Multi-target Therapeutic Strategy of Traditional Korean Medicine for Excitation/Inhibition Imbalance in Autism Spectrum Disorder-Related Aggression: A Narrative Review of Neuropharmacological Mechanisms

Objectives: This study aimed to systematically organize the neuropharmacological evidence for traditional Korean medicine (TKM) prescriptions corresponding to four pathological pathways constituting excitation/inhibition (E/I) imbalance underlying aggression in autism spectrum disorder (ASD).Methods: A narrative review was conducted from January 2024 to May 2025 across PubMed, Google Scholar, CNKI, and OASIS. Of 412 initially identified articles, 79 were selected for final analysis and classified into four pathways: glutamate excess, GABA deficiency, HPA axis hyperactivation, and sleep disturbance.Results: Baekho-tang demonstrated anti-inflammatory effects via nanoaggregate-mediated delivery of antipyretic components. Catalpol from Banggi-jihwang-tang showed GABAA receptor binding affinity (Ki ≈ 28.56 nM) with anticonvulsant effects in seizure models, although direct validation in developmental cortex or ASD models has not been reported. Saikosaponin A from Sayeok-san suppressed CRH expression and serum corticosterone in CUMS depression models, while paeoniflorin restored HPA axis negative feedback through glucocorticoid receptor nuclear translocation. Rhynchophylline from Uncaria rhynchophylla demonstrated the broadest multi-target profile, including non-competitive NMDA receptor antagonism (IC₅₀ 43.2 μM (RHY)), serotonin receptor modulation, and dopamine D2 receptor regulation.Conclusions: TKM prescriptions showed potential alignment with the multi-target therapy paradigm for ASD aggression-related E/I imbalance, with rhynchophylline identified as the most promising candidate. Current evidence is primarily based on preclinical studies of individual components, and whole-formula validation and clinical trials remain critical future priorities.