I specifically took baclofen & gabapentin for this reason, to reduce self intake of these substances, so this "effect" wasn't a negative for me; Second- reduction of effects didn't result in withdrawal symptoms (which one would assume would occur if, say, gabapentin literally was an antagonist at opioid binding sites), but rather, resulted in a reduced psychological "need" of the drug(s)/medications. Thus, i reduced self-intake w/ no ill effect (although baclofen was more effective for this purpose; both these drugs seem ominously similar in their effects, in this way... as i previously said)- I just don't see BA playing any role here... or a very little role if that. But please, correct me (with sources) if i'm most obviously wrong.

 

[amanitadine]

As long we are running with probably worthless subjective descriptions of effects, baclofen has some very curious downstream drama that I associate with a certain type of "pure" DRI. I take 60-120 mg of baclofen daily, have for some time, not even sure why, I think it is a hold over from too much GBL intake long ago, but anyways, if this is divided throughout the day I don't notice much of any effect, but I take it in a dose or two several hours later I get a nice energy and the sex drive of a predator, much like the libido increase of something like MDPV. Huge doses of gabapentin also have this effect, and if I drink strong kava all day for a few days I'm just as, uh, erect and determined when it wears off. Very strange. GABA-A agonists do no such thing, quite the opposite actually. Anyways, dunno how this works. . .

Now, back to our feature programming, I'll save the next boner update for an equally inappropriate time