A Phase 2 interventional study of Ketamine Hydrochloride in saline in Tinnitus, sponsored by New York State Psychiatric Institute. Completed at 1 site in United States. Open to participants aged 21 Years to 60 Years. Per ClinicalTrials.gov, last updated 2026-03-25.
Sponsored by New York State Psychiatric Institute · Phase 2, Interventional, and Treatment
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
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.
Exclusion Criteria:
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
Also known as: Ketamine HCI
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.
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).
Participants recruited by advertisements and word of mouth.
| Milestone | Participants With Tinnitus |
|---|---|
| Started | 42 |
| Participants receiving ketamine | 39 |
| Participants receiving saline | 41 |
| Completed | 39 |
| Not completed | 3 |
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.
| Ratio | Tinnitus Patients |
|---|---|
| Saline scan GABA frame 1 | 2.11 ± 0.19 |
| Saline scan GABA frame 2 | 2.12 ± 0.22 |
| Saline scan GABA frame 3 | 2.09 ± 0.21 |
| Saline scan GABA frame 4 | 2.03 ± 0.16 |
| Saline scan GABA frame 5 | 2.05 ± 0.19 |
| Saline scan GABA frame 6 | 2.07 ± 0.26 |
| Saline scan GABA frame 7 | 2.10 ± 0.23 |
| Saline scan GABA frame 8 | 2.05 ± 0.2 |
| ketamine scan GABA frame 1 | 2.14 ± 0.21 |
| ketamine scan GABA frame 2 | 2.11 ± 0.21 |
| ketamine scan GABA frame 3 | 2.07 ± 0.19 |
| ketamine scan GABA frame 4 | 2.05 ± 0.19 |
| ketamine scan GABA frame 5 | 2.12 ± 0.25 |
| ketamine scan GABA frame 6 | 2.15 ± 0.24 |
| ketamine scan GABA frame 7 | 2.13 ± 0.19 |
| ketamine scan GABA frame 8 | 2.11 ± 0.22 |
| Saline scan GLX frame 1 | 11.92 ± 1.01 |
| Saline scan GLX frame 2 | 11.84 ± 1.09 |
| Saline scan GLX frame 3 | 11.83 ± 1.38 |
| Saline scan GLX frame 4 | 11.84 ± 1.34 |
| Saline scan GLX frame 5 | 11.84 ± 1.34 |
| Saline scan GLX frame 6 | 11.91 ± 1.28 |
| Saline scan GLX frame 7 | 11.80 ± 1.38 |
| Saline scan GLX frame 8 | 11.77 ± 1.55 |
| ketamine scan GLX frame 1 | 11.90 ± 0.79 |
| ketamine scan GLX frame 2 | 11.78 ± 0.87 |
| ketamine scan GLX frame 3 | 11.72 ± 0.84 |
| ketamine scan GLX frame 4 | 11.83 ± 1.09 |
| ketamine scan GLX frame 5 | 11.83 ± 1.28 |
| ketamine scan GLX frame 6 | 11.58 ± 1.40 |
| ketamine scan GLX frame 7 | 11.56 ± 1.47 |
| ketamine scan GLX frame 8 | 11.53 ± 1.35 |
Collected over Duration of study (2-4 weeks). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Tinnitus Patients Ketamine Scan Day | 0/42 (0%) | 0/42 (0%) | 3/42 (7.1%) |
| Tinnitus Patients Saline Scan Day | 0/42 (0%) | 0/42 (0%) | 1/42 (2.4%) |
| Event | Tinnitus Patients Ketamine Scan Day | Tinnitus Patients Saline Scan Day |
|---|---|---|
| dizzinessNervous system disorders | 3/42 | 1/42 |
| Age, Continuous(years) | Participants With Tinnitus |
|---|---|
| Mean | 43 ± 12 |
| Sex: Female, Male(Participants) | Participants With Tinnitus |
|---|---|
| Female | 18 |
| Male | 24 |
| Race (NIH/OMB)(Participants) | Participants With Tinnitus |
|---|---|
| American Indian or Alaska Native | 1 |
| Asian | 4 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 4 |
| White | 30 |
| More than one race | 2 |
| Unknown or Not Reported | 1 |
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New York State Psychiatric Institute