{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:20:28Z","timestamp":1787026828843,"version":"build-2736575974"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>\n                    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\n                    <jats:sub>A<\/jats:sub>\n                    receptors that regulate neuronal signaling in part through their binding affinity for and inhibitory action at extrasynaptic GABA\n                    <jats:sub>A<\/jats:sub>\n                    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\u202fyears 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\u202fmin at 30 mcg\/kg\/h, 30\u202fmin at 60 mcg\/kg\/h, and 300\u202fmin 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\u202fh 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.\n                  <\/jats:p>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:related-object>The study was registered on September 21, 2024, with the identifier number NCT05645432.<\/jats:related-object>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2025.1662226","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T05:12:44Z","timestamp":1763442764000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["An open-label, proof-of-mechanism trial evaluating a neuroactive steroid GABA modulator in tinnitus"],"prefix":"10.3389","volume":"16","author":[{"given":"Luke S.","family":"Watson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio","family":"O\u2019Donnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kemi","family":"Bankole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssef","family":"Toubouti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S.","family":"Tyler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason K.","family":"Johannesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1001\/jamaoto.2016.1700","article-title":"Prevalence, severity, exposures, and treatment patterns of tinnitus in the United States","volume":"142","author":"Bhatt","year":"2016","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"ref2","first-page":"663","article-title":"Tinnitus: diagnosis and management","volume":"103","author":"Dalrymple","year":"2021","journal-title":"Am Fam Physician"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3988\/jcn.2009.5.1.11","article-title":"Tinnitus: characteristics, causes, mechanisms, and treatments","volume":"5","author":"Han","year":"2009","journal-title":"J Clin Neurol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"72","DOI":"10.3390\/audiolres15030072","article-title":"Exploring how blood cell levels influence subjective tinnitus: a cross-sectional case-control study","volume":"15","author":"Maihoub","year":"2025","journal-title":"Audiol Res"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"824","DOI":"10.3390\/biomedicines13040824","article-title":"Fasting glucose, haemoglobin A1C (HbA1c), blood lipid, and triglyceride\u2013glucose index parameters in relation to subjective tinnitus","volume":"13","author":"Moln\u00e1r","year":"2025","journal-title":"Biomedicine"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1007\/s00106-019-0633-7","article-title":"A multidisciplinary European guideline for tinnitus: diagnostics, assessment, and treatment","volume":"67","author":"Cima","year":"2019","journal-title":"HNO"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3766\/jaaa.19022","article-title":"An exploratory step toward measuring the \u201cmeaning of life\u201d in patients with tinnitus and in Cochlear implant users","volume":"31","author":"Tyler","year":"2020","journal-title":"J Am Acad Audiol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1001\/archotol.1993.01880200042006","article-title":"Use of alprazolam for relief of tinnitus: a double-blind study","volume":"119","author":"Johnson","year":"1993","journal-title":"Arch Otolaryngol Head Neck Surg"},{"key":"ref9","first-page":"140","article-title":"Benzodiazepines and GABAergics in treating severe disabling tinnitus of predominantly cochlear origin","volume":"12","author":"Bahmad","year":"2006","journal-title":"Int Tinnitus J"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1097\/01.MLG.0000216812.65206.CD","article-title":"Effect of gabapentin on the sensation and impact of tinnitus","volume":"116","author":"Bauer","year":"2006","journal-title":"Laryngoscope"},{"key":"ref11","first-page":"30","article-title":"GABAA-benzodiazepine-chloride receptor-targeted therapy for tinnitus control: preliminary report","volume":"8","author":"Shulman","year":"2002","journal-title":"Int Tinnitus J"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1177\/014556130108000211","article-title":"Gabapentin for the treatment of tinnitus: a case report","volume":"80","author":"Zapp","year":"2001","journal-title":"Ear Nose Throat J"},{"key":"ref13","first-page":"1","article-title":"GABA and GABA receptors in the central nervous system and other organs","volume-title":"International review of cytology","author":"Watanabe","year":"2002"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"10315","DOI":"10.1523\/JNEUROSCI.2395-06.2006","article-title":"Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABAA receptor subunits \u03b11, \u03b12, \u03b15, \u03b16, \u03b22, \u03b23, or \u03b4","volume":"26","author":"Maison","year":"2006","journal-title":"J Neurosci"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.neuroimage.2014.11.023","article-title":"Decreased auditory GABA+ concentrations in presbycusis demonstrated by edited magnetic resonance spectroscopy","volume":"106","author":"Gao","year":"2015","journal-title":"NeuroImage"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.neuroscience.2008.07.050","article-title":"Neural coding of temporal information in auditory thalamus and cortex","volume":"157","author":"Wang","year":"2008","journal-title":"Neuroscience"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"14974","DOI":"10.1073\/pnas.1107998108","article-title":"Homeostatic plasticity drives tinnitus perception in an animal model","volume":"108","author":"Yang","year":"2011","journal-title":"Proc Natl Acad Sci"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"14822","DOI":"10.1523\/JNEUROSCI.2695-15.2015","article-title":"Human auditory cortex neurochemistry reflects the presence and severity of tinnitus","volume":"35","author":"Sedley","year":"2015","journal-title":"J Neurosci"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"4068","DOI":"10.1038\/s41598-022-07835-8","article-title":"Lower glutamate and GABA levels in auditory cortex of tinnitus patients: a 2D-JPRESS MR spectroscopy study","volume":"12","author":"Isler","year":"2022","journal-title":"Sci Rep"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"779","DOI":"10.3390\/healthcare9060779","article-title":"Review of pharmacotherapy for tinnitus","volume":"9","author":"Kim","year":"2021","journal-title":"Healthcare"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"115067","DOI":"10.1016\/j.bcp.2022.115067","article-title":"Can GABAkines quiet the noise? The GABAA receptor neurobiology and pharmacology of tinnitus","volume":"201","author":"Witkin","year":"2022","journal-title":"Biochem Pharmacol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.brainres.2012.02.014","article-title":"Targeting inhibitory neurotransmission in tinnitus","volume":"1485","author":"Richardson","year":"2012","journal-title":"Brain Res"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1111\/j.1460-9568.2009.06680.x","article-title":"Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for \u03b4-GABAA receptors","volume":"29","author":"Herd","year":"2009","journal-title":"Eur J Neurosci"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"108333","DOI":"10.1016\/j.neuropharm.2020.108333","article-title":"Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator","volume":"181","author":"Althaus","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1046\/j.1365-2273.2001.00490.x","article-title":"Guidelines for the grading of tinnitus severity: the results of a working group commissioned by the British Association of Otolaryngologists, head and neck surgeons, 1999","volume":"26","author":"McCombe","year":"2001","journal-title":"Clin Otolaryngol Allied Sci"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1007\/s40262-022-01155-w","article-title":"Allopregnanolone concentrations in breast Milk and plasma from healthy volunteers receiving Brexanolone injection, with population pharmacokinetic Modeling of potential relative infant dose","volume":"61","author":"Wald","year":"2022","journal-title":"Clin Pharmacokinet"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1176\/appi.ajp.2011.10111704","article-title":"The Columbia\u2013suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults","volume":"168","author":"Posner","year":"2011","journal-title":"Am J Psychiatry"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1046\/j.1525-1497.2001.016009606.x","article-title":"The PHQ-9: validity of a brief depression severity measure","volume":"16","author":"Kroenke","year":"2001","journal-title":"J Gen Intern Med"},{"key":"ref29","volume-title":"ECDEU assessment manual for psychopharmacology","author":"Guy","year":"1976"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1001\/archotol.1996.01890140029007","article-title":"Development of the tinnitus handicap inventory","volume":"122","author":"Newman","year":"1996","journal-title":"Arch. Otolaryngol. - Head Neck Surg."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1097\/AUD.0b013e31822f67c0","article-title":"The tinnitus functional index: development of a new clinical measure for chronic, intrusive tinnitus","volume":"33","author":"Meikle","year":"2012","journal-title":"Ear Hear"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s12955-017-0669-x","article-title":"Tinnitus functional index: validation of the German version for Switzerland","volume":"15","author":"Peter","year":"2017","journal-title":"Health Qual Life Outcomes"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1044\/1059-0889(2012\/12-0010)","article-title":"Psychometric evaluation of visual analog scale for the assessment of chronic tinnitus","volume":"21","author":"Adamchic","year":"2012","journal-title":"Am J Audiol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1055\/s-0042-1748540","article-title":"Reliability of tinnitus loudness matches under procedural variation","volume":"10","author":"Henry","year":"1999","journal-title":"J Am Acad Audiol"},{"key":"ref35","volume-title":"MedRX Tinnometer training manual","year":"2019"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1097\/00004714-199008000-00003","article-title":"Validity and reliability of the observer's: assessment of alertness\/sedation scale","volume":"10","author":"Chernik","year":"1990","journal-title":"J Clin Psychopharmacol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1177\/0194599811403882","article-title":"Tinnitus handicap inventory for evaluating treatment effects: which changes are clinically relevant?","volume":"145","author":"Zeman","year":"2011","journal-title":"Otolaryngol Head Neck Surg"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1001\/jamaoto.2015.1219","article-title":"Repetitive transcranial magnetic stimulation treatment for chronic tinnitus: a randomized clinical trial","volume":"141","author":"Folmer","year":"2015","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"93","DOI":"10.4103\/0253-7613.91876","article-title":"Role of acamprosate in sensorineural tinnitus","volume":"44","author":"Sharma","year":"2012","journal-title":"Indian J Pharmacol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1037\/0033-2909.112.1.155","article-title":"A power primer","volume":"112","author":"Cohen","year":"1992","journal-title":"Psychol Bull"},{"key":"ref41","volume-title":"Version 9.4","year":"2016"},{"key":"ref42","volume-title":"R: A language and environment for statistical computing","year":"2022"},{"key":"ref43","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: Elegant graphics for data analysis","author":"Wickham","year":"2016"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"e276","DOI":"10.1097\/MAO.0000000000001070","article-title":"\u201cMeasurement\u201d of tinnitus","volume":"37","author":"Henry","year":"2016","journal-title":"Otol Neurotol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"S14","DOI":"10.1017\/S0022215115000808","article-title":"The use of benzodiazepines for tinnitus: systematic review","volume":"129","author":"Jufas","year":"2015","journal-title":"J Laryngol Otol"},{"key":"ref46","doi-asserted-by":"publisher","DOI":"10.1177\/0194599814545325","article-title":"Clinical practice guideline: tinnitus","volume":"151","author":"Tunkel","year":"2014","journal-title":"Otolaryngol Neck Surg"},{"key":"ref47","first-page":"PI55","article-title":"The effects of alprazolam on tinnitus: a cross-over randomized clinical trial","volume":"15","author":"Jalali","year":"2009","journal-title":"Med Sci Monit"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1662226\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T05:12:46Z","timestamp":1763442766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1662226\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,18]]},"references-count":47,"alternative-id":["10.3389\/fneur.2025.1662226"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2025.1662226","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,18]]},"article-number":"1662226"}}