20 replies to this topic

[chung_pao]

Hi

Since GABA and glutamate are the most common neurotransmitters in the nervous system, I was reading up on their physiology.

I understand that we often strive to stimulate the activity of cholinergic receptors, by means of alpga-gpc, racetams and so forth.
To me, this is completely understandable, being that glutamate is an excitatory neurotransmitter.

However, GABA is an inhibitory neurotransmitter.
Why would we wan't to increase its activity?

Wouldn't that depress the nervous system and many of the brain-regions implicated in memory and concentration?

Wikipedia:
GABAergic Drugs

• GABA_A receptor ligands
  
• Agonists/Positive allosteric modulators: alcohol,^[43][44][45] barbiturates, benzodiazepines, carisoprodol, chloral hydrate, etomidate, glutethimide, L-theanine, kava, methaqualone, muscimol,neuroactive steroids, z-drugs, propofol, scullcap, valerian, volatile/inhaled anaesthetics.
  Others: GABA (itself), L-glutamine, picamilon, progabide, tetanospasmin.

In theory, wouldn't these drugs have the opposite action of those enhancing cognitive function?
- How can something with the same mechanism of action as alcohol have nootropic properties?!

Something I'm probably missing and haven't found any good information are the locations of their inhibitory/excitatory action.

But maybe someone can put this into layman's terms for me?
Why do people striving for increased cognitive performance use substances to enhance both GABA, which is a inhibitory neurotransmitter and glutamate, an excitatory neurotransmitter?

How can an inhibitory neurotransmitter actually increase cognitive performance?

Thank you in advance for helping me sort this out.

Edited by chung_pao, 12 January 2013 - 03:37 AM.

[Simen]

GABA is indeed an inhibiting neurotransmitter. As such, it generally has a calming or sedating effect. Personally, I'm not sure if I would regard GABA drugs as cognitive enhancers per se. There are, however, a couple reasons why one might seek to enhance GABA in a nootropic regime: (1) in order to combat the negative effects of other noots or stimulants, e.g., L-theanine is supposed to work synergistically with caffeine, reducing caffeine jitters; (2) in order to decrease performance anxiety, increase motivation and mood, all factors that could improve cognitive performance.

However, I'd say most people who take GABA drugs don't do it to improve cognitive performance. Rather, they do it for the mood-altering and anxiolytic effects. Although strictly speaking, "nootropics" might mean cognitive enhancers, many of the supplements and drugs grouped under that banner don't really affect your cognitive functioning, but do affect emotion. Improving quality of life through reducing anxiety, improving sleep quality, and eliminating depression is quite worth it. These factors may indirectly affect cognitive performance, since happy, mentally and physically healthy individuals tend to do better than unhappy, anxious, unhealthy individuals, but that's just a pleasant side-effect.

So to summarize, I don't think most GABAergics are cognitive enhancers per se, nor do I think that is why people take them.

However, it should also be noted that cognitive enhancement is more complicated than simply increasing glutamate or exciting the nervous system in general. Adderall stimulates the nervous system but does not actually increase performance, only gives that illusion; modafinil, on the other hand, appears both to stimulate the nervous system and increase performance.

[Galaxyshock]

GABA is the filter. It helps you focus by filtering excess flow of stimulation (anxiety, hyper-excitation) and protects neurons. The brain is very balanced system, you can't just neglect any neurotransmitter without consequences. You don't drive a car by only pushing gas pedal. In general you however don't want strong, direct GABA-agonist, because their sedative/euphoria-inducing nature and nasty withdrawals from continuous use (alcohol, benzos, phenibut...). Instead substances with more of an indirect GABA-effect like L-theanine, Gotu Kola, Taurine, Ashwagandha, several adaptogens, can be useful and have nootropic action. Often they also synergize nicely with stimulants. But remember that for every action there is a reaction. We want to figure out what can give us good effect initially and can lead to positive changes in the long term and doesn't leave us worse even when ceasing the use. In the search for higher intelligence, don't lose your mind.

Edited by Galaxyshock, 12 January 2013 - 08:33 AM.

[Kompota]

I am 19 months into post-acute benzodiazepine withdrawal. The cognitive impairment (poor memory and focus) is the only symptom that still bothers me and holds me back to go on with my life. GABA agonists have a strong anticholinergic effect and I don't really get where the idea about GABAergics having nootropic properties comes from. There is a "cognitive" subunit within the GABA-A receptor complex and when agonized it leads to cognitive deficits.

The above means that the common "your cognitive issues are due to your anxiety" - mantra of psychiatrists and neurologists is simplistic and very wrong, often leading to more problems.

[chung_pao]

Thanks for some excellent advice and explanations.
Seeing GABA as the filter which draws the line between jittery & hypomanic and calm & focused helps.

The subjective "understanding" of GABA is easily achieved when comparing Tea and Coffee (provided the amount of caffeine is the same).
My preference lies with tea, now I understand why.

Does anyone know where I can read up on the pharmacology and anatomy of the GABA and other receptors in more detail? I love neuroscience.

@Kompota
Don't despair. Just keep striving for cognitive enhancement. I was so deeply obsessed with this quest because of what I lacked in my younger years; confidence and intelligence. I'm far from that now and actually in my first year of medical school. You can change your body any way you want to.

Edited by chung_pao, 12 January 2013 - 09:03 PM.

[Galaxyshock]

I am 19 months into post-acute benzodiazepine withdrawal. The cognitive impairment (poor memory and focus) is the only symptom that still bothers me and holds me back to go on with my life. GABA agonists have a strong anticholinergic effect and I don't really get where the idea about GABAergics having nootropic properties comes from. There is a "cognitive" subunit within the GABA-A receptor complex and when agonized it leads to cognitive deficits.

The above means that the common "your cognitive issues are due to your anxiety" - mantra of psychiatrists and neurologists is simplistic and very wrong, often leading to more problems.

I'm 9 months into post-acute withdrawal from GABAergic abuse (especially Phenibut) and also have cognitive issues. Did you have super cognition in acute phase because lack of gaba-agonism? I don't think so, and even if you had it would be hidden under all that stress from excess glutamate firing. The post-acute cognition impairment is mostly because of adaptive changes in brain due to the hyperactivity period. The brain doesn't simply "know what's wrong" and quickly upregulate those GABA-receptors so that everything could be back to normal. But you're right that direct heavy GABA agonists are cognition-dulling but GABA-modulators like L-theanine don't work quite that way. I haven't looked into how exactly they work but I would guess they alter the release of glutamate, gaba, ach and their affinity in different synapses. You do know that even Piracetam is a cyclic derivative of GABA?

Edited by Galaxyshock, 12 January 2013 - 10:48 PM.

[dear mrclock]

alcohol is direct agonist at GABA and there are many reports on ncbi and medical journals i read of possible neurogenesis from alcohol.

can you exaplin to me how this happens if you people disagree GABA agonism is related to nootropic ability ?

[Kompota]

alcohol is direct agonist at GABA and there are many reports on ncbi and medical journals i read of possible neurogenesis from alcohol.

can you exaplin to me how this happens if you people disagree GABA agonism is related to nootropic ability ?

Maybe that is true (haven't read about it), but I doubt it relates directly to GABA agonism. Also, the common term "neurogenesis" has many aspects. It could be that a substance may help restoring a certain system / receptor type or subtype / pathway, but at the same time have a damaging effect on others.

I'm 9 months into post-acute withdrawal from GABAergic abuse (especially Phenibut) and also have cognitive issues. Did you have super cognition in acute phase because lack of gaba-agonism? I don't think so, and even if you had it would be hidden under all that stress from excess glutamate firing. The post-acute cognition impairment is mostly because of adaptive changes in brain due to the hyperactivity period. The brain doesn't simply "know what's wrong" and quickly upregulate those GABA-receptors so that everything could be back to normal. But you're right that direct heavy GABA agonists are cognition-dulling but GABA-modulators like L-theanine don't work quite that way. I haven't looked into how exactly they work but I would guess they alter the release of glutamate, gaba, ach and their affinity in different synapses. You do know that even Piracetam is a cyclic derivative of GABA?

Actually during the acute phase the fog was so thick, I could barely perform 2+2 math. It has improved greatly since then, but there is still quite a way to go. Progress does happen for sure, but the pace is so slow, that it's discouraging.

One interesting aspect of post-acute withdrawal is the occurrence of "waves" (symptoms get worse) and "windows" (symptoms get better). Nowadays, the fluctuations from my baseline are rather small with only very few bad days far in between. Few days ago I had a great day when my cognition was very near to normal together with the rest of the symptoms (those are minor, only a confirmation of my "illness"). Would that be possible if the damage was of a permanent nature ?

[Galaxyshock]

Actually during the acute phase the fog was so thick, I could barely perform 2+2 math. It has improved greatly since then, but there is still quite a way to go. Progress does happen for sure, but the pace is so slow, that it's discouraging.

One interesting aspect of post-acute withdrawal is the occurrence of "waves" (symptoms get worse) and "windows" (symptoms get better). Nowadays, the fluctuations from my baseline are rather small with only very few bad days far in between. Few days ago I had a great day when my cognition was very near to normal together with the rest of the symptoms (those are minor, only a confirmation of my "illness"). Would that be possible if the damage was of a permanent nature ?

I've got those waves too they were especially strong around months 1-5 but have since flattened altough lately I've had some wierd symptoms reminding me of the acute withdrawal. I guess the brain keeps searching for homeostasis and it's a good sign. I doubt there's any major permanent damage and as long as there is some fluctuation going on recovery is still happening. How long were you on benzos daily? I took Phenibut and other GABAergics pretty much daily for 6 months altough had some small breaks there and would try lowering the dosage. Before that there was also some random usage one or couple times a week for several months. My Phenibut dosage never got very high though I think it was usually around 2-3 grams/day max.

For now I think keeping the basics straight is the best remedy. I've found that trying to fix these problems with heavy supplementing doesn't really work and just causes further confusion. Some adaptogens, mild herbs, a green superfood and a protein supplement are some things that seem to do good for long term. Keeping my days active with exercise, socializing and intellectual acitivities seems to be very therapeutic even though in the morning I struggle to get myself going and in the evening by brain tends to shut down in a wierd way. Sometimes my mind goes really numb when trying to focus on tasks (especially when trying to do some groupwork in school) or get confused but I'm hoping the "fake it till you make it" mentality will eventually deliver results. One thing I've also noticed to have very therapeutic effect is visiting my home town. It can't be a coincidence that around the times of those visits I've had the best windows of normality.

[Galaxyshock]

alcohol is direct agonist at GABA and there are many reports on ncbi and medical journals i read of possible neurogenesis from alcohol.

can you exaplin to me how this happens if you people disagree GABA agonism is related to nootropic ability ?

Alcohol also releases endogenous phenylethylamine, antagonizes NMDA, binds to serotonin and acetylcholine, among other action and its metabolites have affinity at dopamine in mesolimbic pathway. So it's not a "clean" GABA-agonist like benzos. But I think you're right that at least in small amounts even direct GABA-agonists can have positive reactions in the brain. Initially I found small amount of Phenibut rather nootropic - it prevented "emotional excitation" and thus making me able to focus on intellectual aspects profoundly. It was good for my poker sessions to keep calm and not get emotionally involved with the money and game, but I think at the same dulling of certain intuition. I also found that playing pool I made very collected decisions and controlled hits.

[dear mrclock]

alcohol is direct agonist at GABA and there are many reports on ncbi and medical journals i read of possible neurogenesis from alcohol.

can you exaplin to me how this happens if you people disagree GABA agonism is related to nootropic ability ?

Alcohol also releases endogenous phenylethylamine, antagonizes NMDA, binds to serotonin and acetylcholine, among other action and its metabolites have affinity at dopamine in mesolimbic pathway. So it's not a "clean" GABA-agonist like benzos. But I think you're right that at least in small amounts even direct GABA-agonists can have positive reactions in the brain. Initially I found small amount of Phenibut rather nootropic - it prevented "emotional excitation" and thus making me able to focus on intellectual aspects profoundly. It was good for my poker sessions to keep calm and not get emotionally involved with the money and game, but I think at the same dulling of certain intuition. I also found that playing pool I made very collected decisions and controlled hits.

i thought ethanol is a really potent direct gaba agonist and all the rest is weak reactions, like the serotonin and so on. do you think if ethanol does have such profound effect throughout the whole brain is what makes it so difficult to quit once you are used to it ? i mean, in order to get rid of it, you will need like 5 various meds to target each part of the brain seperately. correct me if im wrong ?

[kevinseven11]

I am 19 months into post-acute benzodiazepine withdrawal. The cognitive impairment (poor memory and focus) is the only symptom that still bothers me and holds me back to go on with my life. GABA agonists have a strong anticholinergic effect and I don't really get where the idea about GABAergics having nootropic properties comes from. There is a "cognitive" subunit within the GABA-A receptor complex and when agonized it leads to cognitive deficits.

The above means that the common "your cognitive issues are due to your anxiety" - mantra of psychiatrists and neurologists is simplistic and very wrong, often leading to more problems.

Your effects are NOT from gaba down regulation. Your effects are from glutamate excitotoxicity. They are related but not the same.

Also Ethanol interacts with alot of other receptors as well. Its mainly bad because its toxicity to neurons via aldehyde and others.

Also you should keep in mind that certain GABA subunits are good for memory while others are bad. If I remember correctly, Gaba A is good, the rest are bad.

Edited by kevinseven11, 13 January 2013 - 09:20 PM.

[dear mrclock]

1) so if you stop any GABA agonist, is it best to avoid anything that contains high amounts of glutamate and maybe somehow be able to manage the glutamate excitotoxicity that occurs in withdraw ? im talking about in theory, maybe save you from a severity but im sure its impossible to avoid it completely without some substance help.

2) GABA A good for memory ? i think anything that is agonist at GABA is acting in all areas, not specified like A or B or w/e. do you know if such possibility exist to get something and limit it to just GABA A ?

[dear mrclock]

any responses

[Kompota]

In my withdrawal so far, but particularly in acute withdrawal, processed foods high on glutamate - soy and soy derivates (soy protein, soy sauce), monosodium glutamate - have been revving my symptoms up to the extreme (brain fog got worse as well). On the contrary I experimented with some weak GABA receptor antagonists (wormwood, Ginko) and a single dose of Flumazenil for the test, without an ill effect. So maybe the poster above does really have a point.

Agonizing GABA-A is BAD for memory and cognition overall. Here is the explanation:

http://www.longecity...nt/#entry530672

[dear mrclock]

1) so if you stop any GABA agonist, is it best to avoid anything that contains high amounts of glutamate and maybe somehow be able to manage the glutamate excitotoxicity that occurs in withdraw ? im talking about in theory, maybe save you from a severity but im sure its impossible to avoid it completely without some substance help.

2) GABA A good for memory ? i think anything that is agonist at GABA is acting in all areas, not specified like A or B or w/e. do you know if such possibility exist to get something and limit it to just GABA A ?

any responses ?

[PTShapeShifter]

I am 19 months into post-acute benzodiazepine withdrawal. The cognitive impairment (poor memory and focus) is the only symptom that still bothers me and holds me back to go on with my life. GABA agonists have a strong anticholinergic effect and I don't really get where the idea about GABAergics having nootropic properties comes from. There is a "cognitive" subunit within the GABA-A receptor complex and when agonized it leads to cognitive deficits.

The above means that the common "your cognitive issues are due to your anxiety" - mantra of psychiatrists and neurologists is simplistic and very wrong, often leading to more problems.

I'm 9 months into post-acute withdrawal from GABAergic abuse (especially Phenibut) and also have cognitive issues. Did you have super cognition in acute phase because lack of gaba-agonism? I don't think so, and even if you had it would be hidden under all that stress from excess glutamate firing. The post-acute cognition impairment is mostly because of adaptive changes in brain due to the hyperactivity period. The brain doesn't simply "know what's wrong" and quickly upregulate those GABA-receptors so that everything could be back to normal. But you're right that direct heavy GABA agonists are cognition-dulling but GABA-modulators like L-theanine don't work quite that way. I haven't looked into how exactly they work but I would guess they alter the release of glutamate, gaba, ach and their affinity in different synapses. You do know that even Piracetam is a cyclic derivative of GABA?

@ Kompota -- in your journey with GABAergic use, did you use Picamilon? If so, how did it work for you? How does it compare to Phenibut? THanks in advance for your valuable experience based imput here.

PTShapeShifter

[brainslugged]

1) so if you stop any GABA agonist, is it best to avoid anything that contains high amounts of glutamate and maybe somehow be able to manage the glutamate excitotoxicity that occurs in withdraw ? im talking about in theory, maybe save you from a severity but im sure its impossible to avoid it completely without some substance help.

2) GABA A good for memory ? i think anything that is agonist at GABA is acting in all areas, not specified like A or B or w/e. do you know if such possibility exist to get something and limit it to just GABA A ?

If you stop a GABA agonist, you should do it slowly, reducing the dosage over time. If it was reduced slowly and not an acute withdrawal, they probably would have little to no lasting effect. Acute withdrawal of benzos is also dangerous because of heart problems that could occur, so unless if you have the chance at all, you should taper. Unfortunately, people in prison and some life situations don't have the chance.

Also, the GABA A drugs that are good for memory are inverse agonists, not plain agonists, meaning that they bind to the site, but produce the opposite effect (as opposed to antagonists which just block the receptors). It has to be specific to certain subtypes, though. Some subtypes increase anxiety or cause convulsions.

http://en.wikipedia.org/wiki/ZK-93426
http://en.wikipedia....wiki/Suritozole
http://en.wikipedia.org/wiki/%CE%915IA
http://en.wikipedia.org/wiki/L-655,708

[Kompota]

@ Kompota -- in your journey with GABAergic use, did you use Picamilon? If so, how did it work for you? How does it compare to Phenibut? THanks in advance for your valuable experience based imput here.

PTShapeShifter

No, I took Xanax and then Clonazepam - the "heavy artillery" of the GABAergic family. Biggest error in my life.

1) so if you stop any GABA agonist, is it best to avoid anything that contains high amounts of glutamate and maybe somehow be able to manage the glutamate excitotoxicity that occurs in withdraw ? im talking about in theory, maybe save you from a severity but im sure its impossible to avoid it completely without some substance help.

2) GABA A good for memory ? i think anything that is agonist at GABA is acting in all areas, not specified like A or B or w/e. do you know if such possibility exist to get something and limit it to just GABA A ?

If you stop a GABA agonist, you should do it slowly, reducing the dosage over time. If it was reduced slowly and not an acute withdrawal, they probably would have little to no lasting effect. Acute withdrawal of benzos is also dangerous because of heart problems that could occur, so unless if you have the chance at all, you should taper. Unfortunately, people in prison and some life situations don't have the chance.

Also, the GABA A drugs that are good for memory are inverse agonists, not plain agonists, meaning that they bind to the site, but produce the opposite effect (as opposed to antagonists which just block the receptors). It has to be specific to certain subtypes, though. Some subtypes increase anxiety or cause convulsions.

http://en.wikipedia.org/wiki/ZK-93426
http://en.wikipedia....wiki/Suritozole
http://en.wikipedia.org/wiki/%CE%915IA
http://en.wikipedia.org/wiki/L-655,708

That is what I was trying to explain. Sadly, those selective inverse agonists are not available on the market yet.

[treonsverdery]

Another GABA perspective is that actual ingested GABA stays on the body side of the blood brain barrier, those people that take actual GABA supplements directly are apparently doing it to improve physique as it causes human growth hormone release. I have wondered if taking a bunch of a remodelled molecular version of a brain active chemical that stays on the body side of the blood brain barrier could cause the organism to produce a compensation effect bodywide, which has a slight chance of upproducing a stimulant at the brain.

lots of bodyside only gaba
organism compensates producing more of some chemical that modifies GABA receptor activity or possibly even norepinepherine
brain also just happens to absorb norepinepherine or the different GABA receptor active chemical
thus ingesting GABA powder could cause brain stimulation

this reference http://www.hghhelp.info/gaba.php says
Clinical tests have proven GABA to be beneficial in improving one’s sleep, leading to greater elasticity in the skin, better memory retention, loss of body fat, and a gain in lean body mass. It has also proven to be an effective anti depressant. Most of these effects occur because of its natural stimulation of the production and release of HGH


A plausible approach to creating things with pleasant diazopene effects that actually ncreases the ability to feel the effects, durably even after ceasing the drug is to create a NGF nerve growth factor peptide linked to a benzodiazepine receptor molecule. Everywhere the Benzo goes the Nerve growth factor goes as well stimulating neural growth which causes greater ability at that emotional or cognitive effect. Thus NGFampakine could cause greater intelligence from area specific neural growth at the various racetam receptors. Supporting this idea is that the Doogy mouse which is twice as intelligent is just a mouse genetically modified to produce more NGF, so more NGF everywhere actually causes greater neural function.

recreational drug enthusiasts could actually try making diacetylGABA it might pass the blood brain barrier to produce a benzodiazapene like effect, although just ordering actual benzodiazapenes is more sensible.

Edited by treonsverdery, 05 April 2013 - 05:04 PM.

[Galaxyshock]

recreational drug enthusiasts could actually try making diacetylGABA it might pass the blood brain barrier to produce a benzodiazapene like effect, although just ordering actual benzodiazapenes is more sensible.

There is already an effective GABA-derivate, β-Phenyl-GABA or Phenibut which works well but is quite a habit forming substance and can have benzo-like withdrawals. Picamilon is a combination of niacin and GABA, and also able to cross the bbb.