Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus

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.

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.