CLINICAL TRIAL article
Front. Neurol.
Sec. Neuro-Otology
Volume 16 - 2025 | doi: 10.3389/fneur.2025.1662226
This article is part of the Research TopicThe Multidisciplinary Management of Tinnitus and VertigoView all 3 articles
An open-label, proof-of-mechanism trial evaluating a neuroactive steroid GABA modulator in tinnitus
Provisionally accepted
- 1SAGE Therapeutics, Cambridge, MA, United States
- 2SAGE Therapeutics Inc, Cambridge, United States
- 3The University of Iowa Department of Communication Sciences and Disorders, Iowa City, United States
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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-hour infusion of brexanolone (30 minutes at 30 mcg/kg/hour, 30 minutes at 60 mcg/kg/hour, and 300 minutes at 90 mcg/kg/hour). 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 through 7. All enrolled participants completed dosing day evaluations, and 9 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 hours 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. ClinicalTrials.gov registry identifier: NCT05645432
Keywords: brexanolone, GABAergic inhibition, Neurotology, Otolaryngology, Excitatory-Inhibitory balance
Received: 08 Jul 2025; Accepted: 15 Sep 2025.
Copyright: © 2025 Watson, O'Donnell, Bankole, Toubouti, Tyler and Johannesen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Luke S Watson, SAGE Therapeutics, Cambridge, MA, United States
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