TinnitusPhase 2NCT03336398
Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus
A Phase 2 study testing Ketamine Hydrochloride in saline in people with Tinnitus, run by New York State Psychiatric Institute at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 21 to 60 years
- Conditions the study is for
- Tinnitus
- What is being tested?
- Ketamine Hydrochloride in saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2019to 1 Jul 2024
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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).
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
Read the 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.
- Conditions
- Tinnitus
- Being tested
- Ketamine Hydrochloride in saline
- Medical subject headings
- Tinnitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketamine Hydrochloride in salineDrug
Also called Ketamine HCI
0.5 mg/kg IV of ketamine hydrochloride in saline will be administered with one of the MRS Scan
| Study group | Role | What they receive |
|---|---|---|
| Tinnitus Patients | Experimental | 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. Receives: Drug: Ketamine Hydrochloride in saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Nov 2017
- Study start1 Sep 2019
- Primary completion17 Jun 2023
- Study completion1 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for TinnitusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- New York State Psychiatric Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Diana Martinez, New York State Psychiatric Institute
- Investigators
- Diana Martinez, Principal investigator, NYSPI/Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03336398
- Sponsor's protocol ID
- 7432
- Other IDs
- W81XWH1810221
- Status last verified
- Mar 2026
- First submitted
- 6 Nov 2017
- Last updated
- 25 Mar 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus
- ClinicalTrials.gov ID
- NCT03336398
- Acronym / sponsor ID
- 7432
- Conditions
- Tinnitus
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- New York State Psychiatric InstituteUniversity, hospital or other
- Study start
- 1 Sep 2019 (actual)
- Primary completion
- 17 Jun 2023 (actual)
- Study completion
- 1 Jul 2024 (actual)
- First posted
- 8 Nov 2017 (actual)
- Results
- Posted 25 Mar 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Tinnitus Patients | Experimental | Drug: Ketamine Hydrochloride in salineTinnitus 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. |
Who may qualify
- Ages
- 21 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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).
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketamine Hydrochloride in salineAlso: Ketamine HCI0.5 mg/kg IV of ketamine hydrochloride in saline will be administered with one of the MRS Scan | Drug | Tinnitus Patients |
Primary outcome
GABA and Glutamate (Glx) Levels in the Auditory Cortex Derived From 3T Magnetic Resonance Spectroscopy
Time frame: 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).
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Mar 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Diana Martinez principal investigator
NYSPI/Columbia University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ketamine Hydrochloride in saline in people with Tinnitus, run by New York State Psychiatric Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Mar 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
GABA and Glutamate (Glx) Levels in the Auditory Cortex Derived From 3T Magnetic Resonance Spectroscopy (time frame: 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).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Mar 2026.