AUTHOR=Watson Luke S. , O’Donnell Patricio , Bankole Kemi , Toubouti Youssef , Tyler Richard S. , Johannesen Jason K. 

TITLE=An open-label, proof-of-mechanism trial evaluating a neuroactive steroid GABA modulator in tinnitus

JOURNAL=Frontiers in Neurology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1662226

DOI=10.3389/fneur.2025.1662226

ISSN=1664-2295

ABSTRACT=Imbalances of excitatory and inhibitory signaling within the central auditory pathways are hypothesized to underlie tinnitus pathophysiology. Neuroactive steroids, such as allopregnanolone, are positive allosteric modulators of GABAA receptors that regulate neuronal signaling in part through their binding affinity for and inhibitory action at extrasynaptic GABAA receptors. This pilot, single-arm, proof-of-mechanism trial investigated whether brexanolone, an intravenous formulation of allopregnanolone, may improve tinnitus symptomatology. Adults between 18 and 65 years of age with bilateral, chronic, moderate tinnitus were recruited in this single-arm, open-label study. Ten participants received a 6-h infusion of brexanolone (30 min at 30 mcg/kg/h, 30 min at 60 mcg/kg/h, and 300 min at 90 mcg/kg/h). Primary outcomes were safety and tolerability, including treatment-emergent adverse events. Secondary outcomes were changes from baseline in visual analogue scale scores of tinnitus loudness and annoyance, assessed on day 1 as well as between days 2 and 7. All enrolled participants completed dosing day evaluations, and nine of them completed the final follow-up assessment on day 7. A single, unrelated, non-severe adverse event was reported. A clinically meaningful reduction in perceived tinnitus severity was detected as early as 2 h into the infusion period and remained throughout the post-dose observation week. Brexanolone was well tolerated and appeared to reduce the severity of experienced tinnitus and its related functional consequences relative to baseline. These results provide an important incremental advancement in support of a GABAergic hypothesis of tinnitus manifestation. Further evaluation in randomized placebo-controlled trials is needed to confirm these findings.Clinical trial registrationThe study was registered on September 21, 2024, with the identifier number NCT05645432.