GABA: What It Is and How It Works

Gamma-aminobutyric acid, or GABA, is the main inhibitory neurotransmitter of the central nervous system. On sports-nutrition shelves it appears as a supplement "for sleep and relaxation." But does GABA from a capsule work the same way as GABA synthesized in the brain? The editorial team explains what this substance is, how it acts, and where physiology ends and marketing begins.

What GABA Is

GABA is a non-proteinogenic amino acid, meaning it is not part of proteins but performs a signaling function. It was discovered in the mammalian brain in 1950, and it was later proven to be a key inhibitory transmitter: most neurons of the brain are directly or indirectly under its control. The history of its discovery is described in detail by Bowery and Smart (2006).

The nervous system constantly balances between excitation and inhibition. The main excitatory transmitter is glutamate, the main inhibitory one is GABA. When the balance shifts toward excitation, anxiety and insomnia arise, and in extreme cases — seizures. Insufficient excitation, on the contrary, manifests as sluggishness and drowsiness.

That is precisely why a large group of medications acts on the GABA system: benzodiazepines, barbiturates, some hypnotics, antiepileptic drugs, and muscle relaxants. Alcohol also largely realizes its sedative effects through GABA receptors.

In addition to the brain, GABA is present in peripheral tissues: in the pancreas, intestine, and adrenal glands. Its role there is less studied, but it is precisely peripheral effects that may partly explain why the GABA supplement produces certain noticeable effects, despite the difficulties with entering the brain.

How the body synthesizes and breaks down GABA

In neurons, GABA is formed from glutamate under the action of the enzyme glutamate decarboxylase (GAD). The cofactor of this enzyme is pyridoxal 5-phosphate — the active form of vitamin B6. In other words, the most important excitatory transmitter is literally the "raw material" for the inhibitory one.

After being released into the synaptic cleft, GABA binds to receptors and is then quickly taken back up by special transporters — into neurons and glial cells. There it is broken down by the enzyme GABA transaminase, and the breakdown products return to the Krebs cycle. This "GABA shunt" links neurotransmission to the cell's energy metabolism.

Each of these steps can be affected pharmacologically. For example, the antiepileptic drug vigabatrin irreversibly blocks GABA transaminase, raising GABA levels in the brain, while tiagabine inhibits its reuptake. These agents are prescription-only and are used solely as prescribed by a neurologist.

For comparison: the GABA dietary supplement does not affect the enzymes of synthesis or breakdown. It merely adds exogenous GABA to the bloodstream, and the question is where exactly this substance ends up next.

GABA receptors and the mechanism of inhibition

GABA acts through two main types of receptors. GABA-A are ion channels: when GABA binds to them, the channel opens for chloride ions, the neuron's membrane hyperpolarizes, and it becomes harder for the cell to generate an impulse. This process occurs within milliseconds and provides fast inhibition.

GABA-B are metabotropic receptors linked to G-proteins. They act more slowly, altering the work of potassium and calcium channels and reducing the release of other transmitters. Acting on GABA-B receptors is, in particular, baclofen — a prescription muscle relaxant.

It is important that most drugs acting on GABA-A are not GABA itself: they bind to separate sites of the receptor and enhance its response to the body's own GABA. That is why benzodiazepines are effective when taken orally, whereas for GABA itself the picture is much more complex.

GABA receptors are also present outside the brain — in the peripheral nervous system, in the enteric nervous system, in endocrine cells. This peripheral presence is important for understanding the possible effects of supplements.

GABA as a dietary supplement: the main question

The key problem with the GABA supplement is the blood-brain barrier. Already in early animal experiments (Kuriyama and Sze, 1971) it was shown that labeled GABA from the blood penetrates poorly into the brain. Since then this question has remained debatable: the review by Boonstra et al. (2015) concluded that the data are contradictory and that penetration, if it occurs, is probably limited.

However, "does not enter the brain" does not mean "does not act at all." Researchers consider several possible pathways: an effect on GABA receptors of the enteric nervous system, signal transmission via the vagus nerve, action on brain regions with a less dense barrier. None of these mechanisms has yet been definitively proven.

Clinical data on GABA supplements are mostly obtained in small studies, often funded by manufacturers. The systematic review by Hepsomali et al. (2020) found certain signals regarding reduced stress measures and improved sleep, but rated the evidence as limited due to small samples and heterogeneity of methods.

A pharmacokinetic study by Li et al. (2015) in healthy volunteers showed that orally taken GABA is quickly absorbed and just as quickly eliminated, and at the doses considered is well tolerated. This is consistent with the fact that subjective effects, if any, develop within a short time after intake.

A separate area is the effect of GABA on growth hormone secretion, which interests athletes. Small studies, in particular Powers et al. (2008), recorded an increase in growth hormone levels after taking GABA. However, the link between such short-term changes and gains in muscle mass has not been proven; we examine this in more detail in a separate article about the evidence base.

Sources of GABA and related substances

GABA is naturally found in many foods, especially fermented ones: in some cheeses, kimchi, tempeh, fermented teas. It is produced by lactic acid bacteria, which is why fermentation is the basis for producing "natural" GABA for supplements. Sprouted brown rice and some varieties of tomatoes are also known dietary sources.

Supplements use either synthetic GABA or GABA obtained by fermentation. Chemically it is the same molecule, and the difference between the forms concerns primarily the manufacturing process, purity, and cost.

GABA and its synthetic derivatives, which sometimes appear on the market under similar names, should be clearly distinguished:

• Phenibut— a derivative of GABA with a phenyl ring that penetrates the brain better; in many countries it is a medicine with a risk of dependence and withdrawal syndrome.
• Picamilon— a compound of GABA with nicotinic acid; the FDA in the United States stated that it does not meet the definition of a dietary ingredient.
• Gabapentin and pregabalin— prescription drugs structurally related to GABA, but acting through different targets.

These substances are not "stronger GABA." They have their own pharmacology, risk profile, and regulatory status, so they cannot be regarded as interchangeable with the dietary supplement.

Editorial conclusions

GABA is the brain's main inhibitory transmitter, which the body synthesizes from glutamate with the participation of vitamin B6. It acts through GABA-A and GABA-B receptors, which are affected by numerous drugs — from benzodiazepines to baclofen.

The GABA supplement is the same molecule, but its ability to enter the brain is limited and still debated. Possible effects are explained by peripheral mechanisms, and clinical evidence regarding sleep and stress remains preliminary.

GABA derivatives like phenibut or picamilon are separate substances with a different risk profile, not "improved" GABA.

To learn more, read our materials "The Benefits of GABA for Athletes: The Evidence Base," "Side Effects of GABA," and "How to Take GABA: Dosage, Timing, Duration."

References

1. Bowery NG, Smart TG. GABA and glycine as neurotransmitters: a brief history. Br J Pharmacol. 2006;147(Suppl 1):S109–S119.
2. Boonstra E, de Kleijn R, Colzato LS, et al. Neurotransmitters as food supplements: the effects of GABA on brain and behavior. Front Psychol. 2015;6:1520.
3. Kuriyama K, Sze PY. Blood-brain barrier to H3-gamma-aminobutyric acid in normal and amino oxyacetic acid-treated animals. Neuropharmacology. 1971;10(1):103–108.
4. Hepsomali P, Groeger JA, Nishihira J, Scholey A. Effects of oral gamma-aminobutyric acid (GABA) administration on stress and sleep in humans: a systematic review. Front Neurosci. 2020;14:923.
5. Li J, Zhang Z, Liu X, et al. Study of GABA in healthy volunteers: pharmacokinetics and pharmacodynamics. Front Pharmacol. 2015;6:260.
6. Powers ME, Yarrow JF, McCoy SC, Borst SE. Growth hormone isoform responses to GABA ingestion at rest and after exercise. Med Sci Sports Exerc. 2008;40(1):104–110.
7. Ngo DH, Vo TS. An updated review on pharmaceutical properties of gamma-aminobutyric acid. Molecules. 2019;24(15):2678.