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GABA-B Receptor Antagonist Nootropics

gaba-b agonist nootropic gamma-aminobutyric acid gaba-b receptor selective agonist study antidepressant cognition enhancing novel mechanism of action

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#1 Wizardrous

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Posted 11 October 2016 - 06:53 AM


There is a lot of very compelling research that suggests the efficacy of GABA-B antagonists as antidepressant and cognition enhancing medication. Blocking the GABA-B receptors produces several effects which are believed to contribute to the nootropic potential of antagonists at these receptors. Here is the information I was able to locate on the subject:

The novel mechanism of action of these drugs make them extremely interesting to me; it seems as though they would synchronize well with commonly used nootropics by boosting cognition through a separate mechanism of action than the others. I could also see combining them with an NMDA-modulator like Tianeptine to reduce any potential excitotoxicity that could be caused by the increased NMDA expression (while still allowing moderately increased NMDA expression to improve cognition). They could even have potential for a treatment to Schizophrenia because of their ability to increase NMDA expression, which chronic downregulation of has been linked to the progression of the disease. I'm not sure how well they would work for long-term use, because a lot of the studies show up-regulation of GABA-B receptors after chronic exposure; nonetheless, they seem very promising as potent and fast acting mood and cognition boosters.

 

I honestly cannot see why these compounds have not received more attention, they absolutely fascinate me. If anyone here has any more information on the subject or would like to discuss it in any way it would be much appreciated!

 



#2 gamesguru

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Posted 11 October 2016 - 12:32 PM

Ginseng is a GABA(B) antagonist at physiologically relevant concentrations, and in terms of a supplement, it is more effective as a long-term mainstay than a fast-acting "use in a pinch".  It works well long-term.  It's not clear if this is a result of dopamine re- and co-regulating GABA circuits, or if, in the first place, pharms (phenibut) are just potent & responsible use of ginseng could never result in tolerance.

 

And yes, they do improve NMDA expression.  GABA & NMDA are co-regulatory[1], [2],[3].  Another reason to take ginseng long-term.


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#3 Wizardrous

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Posted 11 October 2016 - 07:18 PM

Ginseng is a GABA(B) antagonist at physiologically relevant concentrations, and in terms of a supplement, it is more effective as a long-term mainstay than a fast-acting "use in a pinch".  It works well long-term.  It's not clear if this is a result of dopamine re- and co-regulating GABA circuits, or if, in the first place, pharms (phenibut) are just potent & responsible use of ginseng could never result in tolerance.

 

Thank you for the suggestion! I looked into it, though, and according to the data I was able to find on it, Ginseng actually boosts the activity of GABA receptors by acting as a reuptake inhibitor. However, it also inhibits the reuptake of glutamate, which seems to be responsible for its excititory effects; this seems of interest to me because by enhancing the activity of both GABA and glutamate, Ginseng could boost your glutaminergic neurotransmission while simultaneously modulating its own effects with the increased GABA activity. It's a very interesting herb indeed.

https://www.thieme-c...5/s-2007-969463

https://www.ncbi.nlm...pubmed/12568354

https://www.ncbi.nlm...les/PMC3659517/

https://www.ncbi.nlm...pubmed/21864652

By the way, on an unrelated note, do you or anyone else who might be reading this know how to change a post title? I meant to type "GABA-B Receptor Antagonist Nootropics" and accidentally typed the opposite lol. Help would be much appreciated!



#4 gamesguru

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Posted 11 October 2016 - 07:59 PM

Biochem Pharmacol. 2004 Oct 15;68(8):1489-95.

Effect of antidepressants on GABA(B) receptor function and subunit expression in rat hippocampus.

Sands SA1, Reisman SA, Enna SJ.

 

Abstract

Laboratory and clinical studies suggest that depression is associated with changes in the hippocampus and that this brain region is a major target for antidepressant drugs. Given the data suggesting that GABA(B) receptor antagonists display antidepressant properties, the present study was undertaken to assess the effect of antidepressant administration on GABA(B) receptors in the rat hippocampus to determine whether changes in this regional receptor system may play a role in the response to these agents. Rats were administered (i.p.) the monoamine oxidase inhibitors tranylcypromine (10mg/kg) or phenelzine (10mg/kg), the tricyclic antidepressant desipramine (15 mg/kg), or fluoxetine (5mg/kg), a selective serotonin re-uptake inhibitor, once daily for seven consecutive days. Two hours following the last drug treatment the hippocampal tissue was prepared for defining the distribution and quantity of GABA(B) receptor subunits using in situ hybridization and for assessing GABA(B) receptor function by quantifying baclofen-stimulated [(35)S]-GTPgammaS binding. All of these antidepressants selectively increased the expression of the GABA(B(1a)) subunit in hippocampus, having no consistent effect on the expression of GABA(B(1b)) or GABA(B(2)). Moreover, except for fluoxetine, these treatments increased GABA(B) receptor function in this brain region. The results indicate that an enhancement in the production of hippocampal GABA(B(1a)) subunits may be a component of the response to antidepressants, supporting a possible role for this receptor in the symptoms of depression and the treatment of this condition.

 

You can't change the title, you would have to make a new thread.  You can request a moderator or admin to make the change, but it's not very polite on your behalf.

 

My understanding is it acts moreso as an antagonist, both at the A and B sites, whereas ginkgo is an antagonist at the A site.  If this is incorrect, I am sorely mistake indeed.

Gen Pharmacol. 1994 Jan;25(1):193-9.

Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors.

Kimura T1, Saunders PA, Kim HS, Rheu HM, Oh KW, Ho IK.

 

Abstract

1. Total saponin fraction decreased the affinity of specific [3H]muscimol binding without changes in Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific [3H]muscimol binding to the high-affinity site. 2. Total saponin fraction increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re and Rf enhanced specific [3H]flunitrazepam binding. 3. Total saponin fraction decreased the affinity of specific [35S]TBPS binding without changes in Bmax. Ginsenosides did not affect specific or non-specific [35S]TBPS binding. 4. Total saponin fraction decreased the affinity of specific [3H]baclofen binding without changes in Bmax. Ginsenoside Rc inhibited specific [3H]baclofen binding.

 

A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system.

 

although i did just come across a study suggesting it's an agonist at the A site:

“... Rg₃ itself-elicited inward current was blocked by GABAA receptor antagonist. The present results indicate that Rg₃-induced GABAA receptor activation via the γ₂ subunit and IGABA enhancement by Rg₃ might be one of the molecular bases of ginseng effects on GABAA receptor.

 

 

bacopa may also have some use, at least in epileptic models:

J Biomed Sci. 2012; 19(1): 25.

Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A

Jobin Mathew,1Savitha Balakrishnan,2Sherin Antony,2Pretty Mary Abraham,2 and CS Paulose2

Abstract Background

Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue.

Methods

In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated.

Results

Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAAά1, GABA, GABA, GABAB and GAD were down regulated (P < 0.001) in epileptic rats. GABAAά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance.

Conclusions

Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management.



#5 Wizardrous

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Posted 11 October 2016 - 09:39 PM

My understanding is it acts moreso as an antagonist, both at the A and B sites, whereas ginkgo is an antagonist at the A site.  If this is incorrect, I am sorely mistake indeed.

Gen Pharmacol. 1994 Jan;25(1):193-9.

Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors.

Kimura T1, Saunders PA, Kim HS, Rheu HM, Oh KW, Ho IK.

 

Abstract

1. Total saponin fraction decreased the affinity of specific [3H]muscimol binding without changes in Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific [3H]muscimol binding to the high-affinity site. 2. Total saponin fraction increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re and Rf enhanced specific [3H]flunitrazepam binding. 3. Total saponin fraction decreased the affinity of specific [35S]TBPS binding without changes in Bmax. Ginsenosides did not affect specific or non-specific [35S]TBPS binding. 4. Total saponin fraction decreased the affinity of specific [3H]baclofen binding without changes in Bmax. Ginsenoside Rc inhibited specific [3H]baclofen binding.

 

A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system.

 

I haven't done enough research to know definitively either, but it is possible that it reduces baclofen binding by working as a competitive agonist at the GABA-B site rather than an antagonist; the reason I say this is because the study you cited says it also increased the flunitrazepam binding to the benzodiazepine site, which further increases the activity of a receptor. It does seem to be an agonist at the GABA-A site, the second and third studies I cited pointed to that specifically. I couldn't actually find any studies that said it had any activity, agonistic or antagonistic, at the GABA-B receptor (I haven't had time to look very hard yet though). The first study I cited said it had effects on the reuptake of GABA (as well as several other neurotransmitters, including glutamate), which could hypothetically increase endogenous GABAergic activity at the GABA-B receptors and competitively lower the binding of baclofen and increase the affinity of benzodiazepine agonists like flunitrazepam to the site. The reuptake inhibiting quality could also explain the stimulating effects of Ginseng, through inhibition of the reuptake of glutamate and catecholamines (namely DA, NA, and 5-HT). If it is indeed a reuptake inhibitor of GABA, Glu, NA, DA, and 5-HT, that would explain why it has both stimulant and relaxant qualities; here is an additional study I found that focuses on a metabolite of ginseng and its ability to inhibit monoamine reuptake: https://www.ncbi.nlm...pubmed/20647027. I haven't found any other studies yet that mention its inhibition of GABA and Glutamate reuptake yet, but it is possible that it increases glutaminergic activity through a monoamine pathway (I know certain 5-HT receptors inhibit GABA; e.g. the 5-HT2A receptor).



#6 gamesguru

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Posted 11 October 2016 - 10:18 PM

It's also possible ginseng binds to GABA autoreceptors, so it increases receptor expression and the activity of other neurotransmitters.

 

Fasoracetam:

Eur J Pharmacol. 1997 Nov 12;338(3):225-32.

Effect of a novel cognition enhancer NS-105 on learned helplessness in rats: possible involvement of GABA(B) receptor up-regulation after repeated treatment.

Shimidzu T1, Itoh Y, Oka M, Ishima T, Ukai Y, Yoshikuni Y, Kimura K.

Abstract

We have previously found that a cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) reversed the inhibition of cyclic AMP formation induced by the GABA(B) receptor agonist baclofen. The GABA(B) receptor has been implicated in the pathophysiology of depressive illness. The present experiment was designed to evaluate the antidepressant activity of NS-105 in the forced swimming and learned helplessness tests in rats. NS-105 (1-100 mg/kg, p.o.) significantly decreased immobility time in the forced swimming test, an effect similar to that of desipramine. Repeated administration of NS-105 also reversed the failure to escape in the shuttle-box test of rats previously exposed to inescapable footshock. Biochemical data showed that repeated administration of NS-105 increased the number of GABA(B) receptors in rat cerebral cortex without affecting the binding properties of beta-adrenoceptors and 5-HT2 receptors. In contrast to other antidepressants, NS-105 did not inhibit monoamine uptake in vitro, nor did it change monoamine concentrations in brain tissues or extracellular fluids. These findings suggest that NS-105, which lacks an effect on monoaminergic systems, has potent antidepressant activity, which may involve up-regulation of GABA(B) receptors after repeated administration.



#7 Wizardrous

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Posted 12 October 2016 - 03:42 AM

 

It's also possible ginseng binds to GABA autoreceptors, so it increases receptor expression and the activity of other neurotransmitters.

 

Fasoracetam:

Eur J Pharmacol. 1997 Nov 12;338(3):225-32.

Effect of a novel cognition enhancer NS-105 on learned helplessness in rats: possible involvement of GABA(B) receptor up-regulation after repeated treatment.

Shimidzu T1, Itoh Y, Oka M, Ishima T, Ukai Y, Yoshikuni Y, Kimura K.

Abstract

We have previously found that a cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) reversed the inhibition of cyclic AMP formation induced by the GABA(B) receptor agonist baclofen. The GABA(B) receptor has been implicated in the pathophysiology of depressive illness. The present experiment was designed to evaluate the antidepressant activity of NS-105 in the forced swimming and learned helplessness tests in rats. NS-105 (1-100 mg/kg, p.o.) significantly decreased immobility time in the forced swimming test, an effect similar to that of desipramine. Repeated administration of NS-105 also reversed the failure to escape in the shuttle-box test of rats previously exposed to inescapable footshock. Biochemical data showed that repeated administration of NS-105 increased the number of GABA(B) receptors in rat cerebral cortex without affecting the binding properties of beta-adrenoceptors and 5-HT2 receptors. In contrast to other antidepressants, NS-105 did not inhibit monoamine uptake in vitro, nor did it change monoamine concentrations in brain tissues or extracellular fluids. These findings suggest that NS-105, which lacks an effect on monoaminergic systems, has potent antidepressant activity, which may involve up-regulation of GABA(B) receptors after repeated administration.

 

 

Yeah, it definitely increases neurotransmitters through some GABAergic pathway among others, and seems to be a pretty good nootropic across the board with its ability to increase both GABAergic and glutaminergic neurotransmission as well as monoamine levels; I've never actually tried ginseng before, but now that I've learned more about it I'm going to place an order when I can afford it.

 

Thanks for sharing that study on NS-105, I could only find the one I posted and am interested in learning as much as possible about its activity at the GABA-B receptors; it seems it antagonizes the receptors but through chronic administration the receptor density gets increased as a form of tolerance buildup. It's very interesting to me because it's the only compound I actually know where to buy with studies pointing to it being a GABA-B antagonist; it is commonly known as fasoracetam. In the study I cited it antagonized the GABA-B receptors to reverse the memory deficit brought on by baclofen, and it is a well known nootropic, so it is a good start for trying out GABA-B agonists; the only problem is that it has activity at a lot of other receptors and isn't as selective a GABA-B agonist as SGS742 (or as well studied for its activity at that site, for that matter). I hope more studies are done on fasoracetam's activity at the GABA-B receptors, I'd love to know more about it.



#8 gamesguru

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Posted 12 October 2016 - 12:07 PM

Yes, besides ginseng it's the only widely available supplement.  Just reading your sentence on baclofen made me do a little research.  It turns out GABA(B) agonists have lots of redeeming qualities, such as promoting cognition, and continued responsible use may not even be anxiogenic.  This may help explain why as compared to teetotalers, light drinkers perform slightly better on cognitive assays and also exhibit fewer on markers of anxiety.  I'm not sure if ginseng is an agonist or antagonist, but either way it seems to be good, perhaps the GABAergic mechanism is completely dominated by the dopamine and glutamate effects.  As for other GABA(B) agonists... Baclofen has more studies showing a nootropic effect than an anxiogenic effect.  Same for phenibut, which though easily abused, can be more of a nootropic than a tranquilizer.  Phenibut in particular seems to be more effective than piracetam at restoring circulation, dispelling amnesia, and enhancing interhemispheral activity in the corpus collosum.  All these properties we would typically assign to piracetam, few would think phenibut could outshine piracetam in these respects.

Sci Rep. 2015; 5: 14474.

Baclofen mediates neuroprotection on hippocampal CA1 pyramidal cells through the regulation of autophagy under chronic cerebral hypoperfusion

Li Liu,1,*Chang-jun Li,2,4,*Yun Lu,2Xian-gang Zong,5Chao Luo,1Jun Sun,a,1 and Lian-jun Guob,2,3

Abstract

GABA receptors play an important role in ischemic brain injury. Studies have indicated that autophagy is closely related to neurodegenerative diseases. However, during chronic cerebral hypoperfusion, the changes of autophagy in the hippocampal CA1 area, the correlation between GABA receptors and autophagy, and their influences on hippocampal neuronal apoptosis have not been well established. Here, we found that chronic cerebral hypoperfusion resulted in rat hippocampal atrophy, neuronal apoptosis, enhancement and redistribution of autophagy, down-regulation of Bcl-2/Bax ratio, elevation of cleaved caspase-3 levels, reduction of surface expression of GABAA receptor α1 subunit and an increase in surface and mitochondrial expression of connexin 43 (CX43) and CX36. Chronic administration of GABAB receptors agonist baclofen significantly alleviated neuronal damage. Meanwhile, baclofen could up-regulate the ratio of Bcl-2/Bax and increase the activation of Akt, GSK-3β and ERK which suppressed cytodestructive autophagy. The study also provided evidence that baclofen could attenuate the decrease in surface expression of GABAA receptor α1 subunit, and down-regulate surface and mitochondrial expression of CX43 and CX36, which might enhance protective autophagy. The current findings suggested that, under chronic cerebral hypoperfusion, the effects of GABAB receptors activation on autophagy regulation could reverse neuronal damage.

 

Eksp Klin Farmakol. 2006 May-Jun;69(3):19-22.

[Comparative evaluation of the neuroprotective activity of phenibut and piracetam under experimental cerebral ischemia conditions in rats].

[Article in Russian]

Tiurenkov IN, Bagmetov MN, Epishina VV, Borodkina LE, Voronkov AV.

Abstract

The neuroprotective properties of phenibut and piracetam were studied in rats with cerebral ischemia caused by bilateral irreversible simultaneous occlusion of carotid arteries and gravitational overload in craniocaudal vector. In addition, the effects of both drugs on microcirculation in brain cortex under ischemic injury conditions were studied. Phenibut and (to a lower extent) piracetam reduced a neuralgic deficiency, amnesia, and the degree of cerebral circulation drop, and improved the spontaneous movement and research activity deteriorated by brain ischemia.

 

Eksp Klin Farmakol. 2009 Jan-Feb;72(1):57-9.

[Effect of phenibut on interhemispheric transmission in the rat brain].

[Article in Russian]

Borodkina LE, Molodavkin GM, Tiurenkov IN.

Abstract

Effects of the nootropic drug phenibut on the transcallosal potential amplitude in the sensomotor brain cortex have been studied in rats. It is established that a single administration of phenibut in a dose of 25 mg/kg (i.p.) increases the transcallosal response amplitude, thus improving the interhemispheric transmission. This effect, being an objective evidence of the nootrope activity, confirms the drug status and corroborates the positive action of phenibut on the learning and memory processes.



#9 Wizardrous

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Posted 12 October 2016 - 11:34 PM

 

Yes, besides ginseng it's the only widely available supplement.  Just reading your sentence on baclofen made me do a little research.  It turns out GABA(B) agonists have lots of redeeming qualities, such as promoting cognition, and continued responsible use may not even be anxiogenic.  This may help explain why as compared to teetotalers, light drinkers perform slightly better on cognitive assays and also exhibit fewer on markers of anxiety.  I'm not sure if ginseng is an agonist or antagonist, but either way it seems to be good, perhaps the GABAergic mechanism is completely dominated by the dopamine and glutamate effects.  As for other GABA(B) agonists... Baclofen has more studies showing a nootropic effect than an anxiogenic effect.  Same for phenibut, which though easily abused, can be more of a nootropic than a tranquilizer.  Phenibut in particular seems to be more effective than piracetam at restoring circulation, dispelling amnesia, and enhancing interhemispheral activity in the corpus collosum.  All these properties we would typically assign to piracetam, few would think phenibut could outshine piracetam in these respects.

Yeah, the GABA-B receptors seem to be one of theirs weird receptors where antagonism and agonism both seem to have antidepressant effects. The main problems with agonists at the receptor is addiction potential and possible amnesic effects; that's why I was initially intrigued by the receptors antagonists, because they seem to improve both mood and cognitive function through the opposite mechanism of action. I just really hope there will be selective GABA-B antagonists (like SGS742) available on the market at reasonable prices eventually, so I can try them out. As for GABA-B agonists, I've tried phenibut but it gave me lethargy and brain fog, but I think I'll try baclofen when I can afford some to see how it works for me; the fact that phenibut gave me brain fog by agonizing the GABA-B receptors is what makes me think that antagonizing those receptors with SGS742 or a different selective GABA-B antagonist will have the opposite effect and cause cognitive enhancement for me.



#10 normalizing

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Posted 15 October 2016 - 12:03 AM

is NS-105 sold anywhere as supplement?



#11 gamesguru

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Posted 15 October 2016 - 12:18 AM

norm, it IS fasoracetam.

http://nootropicsdep...racetam-powder/

#12 Neuronaut91

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Posted 12 December 2016 - 03:40 AM

Fasoracetam increases GABA B receptor density. Have we ever came to the conclusion whether its due to being a Gaba b antagonist or not?

I know for me, fasoracetam is not be of the best nootropics out there

#13 PeaceAndProsperity

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Posted 12 December 2016 - 10:47 AM

If what I am feeling in terms of social """fear"""/"""uncomfortableness""" is due to GABA-B receptor hypofunction (and it should be) then I must say it would be a horrible experience to take an antagonist.

Why not just take an agonist of whatever gaba-b opposes, like the mglur2/3, nmda, etc.? Like nac?

Btw might not be relevant but gaba agonists help me a lot and I have some major issues with too high glutamate (any food with glutamine/glutamate amino acid sends me into a rage and more) yet my learning is definitely not good. I also respond poorly to mglur2/3 agonists.

It's obvious though that autistic savants generally have low gaba activity which is what causes both their epilepsy but also their large memory retention and so on. 



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#14 PeaceAndProsperity

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Posted 12 December 2016 - 10:52 AM

Fasoracetam increases GABA B receptor density. Have we ever came to the conclusion whether its due to being a Gaba b antagonist or not?

I know for me, fasoracetam is not be of the best nootropics out there

Yes, we have. Fasoracetam is not a gaba-b antagonist. It's based upon a misunderstanding, it seems. It doesn't bind to gaba receptors but it causes a downstream effect via mglur2/3 agonism I believe. https://www.reddit.c...bab_antagonist/

 

Anyway, I've tried it and I don't like it. Maybe what I bought wasn't the real deal but I definitely did not feel the gaba-b upregulation and the drug itself gave me anxiety and an "out of it" feeling. Not comfortable. 







Also tagged with one or more of these keywords: gaba-b, agonist, nootropic, gamma-aminobutyric acid, gaba-b receptor, selective agonist, study, antidepressant, cognition enhancing, novel mechanism of action

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