http://www.mywayout.org/community/f20/baclofen-withdrawl-syndrome-42956.html

[Jamshyd]

I actually tried registering on that forum just to engage these people in conversation, but it appears I'd been banned automatically before even making my first post.

With that, I'd say stay away from this place since I can only guess it belongs to someone who wants to make a ton of money out of people's misery. And I say this truly in the spirit of Harm Reduction.

 

[negrogesic]

Yes, phenibut is far less point, but if you are in acute baclofen withdrawal and have little resources, it will effectively replace the baclofen. Tthey are structurally and functionally almost identical, aside the issue of potency. Baclofen has the same structure, but is more potent becuase of the 4-chloro substitution on the phenyl group.

Phenibut can be used, with a scale, to wean yourself off a baclofen habit. It must be done systematically and accurately.

You can quote me on this. Negrogesic has no meaning. Perhaps a mixture of my 1/16 african heritage and taste for analgesics.

 

[seep]

Anyone know anything about analogues? Always wondered what a bromine rather than clorine might do. Yes flourine will probably create a more phenibut type drug but bromine?? Desperatly interested. Anyone have any analogue research links?

More druglike are some cyclic variations. Googling baclofen analogues leads to many possibilities. An Egyptian paper cites the benzyl oxazepine

as an especially solid gaba-b agonist, but there are many others written about over the past couple of decades.

That chloro group is just to enhance its ability to cross the BBB....

From a 2001 Italian paper: "The ability of being involved in aromatic-aromatic pi interaction is the distinctive feature of the p-chlorophenyl moiety of baclofen . . . the p-chlorophenyl moiety of baclofen is disposed into a pocket formed by Tyr366 and Tyr395" on the receptor.

 

[Phener]

Yes, phenibut is far less point, but if you are in acute baclofen withdrawal and have little resources, it will effectively replace the baclofen. Tthey are structurally and functionally almost identical, aside the issue of potency. Baclofen has the same structure, but is more potent becuase of the 4-chloro substitution on the phenyl group.

Phenibut can be used, with a scale, to wean yourself off a baclofen habit. It must be done systematically and accurately.

You can quote me on this. Negrogesic has no meaning. Perhaps a mixture of my 1/16 african heritage and taste for analgesics.

Sorry to pick holes, I appreciate where you are coming, I would have equally made the exact same suggestion was it not for personal experience. can I ask have you yourself been addicted to baclofen (high dose I.e 160mg+ daily)? and subsequently transfered this to phenibut?

Without your personal experience, you would be talking from a purely hypothetical stance.

I had tried both drugs previously on acute episodes and would have made the exact same comment until recently

When transfering from 160 - 200mg daily (on dosing scheme for a while) to phenibut there really were almost straight away (well the day after) MASSIVE problems. Like I say baclofen seemed such a clean selective PURE gaba-B agonist (sure it's the drug of choice in GABA-B receptor research studies - why? it's highly selective), the differences in pharmacology really became apparant when transfering, also like I say dosing times were different + length of action were different adding to complexities, there was extreme nausea in the conversion and it really did feel like kidneys were knackered.

One hypothesis (and it's just that) is I had read that phenibut as well as acting as a GABA-B agonist ALSO blocks many of the effects of PEA (Phenylethylamine). I am quite aware that baclofen may do the same thing but if I was to hazard a guess, due to the large dose phenibut requires - I would predict PEA blocking would be CONSIDERABLY higher compared to GABA-B activity with phenibut. Hence one MAJOR difference in pharmacology.

From a 2001 Italian paper: "The ability of being involved in aromatic-aromatic pi interaction is the distinctive feature of the p-chlorophenyl moiety of baclofen . . . the p-chlorophenyl moiety of baclofen is disposed into a pocket formed by Tyr366 and Tyr395" on the receptor.

prescisly, the chloro makes baclofen FAR more selective for GABA-B. It's like comparing DOM with DOB, or 2C-D with 2C-B, both psycadelics but most would agree VERY different.

 

[Phener]

More druglike are some cyclic variations. Googling baclofen analogues leads to many possibilities. An Egyptian paper cites the benzyl oxazepine

as an especially solid gaba-b agonist, but there are many others written about over the past couple of decades.

Interesting stuff, really must find the time to do a FULL search of all GABA-B agonists. Would be very interested to read about partial GABA-b agonist.

Still even more desperate to find a paper comparing the simple halogen substitutions. I am guessing it is information either in russian (I.e the invetors of phenibut) or with Novartis - manufacturers of lioresal (who probably ripped the idea of phenibut and started modifying it + came up with their highly selective GABA-B)

 

[negrogesic]

Sorry to pick holes, I appreciate where you are coming, I would have equally made the exact same suggestion was it not for personal experience. can I ask have you yourself been addicted to baclofen (high dose I.e 160mg+ daily)? and subsequently transfered this to phenibut?

Without your personal experience, you would be talking from a purely hypothetical stance.

I don't have any person experience. Based on structure-activity I assumed that Phenibut would provide relief a withdrawal caused by its para-chloro substituted cousin. I would assume they would roughly substitute, but this is again is just what makes sense on paper.

Why not slowly decrease the baclofen dose, and maybe switch to phenibut when possible.

Oh, I read an interest thing in a Russian study about phenibut:

Chronic i.p. administration of PB in mice antagonized
the development of morphine dependence

Full text of the Russian article

 

[Phener]

Anxiolytic activity of BAC. Since BAC is a p-chloro derivative of PB, we considered the possibility that its psychotropic activity profile may be similar to that of PB. Therefore, we evaluated BAC under experimental conditions similar to those with PB. As an antianxiety drug in mice and as an antagonist of the sedative and tranquilizer effects of PEA, BAC had PB-like effects. However, its effective doses were 10 to 12 times lower than those of PB (27,28,30,42). The anticonflict effect of BAC appears to be mediated by GABAB receptors (44). As an analgesic, BAC is much stronger than PB. It has antinociceptive
activity when administered by either parenteral or intrathecal routes. Intrathecal administration of BAC in the rat hind paw formalin test produced addictive analgesia (12). BAC has been reported to increase aggressivity in mice at a low dose (3 mgkg i.p.) and to CNS Drug Reviews, Vol. 7, No. 4, 2001
476 I. LAPIN decrease aggressivity at a higher dose (15 mgkg i.p.). The behavioral effects of BAC appear to be similar to those of benzodiazepines (46).

Thanks very interesting article. Good to have a 10-12 x potency figure (had searched previosly and only got anecdotal reports. ) Had previously been working from a google search result of "I'd say 50mg of baclofen was imo, roughly equivalent to about 1.8g of phenibut.", possibly dosed too high.

Interesting though "PB-like effects" - I am still convinved baclofen is an extremely pure gaba-b agonist (+other effects) whilst phenibut is more crude +softer.

 

[P A]

In fact, Rohypnol has stronger action on GABA-B than Baclofen, with action on GABA-A added for fun.

Indeed - Rohypnol does everything baclofen does better than baclofen. So why aren't you roofying yourself out of your alcohol addiction? Hint: it has nothing to do with rape.

Flunitrazepam is a positive modulator of selected GABA-A subtypes, and to a lesser extent, a calcium channel blocker. It does not bind the GABA-B receptors. At all.

 

[Jamshyd]

^ I was under the impression that all Benzodiazepines are positive allosteric modulators at all GABA sites but are more selective for the A subtype?

 

[P A]

I was under the impression that all Benzodiazepines are positive allosteric modulators at all GABA sites but are more selective for the A subtype?

As the GABA-B receptors are metabotropic GCPRs, they [as a rule] aren't as subject to simple allosteric modification by putative ligands such as benzodiazepines as the ionotropic GABA-A subtypes. Since they lack an ionophore composed of multiple interchangeable subunits, they can't house such proximal allosteric sites as the benzodiazepine receptors, the sites to which flunitrazepam and its cousins selectively bind.

 

[Jamshyd]

Thank you for pointing this out. I admit I had been confusing GABA-B with the β-subunit of the BZD complex.

 

[P A]

Thank you for pointing this out. I admit I had been confusing GABA-B with the β-subunit of the BZD complex.

If you're interested, there's quite a bit of literature on the topic. The GABA-B receptors are pretty unique [and odd] in action, bearing close similarity to metabotropic glutamate receptors. Most of the studies use the well-known high-affinity ligand, baclofen, a drug that I hope to get my hands on in the near future.

By the way, is your first name actually Jamshid, or is it some kind of reference to that Zoroastrian king?

 

[Jamshyd]

^ Wow, not many people catch that, but yes, it is a reference to the mythical king who let his pride get the best of him. But I do like the name itself as well.

I definitely have some interest in this receptor, but my experiences with both Baclofen and Phenibut were uneventful at best, and with GHB absolutely devastating at worst.

 

[P A]

but my experiences with both Baclofen and Phenibut were uneventful at best, and with GHB absolutely devastating at worst.

That's shitty to hear, but a pretty run-of-the-mill report. As far as mind-blowing "recreational" aspects are concerned, the GABA-B agonists present a disappointing dearth. I guess my circumstances are entirely too unique to generalize to common experience - I have an apparently intractable neuropyschiatric syndrome resembling the clinical manifestations of a frontal lobotomy: dissociation, cognitive fuckups, apathy, avolition, social disinhibition [i.e. acting like an ass], and severely blunted affect. A few moths ago, I wantonly ingested a large-ish dose of phenibut, which to my shock, fully reversed all but the depersonalization and the cognitive issues, while marginally worsening the former (this wasn't exactly a big deal, in light of the incredible result). I'm on the verge of a mechanistic explanation, and I hope some trials with the considerably more potent baclofen can shed some light on whether my sole window within two years' misery was little more than a fluke.

I only mention this to highlight some of the GABA-B receptors' "weirdness" compared to the other GCPRs. Though the overtly striking/recreational properties of the selective agonists may be lacking, the receptors'/ligands' modulatory influence on other neurotransmitter systems and drug effects is worth looking into. As an example:

Attenuation of morphine withdrawal signs by a GABAB receptor agonist in the locus coeruleus of rats

Abstract

In the present study, the effects of intra-locus coeruleus (LC) injection of GABAB receptor-interacting agents on naloxone-induced withdrawal signs of morphine-dependent rats were examined. The GABAB receptor agonist and antagonists were injected 5 min prior to naloxone injection. Baclofen, a GABAB receptor agonist, decreased the TWS in a dose-dependent manner but CGP35348, a GABAB receptor antagonist, alone had no effect. On the other hand, baclofen effects were reversed by CGP35348. It may be concluded that activation of GABAB receptor mechanisms in the LC reduces precipitated withdrawal symptoms from chronic morphine treatment.

Supporting its use as a more-than-palliative grain ethanol abstinence aid:

http://alcalc.oxfordjournals.org/cgi/content/full/37/5/499

 

[Phener]

Yeah to give the big now famous Dr a point, there is definately something about baclofen and addictive reward pathways. Can certainly vouch for that.

Whether baclofen itself is a suitable agonist or whether constantt gabaB agonism is the answer?? time will no doubt tell.

There desperatly needs to be more research in this area, which if nothing else I hope the Dr has stimulated. Just hopefully not at the cost of too many people suffering severe baclofen withdrawal/associated problems.

Hell it's amazing there are such few gabaB agonists about:
GHB (not pure gabaB)
phenibut
baclofen
various antagonists (of the baclofen analogues)
? others

GABA-BIHKAL - needs to be done, get the legend on it! He'll sort it, Seriously someone needs to clone that man!

 

[amanitadine]

thank you PA for chiming in. I wasnt about to try and nitpick the above posters claims that flunitrazepam has more action on GABA-B than baclofen itself. Nonsense. And as I stated above, i've been very suprised thus far in baclofens selectivity for GABA-B and its effect of "craving suppression" and interrupting of the addiction-reward cycle. I really didnt want to place much creedence in this work at all, and hen pecked it, until I actually tried it myself. And i would agree with all of pheners subjective descriptions. It really does become a different tool once you cross over into daily high dose dosing. And so much more refined than phenibut. If i am in a good 24/7 cycle of GBL/GHB it takes me around 3 grams of phenibut to erase most of the withdrawal (excepting some of the more peripheral effects) and at this dosage the side effects really start to creep in...stomach and kidney pains, muscle aches, etc) whereas around 60 mg of baclofen will do the same thing. I never have had any of the cognitive and memory problems i got from BZDs, or any of the "chasing of the high" i get with BZDs or GHB. I've always been able to safely titrate down fairly rapidly with minimal discomfort. Just like any other GABAergic, you cant just go cold turkey. And in the spirit of harm reduction, I dont think you could do much better than swapping out alcohol, BZDs, GHB, etc (and all of their neurovegetative and neurotoxic side effects) for the fairly benign effects of baclofen.

 

[negrogesic]

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.

 

[Jamshyd]

thank you PA for chiming in. I wasnt about to try and nitpick the above posters claims that flunitrazepam has more action on GABA-B than baclofen itself. Nonsense.

In case you haven't noticed, "the above poster" conceded that he'd been wrong and mixed up two different things.

 

[amanitadine]

Jamshyd- I noticed. I apologise if I was "curt", Ive just been recently thrust into (not so much here) defending a position that until recently I publicly ripped a new one, albeit under a different user name,, and it makes me defensive. My own personal experiences have forced me to reconsider. When people hear of GABA-B and baclofens unique effects, they often have a knee jerk response equating this with GHB or GABA-A agonists, and this is profoundly not the case. These distinctions are arguably of the utmost importance. There is a huge number of animal studies showing baclofens modulation of self administration of GABAergics as well as opiates, cocaine, amphetamines, etc etc, and a growing number of human trials.

Negro- I agree this is a very poorly understood niche. It is only in the past couple of decades that the differences between the ligand gated ion channels and the g protein coupled receptors (GABA-A vs GABA-B), the vagaries of the balance between, the aforementioned neurosteroids, the BZD specific GABA-A-p subclass,or even the differing mechanisms of action between agonists (say, increasing the pore size opening vs the time the pore is opened). And it doesnt make things any simpler by the fact that GABA itself is an inhibitory neurotransmitter, profoundly modulating serotonin, glutamate, dopamine, acetylcholine, etc. Its a mess!While I would never be a proponent of a "magic bullet" theory in regards to addiction, I think there is much promise to be had in increasing our understanding of GABA, and in particular, the unique role baclofen has been shown to play. cheers.

 

[Jamshyd]

^ I will agree that this is certainly a very interesting receptor, and that this thread has opened my mind to the possibility of the role it plays with tolerance and/or addiction.

Although I may have been wrong in confusing Benzos' action on the β-subunit with action at the GABA-B receptor, my point still stands: that baclofen itself is just as addictive as benzos or GHB, and that escaping an addiction only to find yourself mired in another is NOT harm reduction, which is what this website is all about.