Acute and chronic dosing of the GABA A alpha 2,3 selective agonist BAER-101 do not alter behavior but may impact auditory-evoked EEG responses in adults with fragile X syndrome

Background: Fragile X syndrome (FXS) is characterized by sensory hypersensitivity and neural hyperexcitability linked to GABAergic dysfunction. BAER-101, formerly known as AZD7325, is a positive allosteric modulator of GABA _A receptors with functional selectivity for α2/α3 subunits, designed to enhance inhibitory tone while minimizing sedation associated with α1 activation. Methods: This study evaluated the acute and chronic effects of BAER-101 on behavioral and electrophysiological outcomes in individuals with FXS. The study employed a within-subject 3 × 2 factorial design, with three dosing conditions (Low Dose: 5 mg; High Dose: 15 mg; Placebo, all twice a day) and two time factors (Acute: same-day pre-/post-dose comparison; Chronic: after two weeks of consecutive dosing). Behavioral endpoints included clinician- and parent-rated symptom severity and laboratory measures of attention and memory, while electrophysiological endpoints comprised resting-state and auditory-evoked scalp-recorded 128-channel EEG metrics including bandpower, inter-trial coherence, and event-related potentials. Results: Behavioral results showed limited evidence for improvements: across tasks, most effects were nonsignificant, with only marginal dose-related trends. The isolated findings lacked consistency or dose-dependence and are likely attributable to random variation. Test–retest reliability of behavioral measures was generally lower than published estimates (ICC ≈ 0.4–0.75), suggesting that measurement noise and small sample size may have obscured true drug effects. EEG spectral power analysis showed significant drug × time interactions, but follow-up comparisons did not support consistent pre-/post-drug changes, suggesting these effects reflected noise rather than drug response. ERP analyses indicated small, nonsystematic reductions in amplitude of onset-evoked potentials during chirp and habituation paradigms following BAER-101 treatment, without clear dose dependency. Test–retest reliability for EEG measures was lower than previously reported, with intraclass correlation coefficients ≈ 0.6 relative to prior work. Conclusions: Overall, no robust behavioral or electrophysiological improvements were observed with BAER-101 at the tested doses and durations.