GABA and Glutamate Imbalance in Autism and Their Reversal as Novel Hypothesis for Effective Treatment Strategy: An update

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by social communication challenges and repetitive behaviors. Recent findings suggest that disruptions in the brain’s excitatory-inhibitory balance—particularly involving glutamate and GABA (gamma-aminobutyric acid)—play a significant role in ASD symptoms and related neuronal damage.

Research indicates that individuals with ASD often show elevated glutamate levels in blood and platelets, possibly due to impaired gut and blood-brain barriers, reduced GABAergic neurons in the cerebellum, and lower expression of GABA-synthesizing enzymes. This imbalance may lead to glutamate excitotoxicity, which damages neurons and contributes to behavioral and cognitive deficits.

As a result, GABA supplementation is emerging as a promising approach to restore inhibitory signaling in the brain. GABA supplements may help improve social behavior, reduce repetitive actions, and regulate sleep and anxiety levels in autistic individuals. Moreover, GABA plays a central role in the gut-brain axis, highlighting the importance of microbiota-targeted therapies in ASD.

This updated hypothesis proposes a multi-targeted strategy that includes:

• GABA supplementation for neurological balance
• Regulation of magnesium and chloride levels
• Vitamin D to support neurotransmitter health
• Probiotics to enhance GABAA receptor and glutamate decarboxylase (GAD) activity
• Memantine to modulate NMDA receptors and enhance glutamate transport

Together, these interventions may improve GABA calm, reduce hyperexcitability, and mitigate the progression of neuronal damage in ASD. Additionally, GABA benefits may extend to supporting sleep quality (GABA for sleep) and emotional regulation (GABA for anxiety), offering a more holistic approach to ASD treatment.