GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the central nervous system — it is synthesised from the glutamate (the primary excitatory neurotransmitter) by the glutamate decarboxylase (GAD) enzyme, and it is the key regulator of the neuronal excitability throughout the brain and the spinal cord. The GABA is the most important inhibitory neurotransmitter in the human brain — it is present in approximately 40% of all synapses, and it is responsible for the regulation of virtually every aspect of the brain function, including the anxiety, the mood, the sleep, the muscle tone, the seizure threshold, and the pain perception. The GABA acts on two types of receptors — the GABA-A receptors (which are ligand-gated chloride channels that mediate the fast inhibitory synaptic transmission) and the GABA-B receptors (which are G-protein-coupled receptors that mediate the slow inhibitory synaptic transmission). The GABA-A receptors are the primary target of the benzodiazepines (diazepam, alprazolam, clonazepam), the barbiturates, the alcohol, and the inhaled anaesthetics — which all potentiate the GABAergic inhibition by binding to specific sites on the GABA-A receptor complex and increasing the frequency or the duration of the chloride channel opening. Without adequate GABA and inhibitory neurotransmission, the neuronal excitability is unchecked, the brain is in a state of chronic hyperexcitability, and the symptoms of the anxiety, the insomnia, the muscle tension, and the seizures develop — the hallmark of the GABA deficiency and of the hyperexcitable brain states. The typical supplement dose is 250-2000mg of GABA daily — though the evidence for the oral GABA supplementation is less robust than for the other neurotransmitters, because the GABA does not cross the blood-brain barrier efficiently in all individuals (the BBB permeability of the GABA is variable and subject to individual genetic factors).
GABA and the Anxiety Regulation
GABA is the primary regulator of the anxiety — the GABAergic neurons in the amygdala, the prefrontal cortex, and the hippocampus are the key regulators of the anxiety and the fear responses, and the activation of these GABAergic pathways is the primary mechanism of the benzodiazepines and the other anxiolytic drugs. The GABA exerts its anxiolytic effect primarily through the activation of the GABA-A receptors in the amygdala and in the prefrontal cortex — these receptors increase the chloride conductance, hyperpolarise the neurons, and reduce the neuronal firing rate, thereby reducing the anxiety and the fear responses. The GABA also regulates the anxiety through the GABA-B receptors (which are located on the presynaptic terminals and which mediate the inhibition of the neurotransmitter release — including the inhibition of the glutamate release, which further reduces the neuronal excitability and the anxiety). The GABA deficiency is one of the most important neurobiological correlates of the anxiety disorders — the people with the panic disorder, the social anxiety disorder, the PTSD, and the generalised anxiety disorder have been shown to have reduced GABA levels in the brain (as measured by the magnetic resonance spectroscopy, MRS) and reduced GABA-A receptor density — which suggests that the GABA deficiency is both a cause and a consequence of the chronic anxiety states.
The clinical importance of the GABA for the anxiety and for the sleep is underscored by the observation that the GABA supplementation reduces the anxiety and improves the sleep in people with the anxiety disorders and in the healthy adults. A study in 18 adults with the anxiety found that the GABA supplementation at 250mg daily for 4 weeks significantly reduced the anxiety symptoms (by 25-30%, as measured by the Hamilton Anxiety Rating Scale) — demonstrating the potent anxiolytic effect of the GABA in humans. Another study in 13 adults with the insomnia found that the GABA supplementation at 300mg taken 1 hour before the bedtime significantly improved the sleep onset latency (by 15-20 minutes) and increased the total sleep time (by 30-45 minutes) — demonstrating the sleep-promoting effect of the GABA in humans.
Practical Application
For general GABA supplementation for the anxiolytic and sleep support, the evidence-based approach is to supplement with 250-1000mg of GABA daily (as the pure GABA powder or capsule, taken in divided doses). The GABA should be taken sublingually (held under the tongue for 1-2 minutes before swallowing) for the best absorption, because the sublingual route bypasses the first-pass metabolism and delivers the GABA more directly to the brain — though the sublingual absorption is variable and may not work in all individuals. The GABA should be taken in the evening for the sleep (because the GABA has a sedating effect that can interfere with the daytime function if taken during the day), and it should be taken with the glycine or the taurine (which have complementary inhibitory effects on the neuronal excitability and which work synergistically with the GABA for the calming and the sleep-promoting effects). The GABA is generally well-tolerated with no significant adverse effects at doses up to 3000mg daily, and it does not have the dependency and the withdrawal liability of the benzodiazepines — though it may cause the drowsiness, the hypotonia, and the respiratory depression at the high doses, particularly if combined with the alcohol or the other CNS depressants. For comprehensive GABAergic and anxiolytic support, GABA pairs well with the L-theanine (which is another natural compound that promotes the relaxation and the sleep by increasing the GABA levels and by modulating the alpha brain wave activity), with the passionflower extract (which is a natural anxiolytic that works through a complementary mechanism involving the GABA modulation), with the valerian root extract (which is a natural sedative that works synergistically with the GABA for the sleep promotion), and with the magnesium (which is a calcium antagonist and which works synergistically with the GABA for the reduction of the neuronal excitability and for the calming effect).
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