Segra International | GABA
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Segrapedia

GABA

By Kevin She
28 Dec 2015

GABA dietary supplements have been touted by some to aid anxiety, nervousness, and stress or to improve sleep, among other claims such as improving cognitive function or to promote muscle and strength gain.

Does dietary GABA actually help anxiety, insomnia, and other neurological conditions?

Almost certainly not. Does dietary GABA supplementation have body building benefits? Possibly, but the evidence is weak and often misconstrued in order to sell product. Are there any benefits to dietary GABA? There’s some interesting experimental research in GABA and autoimmune diseases, but the immune effects of dietary GABA in human patients is not yet well documented.

What is GABA?

Figure 1. GABA: What’s Going On?

The figure is a space filling model of a single GABA molecule. The blue ball represents a single nitrogen atom, the dark grey balls are carbon atoms, and the two red balls are oxygen atoms, and the white balls are hydrogen atoms. It takes 1 x1022 molecules of
GABA to weigh as much as a Canadian dime (1.3 x1022 molecules per American dime) – that’s 1 followed by 22 zeros!

GABA is the acronym for gamma-amminobutyric acid (γ-aminobutyric acid), an amino acid. Amino acids are small molecules that have an amino end (the nitrogen atom) and a carboxyl end (the carbon with atom with two oxygen atoms attached to it). About 500 different naturally occurring amino acids have been described. Proteins in humans, animals, and plants are commonly made from 22 different proteinogenic (makes proteins) amino acids, although there are rare exceptions. In humans, our cells are able to make 13 of these from other molecules but need to have enough of the other 9 amino acids in our diet to remain healthy.

While GABA is an amino acid, it is not used to make proteins. Our cells are able to easily make GABA from glutamic acid on demand (in our bodies and in whole foods, glutamic acid usually exists in the form of glutamate), a very common and abundant amino acid. GABA is also abundant in some foods such as tomatoes and berries, and is also found in fermented foods where it is made by the fermenting bacteria. Similarly, many black teas are fermented as part of their production process and GABA is produced by these microorganisms as well.

Why do bacteria and plants make GABA? It’s not known for certain, but GABA is very easily made from glutamate, a very common amino acid. Some research suggest that converting glutamate to GABA uses up protons [free hydrogen atoms] and this is one of many ways to maintain the correct pH balance within cells. There is some evidence that some plants can use GABA as a way to send messages between cells in different parts of the plant and is involved in growth and fertility.

In mammals, including humans, GABA is made primarily in the brain, other nerve tissues, and in a select few other cells as well. The main role of GABA in humans is as an inhibitory neurotransmitter. Neurotransmitters are small molecules that send messages from one nerve cell to another. Inhibitory neurotransmitters encourages neurons (a type of cell in the brain) not to activate and pass on messaging whereas excitatory neurotransmitters encourages neurons to activate and pass on messaging.

Neurotransmission is extraordinarily complicated and very highly controlled. The human brain has about 100 billion neurons and approximately 150 trillion synapses, the points of contact between neurons through which they communicate with one another. Each neuron has about 1,500 synapses although some have considerably more and some considerably less. 150 trillion is a very large number, about 500 times the total number of stars in the entire Milky Way galaxy. Approximately 30% of these synapses are inhibitory and the rest are excitatory. Epilepsy and seizures are an extreme example of improper neurotransmission, usually a runaway effect of too much, or otherwise uncontrolled, excitatory neurotransmission.

Neurons in the brain are constantly communicating with one another in a very highly regulated manner and the incredibly complex constellation of inhibitory and excitatory signals are carefully balanced in order for us to properly perceive and respond to the world around us. When GABA is released into asynapse, it is very quickly pumped back into cells for re-use or is very rapidly broken down by GABA transaminase, an enzyme, to stop its effects.

At inhibitory synapses, the pre-synaptic neuron has stores of vesicles (small bags) filled with GABA and glycine (another amino acid) to be released into the synaptic cleft between the two neurons. At these synapses, the post-synaptic neuron has receptors for the amino acid GABA and opens when it senses its presence (and the presence of glycine). GABAA receptors are ionotropic meaning that they let particular ions through when they sense their ligand, in this case, GABA. GABAA receptors let in chloride ions which are negatively charged. Neurons are constantly pumping different ions into or out of their bodies to maintain an overall negative membrane potential, the difference in ionic concentration between the inside and outside of the cell. When excitatory receptors are stimulated by their neurotransmitter, they let in a net number of positively charged ions into the cell and increase the membrane potential. When the membrane potential reaches a certain threshold, it triggers the progressive opening of other ion channels and causes the cell to fire and propagates the signal to other neurons. Simplistically, GABAA receptors, when stimulated with GABA and allows negatively charged ions to enter the cell, help maintain a negative membrane potential and counteract the effects of excitatory receptor signaling.

GABAA receptors are complex proteins made up of five intertwining subunits that forms a pore that can open and close. Normally, the pore is closed but when GABA and glycine transiently binds to specific parts of the receptor this changes the shape of the receptor causing the pore to transiently open and allows negatively charged chloride ions to pass through. In addition to these sites, other small molecules can bind to GABAA receptors, usually at different parts than those that GABA and glycine bind to. Alcohol, barbiturates, benzodiazepines, chloral hydrate, and others can affect GABAA receptors. These can either directly cause the receptor to open its pore or, more commonly, change how easily or for how long the pore opens in response to GABA. Molecules that change the properties of GABAA receptors but not directly cause them to open are called allosteric modulators. Many herbs have small molecules that can pass through the blood-brain-barrier either directly or are escorted through via active transporter proteins and allosterically modulate GABAA receptor function. Such herbs include but are not limited to hops, kava, skullcap, and valerian root.


What about dietary GABA supplements for neurological conditions?

Signaling in the brain is extraordinarily complex, very highly regulated, each signal uses only a minute amount of neurotransmitter, and the neurotransmitters are very quickly removed after the signal is sent. Many foods contain abundant amounts of GABA and dietary GABA can be absorbed through the stomach and into the blodstream; if GABA from food can directly affect neurons in the brain, the brain would not be able to function properly.

The chemical makeup and structure of GABA has been known for a very long time and it was first chemically synthesized in 1883. However, it was only known as a metabolic product in plants and microbes. It wasn’t until the 1950’s that GABA was recognized to be an inhibitory neurotransmitter in the brain. Oddly enough, it was demonstrated definitively in 1966 that GABA given orally cannot enter the brain (Fisher &al., 1996).

In the 19th century, bacteriologist Paul Ehrlich noted that some intravenously injected dyes leaked out of intact capillaries, small blood vessels, and into tissues and organs of the body. However, this was not true for the brain. His student, Edwin Goldmann, was able to demonstrate that the vessels supplying blood to the brain was different than other blood vessels. It wasn’t until the 1960’s with the advent of electron microscopy that Tom Reese, Morris Karnovsky, and Milton Brightman were able to show that the blood vessels serving the brain had an additional layer around them that prevent the passage of certain materials (Reese & Karnovsky, 1967, Brightman & Reese, 1969). This additional layer is called the ‘blood-brain-barrier.’ Neurons require and rely on large amounts of glucose in order to function. Constantly pumping ions into and out of cells against the flow to create a membrane potential requires an extraordinary amount of energy. Interestingly, in addition to blocking GABA and many other small molecules, the blood-brain-barrier also blocks the passive transfer of glucose into the brain. This paradox is explained by the presence of specific active transporters – for glucose and other critical molecules and ions – that uses a small amount of energy to specifically move these molecules from one side of the blood-brain-barrier to the other.

Anxiety, insomnia, and other neurologic conditions are indeed related to dysfunctions or perturbations in inhibitory neurotransmission involving GABA. Due to the blood-brain-barrier, however, dietary GABA cannot reach the brain and bring about calmness or sleep. Also, since neurotransmission is so tightly regulated, excess GABA is rapidly removed or degraded. Additionally, the causative dysfunctions or perturbations are generally very locationally specific and are typically minute. An analogy would be one wonky gear in a mechanical wristwatch causing the watch to run fast. Flooding the brain with GABA would be like using a pipewrench to try to fix that one tiny gear.

However, other small molecules such as alcohol (ethanol), barbiturates, benzodiazepines, or those found in some herbs can either cross the blood-brain-barrier directly or can be transported past this barrier. At the correct doses, these small molecules can modulate properties of GABAA receptors and return neuronal signaling closer to normal. Because these molecules affect the entire brain whereas the dysfunctions or perturbations are typically very locationally, dosing is very important. For example, while barbiturates are very effective for sedation, reducing anxiety, and as an anticonvulsant the therapeutic window – the dose where the desired effect is produced with acceptable severity of side effects – for barbiturates is incredibly narrow and lethal overdoses are easily achieved since they modulate the properties of GABAA receptors very strongly and at higher doses can directly cause GABAA receptors to open, and remain open for inappropriately long periods of time.

There are a number of plant derived products that have been clinically proven to benefit symptoms of anxiety or to help decrease the time of sleep onset and help maintain sleep throughout the night. For example, small molecules within hops (humulone or alpha-acids) and valerian root (valerenic acid) can pass through the blood-brain-barrier and modulate the properties of GABAA receptors response to the brain’s own GABA. In contrast with barbiturates these small molecules changes the function of GABAA receptors more mildly and do not directly open GABAA receptors even at very high doses. These properties contribute to a much wider therapeutic window with undetectable, fewer, or less severe side effects even at very high doses.

Does dietary GABA help with gaining muscle mass for strength and endurance training?

Human growth hormone, known technically as somatotropin, is produced in and secreted by somatotropic cells in the anterior pituitary gland, to which dietary GABA does theoretically have access. Growth hormone is anabolic in itself and it also stimulates the production of insulin-like growth factor 1 which has further anabolic effects. These effects can include calcium retention which strengthens and increases the mineralization of bone, increase muscle mass through sarcomere hypertrophy, increases protein synthesis, increases the production of glucose in the liver, and promotes the breakdown of lipids (fats).

Indeed, dietary GABA can increase serum growth hormone levels but there are a number of caveats.

The doses required to increase serum growth hormone are large; between 5 and 18g (Cavagnini &al., 1980, Powers &al., 2008). At these doses, the serum level of growth hormone does increase and peaks at 3 hours and returned to baseline 3 hours later.

Of particular interest is that dietary GABA at these doses increases growth hormone levels by about 4 times over baseline. Actually doing some exercise increases serum growth hormone levels by about 16 times over baseline. Unfortunately, taking GABA and exercising isn’t much better than just exercising. Also, exercise stresses muscle, bone, and tendon cells such that they are primed to respond to anabolic signals. Without the exercise, raising serum growth hormone levels aren’t expected to be very effective.

Additionally, there is rapid desensitization; GABA supplements rapidly lose the ability to increase serum growth hormone levels when taken more than a few days and there is very rapid clearance of GABA from the serum with a half-life of about 20 minutes (Gamel-Didelon &al., 2003). GABA is an amino acid, other amino acids such as arginine, when taken in similar doses, can also transiently increase serum growth hormone levels by about 3 times over baseline (Paddon-Jones &al., 2004, Kanaley 2008).

While taking GABA supplements are likely not to be effective for helping to increase strength and muscle mass, its quick elimination rate from the bloodstream suggests that it is unlikely to be harmful unless there you are predisposed or have an existing kidney condition.


Potential benefits of dietary GABA?

Recently there has been a flurry of popular media reports suggesting that GABA producing intestinal microbes can affect one’s mood through modulating the function of the brain. This conclusion is confused at best or perhaps even intentionally misleading. The connection between intestinal microbe-derived GABA and brain function is specious.
That’s not to say, however, that a healthy intestinal flora (collection of microbes) does not affect brain function and mental health. It is well known that there is a gut-brain axis where conditions in the intestines really do affect brain function and mental health. However, the exact mechanism isn’t entirely known although early research from patients undergoing radiation/chemotherapy provides some clues.

Radiation/chemotherapy work based on targeting rapidly dividing cells, typically by disrupting DNA replication and/or repair; cancer cells grow and divide much more rapidly than most other cells in the body. However, there are certain cells in the body that grow and divide quite quickly such as intestinal epithelial cells that line the intestine. Diarrhea and nausea are common side effects of radiation/chemotherapy and is caused by damage to these cells in the intestine. These damaged cells become “leaky” and more microbial products (the PAMPS mentioned in the protein article) are released into the bloodstream than usual where they are encountered by circulating immune cells which respond by producing pro-inflammatory cytokines and other pro-inflammatory signals. These in turn can lead to increases in the production of cortisol, a steroid hormone that indicates stress, which can access neurons in the brain and alter their function.

Regardless, there is emerging data that GABA may be beneficial for a number of conditions such as high blood pressure (hypertension) and diabetes, although much of the research has only been performed in animal models. Of the human clinical trial studies, some have reported benefits to people with high-end-of-normal or borderline hypertensive patients but the effects, while significant, are not large (Shimada &al., 2009).

References

1. Brightman, MW., & Reese, TS. Junctions between intimately opposed cell membranes in the vertebrate brain. J. Cell Biol. 1969; 40: 648-77

2. Cavagnini, F., Invitti, C., Pinto, M., Maraschini, C., Di Landro, A., Dubini, A., & Marelli, A. Effect of acute and repeated administration of gamma aminobutyric acid (GABA) on growth hormone and prolactin secretion in man. Acta Endocrinol (Coopenh) 1980; 93(2): 149-54

3. Fisher, MA., Gagen, DQ., & Colvin, RB. Aminooxyacetic acid: interactions with gamma-aminobutyric acid and the blood-brain barrier. Science 1966; 153(3744): 1668-70

4. Gamel-Didelon, K., Kunz, L., Fohr, KJ., Gratzl, M., & Mayerhofer, A. Molecular and physiological evidence for functional gamma-aminobutryic acid (GABA)-C receptors in growth hormone secreting cells. J. Biol. Chem. 2003; 2778(22): 20192-5

5. Kanaley, JA. Growth hormone, arginine and exercise. Curr. Opin. Clin. Nutr. Metab. Care 2008; 11(1):50-4

6. Paddon-Jones, D., Borsheim, E., & Wolfe, RR. Potential ergogenic effects of arginine and creatine supplementation. J. Nutr. 2004; 134(10, Suppl): 2888S-94S

7. Powers, ME., Yarrow, JF., McCoy, SC., Borst, SE. Growth hormone isoform responses to GABA ingested at rest and after exercise. Med. Sci. Sports Exerc. 2008; 40(1): 104-10

8. Reese, TS & Karnovsky, MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 1967; 34: 207-17

9. Shimada, M., Hasegawa, T., Nishimura, C., Kan, H., Kanno, T., Nakamura, T., Matsubayashi, T. Anti-hypertensive effect of gamma-aminobutyric acid (GABA)-rich Chlorella on high-normal blood pressure and borderline hypertension in placebo-controlled double blind study. Clin. Exp. Hypertens. 2009; 31(4): 342-54