Snake oil - Oral GABA supplements

[panic_down_under]

Oral GABA supplements are often promoted as an effective treatment for anxiety disorders and/or as a 'natural' alternative to benzodiazepines. Unfortunately, they are snake oil.

No functioning brain is deficient in the amino acid GABA (γ-aminobutyric acid) which is the main (usually) inhibitory neurotransmitter of the brain. It is a by-product of the Krebs/citric acid cycle which converts glucose to Adenosine triphosphate (ATP) the main energy source of brain cells (and other cells of the body). As a result the brain is so awash with GABA (up to a 1,000 times more than of neurotransmitters like serotonin [1]) the blood-brain-barrier contains billions, perhaps trillions, of tiny molecular pumps to remove the excess into the blood stream for disposal [2].

What the anxious brain lacks is benzodiazepine binding sites on GABA receptors which increase the effectiveness of these receptors [3]. This is also the case for some types of epilepsy [4]. Trying to overcome this deficiency by adding more GABA is akin to trying to fix faulty spark plugs by overfilling the petrol/gas tank. Benzodiazepines work by ensuring the benzodiazepine binding sites which do exist function at maximum efficiency, not by increasing brain GABA levels as is often claimed.

References:

[1]
Olsen RW, DeLorey TM
GABA Synthesis, Uptake and Release in
Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition
George J Siegel ed., Lippincott Williams & Wilkins, 1999
ISBN-13: 978-0397518203

[2]
Kakee A, Takanaga H, Terasaki T, et al (2001)
Efflux of a suppressive neurotransmitter, GABA, across the blood-brain barrier.
J Neurochem. Oct;79(1):110-8 [Abstract | Full text PDF]

Terasaki T1, Hosoya K. (1999)
The blood-brain barrier efflux transporters as a detoxifying system for the brain.
Adv Drug Deliv Rev. 1999 Apr 5;36(2-3):195-209 [Abstract]

[3]
Hasler G, Nugent AC, Carlson PJ, et al. (2008)
Altered cerebral gamma-aminobutyric acid type A-benzodiazepine receptor binding in panic disorder determined by [11C]flumazenil positron emission tomography.
Arch Gen Psychiatry. Oct;65(10):1166-75 (Abstract)

Geuze E, van Berckel BN, Lammertsma AA, et al. (2007)
Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder.
Mol Psychiatry. 2008 Jan;13(1):74-83 (Abstract)

Cameron OG, Huang GC, Nichols T, et al. (2007)
Reduced gamma-aminobutyric acid(A)-benzodiazepine binding sites in insular cortex of individuals with panic disorder.
Arch Gen Psychiatry. Jul;64(7):793-800. (Abstract)

Bremner JD, Innis RB, Southwick SM, et al. (2000)
"Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder."
Am J Psychiatry Jul; vol 157(7):1120-6 (Abstract)

Bremner JD, Innis RB, White T, et al (2000)
"SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder."
Biol Psychiatry Jan 15; vol 47(2):96-106 (Abstract)

Malizia AL. (1999)
"What do brain imaging studies tell us about anxiety disorders? "
J Psychopharmacol Dec; vol 13(4):372-8 (Abstract)

Morimoto K. 1999
Benzodiazepine receptor imaging in the brain: recent developments and clinical validity
Kaku Igaku. May;36(4):307-13. (Abstract)

Malizia AL, Cunningham VJ, Bell CJ, et al. (1998)
"Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study." Arch Gen Psychiatry Aug; vol 55(8):715-20 (Abstract)

Tokunaga M, Ida I, Higuchi T, Mikuni M. (1997)
"Alterations of benzodiazepine receptor binding potential in anxiety and somatoform disorders measured by 123I-iomazenil SPECT." Radiat Med May-Jun; vol 15(3):163-9 (Abstract)

Uchiyama M, Sue H, Fukumitsu N, et al. (1997)
"Assessment of cerebral benzodiazepine receptor distribution in anxiety disorders by 123I-iomazenil-SPECT: comparison to cerebral perfusion scintigraphy by 123I-IMP."
Nippon Igaku Hoshasen Gakkai Zasshi Jan; vol 57(1):41-6 (Abstract)

[4]
Vivash L, Tostevin A, Liu DS, et al. (2011)
"Changes in hippocampal GABAA/cBZR density during limbic epileptogenesis: relationship to cell loss and mossy fibre sprouting."
Neurobiol Dis. Feb;41(2):227-36. (Abstract)

Morimoto K. (1999)
"Benzodiazepine receptor imaging in the brain: recent developments and clinical validity."
Kaku Igaku May; vol 36(4):307-13 (Abstract)

Savic I, Pauli S, Thorell JO, Blomqvist G. (1994)
[i]"In vivo demonstration of altered benzodiazepine receptor density in patients with generalised epilepsy."
J Neurol Neurosurg Psychiatry. Jul;57(7):797-804. [Abstract]

[lifeofbrian]

What's your opinion on this video?

https://youtu.be/eOScYBwMyAA

[MyNameIsTerry]

Hi Ian,

GABA was banned in the UK some years ago as the date rape drug GHB was in the news a lot with calls to remove it. GABA got banned along with it despite the lack of science to compare them beyond mechanism of action. Because of the ban, it can't be sold in the UK but some US sellers pose as UK sellers (one big company uses it's post office box address in London) so people think it's coming from inside the UK. It then just comes from the US branch of the company and can be intercepted by Customs and confiscated.

The funny thing is, prior to this I did use GABA powder briefly for my weight training. From the very first dose I had a flushed face and my mood became positive & focused with minutes. Since this couldn't pass the BBB, I find that interesting.

This was long before my anxiety and I only purchased it for the merits of training. I can't recall positive mental benefits being claimed but this must have been nearly 20 years ago. It wouldn't have been placebo effect as I wasn't aware that was part of the effect in the first place.

I can't remember the reasons for taking it as a bodybuilding supplement. Likely it would be the ATB to increase training intensity.

I've read about GABA potentially "leaking" through gaps in the BBB, in a similiar way to the leaky gut issue. It seemed unconfirmed at this point and lacking credibility.

I wondered in my case whether it was the gut? Science is still working out the importance of the gut in influencing the brain more directly. Studies have shown how the gut can trigger the fight or flight if the brain-to-gut channel is severed in rats but I don't know about positive influences.

[panic_down_under]

GABA got banned along with it despite the lack of science to compare them beyond mechanism of action.

Good things do sometimes come from dubious decisions.

I wondered in my case whether it was the gut? Science is still working out the importance of the gut in influencing the brain more directly. Studies have shown how the gut can trigger the fight or flight if the brain-to-gut channel is severed in rats but I don't know about positive influences.

The enteric nervous system does have GABA receptors, but it is still unclear what they do, although it may have some connection to the immune system (which is also implicated in anxiety and depression). Some gut microbes also need GABA. So a beneficial action on anxiety via the gut is a possibility.

It might also have been something else in the supplement. Adulteration with pharmaceutical drugs is not unheard of and seems to be more prevalent in products aimed at the body building market.

I've read about GABA potentially "leaking" through gaps in the BBB, in a similiar way to the leaky gut issue. It seemed unconfirmed at this point and lacking credibility.

I doubt it. It would make the brain a hostage of what we ate. Plus, even if GABA molecules were to leak through they would have to avoid being immediately pulled back out by the GABA pumps, and travel to the right synapses at just the right time and even then they would be competing with all the other GABA molecules being produced in the neurons.

[MyNameIsTerry]

When I took GABA it was very basic stuff. It wasn't muddied with all the extracts they bulk together these days. I can't remember there being any beta alanine in it, which causes flushing for the same few minutes, but I guess it's a possibility.

What's the deal with all these GABA enriched teas & foods in Japan, Ian? I was ordering some tea and spotted them but I've never really heard of them. I think they must be quite niche still in the UK. I'm guessing you will know a lot more about them with being closer and I gather they've been around for decades?

There surely isn't any credible science going back that far to support them?

All tea has GABA in it and I think most have L-Theanine. The latter seems the more likely to be doing anything but I don't know if they enrich it along with the GABA?

GABA rice was another. Never heard of it before.

So, maybe those receptors you mentioned have some use in this? Experiments in rats show how the gut can influence the brain's fight or flight when the brain-gut channel has been severed. When I read that study I can't recall mention of specific neurotransmitters but this is going to be where it becomes more about their more general roles i'm guessing?

[panic_down_under]

What's the deal with all these GABA enriched teas & foods in Japan, Ian? I was ordering some tea and spotted them but I've never really heard of them. I think they must be quite niche still in the UK. I'm guessing you will know a lot more about them with being closer and I gather they've been around for decades?

There surely isn't any credible science going back that far to support them?

Not that I'm aware of and I doubt there ever will be. Even if it were possible to get GABA through the BBB it would have to avoid the efflux pumps in the BBB trying to suck it back out then get to the right neurons where it would have to compete with all the local GABA. It is probably not a coincidence that GABA in forms which can penetrate the BBB such as the pregabalin and vigabatrin analogues don't activate GABA receptors in the brain, but target positive ion channels instead.

So, maybe those receptors you mentioned have some use in this?

GABA receptors in the gut may have some affect on the brain via the enteric nervous system, but I'm cautious about overstating a role for oral GABA as I think most brains are well protected against becoming hostage to what we eat. A few may be vulnerable because of genetic factors, or perhaps during some illnesses which trigger blood vessel inflammation, etc, but they would be very much the exception.

Imho, GABA supplements are best taken by flushing them down the 'S' bend directly from the packet. That way you get the exact same outcome without the risk of choking while swallowing them. The same is true for L-Tryptophan and 5-HTP.