Journal article
An open-label, proof-of-mechanism trial evaluating a neuroactive steroid GABA modulator in tinnitus
Frontiers in neurology, Vol.16, 1662226
11/18/2025
DOI: 10.3389/fneur.2025.1662226
PMCID: PMC12668930
PMID: 41341514
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 GABA A receptors that regulate neuronal signaling in part through their binding affinity for and inhibitory action at extrasynaptic GABA A 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.
Details
- Title: Subtitle
- An open-label, proof-of-mechanism trial evaluating a neuroactive steroid GABA modulator in tinnitus
- Creators
- Luke S. Watson - Sage TherapeuticsPatricio O’DonnellKemi Bankole - Sage TherapeuticsYoussef Toubouti - Sage TherapeuticsRichard S. Tyler - University of IowaJason K. Johannesen
- Resource Type
- Journal article
- Publication Details
- Frontiers in neurology, Vol.16, 1662226
- DOI
- 10.3389/fneur.2025.1662226
- PMID
- 41341514
- PMCID
- PMC12668930
- NLM abbreviation
- Front Neurol
- ISSN
- 1664-2295
- eISSN
- 1664-2295
- Publisher
- FRONTIERS MEDIA SA
- Grant note
- Sage Therapeutics, Inc.
The author(s) declare that financial support was received for the research and/or publication of this article. This study was sponsored by the Sage Therapeutics, Inc., which had a role in the conceptualization, design, data collection, analysis, decision to publish, and preparation of the manuscript.
- Language
- English
- Date published
- 11/18/2025
- Academic Unit
- Communication Sciences and Disorders; Otolaryngology; University College Courses
- Record Identifier
- 9985033758002771
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