GABA-B agonist abuse and the changes to brain

[Vieno]

Hello everyone

I've been wondering something and would like to get some input from the experts here. I don't think many of you are aware of this puzzling phenomenon so I'll try to explain it in detail, feel free to ask questions. I would like to understand what on earth is the culprit to this. So here we go:







There is anecdotal evidence that the abuse of GABA-B agonists (at least GHB and phenibut) sometimes causes a post-acute withdrawal syndrome (PAWS) different from the PAWSs of other drugs which consists of the following symptoms:

1) pleasure doesn't occur anymore in response to pleasurable stimuli: consummatory anhedonia*

2) opioids do not function anymore: diminished or zero response to exogenous opioids in terms of all effects including euphoria, analgesia and respiratory depression

3) rewarding drugs lose their euphoric and pleasurable effects: stimulants, benzos etc.

4) high tolerance to GABA-B agonists persists especially in terms of the pleasant effects: the threshold for phenibut and GHB goes up to many grams and pleasant effects may be impossible to induce regardless of the dose

*Consummatory anhedonia is a completely distinct phenomenon from the typical anhedonia which may more accurately be described as anticipatory anhedonia. In essence, consummatory anhedonia (CA) means the inability to experience pleasure in response to pleasurable stimuli such as music, sugar or sexual stimulation, however it does not include emotional and motivational dysfunction like the normal anhedonia does. The CA concept is explained in this free article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005986/

We shall continue. The anecdotal evidence I'm talking about comes from the following sources:

http://www.bluelight.ru/vb/threads/249518-GABAergic-withdrawal-resembling-D2-antagonism (feel free to ignore the "resembling D2 antagonism" theory)

Extreme anhedonia

--

I have also personally experienced a MARKED (almost complete) reduction of the euphoric effects of dopaminergic drugs.

--

A speedball made me feel "high" but not as blissful as a speedball should be.

Think i've experienced this, was using GBL uh probably "too often" heh, and some benzo's as well, after stopping both suddenly, I found that I could eat 30mg hydrocodone, and feel almost 'nothing'... no opiate tolerance..

http://www.longecity.org/forum/topic/59549-the-anhedonia-thread/page__st__270#entry587617

For a period of time after my withdrawal from Phenibut last year I experienced consummatory anhedonia in that I really anticipated and wanted to experience pleasure but I never got the response. Pretty sure I would have been immune to opioid drugs.

There were a couple of other threads too, can't find them at the moment but I'll try to dig them up.

The point is that apparently excess use of GABA-B agonists can damage the brain's pleasure pathways in such ways that the four symptoms I mentioned occur. The question is: what on earth could be the culprit to this?







It seems sensible that when the acute withdrawal ends the GABA-B receptors have upregulated back to the pre-abuse state. As the consummatory anhedonia (CA) may persist or even emerge after the acute withdrawal, it appears to be caused by something else than downregulated GABA-B receptors. I can think of many mechanisms that theoretically could be responsible for the CA, the opioid tolerance and the lack of drug pleasure, however

1) apparently nobody has found anything to effectively remove the symptoms and

2) not a single theory explains why tolerance to GABA-B agonists remains high even after months have passed since cessation and the acute withdrawal is only a memory and it appears that the GABA-B receptors have upregulated back to normal state

Does anyone have any idea on what's going on in the brains of those who once abused GHB or phenibut and were left with CA and the other mentioned symptoms? It's quite staggering how opioids can lose their effects - this clearly indicates that the problem is a big one and that it has nothing to do with psychological issues nor with the normal, or "anticipatory" anhedonia.

And why am I asking this - did I abuse those drugs? No. But I've got the same symptoms. I believe I have an endogenous condition resembling GABA-Bergic post-acute withdrawal syndrome. I have consummatory anhedonia (no problems with motivation, anticipation and emotions yet I feel zero pleasure when having sex, listening to music, eating candy and so forth), zero reaction to opioids (morphine, codeine), no pleasure from rewarding drugs (stimulants, depressants, hallucinogens) and extremely high threshold for GABA-Bergics (phenibut, GHB).

I have a ton of ideas of what could help but so far the 28 drugs I have tried have not worked. I'll be glad to discuss my ideas (many of them invented by SWIM!) but I'm not gonna mess up this post with them, I'll let you give your input first...

Say it loud whatever you've got in your mind. I hate brainstorming but I have to resort to it now.

Thank you!

Vieno

 

[bronson]

BDD --> ADD at the request of the OP.

 

[Vieno]

Thank you!

 

[bunge]

Some of the literature ive read recently spoke of using GABA B agonists in treatment of drug addiction.
I think its mainly been looked at for cocaine addiction and only in rats but it appears that GABA B agonists like baclofen are capable in low doses of interrupting the reinforcing properties of dopaminergic drugs like cocaine.
I couldnt find any studies iinvolving humans, so i cant say how GABAB agonists would work in this capacity but maybe agonisim of the B receptor affects the dopamine 'pleasure/reward' pathways? and maybe over-stimulation of this receptor can raise the pleasure threshold so high that it very difficult to surmount it, even with natural reward activities like eating sugary stuff or sex.
It seems that agonists at certain GABA receptors can have weird paradoxical effects, like GABA a receptors. I believe this is why benzos arent strictly agonists of GABA a but are allosteric modulators....
To be honest, its a little bit beyond my knowledge and im sure some of the guys here in ADD will have a better answer but thank you for posting the question as i find this whole area really interesting and im interested to find out what the experts think.

 

[Vieno]

Baclofen seems to be the only GABA-B agonist inhibiting reinforcing effects of drugs so it's not specifically about GABA-B but about something else. Phenibut and GHB combine wonderfully with many drugs and add to their euphoria. I'm also not sure if baclofen inhibits specifically the reinforcement or the pleasure/euphoria - they are distinct phenomena. The reinforcement is primarily a dopaminergic thing whilst the mechanisms of pleasure/euphoria remain not well understood. The idea of "dopamine pleasure/reward pathways" is actually an outdated idea, dopamine has nothing to do with pleasure/euphoria although it is strongly implicated in reinforcement.

You made a good point regarding agonism vs. allosteric modulation, muscimol indeed is very different from benzos... too bad there are not any allosteric modulators of GABA-B available. Would definitely want to try one. Which brings me to the fact that I'm going to try baclofen, it's so different from GHB and phenibut that I'm wondering if it actually could do something despite the apparent GABA-B tolerance. It does seem that my GABA-A system is working normally as both alcohol and benzos seem to have normal effects on me (although they lack their pleasurable/euphoric effects) though I haven't tried muscimol so here's a crazy theory: my GABAergic tolerance is not specifically about GABA-B but instead about direct agonism: direct agonism of both GABA A and B doesn't work but allosteric modulation of both does work. But I'm almost certain this is not the case. Just saying it because of... brainstorming!!!!

Your idea about over-stimulated GABA-B is something I've actually considered, although it's an odd theory since how on earth could GABA-Bergic abuse cause hyperactivity of GABA-B receptors? Also like I said, the differences in baclofen's and phenibut/GHB's effects is puzzling. Experimentation is the key I believe.

There is no certainty that my condition shares the mechanisms of GABA-Bergic PAWS, but the similarities are striking.

Thank you too for your response

 

[bunge]

By over-stimulation, i was referring the down-regulation causing tolerance, sorry if it was confusing, as i said im slightly out of my depth.lol
In the study that i read, they did have an GABA B modulator to test alongside the full agonist but ot didnt appear to have any effect in the studies goal of interrupting coke addiction. I cant recall off the top of my head the name of said chemical as it was just a chem id number but i will dig out the studies and link it, if you would like?.
Muscimol was exactly what i was thinking of when i wrote that bit of my post and its hallucinatory and micro/macro type illusions are particularly interesting, to have such a difference in effect from the benzos, im guessing theres a fair bit of downstream activity.
I was unaware that my view on dopamine is outdated but i will be sure to re-educate myself at some point today.
I have another theory as to why your experiencing your issues but im gonna polish it a bit before i post it and embarrass myself. :-D

 

[Vieno]

Hmm so when you said: "and maybe over-stimulation of this receptor can raise the pleasure threshold so high that it very difficult to surmount it, even with natural reward activities like eating sugary stuff or sex."

You meant that the GABA-B tolerance ie. downregulation raises that pleasure threshold? That could be true as it appears that the GABA-system (the B receptor in particular) alongside the opioid system is more implicated in pleasure than any other system. Although it's puzzling how could I have GABA-B tolerance, what would cause it? And how would I then not suffer from the typical GHB/phenibut/baclofen withdrawal syndrome if my GABA-B receptors indeed are downregulated? Also it is noteworthy that even though I do get effects from GHB with high doses (threshold over 2g) I don't get any pleasure/euphoria from it (3,5g). Someone suggested me that it's possible to feel quite normal even if the GABA-B receptors are highly downregulated since the body can adapt to that by upregulating GABA-A or something, but this was just guessing I think.

I might actually give muscimol a try to see the effects... I don't want to trip but maybe a low dose is enough to reveal something.

Yes, please dig up that study, I'd like to read it

As for the view on dopamine, check out the article in the first post that discusses consummatory anhedonia. It's a good introduction to the topic. DA is strongly implicated in reward-seeking behavior but the reward itself (assuming reward means pleasure) is mediated via mechanisms unrelated to DA, possibly opioidergic and/or GABAergic and surely some unknownergic.

As for your theory, I'm looking forward to it

 

[bunge]

Thank you, your very kind but im not sure how much water my theories actually hold as they are mainly intuitive and (partly) educated guesses!lol
Im glad you can translate my babblings as GABA B tolerance causing a rise in pleasure theshold is exactly what i meant.
As to the theory that GABA A can be up-regulated by the body in response to a natural down-regulation of GABA B...im not too sure, but i know they are distinctly different types of receptors so i feel that theory would be a vast over-simplification of the actions of these receptors.
Your muscimol experiments could be very interesting. I too, would keep to doses very low as therapeutic doses of any drug are always alot lower then recreational doses and im guessing that you have access to pharma grade muscimol because i would think that amanita mushrooms prob have alot of active chemicals present, not to mention the dangers of picking the wrong kind!lol

 

[Vieno]

Patiently waiting for your possibly water leaking theory!

The idea was not just about GABA-A upregulation but about many other adaptative mechanisms too like NMDA, glutamate and neuropeptide related stuff, but it wasn't anything specific.

Anyway I'll try to get my hands on muscimol and baclofen to find out more about my GABA system. A lot of amanita growing around here soon in the autumn but somehow I do not want to mess with them... my folks planted a deep fear of them to me when I was a kid. Btw I would so love to try phaclofen/saclofen to see their effects - I seem to have tolerance to GABA-B agonists but how about antagonists? - but I have no idea how to get these experimental substances.

Also I'm wondering if opioid antagonist would do something, I've got some naltrexone here so I could try it. What's your guess people, if opioid agonists do nothing to me would an antagonist do something?

E: The idea is simply to do medical experiments so preparing actual mushrooms is a bit too indefinite. I always try to obtain pure pharmaceutical preparations unless a raw form is known to be more useful regarding some particular use.

 

[Limpet_Chicken]

A.muscaria are toxic, to a degree, but not THAT toxic. At least, when prepared correctly (long, slow heat curing, I do them on foil-lined trays at least overnight, in the oven at lowest possible heat) I find them very useful in staving off the harsh winters of the last few years.

 

[atara]

Has this been observed with phenibut alone, or is the effect specific to GHB and GBL?

GHB is in addition to GABA-B an agonist at the aptly named GHB receptor, which is linked to neurotoxicity, severe neurotoxicity in rats in fact. While large retrospective studies regarding sodium oxybate [Xyrem] use fail to observe significant toxicity, it is nonetheless totally possible that abuse of GHB agonists could reproduce the lesioning effects (!!!) seen in rodents. The large difference in the observed toxicity of GHB in rats and humans under pharmaceutical conditions may be due to the very careful use of GHB in the treatment of narcolepsy, where it has been nothing short of a miracle.

Of course, this wouldn't be the first time we've seen differing effects in rats and humans: see also NMDA antagonist neurotoxicity, empathogen neurotoxicity, cannabis (maybe), ...

 

[Hammilton]

For what it's worth, GHB binds with high affinity to GABA-A composed of alpha 4, beta and delta subunits. I don't believe these are widely expressed receptors but they likely contribute in an important way to GHB' s pharmacology. As a result of their relative uncommon nature, I don't have a clue as to what they do... so yeah..

Additionally, the OP I believe said that there were not allosteric modulators of GABA-B. That's not true, actually. There are a few.

The composition, function and operation of GABA-B is completely different from GABA-A receptors. I haven't researched GABA-B receptors all that much, but it is a mistake to think that because they share a common ligand they must have something else in common. GABA is about all they have. GABA-A receptors are like five plants growing in a circle (or pentagon, I suppose) with a light shining up from the center. They can bend and twist and depending how they're bent, some of that light might make its way through. Diazepam, an allosteric modulator, gets stuck in between two of the plants, but it doesn't open them up enough for the light to get through. It does however adjust the branches enough that GABA is more able to fit in there, letting the light through. It doesn't make more light go through in any one time that GABA binds, but it does make it so that the light is shining through much more often.

When a barbiturate binds between its two plants, it also doesn't let any light through itself, but when GABA binds at the same time, it causes the GABA molecule to stay stuck longer and so more light is able to get through.

I can't think of a useful metaphor for the GABA-B receptor. It's a GPCR but I think it's sort of an unusual one because it's somehow coupled to potassium channels (I think?)


I find this idea interesting, but given the fact that a couple GABA-B agonists have abuse potential themselves, I have a feeling it won't pan out. Meaning, I have a feeling that an empirical study would find that these drugs will indeed retain their addictive qualities post withdrawal.

The claims here would also suggest that saclofen would have CA as a side effect, and that it would quench the euphoria from other drugs. I don't believe that it has been shown to reduce self administration. Indeed, as it has been noted, baclofen has been used for this purpose. If withdrawal from the drug causes the same effect that taking the drug has, I would tend to think that not taking the drug at all would also have that effect (that is, the effect is placebo).

I'm about to run out of battery here, but can someone find a paper saying that saclofen blocks the addictive properties of cocaine or morphine- or any other addictive drug, but those two are the gold at standards usually.

It would certainly be nice if there was a pill that would turn addiction off.

 

[Vieno]

atara: apparently this has happened with both phenibut and GHB/GBL. I don't know if baclofen can do the same and as it is abused much less we're not likely to find that out anytime soon. I have a general understanding of the GHB receptor and GHB's neurotoxicity and because of the CA has happened with phenibut too I doubt those are implicated.

Hammilton: yeah it's became pretty clear that GABA-B is quite unique. Thank you for your elaboration, I might look more deeply into the specifics of GABA-B function compared to those of GABA-A.

But I think you got me wrong. I'm not sure what "idea" of mine you find interesting as I didn't propose a specific cause for CA - merely vaguely suggested that apparently GABA-Bergic abuse can cause it. So firstly, it appears that most of GABA-Bergic abuse does NOT cause CA. CA seems to occur very rarely. We also know based on anecdotal evidence that people's withdrawal experiences from GABA-Bergics variy dramatically from short-lived unpleasantness to years of agony that makes opioid withdrawal look like picnic. And for example, the guy who got CA (for a couple of months) from phenibut had a very easy acute withdrawal followed by a short period of almost no symptoms, and then started to have issues - first CA, later AA (anticipatory anhedonia) among other more physical things.

So what I'm suggesting is that there is a link between GABA-Bergic abuse induced changes to brain and CA, and there's probably similarities in those changes to the changes that have occurred in my brain during the last four years (causing CA). I think whatever the link, it's much more complicated than something like "downregulation/antagonization of GABA-B receptors causes CA". No, that doesn't happen. So I don't believe saclofen/phaclofen cause CA. Yet I'd like to try these substances just to get more insight into how my brain works. Some drug reactions have been staggeringly odd like the total lack of response to opioids and the high threshold for GABA-Bergics.

It has been proven many times that DA has nothing to do with the pleasure itself even though it modulates the behavior of seeking it. Similarly serotonin, NE and many common drug targets seem to play little if any role in pleasure/euphoria. Insted the opioid system may be involved even though the endorphin theory is largely outdated and proven wrong. My guess is that GABA-B has a role but it's rather indirect, similarly to how GABA-Bergic abuse may but probably doesn't cause CA.

PEA apparently possesses antagonistic properties againts GABA-B, I need to look more into it.

E: Also the idea of being immune not to GABA-Bergics but instead to GABA A and B direct agonists was something I do not believe in, just one idea among other things that needs to be said out loud.

---

I did some searching and it appears that baclofen does not specifically inhibit the euphoric effects of drugs but instead inhibits reinforcement and cravings. I don't think GABA-B agonism can block pleasure, prove me wrong if you disagree.

I'm not sure but maybe baclofen can block stimulants' euphoric effects but it's probably limited to that, not inhibiting opioid, depressant or naturally (without drugs) induced euphoria. I'm pretty sure neither GABA-B agonists or antagonists directly interfere with pleasure, however it is clear that GABA-Bergic abuse is capable of inhibiting pleasure (and at the same time, the whole mu-opiod receptor). The mechanism must be indirect. I'm very certain the mechanisms responsible for the inhibition of pleasure and mu have nothing to do with the basic monoaminergic or catecholaminergic transmissions as the modulation of those never a) induces CA or b) removes CA.

E: This for example states that baclofen enhances opioid analgesia, I'm guessing it'd enhance the euphoria as well: http://www.ncbi.nlm.nih.gov/pubmed/8552232

E2: There are no GABA-B allosteric modulators available outside research institutions' laboratories are there?

E3: Hmm well this is interesting: http://mindandmuscle.net/forum/12219-phenibut-pleasure-killer

Perhaps it's highly individual whether the GABA-B agonists inhibit pleasure or not, just like it appears highly individual whether the GABA-B agonist abuse causes CA in withdrawal?

 

[Vieno]

bunge: where's your theory?

Hammilton: could you elaborate more on the tecnicalities of the differences between GABA A and B? You are making it very clear that they're two very, very different kind of receptors, but I have no idea how.

 

[Vieno]

The claims here would also suggest that saclofen would have CA as a side effect, and that it would quench the euphoria from other drugs. I don't believe that it has been shown to reduce self administration. Indeed, as it has been noted, baclofen has been used for this purpose. If withdrawal from the drug causes the same effect that taking the drug has, I would tend to think that not taking the drug at all would also have that effect (that is, the effect is placebo).

I'm about to run out of battery here, but can someone find a paper saying that saclofen blocks the addictive properties of cocaine or morphine- or any other addictive drug, but those two are the gold at standards usually.

http://www.ncbi.nlm.nih.gov/pubmed/11430864

Food intake is significantly increased by administration of mu-selective opioid agonists into the nucleus accumbens, particularly its shell region. Pretreatment with either opioid (mu, delta(1), delta(2) or kappa(1)) or dopaminergic (D(1)) receptor antagonists in the nucleus accumbens shell reduce mu opioid agonist-induced feeding. Selective GABA(A) (muscimol) and GABA(B) (baclofen) agonists administered into the nucleus accumbens shell each stimulate feeding which is respectively and selectively blocked by GABA(A) (bicuculline) and GABA(B) (saclofen) antagonists. The present study investigated whether feeding elicited by the mu-selective opioid agonist, [D-Ala(2),NMe(4),Gly-ol(5)]-enkephalin in the nucleus accumbens shell was decreased by intra-accumbens pretreatment with an equimolar dose range of either GABA(A) or GABA(B) antagonists, and further, whether general opioid or selective GABA antagonists decreased feeding elicited by GABA(A) or GABA(B) agonists in the nucleus accumbens shell. Feeding elicited by the mu-selective opioid agonist was dose-dependently increased following intra-accumbens pretreatment with GABA(A) (bicuculline) antagonism; this enhancement was significantly blocked by pretreatment with general or mu-selective opioid antagonists. In contrast, mu opioid agonist-induced feeding elicited from the nucleus accumbens shell was dose-dependently decreased by GABA(B) (saclofen) antagonist. Neither bicuculline nor saclofen in the nucleus accumbens shell altered baseline food intake. Whereas muscimol-induced feeding elicited from the nucleus accumbens shell was reduced by bicuculline and naltrexone, but not saclofen pretreatment, baclofen-induced feeding elicited from the nucleus accumbens shell was reduced by saclofen, but not by bicuculline or naltrexone. These data indicate that GABA(A) and GABA(B) receptor subtype antagonists differentially affect feeding elicited by mu opioid receptor agonists within the nucleus accumbens shell in rats.

Apparently GABA-B antagonism in the NAcc is capable of blocking mu-agonist induced pleasure, but it doesn't seem to block natural pleasure if I'm reading that correctly. It's a complicated topic.

Btw guys, I'd really appreciate answers to my questions, I'm in desperate need of your ideas!

 

[atrollappears]

Completely theoretical... But GABA interneurons play an important role in the nucleus accumbens, an area associated with reward (but distinct from that associated with wanting). Incidentally, the GABA neurons are actually inhibitory to reward in that area. It could be that extended GABA-B mediated suppression of cAMP abolishes LTP in the area.

Edit: wow I didn't even read the rest of the thread. Sounds like you guys are on the right track. But I would look more toward neuroadaptations than acute GABA-B effects...

 

[bunge]

I havent disappeared vieno, so dont worry.lol Ive just been very busy and havent had the time to engage my brain on this properly.
I have to read up everyones posts so far and cross referrence/read the studies.
I will have something for you by sometime in next 24hrs.lol
Alot of this goes beyond my level of education and i just want any theory i present to have merit (or at least not be a joke.lol).

 

[Vieno]

Completely theoretical... But GABA interneurons play an important role in the nucleus accumbens, an area associated with reward (but distinct from that associated with wanting). Incidentally, the GABA neurons are actually inhibitory to reward in that area. It could be that extended GABA-B mediated suppression of cAMP abolishes LTP in the area.

Edit: wow I didn't even read the rest of the thread. Sounds like you guys are on the right track. But I would look more toward neuroadaptations than acute GABA-B effects...

Yeah, I recently read a paper summarizing the recent research results on the mechanisms behind reward 'liking', GABA and opioids in the NAcc and ventral pallidum appear central to 'liking' reward. But it's terribly difficult to treat these issues with general drug administrations, as neurotransmitters have different effects in different brain areas, most certainly I can't antagonize all my GABA receptors just to enable the pleasure in NAcc.

However even though direct manipulation of GABA may not be helpful, surely it would be good to better understand the pathogenesis here. So I'd appreciate a lot if you'd elaborate more on this: "It could be that extended GABA-B mediated suppression of cAMP abolishes LTP in the area."

And equally, I'd be very interested in your thoughts on neuroadaptations. I'm not sure what exactly do you mean by them in this context.

I havent disappeared vieno, so dont worry.lol Ive just been very busy and havent had the time to engage my brain on this properly.
I have to read up everyones posts so far and cross referrence/read the studies.
I will have something for you by sometime in next 24hrs.lol
Alot of this goes beyond my level of education and i just want any theory i present to have merit (or at least not be a joke.lol).

: )

Whatever ideas you have I will appreciate them a lot. I'm a bit impatient because it's getting unbearable to live with this but knowing someone out there is about to present an idea is encouraging. Looking forward to it!

 

[bunge]

I can imagine that this is a distressing condition to be in, after all what is life without pleasure? Its humankinds driving force!.
Since your CA isnt caused by drug abuse it might be wrong to only look at the GABA complex when it could be a 'malfunction' much futher downstream. Kind of like looking at a flower when you should be checking the root....
Couple of questions, they prob seem daft (and might well be, but once i have a train of thought i like to run with it.lol
1. You state you have tried various drugs to cure this state (28, i think) could you give a brief rundown of any that had any noticeable effect on your CA or any that had any memorable effect at all (beyond physiological side effects of course.lol).
2. Did you have a normal response to opioids before the CA?
Its just that although all the posts in this thread are interesting, it seems to have drifted just a little aas you stated your CA isnt caused by drug abuse so maybe the GABA b receptor is the wrong place to look. Could the issue be with the opiate receptors? I know im asking alot more then im answering at the moment but your issue is a real brain tickler (obviously no problem with CA for me!lol).

 

[bunge]

I just read an abstract from a study that stated a group of rats were given a pleasure inducer (sucose solution) and when it was established with the group, before each administration, a stressor was added. In this case a restraint for 60mins. Anhedonia was observed with the falling pleasure levels but when naloxone was administered, pleasure levels were normalised.
I dont know how helpful that is as the abstract (and likely, the whole study) was pretty sparse but its where my thinking is added.
Does this train of thought have merit? Or am i on the wrong route?lol.