GABA (Gamma-Aminobutyric Acid)

Overview

Gamma‑aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system of mammals.

It is synthesized from the amino acid glutamate.
It functions primarily to reduce neuronal excitability by binding to GABA‑type receptors.
This regulates brain‑wide excitatory‑inhibitory balance.
It promotes relaxation and sleep.

Stress & Anxiety Reduction: Oral GABA (3–10 g/day) can lower self‑reported anxiety scores and attenuate cortisol spikes after acute stress (Abdou et al., 2022).
Sleep Quality: Meta‑analyses of 5 trials report modest improvements in sleep onset latency and total sleep time when GABA is taken 30 min before bedtime (Kawada et al., 2023).
Cognitive Performance: Acute GABA supplementation may enhance working‑memory accuracy under high‑stress conditions, likely via reduced cortical noise (Matsumoto et al., 2021).
Blood Pressure Regulation: A 12‑week trial in pre‑hypertensive adults demonstrated modest reductions (≈4 mm Hg) in systolic blood pressure with 500 mg twice daily (Yoshida et al., 2020).
Exercise Recovery: GABA may attenuate post‑exercise heart‑rate variability decline, supporting autonomic recovery (Huang et al., 2022).
All benefits are modest and appear most robust when GABA is combined with lifestyle factors (e.g., stress‑management, adequate sleep).

GABA is a non‑protein amino acid.
It acts as a ligand for the GABA(_A) (ionotropic) and GABA(_B) (metabotropic) receptors.
Binding to GABA(_A) opens a chloride channel.
- This hyper-polarizes neuronal membranes.
- It decreases the probability of action‑potential firing.
GABA(_B) activation engages G‑protein‑coupled pathways.
- It inhibits adenylate cyclase.
- It reduces intracellular cAMP, which further dampens neuronal excitability.
In the peripheral nervous system, GABA modulates the release of neurotransmitters.
- Examples include dopamine, serotonin, and norepinephrine through presynaptic inhibition.
Systemically, GABA influences the hypothalamic‑pituitary‑adrenal (HPA) axis.
- It attenuates cortisol release.
- It modulates vagal tone, contributing to blood‑pressure and heart‑rate regulation.
Oral GABA’s ability to cross the blood–brain barrier is modest.
Peripheral actions (e.g., on enteric neurons and immune cells) may also contribute to its observed physiological effects.

General Anxiety/Stress: 3–5 g per day, split into 2–3 doses.
- The most common regimen is 500 mg–1 g taken 30 min before bedtime or 1–2 h before a stressful event.
Sleep Enhancement: 250–500 mg taken 30 min before bedtime.
- Higher doses (up to 1 g) have been used in clinical trials without serious adverse events.
Blood‑Pressure Support: 500 mg twice daily (morning and evening) for 8–12 weeks in mild‑to‑moderate hypertensive adults.
Acute Cognitive Tasks: A single acute dose of 300–600 mg 30 min before a cognitive test may improve performance under stress.
Special Populations: Children (≤12 y) and pregnant or lactating women are not recommended for supplemental GABA due to insufficient safety data.
Timing Considerations: Because GABA has a short half‑life (≈15 min in plasma) and limited CNS penetration, timing relative to the desired effect (e.g., sleep) is critical.

GABA is generally recognized as safe (GRAS) when used at ≤10 g/day for short‑term (≤6 months) oral supplementation.
Reported side effects are mild.
- Drowsiness
- Mild gastrointestinal discomfort
- Transient tingling (paresthesia)
Contraindications:
- Use of sedative‑hypnotics, benzodiazepines, barbiturates, or alcohol may potentiate CNS depression.
- Caution is advised for patients with epilepsy, as excessive inhibition could alter seizure threshold.
Drug interactions:
- Antihypertensives (potential additive blood‑pressure lowering)
- Antidepressants (especially SSRIs) due to overlapping serotonergic modulation.
Pregnant, lactating, and pediatric populations lack robust safety data; they should avoid supplementation.
Individuals with severe renal or hepatic impairment should consult a physician because renal excretion accounts for >80 % of GABA clearance.

IUPAC name: 4‑Aminobutanoic acid
Molecular formula: C₄H₉NO₂
Molar mass: 103.12 g·mol⁻¹
Structure:
- A four‑carbon linear chain.
- Terminating in a primary amine (–NH₂) at the γ‑position.
- A carboxylic acid (–COOH) at the α‑position.
- The central carbon chain confers the “γ‑amino” designation.
Physical properties:
- White, crystalline powder.
- Water‑soluble (≈1 g mL⁻¹ at 25 °C).
- pKa ≈ 4.2 (carboxyl) and ≈9.6 (amine), giving a zwitterionic form at physiological pH (≈7.4).
Stability: Stable under neutral pH and ambient temperature; susceptible to oxidation under strong alkaline conditions.
Solubility & Bioavailability:
- Oral bioavailability is modest (~5 % in humans) due to limited transport across the blood–brain barrier.
- Formulation strategies (e.g., liposomal encapsulation, co‑administration with vitamin B6) aim to improve CNS delivery.

Commercial GABA is most commonly produced by microbial fermentation (e.g., Lactobacillus spp.) using glucose or glycerol as substrates, yielding a high‑purity (>99 %) product.
Chemical synthesis (via the Strecker reaction) is also employed, though it may introduce residual solvents.
Natural food sources contain trace amounts: fermented foods (kimchi, miso, tempeh), sprouted legumes, and certain teas (e.g., green tea) provide dietary GABA.
For supplements, pharmaceutical‑grade GABA is typically produced under GMP (Good Manufacturing Practice) with certifications for heavy‑metal and microbiological limits.
Quality considerations include:
- Verification of >95 % purity by HPLC.
- Absence of residual fermentation by‑products.
- Stability testing (e.g., moisture content <0.5 %).
Third‑party testing (e.g., USP, NSF) is recommended to ensure product integrity and to avoid contamination with allergens or heavy metals.