Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus

Tinnitus, or ringing in the ears, is a very common problem that often accompanies hearing loss. It affects up to 1 in 10 adults, and about 30% of people who experience chronic tinnitus find it very distressing. In these patients, symptoms of depression and anxiety often accompany tinnitus and there are no approved treatments. Clinical trials are ongoing to test a glutamate NMDA receptor antagonist (called esketamine), which is injected into the inner ear. However, the preliminary results with this medication show that it only works for tinnitus that results from acute injury. It does not treat tinnitus resulting from progressive hearing loss.

Research in humans and animals suggest that the neurotransmitters glutamate and GABA are important in the development and maintenance of tinnitus. This data shows that over-activation of the NMDA receptor and a decrease in GABA signaling in the brain play a crucial role. Previous studies show that ketamine, which an antagonist at the NMDA receptor, increases GABA levels in the brain in participants with depression. Thus, in this experiment, this study will test the effect of ketamine on tinnitus, since it blocks the NMDA glutamate receptor and increase GABA levels.

Two groups of participants will be included in this study: those who experience distress (symptoms of anxiety or depression) with tinnitus and those who have tinnitus but do not experience distress. Each participant will receive both ketamine and placebo on different days. Magnetic Resonance Spectroscopy (MRS) scans will be

Study Overview

• Status: Completed
• Conditions: Tinnitus
• Intervention / Treatment: Drug: Ketamine Hydrochloride in saline

Detailed Description

Tinnitus has a prevalence of approximately 1 in 10 adults in the United States. Among those with tinnitus, 36% had nearly constant symptoms and almost 30% of those report that their tinnitus as a big or a very big problem. Currently there are few effective treatments for tinnitus, and no approved medications. Cognitive behavioral and retraining therapy provide some relief, but many patients fail to respond.

Animal research and human studies indicate that maladaptive plasticity plays a role in tinnitus, which involves glutamatergic signaling largely at the NMDA and AMPA receptors. Additionally, GABA signaling has been shown to be impaired in tinnitus. Rodent models show a diminished sensitivity to GABA signaling and human magnetic resonance spectroscopy (MRS) studies show decreased GABA levels in the auditory cortex.

Ketamine is a non-competitive NMDA receptor antagonist that has also been shown to activate AMPA receptors, and modulates ongoing plasticity. Additionally, ketamine activates a subpopulation of cortical GABAergic interneurons and projection neurons and increases GABA levels in the human brain, measured with MRS. Ketamine is FDA approved as an anesthetic, and recent work has demonstrated its efficacy in treating refractory depression and chronic pain. Importantly, these demonstrate that low dose ketamine, at doses lower than those required for anesthesia, are effective in lifting depressed mood and improving the sensation of chronic pain.

For many, tinnitus has an important affective component to it, with distress and co-morbid symptoms of depression and anxiety. The onset and severity of tinnitus can correlate with stressful events, and it has been posited that stress lowers the threshold of perception, and unmasks tinnitus. Tinnitus then triggers more anxiety and depressed mood, which in turn reinforces the symptoms. An advantage of ketamine may be its effect on depression and anxiety, in addition to tinnitus, to interrupt this cycle.

The goal of this study is to perform a proof-of-concept preliminary study of ketamine in tinnitus associated with sensori-neural hearing loss. This will be studied both in participants who report depressed mood and anxiety and those who do not. MRS imaging will be used to assess ketamine-induced changes in GABA in the auditory cortex.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • 1051 Riverside Drive

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant aged 21-60
• Tinnitus associated with at least mild sensori-neural hearing loss of at least 6 months duration
• Score at least 32 on the Tinnitus Handicap Inventory and a score of 5dB or greater on the minimum masking level
• Tinnitus not due to medical disease (other than sensorineural hearing loss)
• Score of at least 14 on the Hamilton Depression Rating Scales with a score of at least 2 on the Hamilton Anxiety Rating Scale (in the distressed group).

Exclusion Criteria:

• DSM-V psychiatric disorders other than mild-moderate depression and anxiety, including substance use disorder.
• History of recreational ketamine use, recreational PCP use,exposure to ketamine as an anesthetic, or an adverse reaction to ketamine
• Currently taking psychotropic medication (e.g.antipsychotics, antidepressants, benzodiazepines)
• Presence or positive history of significant medical or neurological illness, including high blood pressure (SBP >140, DBP > 90), cardiac illness, abnormality on EKG, head injury.
• Pregnancy, abortion, or lack of effective birth control during 15 days before the scan
• Metal implants, pacemaker, other metal (e.g. shrapnel or surgical prostheses) or paramagnetic objects contained within the
• Medicinal patch that cannot be removed for the scans.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tinnitus Patients; Tinnitus patients with symptoms over 6 months duration. This group will receive both 0.5 mg/kg ketamine hydrochloride in saline and placebo, saline, with Magnetic Resonance Spectroscopy scans and audiometry testing and scales.	Drug: Ketamine Hydrochloride in saline; 0.5 mg/kg IV of ketamine hydrochloride in saline will be administered with one of the MRS Scan; Other Names: Ketamine HCI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GABA and Glutamate (Glx) Levels in the Auditory Cortex Derived From 3T Magnetic Resonance Spectroscopy	The GABA and Glutamate/Glutamine (Glx) peaks will be quantified as ratios (relative to water) and are obtained from the auditory cortex using 3T Magnetic Resonance Spectroscopy (MRS). Brain spectra containing GABA and Glutamate/Glutamine (Glx) resonances will be acquired of the auditory cortex using the volume-selective PRESS J-editing difference method. Data will be acquired from a voxel centered on Heschl's sulcus. The GABA and Glx peak areas will be quantified as ratios relative to the area of the unsuppressed voxel tissue water. The primary outcomes are GABA and GLX levels (relative to water) as they are obtained over time in frames reported as least squares mean with standard error. The first two frames serve as baseline measures, while frames 3 through 8 occur after the infusion over 40 minutes. This will be reported for saline and ketamine scans. An increase in GABA/water may correlate with tinnitus improvement, based on previous MRS studies showing low GABA/water in tinnitus.	GABA and GLX are binned into frames before and after the infusion. The pre-infusion frames (1 and 2) include about 12 minutes of data. The post-infusion frames occur over 40 minutes following the delivery of ketamine/saline (frames 3 through 8).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in The Brief Psychiatric Rating Scale (BPRS)	The Brief Psychiatric Rating Scale (BPRS) is a rating scale used by a clinician to measure psychiatric symptoms. The scores range from a minimum 16 to maximum of 112. Higher scores indicate a more severe disorder.	Baseline, at the end of MRS scan, 110 minutes after ketamine or placebo infusion
Change in The Tinnitus Handicap Inventory (THI)	The Tinnitus Handicap Inventory is a self-administered test to determine the degree of distress in tinnitus patients. Scores range from 0 to 100 with higher scores indicating a greater degree of distress from tinnitus.	screening, pre and post ketamine and placebo sessions
Change in Visual Analogue Scale (VAS)	Visual Analogue Scale (VAS) is a scale that consists of a straight line with gradients from 0 (no tinnitus) to 10 (severe tinnitus). (maximal experience of tinnitus)	screening, pre and post ketamine and placebo sessions, then daily
Change in the Beck Depression Inventory (BDI) Depression Inventory (BDI)	The Beck Depression Inventory (BDI) is a multiple choice inventory for depression	screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions
Change in Profile of Mood States (POMS)	The Profile of Mood States (POMS) is used to assess mood states.	screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions

Collaborators and Investigators

• Sponsor: New York State Psychiatric Institute
• Investigators: Principal Investigator: Diana Martinez, NYSPI/Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Actual): June 17, 2023
• Study Completion (Actual): July 1, 2024

Study Registration Dates

• First Submitted: November 6, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 8, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Ear Diseases; Hearing Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Tinnitus; Organic Chemicals; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Inorganic Chemicals; Chlorine Compounds; Sodium Compounds; Chlorides; Hydrochloric Acid; Ketamine; Sodium Chloride
• Other Study ID Numbers: 7432; W81XWH1810221 (Other Grant/Funding Number: U.S. ARMY MEDICAL RESEARCH)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No