Is Memantine a Real Contender As a Tinnitus Therapy?
A recently-published randomized controlled trial from an Iranian research group [Pourayyoubi B, et al.The Evaluation of Memantine Effect on Tinnitus Severity. Brain Behav. 2025 Jul;15(7)] has revived interest in whether a medication called memantine may be effective as a treatment for tinnitus. In this blog post, I’ll discuss the scientific rationale for memantine as a potential therapy for tinnitus and review the clinical research that has tested its effectiveness.
Mechanism of Action: Why Memantine Was Considered for Tinnitus
Memantine is a low- to moderate-affinity, uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. These receptors are proteins that sit on the surface of our neurons and play a role in certain types of communication between neurons that use glutamate as a neurotransmitter. NMDA receptors are key mediators of excitatory neurotransmission and synaptic plasticity in the central nervous system.
Many current models of tinnitus generation and persistence involve maladaptive neuroplasticity and hyperexcitability within the auditory pathway, most commonly after some type of inner ear damage (loud noise, age-related hair cell degeneration, etc). Following peripheral hearing damage, reduced input from the cochlea can trigger altered neuronal firing behavior in central auditory structures such as the dorsal cochlear nucleus and auditory cortex.
Glutamatergic neurotransmission—and specifically NMDA receptor activation—has been implicated as a likely player in these auditory signalling changes. Excessive glutamate signaling may lead to excitotoxicity and persistent neural hyperactivity in the auditory pathways, changes frequently implicated in tinnitus models. By blocking NMDA receptors in a voltage-dependent manner, memantine theoretically could reduce pathological excitatory signaling while preserving normal synaptic transmission. For these reasons, many researchers were very excited about the prospects of memantine as a treatment for tinnitus in the early 2000s. In addition, memantine was FDA approved as a treatment for Alzheimer’s disease in 2003.
Preclinical Evidence
Animal studies initially supported NMDA modulation in tinnitus models. Salicylate-induced tinnitus and noise trauma animal models demonstrated increased NMDA receptor activity in auditory structures. Some NMDA antagonists reduced tinnitus-like behavior in rodents. These results made researchers even more excited about testing memantine as a therapy for tinnitus in humans.
Clinical Trial Evidence in Humans
A randomized trial by Figueiredo et al. (2008) did not show a significant benefit for memantine over placebo in the treatment of tinnitus, though the study was quite small (60 participants) so it lacked the statistical power to detect a small treatment effect. This result seemed to cool the enthusiasm about memantine in the research community, though testing of other NMDA receptor antagonists (flupirtine, caroverine, nitrous oxide, AM-101, OTO-313) for the treatment of tinnitus continued. Unfortunately, the results for these other agents were similarly disappointing.
The 2025 Pourayyoubi Trial: Renewed Interest — With Important Design Nuances
The 2025 Pourayyoubi et al. study has revived interest in memantine after reporting improvements in tinnitus severity. Their study involved 70 participants. Half of subjects received cinnarizine (a calcium channel blocker with antihistaminic and vestibular suppressant properties that is not used in the USA but is widely prescribed in Iran) and the other half received memantine and cinnarizine. The treatment period was 60 days. The outcomes measured were the Tinnitus Severity Index (TSI) and the Numeric Rating Scale (NRS).
What did they observe? They reported that the group receiving memantine and cinnarizine experienced a 68% reduction in their NRS scores and a 59% improvement in their TSI. These changes were statistically significant in comparison with the group only receiving cinnarizine.
Should we believe these results? Well, there are several methodological limitations in this study:
The outcome measures used (TSI and NRS) are somewhat less commonly used in large international tinnitus trials compared with instruments such as the Tinnitus Functional Index (TFI) or Tinnitus Handicap Inventory (THI). While TSI is a tinnitus-specific multi-item questionnaire with published validation work, it has a smaller independent validation base and less standardized interpretation of clinically meaningful change. The NRS, while widely validated for symptom intensity in general, is not a tinnitus-specific multidimensional outcome measure. Together, this makes comparison with prior tinnitus drug trials more difficult and introduces some uncertainty about the functional significance of the reported improvements.
Because both treatment groups also received cinnarizine, it’s not possible to say that the treatment effect was solely due to memantine. It is possible that memantine and cinnarizine worked synergistically to produce the benefits. This raises uncertainty about what memantine is doing and limits our ability to compare the results to the prior trial from Figueiredo et al.
The study was relatively small, consisting of just 35 subjects in each arm.
Short follow period of 60 days
Single institution study- meaning a potentially homogeneous subject population that limits generalizability to other groups and healthcare settings
Where Do We Go From Here?
Although this recent trial has flaws, the results certainly revive the possibility that memantine may have a role in tinnitus therapy. It is an agent that is already FDA-approved for another indication (Alzheimer’s disease) and has a quite favorable side effect profile. A larger placebo-controlled trial perhaps with three arms: placebo, memantine, and memantine/cinnarizine would help clarify this clinical question. I’ll continue to follow this research and keep you updated.
Clinical Bottom Line:
At present, memantine remains biologically plausible but clinically unproven for tinnitus, and routine use cannot be recommended based on existing evidence.
