Tinnitus Treatment Report

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First Look at 6B-001, 65Bio’s Preclinical Drug Candidate for the Treatment of Chronic Tinnitus

Some new information about 6B-001, a preclinical tinnitus (and hearing loss) drug that is currently being developed by 65Bio Inc, a biotech startup based in Wellesley, MA.

Here is what we know so far, starting with a description from the Product page of the 65Bio company website:

65Bio lead product is 6B-001 an orally available small molecule found to be well tolerated in human. 6B-001 is in preclinical development phase for the treatment of auditory pathologies. The initial focus is on the treatment of chronic tinnitus and the longer-term focus is on hearing loss and vertigo.

6B-001 appeared tinnitus meme

While this official description does not tell us very much about the drug… it does provide clues that can potentially reveal more details about the drug, and lead us to its [plausible] mechanisms i.e., how it might treat tinnitus and/or hearing loss, etc.

The raw facts:

  • 6B-001
  • orally available
  • small molecule
  • safe/tested in humans
  • tinnitus, hearing loss, vertigo, auditory pathologies

Together, these facts strongly suggest that we are probably looking for an existing drug that has completed phase 1 clinical trials and met safety endpoints. Which also means the drug is one that is being studied and tested for other health conditions… and “6B-001” is the codename for its tinnitus-related use.

Of course, those details alone do not narrow down the list of plausible 6B-001 candidates. What we need is a short list of possible drugs that “6B-001” might represent.

Fortunately, our hunt for this mystery drug becomes dramatically easier when we add certain constraints.

In this case, limiting our “suspects” to drugs that are currently being developed by other companies that are funded by the same group as 65Bio Inc. Follow the money…

So, we know that 65Bio Inc is backed by Extera Partners.

According to the Extera Partners website, Extera has a portfolio of biotech companies. And we can see that six of these companies are in the same category (“venture creation”) as 65Bio.

These other five companies are where we want to look for clues and connections… in hopes of finding drugs that seem like they might be strong candidates for treating tinnitus. According to existing research and known/suspected mechanisms… as well as overlapping health conditions that are often associated with tinnitus.

Put another way, we want to investigate the drug development pipelines of these five other companies… to see if we can find any drugs that might involve mechanisms/targets that are associated with tinnitus or hearing loss or vertigo…

By doing this, we might be able to identify which of these drugs is likeliest to be “6B-001” (or some variation of it, with a different name, for a different condition, or perhaps in combination with something else),

This approach assumes that 65Bio Inc is a “spinoff” of one of Extera’s properties. Created for the potential tinnitus-treating component (and auditory pathology related components) of a drug or drugs that are hiding somewhere in the pipelines of one or more of their portfolio companies.

The strong overlap between the people involved in 65Bio and these five other companies and Extera… is another reason why we suspect to find the drug identity within the Extera portfolio.

Sure enough, that seems to be the case.

At least, we now have some plausible candidates and clues.

COMMENT: As of right now [7/23/2021], I cannot confirm the mechanism behind 6B-001. But I have found some leads…

After reviewing the drug portfolios of the five other Extera Partners-backed ventures (Janus, Censa, Acatama, Acer, Intera), here is a list of some possible drugs/mechanisms/targets that are possibly related to 6B-001 — presented in no particular order:

  • anti-TLR drug (toll-like receptor antagonism) — autoimmune/inflammation connection + known overlap between tinnitus and Sjogren’s, SLE, etc..
  • vatiquinone, PTC743, EPI-743 — epilepsy + mitochondrial connection
  • PTC857, 15-lipoxygenase — inflammation/oxidative stress connection
  • unesbulin, PTC596, BMI-1 inhibitor — BMI-1 + hair cell connection
  • sepiapterin  — tetrahydrobiopterin disorder connection, autism overlap connection
  • TO BE CONTINUED [last updated: 7/23/2021 at 1:56 PM EST]
[Work in progress. Draft copy.]

This is an incomplete “short list” of possible drugs that might be repurposed for tinnitus and/or hearing loss or reformulated… and called “6B-001” (or 6B-002). Furthermore, this is unofficial information. It is patchy guesswork. As such, it should be considered nothing more than an educated and semi-structured form of good ol’ fashioned wild speculation.

Having said that, it also provides us with the raw ingredients to make sense of 6B-001… until 65Bio decides it is time to relieve us of our nagging curiosity… and issue a press release or add a couple more paragraphs to their website. (If anyone reading wants to email them and ask “What is the mechanism behind 6B-001 for chronic tinnitus?”, have at it: admin@65bio.com) Oh, and if anyone does this… and forwards me the reply… I will happily send them a copy of my next email newsletter anywhere from 12-24 hours before I email it to everyone else. (Super ultra early access, or whatever you want to call it.)

Last but not least… since I have not had the time to dig deeper into any of these “short list” drugs for 6B-001… and there might also be a few missing… I am hoping this draft article and these breadcrumbs are enough to fuel some more in-depth discussions in places such as reddit’s r/tinnitusresearch community, Tinnitus Talk (research section… also, shout out to My Posting Place crew), and…  our international friends in places such as MyTinnitus.de. (Speaking of which, if you run or manage a tinnitus forum that I have not yet linked to… and, your community discusses these newsletter issues and this website… feel free to send me an email and say hello. I always want to help people find places to discuss this research… and there’s a tinnitus forum out there for everyone.)

6B-001 Updates

If you would like to receive email updates regarding the development of 6B-001 for chronic tinnitus, subscribe to the Tinnitus Treatment Report email newsletter. It’s free, no spam, no third parties, your privacy is respected. It is an email newsletter that is sent 1-2 times per week. For anyone who wants to know about promising new tinnitus treatments (including experimental treatments and preclinical drugs such as 6B-001) — as early as possible… weeks, even months, before any other publication…

References

oliver twist please sir may i have a source meme

Yes, you may. More:

July 2021 update on Cognosetta’s tinnitus drug: CS0022

“These findings suggest that this pharmaceutical treatment may serve as a potential therapeutic in suppressing tinnitus symptoms.”

Reduction of Behavioral Manifestation of Tinnitus Through the Utilization of BK Channel Opener

Manisha Antony & Aarti Patel

Faculty Mentor: Joseph Walton (Department of Communication Sciences and Disorders)

Tinnitus, or “ringing in the ears”, is a prevalent hearing disorder. This study evaluates the effect of the drug candidate, CS0022, on the behavior of male CBA/CaJ mice with acoustic trauma (AT)-induced tinnitus. This compound is known to target the large-conductance calcium and voltage-activated potassium channel, or BK channel. This channel regulates neuronal excitability in the peripheral and central nervous system. Our hypothesis is that positive modulation of BK channel function mitigates changes in central auditory system activity that support the tinnitus percept. Behavioral evidence of tinnitus in mice models can be assessed through the quantification of the acoustic startle reflex and prepulse inhibition.

This study used Gap-Prepulse-Inhibition of the Acoustic Startle Response (GPIAS) to determine the presence and extent of tinnitus in the subjects. The GPIAS assay was first conducted on each mouse for baseline readings prior to AT with a 16 kHz narrowband noise. Post-AT behavioral assessments were conducted 7 to 9 weeks after trauma to select mice that developed tinnitus, while effect was assessed 10 to 11 weeks after trauma. Consecutively, Auditory Brainstem Responses (ABR) were collected to determine hearing thresholds of the subjects and helped evaluate the severity of threshold shifts. The findings suggest that treatment with CS0022 can improve AT-induced tinnitus in mice by modifying BK channels. The GPIAS results were statistically analyzed using a computational approach called Gstar. The ongoing analysis will focus on determining the relationship between the presence of tinnitus and the influence of treatment on permanent hearing loss.

Administration of BK Channel Agonist to Reduce Behavioral and Neural Manifestations of Tinnitus in Mice after Induced Acoustic Trauma

Kristie Labib & Malak Ibrahim

Faculty Mentor: Joseph Walton (Department of Communication Sciences and Disorders)

Tinnitus is a hearing disorder affecting approximately one third of all adults, and unfortunately has no FDA approved curative treatments. The deafferentation of central auditory structures as a result of ARHL or acoustic trauma (AT) causes a reduction in auditory sensory input. This then causes compensatory shifts in the balance of excitation and inhibition of the firing rate of the neurons within the CAS, which most often translates to hyperactivity. One particular BK channel modulator, known as CS0022, has been studied for its effect on hyper-excitability and inhibition in animal models. As a result, this study seeks to investigate this BK channel modulator therapy further and examine its effects on tinnitus in order to support its advancement and clinical usage. Auditory Steady State Responses (ASSRs) are electrophysiologic responses that display hearing sensitivity by evoking periodic amplitude-modulated tones (AM tones). They elicit steady state responses through neural phase-locking, which demonstrates auditory perceptive abilities. The study’s first objective is to examine the effects of AT on ASSR responses, as it is hypothesized that AT suppresses neural phase locking abilities. The study’s second objective is to examine the effect of CS0022 on the ASSRs of animals with AT-induced tinnitus, as it is hypothesized that CS0022 would enhance neural phase locking abilities. The data demonstrated that animals with tinnitus generally exhibited decreases in ASSR peak amplitudes following AT and increases in ASSR amplitudes following CS0022 administration. These findings suggest that this pharmaceutical treatment may serve as a potential therapeutic in suppressing tinnitus symptoms.

Meet the Researchers

This is from a June 2021 news article on the USFRI website’s newsroom:
https://www.usf.edu/research-innovation/news/2021/florida-corridor-students.aspx

MANISHA ANTONY

Research: Developing a novel therapeutic for treating tinnitus

Faculty Advisor: Professor Joseph Walton

Industry Partner: Cognosetta

Manisha Anthony recently graduated from USF with a degree in biomedical science and plans on attending medical school. She has been doing research at USF Professor Joseph Walton’s auditory neuroscience lab in the Department of Communication Science and Disorders for nearly two years. The lab focuses on studying tinnitus, a hearing disorder caused by age-related hearing loss or noise-induced trauma, and for which there are few effective treatments to lessen symptoms and no cure. She joined a project in Dr. Walton’s startup, Cognosetta, in 2020 that is working to develop a new drug to address tinnitus.

“Through my experience at Cognosetta, I was able to gain substantial knowledge that will help me with my future endeavors. I was able to be involved in various aspects of the research and the challenges I faced in this research has helped me be more independent and develop critical thinking skills. The most rewarding part for this experience was the wonderful opportunities for our team to present our accomplishments at the Undergraduate Research Conference and Association for Research in Otolaryngology. I am grateful to be a part of this research lab as it has opened an interest in neuroscience for me, which I hope to continue to study in the future. Most importantly I would like to thank my mentors Dr. Joseph Walton, Dr. Luisa Scott and Dr. Collin Park for guiding me and helping me achieve this honor.”

KRISTIE LABIB

Research: Developing a novel therapeutic for treating tinnitus

Faculty Advisor: Professor Joseph Walton

Industry Partner: Cognosetta

Kristie Labib recently graduated with a Bachelor of Science degree in biomedical sciences and will be starting at the USF Morsani College of Medicine in the fall of 2021. She also worked as an undergraduate in Dr. Walton’s lab on research projects on pharmaceutical and therapeutic methods at alleviating symptoms of tinnitus.

“My most valued experience in this research was my involvement in a project that examined the effectiveness of a new drug at suppressing symptoms of tinnitus. I was fortunate to work diligently on it with the support of my mentors Dr. Joseph Walton, Dr. Luisa Scott, and Dr. Collin Park. We observed successful results, which then drove me to write a USF Honors thesis on the neurological benefits of the drug on tinnitus symptoms. Additionally, we had the data presented on posters at both the Undergraduate Research Conference and the Association for Research in Otolaryngology. As part of the Cognosetta, Inc., team our work allowed us to be selected as one of the 21 Fibonacci Finalists in the Cade Prize research competition for Florida’s most innovative startups. Being able to share these achievements with my colleagues allowed us to grasp the impact we have on medicine through this project.
“I will forever be indebted to USF and my mentors, as this journey in tinnitus research fueled my desire to pursue a career in medicine. Although my experiences were unforgettable, I wish that this would only be the beginning of my journey, as I would like to pursue a career as an otolaryngologist after medical school.”

MALAK IBRAHIM

Research: Developing a novel therapeutic for treating tinnitus

Faculty Advisor: Professor Joseph Walton

Industry Partner: Cognosetta

Malak Ibrahim recently graduated from USF with a major in biomedical sciences and a minor in psychology. She will start at the Florida International University Herbert Wertheim College of Medicine in the fall. She conducted her undergraduate research on a potential pharmaceutical to treat tinnitus at USF’s Global Center for Hearing and Speech Research under Dr. Walton with the additional mentorship of Dr. Collin Park and Dr. Luisa Scott.

Malak conducted her USF Honors thesis work on the neurological testing used to evaluate a novel therapeutic theorized to alleviate the symptoms of tinnitus, as well as presented this research at USF’s 2021 Undergraduate Research Symposium. She hopes to continue conducting promising research as a future medical student and physician in order to advance medicine and healthcare.

“My years conducting research under Dr. Walton have proved to be an invaluable experience. I learned how to innovate and adapt in a professional, collaborative manner, skills that I am sure will aid me in my next step as a medical student. I also gained an appreciation for the medical applications of scientific exploration and how transformative they can be in healthcare.”

Updates

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References

Anti-Tinnitus Effects of “Prism Adaptation” Glasses: Researchers in France to Begin Major Study Next Month (August 2021)

New research project will investigate the therapeutic effects of a short exposure to prisms on hearing deficits of tinnitus.

Could special glasses offer relief to people with tinnitus? According to the science, it’s not such a crazy question…

anti-tinnitus prism glasses possible style?
Image Source / Credit: Stoelting Inc © Stoelting Co.

And a research project (led by Carine Michel) dedicated to finding out the answer has received a grant worth 213,408 euros (around $250,000 USD) from the ANR (France’s Agence Nationale De La Reserche).

Yes, the glasses may seem gimmicky, at first. But the science is fascinating…

From the official project description (emphasis ours):

Glasses to ear differently – GLAD

Our project aims at better understanding the link between visuo-motor plasticity (by using a short exposure to glasses shifting the visual field) and auditory perception to propose an innovative therapeutic method to reduce hearing loss. There are many evidences showing the therapeutic effects of prism adaptation on lateralized impairments, while our recent innovative result shows the effect of prism adaptation on auditory perception in healthy individuals (Michel et al., 2019; Bonnet et al., submitted).

Our project has two main objectives:

1) from a fundamental point of view, we will deepen our understanding of the effects of prism adaptation on auditory processes in healthy participants, and

2) from a clinical point of view, we will investigate the therapeutic effects of a short exposure to prisms on hearing deficits of tinnitus and presbycusis.

Importantly, this avenue of research builds on recent studies related to “visuo-motor plasticity” and something called “cross-modal enhancement”.

In short, the idea that tinkering with one sense (such as vision) can have an effect on another sense (such as hearing). And, hopefully, in a predictable way… that will allow such tinkering to perhaps someday serve as a volume knob for tinnitus. Or augment auditory perception by using the auditory’s connections to eyesight and visual areas of the brain (becoming well-established).

Some background and related research:

Modifying auditory perception with prisms? Aftereffects of prism adaptation on a wide auditory spectrum in musicians and nonmusicians
December 2020
https://www.sciencedirect.com/science/article/pii/S0001691820305436

Prism adaptation consists of pointing to visual targets while wearing prisms that shift the visual field laterally. The aftereffects are not restricted to sensorimotor level but extend to spatial cognition. There is a link between spatial representation and auditory frequency, with an association of low frequencies on the left side and high frequencies on the right side of space.

Influence of Visual Prism Adaptation on Auditory Space Representation
https://journals.sagepub.com/doi/full/10.1177/2041669517746701

We here show that there is indeed a slight influence of visual adaptation on the perceived direction of acoustic sources.

The research dollars appear to be attracted as well…

The Swiss National Science Foundation also recently funded a project related to audio-visual cross-modal effects: “Cross-modal interaction after brain lesion – the influence of auditory stimulation on visual neglect”. The project began earlier this year and will continue until February 2025.

From the project description (emphasis ours):

The relevance of our project is twofold. First, the project will shed light on the neuronal mechanisms underlying audio-visual cross-modal effects. Second, by clarifying how and to which degree audio-visual cross-modal effects may improve visuospatial attention in neglect patients, the project will potentially allow to develop new therapeutic approaches.

And if the connection to tinnitus still seems like a stretch… consider this paper from last year, “Increased risk of tinnitus in patients with early-onset cataracts: a nationwide population-based case-control study”, which concluded that “patients with early-onset cataract are at an increased risk of developing tinnitus in subsequent years”.

Note: that particular paper points to ROS (reactive oxygen species) as the main contributing factor… but it’s hard to ignore the eye-ear connection given the other emerging research and ongoing projects on the topic.

It gets the noggin’ joggin’:

Could a change in eyesight create a mismatch in auditory perception, and influence the central gain cause of tinnitus?

Hmmm…

It’s certainly a fair question.

Which might explain why some other big, familiar institutions are also investigating this vision-tinnitus axis.

For instance, this Johns Hopkins University project that began last July. Titled, “Cross-modal enhancement of auditory plasticity and performance in adults”, the project has received nearly $1 million USD in funding so far and will continue until June 2025, if everything goes as planned.

The project aims to discover the “mechanisms that can recover adult cortical plasticity is of essence to benefit recovery of hearing or for treating abnormal auditory processing as occurs with tinnitus.”

Here is the full project description — certainly worth a read (formatting and emphasis ours):

Cross-modal enhancement of auditory plasticity and performance in adults

It is well documented that the ability of the brain to undergo plasticity becomes limited in adults. In particular, sensory experience-dependent plasticity of cortical circuits is rather confined to a limited time during development, termed the critical period. Recovery and refinement of sensory processing is therefore difficult in adults. For example, the success rate of speech recognition in artificial cochlear implant patients becomes quite low, if the surgery is done later in life.

Hence discovery of mechanisms that can recover adult cortical plasticity is of essence to benefit recovery of hearing or for treating abnormal auditory processing as occurs with tinnitus.

We found that temporary visual deprivation is quite effective at producing large-scale plasticity in the adult primary auditory cortex (A1) of mice. Such changes occurred as potentiation of feedforward excitatory synapses from the primary auditory thalamus (MGBv) to layer 4 (L4) as well as L4 to L2/3. This was accompanied by weakening of synapses arising from lateral intracortical sources to L2/3 of A1. In parallel, we also observed refinement of cortical circuits of A1 L4 and L2/3. Collectively, these changes suggest that A1 circuit adapts to allow better processing of bottom-up auditory inputs, which is consistent with our published observation of refinement of A1 L4 neuronal receptive field and lowering of detection threshold in visually deprived mice. In this application, we aim to determine the mechanisms involved in driving adult A1 plasticity with visual deprivation, and whether visual deprivation improves auditory behavior in adults. Based on our observation that visual deprivation induced potentiation of thalamocortical (TC) inputs to A1 L4 requires audition, but no due to changes in the auditory environment, we surmise that there is central adaptation in circuits mediating auditory signals going through the thalamus and the cortex.

In particular, we hypothesize that short-term visual deprivation promotes A1 plasticity in adults by regulating inhibitory circuits at the level of thalamus and cortex (Aim 1). The circuit and synaptic adaptation seen in A1 following vision loss accompanied refinement of A1 L4 neural function, and is predicted to enhance auditory function.

We will examine how short- term visual deprivation alters auditory behavioral tasks in adults, and investigate whether this is due to changes in A1 neuronal responses and population encoding during auditory tasks using in vivo 2-photon imaging (Aim 2).

Results from our proposed study will provide mechanistic understanding on how short-term visual deprivation enables plasticity of adult A1 via regulation of thalamic and cortical circuits, and will provide means to enhance auditory processing in the adult brain that could benefit development of treatment options for enhancing or recovering auditory function as would be needed for better prognosis of artificial cochlear implants. Furthermore, our results can be generalized to provide insights into how cortical circuits adapt to losing major inputs as it may happen during injury, stroke, and neuronal degeneration.

Public Health Relevance

Discovering mechanisms to enhance adult brain function is of utmost importance when devising therapeutics to recover and refine normal brain function later in life. We found that temporarily depriving vision leads to recovery of plasticity in the adult auditory cortex, which can benefit auditory function. In this proposal, we aim to determine the mechanisms that allow recovery of adult brain plasticity, and whether temporary visual deprivation improves auditory performance in adults.

Interesting.

And perhaps even substantial enough to give those “gimmicky” glasses — which could potentially increase auditory perception (via multiple mechanisms)… and possibly alter or diminish tinnitus perception (to be determined) — some legitimacy. And in the context of all this research, perhaps this anti-tinnitus glasses project happening in France does not seem so “wacky” anymore…

But first, a quick rant:

Speaking of “wacky”, I have noticed an influx of Hope Police commenting on my articles and notes. “Hope Police” is the label I assign to people who feel the need to protect others from False Hope. They can be found commenting on articles like this one in Facebook groups or Reddit posts. They are easy to spot because they are Very Serious about making it clear that “THIS IS NOT THE TINNITUS CURE EVERYONE HAS BEEN WAITING FOR” and other variations of “NOTHING TO SEE HERE, KEEP IT MOVING.” In reality, what they really spread is False Nope. The opposite of False Hope and… a much bigger villain. Often these Hope Police and Protectors of Truth do not even bother reading the article. And so their criticisms are limited to the atmosphere of the article… what the article implied, apparently… or, get this… they explain how the problem with the article is that it could potentially be perceived by someone as suggesting the treatment in question is a cure. In other words, these Hope Police protect imaginary people from imaginary scenarios involving imaginary problems. Anyway, if you can’t already tell… it bugs me. But after giving it some more thought, I have decided to take the high road and… instead of publicly shaming these straw-treatment “debunkers”… I have decided to offer them a very special meme that will hopefully clear things up:

keep calm and realize this article does not claim these prism glasses are the tinnitus cure everyone has been waiting for
To: “Hope Police”
From: Love, Michael

That’s a peace offering.

As for everyone else…

I offer an invitation to join the newsletter (email updates)… that gives you “early access” to tinnitus treatment-related news and updates (that you won’t find anywhere else) — mostly pertaining to experimental not-yet-available tinnitus therapies. I send 1-2 issues per week. But only when something good is happening. See link below:

Updates

If you would like updates on the development of these “anti-tinnitus prism adaptation glasses” (as well as other experimental tinnitus-related treatments and not-yet-released drugs), subscribe to the email newsletter.

Last but not least, references for this [draft] article.

References

Impact of Sazetidine-A and Similar Nicotinic Drugs on Tinnitus

DRAFT COPY — you are seeing an “early access” version of this article. This report is sent to email newsletter subscribers, who receive it up to a week early.

Researchers at the Southern Illinois University School of Medicine have successfully tested a drug (sazetidine-A) related to the smoking cessation drug Chantix, in a sound-exposure animal model of tinnitus. Human clinical trials could begin as early as 2022…

This information is unclassified and from an Annual Progress Report prepared for the U.S. Army Medical Research and Development Command. From the report:

Tinnitus is the perception of sound in the absence of an environmental stimulus. This phantom sound in the head, is most commonly caused by noise exposure, resulting in damage to the inner ear. Within the veteran population seeking VA care, 16-27% suffer from serious hearing loss and tinnitus. Unfortunately, those most affected are bound to the sounds in their heads have difficulty concentrating, suffer from depression and may even contemplate suicide. We posit that breaking the bond between attention and tinnitus will ameliorate the impact of tinnitus. Drugs acting at receptors that bind the brain chemical acetylcholine (nAChRs), a substance involved in brain circuits that control attention could ameliorate tinnitus. We have successfully tested the drug (sazetidine-A), in an established sound-exposure animal model of tinnitus.

SOURCE: https://apps.dtic.mil/sti/pdfs/AD1114579.pdf

Preliminary studies are now starting to support their hypothesis: drugs that act at specific receptors that bind the brain chemical acetylcholine (nAChRs), a substance released by brain circuits that control attention, could alleviate tinnitus.

And these drugs, which include sazetidine-A (related to smoking cessation drug Chantix) and varenicline, could allow tinnitus sufferers with “habituation-proof” tinnitus to finally find relief thanks to a pill that — hypothetically — works to “disconnect” the looped circuit that may be preventing habituation (or extinguishment) from taking its normal course.

The result? Hopefully a way for people with severe disabling tinnitus to “get used to it” and have their tinnitus diminish, on its own, like most people… thanks to a drug involving the chemical substance involved in brain circuits that control attention. By addressing that chemically-based “habituation-proof” circuit, it could unlock the normalizing process.

Whether these drugs can do that remains to be proven. But the evidence from preliminary studies suggests it might be possible. That’s what this project is exploring.

From the progress report (which is dated August 2020 but only released publicly more recently):

4. Impact The results form SA1, delineated above, are the first of their kind to show significant tinnitus-related attentional abnormalities in principal AI output neurons. First they show significant abnormalities in the number and size of the presynaptic excitatory messages arriving at these neurons. Secondly they show significant tinnitus-related differences in nAChR sensitivity at different doses of acetylcholine. Since we will be pharmacologically targeting these receptors in attempts to normalize their tinnitus pathology, understanding these tinnitus-related differences is critical. The ability of sazetidine-A to effect disproportional changes in resting membrane potential and action potential threshold in animals with behavioral evidence of tinnitus suggests a unique receptor target. Finally, preliminary data suggests that sazetidine-A was able to normalize a tinnitus-related increased sensitivity to acetylcholine. Collectively, we feel these are exciting and highly publishable findings when matured. They also support the proposed SA2&3 studies.

The SA1, SA2, SA3 refer to “Specific Aims”, which are like goals/stages of the project. Right now, the researchers are in the final “stage” of this project. Human clinical trials would be a separate project that follows the completion of this one. I’m speculating, and I don’t know the future. But that’s where this is headed, as of now.

These findings and the theory behind these exciting hypotheses will continue to be studied and tested as part of this ongoing research project, “Nicotinic Receptor Pathology in Tinnitus: Auditory Cortex and Selective Desensitizing Nicotinic Agents” — which is supported by a grant of nearly $1.8 million, courtesy of the Department of Defense and the Congressionally Directed Medical Research Program.

Importantly, the research is aimed at treating the most severe cases of tinnitus: tinnitus that cannot be ignored or simply tuned out. Their goal is to develop new drugs capable of ameliorating tinnitus in “those most affected”, the people who are “bound to the sounds in their heads” and who “cannot do regular work”, “have great difficulty concentrating”, and “may even contemplate suicide”.

This is described in the project abstract (see below) along with more details about what is being studied and the hypothesis behind this new area of exploration in the realm of chronic tinnitus treatments.

As for the project itself… it is scheduled to complete in July 14, 2022 and… barring any surprises… it looks like human clinical trials could follow shortly after. Why so soon? Because the “new” drugs in question are closely related to already-approved smoking cessation drugs (such as Chantix)… in fact, Chantix might be a viable candidate, though we will have to wait and see to know for sure. In any case, the clinical trial process would likely be faster and less complex, as the safety profile of the drug is already well established in humans.

So it’s got that goin’ for it, which is nice.

Here are the details, including both abstracts (the second one is heavier on the science):

Nicotinic Receptor Pathology in Tinnitus: Auditory Cortex and Selective Desensitizing Nicotinic Agents

Principal Investigator: CASPARY, DONALD M
Institution Receiving Award: SOUTHERN ILLINOIS UNIVERSITY SCHOOL OF MEDICINE
Program: PRMRP

PUBLIC ABSTRACT

Tinnitus is the perception of sound in the absence of an external environmental stimulus. This phantom sound in the head, sometimes referred to as “ringing in the ears,” is a Fiscal Year 2018 Peer Reviewed Medical Research Program topic area. It is most commonly caused by noise exposure, resulting in damage to the inner ear containing the hair cells and nerve fibers that carry sound to the brain. The military working environment presents many high noise situations with noise levels often so intense that standard hearing protection is not adequate. A recent study found that Soldiers deployed to battle zones were ~52 times more likely to suffer auditory damage than non-deployed Soldiers. The American Tinnitus Association reports that within the Veteran population seeking Department of Veterans Affairs (VA) care, 16%-27% suffer from serious hearing loss and tinnitus. The VA awarded disability compensation for serious hearing loss tinnitus to approximately 972,000 Veterans with an annual aggregate cost of nearly $1.5 billion. The U.S. Centers for Disease Control and Prevention estimates that more than 50 million Americans – nearly 15% of the population – experience some form of tinnitus, with 10%-15% of this total suffering extreme and debilitating tinnitus. Conversely, the majority of chronic tinnitus sufferers are able to ignore their tinnitus, tuning out the din while going about their daily lives. Unfortunately, those most affected are bound to the sounds in their heads; they have great difficulty concentrating, suffer from depression, cannot do regular work and may even contemplate suicide. Studies proposed here are focused on developing a treatment for those individuals most impacted by tinnitus. Our hypothesis postulates that breaking the bond between attention and tinnitus will ameliorate the impact of tinnitus, allowing patients to return to a more normal life. We propose that drugs that act at specific receptors that bind the brain chemical acetylcholine (nAChRs), a substance released by brain circuits that control attention could ameliorate tinnitus. Our preliminary studies have successfully tested a drug (sazetidine-A) related to the smoking cessation drug Chantix, in a sound-exposure animal model of tinnitus. All proposed studies will be carried out in our well-established rat tinnitus model, and our laboratories have significant experience in all proposed methods. Proposed studies will test the ability of Chantix to ameliorate tinnitus. Similar to what is seen in human tinnitus patients, our recent studies in a rat tinnitus model finds tinnitus-related deficits in selective attention. We will test if both these drugs related to nicotine can normalize selective attention in our animal model. Proposed basic science studies will test if these agents can normalize aberrant brain cell response properties recorded in structures located at the highest level of the central auditory system, the auditory cortex. Preliminary receptor binding studies suggest that nicotinic acetylcholine receptors are altered in animals with evidence of tinnitus. Proposed studies will map the markers for the different receptor subtypes that make up these acetylcholine receptors in animals with and without tinnitus. Using brain slices from auditory cortex of animals with and without tinnitus, proposed studies will examine the function and the pharmacology of these receptors and the impact of Chantix and similar nicotinic drugs on the response properties of these brain cells. Collectively, these studies will provide new pharmacologic information on possible novel treatments for tinnitus while improving our understanding of the relationship between attention and tinnitus suffering and the cellular mechanisms that underpin this hypothesis.

TECHNICAL ABSTRACT

Tinnitus is defined as a phantom sound (ringing in the ears) that can significantly affect the quality of life for those who suffer its effects. Noise exposure, with its consequent acoustic damage, is the most common cause of tinnitus. The military working environment presents many situational high noise levels, frequently so intense that standard hearing protection is inadequate. There is a growing awareness that maladaptive attentional mechanisms are involved in the pathology of tinnitus. Individuals most disturbed by their tinnitus have their attention bound to the percept while showing significantly impaired selective attention. Basal forebrain neurons involved in attentional circuits can increase release of the neuromodulator acetylcholine (ACh), where it acts at nicotinic cholinergic receptors (nAChRs), located on terminals and neurons in the primary auditory cortex (AI). This forebrain cholinergic system is a component of a perceptual network that may enhance attention to tinnitus as well as generating emotional reactions to tinnitus. The proposed basic science and translational studies will use a novel pharmacologic approach to treat individuals whose attention is inextricably bound to phantom sounds in their head. Our preliminary data indicate that the nAChR-Beta2 selective partial agonist and desensitizer sazetidine-A reduced the impact of tinnitus in our animal model. The focus of the present proposal is to examine the therapeutic potential of two nAChR partial agonists, sazetidine-A and the smoking cessation drug varenicline. Preliminary binding and subunit expression studies suggest that nAChR subunits are altered in AI of animals with behavioral evidence of tinnitus. All specific aims (SAs) will use an established sound-exposure rat model of tinnitus. SA1A will use immunoprecipitation and florescent in situ hybridization (FISH) to characterize tinnitus-related changes in heteromeric and homomeric nAChRs in AI neurons from animals with and without behavioral evidence of tinnitus. nAChRs comprising different combinations of subunits are present on presynaptic terminals/inputs that innervate neurons across layers of AI. Our preliminary studies show altered numbers and affinity of nAChRs in AI layers IV and VI. SA1B will characterize functional pharmacology of tinnitus-related changes in acetylcholine (ACh) evoked synaptic currents from AI layers IV and VI neurons in an AI slice preparation. SA1C will examine the pharmacologic responses of bath applied sazetidine-A and varenicline on ACh evoked synaptic currents from AI layer IV and VI neurons as in SA1B. SA2A will catalog and compare tinnitus-related changes in AI single-unit responses from awake animals with and without behavioral evidence of tinnitus, while attempting to normalize tinnitus-related aberrant unit responses with systemic injections of sazetidine-A and varenicline. SA3A will test whether varenicline, similar to sazetidine-A, can ameliorate tinnitus in our animal model. SA3B is based on findings that animals with behavioral evidence of tinnitus, similar to human tinnitus sufferers, show impaired selective auditory attention. Others have shown that sazetidine-A can normalize impaired visual attention. SA3B will examine the ability of sazetidine-A and varenicline to normalize impaired selective attention in animals with behavioral evidence of tinnitus. Collectively, results from these proposed studies will directly test the hypothesis that tinnitus can be ameliorated using attention-altering drugs while examining basic science mechanisms underpinning this hypothesis at the level of the auditory cortex.

That’s all for now.

This article is a DRAFT and you are receiving early access because you are subscribed to email updates (or the link was shared by someone who is subscribed). How to get updates:

Updates

I will be releasing more updates and progress reports on this project, as they become available, leading up to July 14, 2022. Sign up for the TinnitusTreatmentReport.com newsletter to get these articles (it’s free and I send updates that do not appear on the front page of this website). I am not involved in the study and I do not have any information about human trials!

References

Sulodexide Anticoagulant Therapy for Chronic Tinnitus: Phase 3 Clinical Trials — When?

American Tinnitus Association sulodexide article screenshot

An important update on the development status of sulodexide, an anticoagulant drug that significantly reduced tinnitus severity scores in a phase 2 clinical trial in patients with chronic subjective tinnitus.

Background:

Sulodexide is a “highly purified mixture of glycosaminoglycans composed of low molecular weight heparin (80%) and dermatan sulfate (20%).”

It successfully completed a phase 2 study, “Randomized Double Blind Controlled Trial on Sulodexide Efficacy in Chronic Idiopathic Subjective Tinnitus”, and the results have already been published.

Quick summary:

  • Sulodexide decreased tinnitus severity in patients with chronic subjective tinnitus. The results were statistically significant and sulodexide outperformed the placebo. It also reduced tinnitus regardless of whether someone started the treatment with severe tinnitus or mild tinnitus.
  • The trial was randomized, double-blinded, and included a placebo group. The results demonstrated that people who received sulodexide experienced greater decreases in their tinnitus scores compared to people who only received a placebo.
  • The treatment regimen involved taking 2 oral tablets each day (one in the morning, one in the evening) for 40 consecutive days. Half the group received the real sulodexide tablets and the other half received placebo tablets.

Journal article sulodexide sagepub screenshot

What happened AFTER the results were published…

These phase 2 results were first published a little over three years ago, on May 1, 2018, in a paper titled, “Sulodexide Monotherapy in Chronic Idiopathic Subjective Tinnitus: A Randomized Controlled Trial” and… the results were so impressive, the American Tinnitus Association wrote glowingly about sulodexide in that year’s Summer issue of Tinnitus Today, their flagship publication. From the article, “Anticoagulant Sulodexide Therapy for Tinnitus”:

After the 40-day administration of placebo or sulodexide, a significantly lower THI score was found in the group that had taken sulodexide, compared to those taking placebo (THI score of 30.1 and 40.5, respectively). Scores on the Mini-TQ also demonstrated a greater decrease for those taking sulodexide (average of 9.7 vs. 12.5). Further analysis showed that those taking sulodexide demonstrated decreased scores on the THI and Mini-TQ, regardless of their beginning score. The mechanisms by which sulodexide may improve tinnitus are not yet understood. However, this study demonstrated that this drug has potential to reduce the severity of tinnitus and holds promise for further study in this area.

Since then, sulodexide continues to be mentioned in a growing number of scientific papers. Most recently, the study of sulodexide was cited in a paper from April 16, 2021, titled, “Methodological Aspects of Randomized Controlled Trials for Tinnitus: A Systematic Review and How a Decision Support System Could Overcome Barriers”, published in the Journal of Clinical Medicine.

Another paper, also published within the last 12 months, titled “Auditory Neural Plasticity in Tinnitus Mechanisms and Management”, described how certain mechanisms behind sulodexide are connected to tinnitus:

There are also reports of drugs that can improve the microcirculation of the cochlea by improving the blood flow and thus increasing the clearance of ROS through the bloodstream […] and sulodexide has antithrombotic and anticoagulant activities, both of which have been shown to have positive effects in tinnitus patients […] mainly by improving the subjective perception and emotional response to tinnitus. However, the changes of inner ear microcirculation in tinnitus are not completely clear yet, and various antioxidants still need to pass through the blood-labyrinth barrier; thus, the therapeutic effect is not very precise.

Meanwhile, further recognition of its therapeutic potential (emphasis: potential) can be found in other credible sources, too. For example, in a 28-page clinical policy bulletin from health care giant, Aetna, on the topic of tinnitus treatments. Within that document, sulodexide — “a natural glycosaminoglycan with anti-thrombotic, profibrinolytic and vascular anti-inflammatory properties” — is categorized as an experimental and investigational tinnitus treatment option and the bulletin mentions how researchers believe sulodexide holds promise.

And yet…

Here is what is happening right now:

Sulodexide is currently “stuck” between phase 2 and phase 3 clinical trials.

And nothing has happened for the last three years. Its advancement toward a potential approval for use in chronic tinnitus has been frozen.

But unlike other promising treatments that seem to mysteriously “vanish”… and which receive a lot of attention and fanfare… only to “ghost” the tinnitus community without explanation…

The reason sulodexide “ghosted” actually has nothing to do with a clinical trial failure, retraction of results, some scary side effect that was later discovered, patent issues, lawsuits… nor does it have anything to do with some Big Pharma conspiracy to withhold a possible tinnitus treatment because it’s not profitable enough.

The reality of the situation is much more complex. But also simple to explain:

The geopolitical situation in the country where sulodexide was being studied and where the clinical trials took place (and conceivably, would have continued to take place) is not able to support its further advancement into phase 3 at this time.

I am going to respect the privacy of the individuals I contacted while investigating the situation here…

But that’s the situation.

To reiterate: there exists, at this very moment, a phase 3-worthy tinnitus treatment (a drug) that seems to hold great promise… and it is NOT moving forwarad — at all.

It is “stranded” in between phase 2 and phase 3.

It has been so for years. Nothing has happened, with respect to its advancement toward phase 3 and perhaps some day an approval, since the end of the last phase 2.

I know that might be sad to read for some people.

But the good news is, there is no “expiry date” and it can be unfrozen, unstuck, unpaused, and…

Unforgotten.

The only danger is for the community and research community to “forget” about sulodexide (or any other promising candidate, for that matter).

That appears to be what has happened. Consider this: big budget marketing campaigns and savvy PR departments exist to make sure you don’t forget about FX-322, Lenire, etc. But there is nobody actively working to make sure sulodexide receives your attention and driving its advancement and funding.

Whether that changes will ultimately be up to you — the community — and the organizations and people who are in a position that allows them to make the necessary arrangements required to give sulodexide (and the people who study it) a chance at continuing the next leg of this valuable work.

My hope is that this article can get the process started and put sulodexide back on the radar. (Side note: A few people on TinnitusTalk did notice, back in 2018. But that, sadly, was not enough. The thread, for whatever reason, did not grab the attention of the rest of the community at the time, and became inactive.)

The community — which means YOU — can decide whether it is worth discussing. Worth emailing organizations asking them for their position on this treatment. Talking about it on reddit, TinnitusTalk, Facebook, wherever else.

See what happens.

How to get updates on this situation:

Please remember to sign up for the TinnitusTreatmentReport.com email newsletter for ongoing updates about sulodexide and other promising tinnitus drug candidates.

References

https://journals.sagepub.com/doi/10.1177/0194599818767618

https://clinicaltrials.gov/ct2/show/NCT02737670

https://www.aetnabetterhealth.com/pennsylvania/assets/pdf/provider/guidelines/medical/Medical/Tinnitus-Treatments.pdf

https://www.mdpi.com/2077-0383/10/8/1737

https://www.hindawi.com/journals/np/2020/7438461/

https://en.wikipedia.org/wiki/Sulodexide

https://www.tinnitustalk.com/threads/sulodexide-possibly-benefits-chronic-tinnitus.17918/

https://clinicaltrials.gov/ct2/show/NCT02737670

New Research from Susan Shore Explores Connections Between Tinnitus, Hyperacusis, and Signal Processing in Noisy Environments

Very short update:

A new Susan Shore research paper was just posted online.

It is a preprint (not-yet-peer-reviewed) and was added to bioRxiv a few days ago on May 21, 2021.

The title of the paper is, “Cochlear nucleus small cells use olivocochlear collaterals to encode sounds in noise”. The authors are Susan E. Shore, Calvin Wu, Adam Hockley.

Here is the abstract:

Abstract

Understanding speech, especially in noisy environments, is crucial to social interactions. Yet, as we age, speech processing can be disrupted by cochlear damage and the subsequent auditory nerve fiber degeneration. The most vulnerable-medium and high-threshold-auditory nerve fibers innervate various cell types in the cochlear nucleus, among which, the small cells are unique in receiving this input exclusively. Here, we characterize small cell firing characteristics, demonstrating superior temporal as well as intensity coding. We show that small-cell unique coding properties are facilitated by direct cholinergic input from the medial olivocochlear system. These results highlight the small cell-olivocochlear circuit as a key player in signal processing in noisy environments, which may be selectively degraded in aging or after noise insult.

Here is a link to the full text version (PDF):

https://www.biorxiv.org/content/10.1101/2021.05.20.444983v1.full.pdf

As you probably noticed, the word “tinnitus” is not mentioned up front. Nowhere in title, nowhere in abstract.

But it does appear deeper in the text. As does the word “hyperacusis”, another connection here.

new shore paper screenshot with word tinnitus and hyperacusis

This post is just a quick share. I have not had time to go through the paper and analyze its findings. I only learned about it within the past hour.

But from what I have seen so far, the connections to tinnitus and hyperacusis that Shore references here are quite interesting. And they become more clear once we take a look at the research she cites.

Here is a link to that paper, “Increased contralateral suppression of otoacoustic emissions indicates a hyperresponsive medial olivocochlear system in humans with tinnitus and hyperacusis”:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269714/

That’s all for now. Because it is 12:58 AM here in Montreal, Quebec and I just wanted to share this brand new Susan Shore research preprint update with you before going to bed.

The source of this information:

Like most of the research I post and highlight, this preprint appeared on my radar thanks to the fully automated system that monitors, collects, filters, and organizes the research papers listed on TinnitusTreatmentReport.com. This system runs 24/7 and specifically tracks tinnitus-related research (and news, and clinical trials, and…) from a fairly long list of sources – one of which is bioRxiv, the biology preprint server hosted down at the Cold Spring Harbor Laboratory.

This meme captures the essence of how this system helps me keep up with freshly posted Susan Shore research:

Susan Shore research appeared meme

Goodnight.

This update is for Tinnitus Treatment Report email subscribers. If you are reading this but have not yet subscribed — you can join the email updates list here. It’s free. There is no spam. No promotional emails. And your information is kept private. Expect between 1-3 emails per week (but only the good stuff).

Efficacy of donepezil in patients with chronic tinnitus

Researchers in Brazil are studying the effects of donepezil in patients with chronic tinnitus.

Some quick details on donepezil and the new phase 2 trial:

Donepezil is a drug that is similar to memantine, rivastigmine, and galantamine.

From Wikipedia:

Donepezil was approved for medical use in the United States in 1996. It is available as a generic medication. In 2018, it was the 128th most commonly prescribed medication in the United States, with more than 5 million prescriptions.

It is a cholinesterase inhibitor that “inhibits voltage-activated sodium currents reversibly and delays rectifier potassium currents and fast transient potassium currents.” More detailed information available here: https://www.ncbi.nlm.nih.gov/books/NBK513257/

It is already approved and used to treat other conditions (such as Alzheimer’s disease) – though its effects are apparently small and its mechanism still not fully understood.

And now it is being investigated as part of a phase 2 trial to determine whether or not it can help people with chronic tinnitus caused by sensorineural hearing loss.

The study was registered about 6 months ago on November 3, 2020.

It will enroll up to 50 participants.

According to the study record, the date of first enrollment = January 29, 2021.

But according to that same study record, the study status = Not yet recruiting.

Which means there was probably either a delay in starting the trial or a delay in updating parts of the study record. (Probably the latter.)

This information is current as of May 17, 2021. However, it is based on records that are only current as of February 23, 2021. So, the current status might actually be recruiting. We just can’t tell from the current study record.

But it does tell us about outcomes and the hypothesis:

Primary Outcome(s)
Improvement is expected from patients with tinnitus who will use the medication comparing to placebo group. The methods Student’s t test and ANOVA analysis will be used, before and after placebo and active drug therapy, for quantitative variables. Statistical significance level of 0.05 or 5% will be adopted for two-tailed samples and study power of 95%. The qualitative variables will be described by their frequency of presentation.

Secondary Outcome(s)
The memory improvement is expected from patients who will use the medication comparing to placebo group. The methods Student’s t test and ANOVA analysis will be used, before and after placebo and active drug therapy, for quantitative variables. Statistical significance level of 0.05 or 5% will be adopted for two-tailed samples and study power of 95%. The qualitative variables will be described by their frequency of presentation.

That’s all for now.

This article is a PREVIEW COPY [draft]. As a subscriber to TinnitusTreatmentReport.com email updates, you get access to it a few days early – before it is posted to the front page.

Not signed up? Subscribe here. It’s free and you can expect between 1-3 emails per week (but only if something is happening). No spam, no promotional emails, privacy respected.

References

Further reading

Important Reminder

  • nothing on this website qualifies as medical advice and is not intended to guide treatment decisions
  • everything you read or see here is for entertainment or informational purposes only
  • do not attempt to “copy” this trial’s intervention or try a “do-it-yourself” regimen
  • donepezil can have extremely serious side effects for some people (including withdrawal effects)
  • always talk to a doctor or qualified professional when making treatment decisions
  • have a nice day

Ketamine + HD-tIPNS for tinnitus: Professor Dirk De Ridder investigates effects of new “drug/device combo” therapy

Professor Dirk De Ridder, a world-leading expert in tinnitus, is investigating the combined effect of ketamine and brain stimulation on tinnitus loudness and distress, as part of a new phase 1/2 clinical trial.

The aim of the study is to determine if low dose ketamine, through its effects on brain plasticity, is able to catalyze transcranial electrical stimulation, and reduce tinnitus severity as a result.

Starstim 32 neuroelectric headset for ketamine tinnitus trial
Behold… The Starstim 32 headset (device) that will be used alongside ketamine (drug), for this device/drug combination therapy trial.

A total of 24 participants with chronic tinnitus will get a chance to receive treatment with the experimental drug/device combination therapy, at the University of Otago Dunedin School of Medicine, in New Zealand. The treatment will be delivered twice, 10 days apart.

ketamine molecule
Ketamine molecule. Not quite as cool-looking as the headset device. But still, an essential part of the combo therapy.

Inclusion criteria: Adults aged between 18-70 years with constant subjective tinnitus and a grade of 3 or higher (considered “moderate to severe”) on the tinnitus questionnaire.

The trial (Registration number: ACTRN12621000119897p), titled “Effect of ketamine and concomitant multi-target high definition transcranial electrical stimulation on tinnitus loudness and distress in adults- A feasibility and safety study”, is registered prospectively on the Australia New Zealand Clinical Trials Registry.

Ketamine device/drug combination therapy trial for tinnitus screenshot

As of May 12, 2021, it is unclear whether or not anyone has been enrolled (yet) or if the coordinators have begun recruiting participants.

The anticipated date of first enrollment is listed as February 15, 2021. However, according to the provisional study record, the trial’s ethics application is still awaiting approval.

Here is some more information, taken directly from the provisional study record (emphasis/formatting ours):

Ketamine and High Definition, Trancranial Infraslow Pink Noise Stimulation (HD-tIPNS)

The intervention arm will receive a low dose of subcutaneous ketamine (0.5mg/kg) as a bolus, from a clinician experienced in administration. This will be followed by HD-tIPNS administered for a single session of 30 minutes duration, beginning ~25 minutes after ketamine delivery, by a researcher experienced in administering neuromodulation techniques.

A battery-driven wireless 32 channel transcranial current stimulator (Starstim32 TCS®, Neuroelectrics) will be used to deliver stimulation while the participants are comfortably and quietly seated. Simulation [sic] is delivered by AgCl electrodes placed in the international 10-20 arrangement, secured in a neoprene cap (see Neuroelectrics website for headset image). For the active treatment group, the stimulation will be delivered at a current strength of maximum of 2mA for 30min, with 60s ramp up and ramp down at the beginning and end of each stimulation session, with continuous stimulation in between. For sham stimulation, to create an identical skin sensation to the active stimulation, the current will be applied for a 60s ramp up (0-2mA) and 60s ramp down (2-0mA) at the beginning and the end of each stimulation session, without any current for the remainder of the stimulation period.

This Intervention will be delivered twice, spaced 10 days apart. Intervention duration will be a total of 2 hours in length to allow for safety monitoring. After a 20 day washout, both groups will transition to the intervention, delivered twice again, 10 days apart.

The delayed start occurs as follows: Participants can be allocated to start with Ketamine + Active Stimulation or Ketamine + Sham Stimulation. Both the sham stimulation and the active stimulation groups will receive active stimulation after the 20 day washout (the Ketamine + Sham stimulation is the active control). Therefore the Ketamine + Sham stimulation (Active control) receives a delay to the start of active intervention.

Participants will undergo treatment at the Department of Psychological medicine laboratory at the Dunedin School of Medicine, University of Otago.

  • Intervention [1] Treatment: Drugs
  • Intervention [2] Treatment: Devices

Comparator / control treatment: Participants in the control arm will receive a low dose of subcutaneous ketamine (0.5mg/kg) as a bolus, from a clinician experienced in administration. This will be followed by Sham stimulation, designed to create identical skin sensations to active stimulation. Participants will use identical equipment to that of the active group, and will receive a short dose of the treatment protocol, mimicking the initial tingling/prickling commonly experienced with Transcranial electrical stimulation.

Primary outcome
Tinnitus Functional Index (TFI). The TFI has eight subscales that address the intrusiveness of tinnitus, the sense of control the patient has, cognitive interference, sleep disturbance, auditory issues, relaxation issues, quality of life, and emotional distress. This provides an overall measure of how much of a problem tinnitus is for participants (severity).

  • Adults aged between 18-70 years with constant subjective tinnitus and a grade of 3 or above on the tinnitus questionnaire.
  • Minimum age 18 Years
  • Maximum age 70 Years
  • Gender Both males and females

This article will be updated as more information is added to the study record.

For additional updates related to this ketamine/brain stimulation combination therapy (and other experimental not-yet-available tinnitus treatments), subscribe to the Tinnitus Treatment Report newsletter (email updates). It’s free, there’s no spam or sneaky promotional emails, and your information is kept private.

References

Questions? Comments? Feedback? Send an email to michael@urgentresearch.com and say hello.

Researchers evaluating the effects of bitter almond oil and cinnarizine on chronic tinnitus severity

A new phase 3 clinical trial for tinnitus has begun recruiting at Mazandaran University of Medical Sciences, a top medical university in Iran.

Researchers will investigate whether or not a combination of bitter almond oil and cinnarizine can reduce tinnitus severity in patients with chronic tinnitus.

The title of the study is “The Efficacy of bitter almond oil on the severity of chronic tinnitus.”

Iran bitter almond oil tinnitus study
This study was found “hiding” on a little-known Iranian clinical trial registry. We verified it by cross-referencing the study’s unique registration identifiers in a WHO database as well as the Cochrane Central Register of Clinical Trials.

Participants in the treatment group will receive a combination of bitter almond ear drops and cinnarizine tablets, twice daily (every 12 hours), for one month.

Tinnitus severity will be measured thrice three times: 1) immediately before treatment begins, 2) after two weeks of treatment, and 3) after 4 weeks of treatment, using VAS and THI scores.

This trial was registered on February 16, 2021 and will enroll up to 70 patients with doctor-confirmed chronic tinnitus, between the ages of 17 and 75, male and/or female.

As of March 1, 2021, recruiting for this study was set to begin on March 5, 2021. No reason to assume that date has changed. But we will update this post as we get more information.

As for the treatment itself – a unique combination of ear drops and tablets – here is some very basic background information:

More information on bitter almond oil will follow. For now, an important warning:

WARNING: “bitter almond oil” might sound like a harmless natural ingredient, but in reality it is associated with some extremely serious chemical compounds (i.e. cyanide). Needless to say, there is NO safe (or legal) do-it-yourself approach to copying this trial. Or any trial, for that matter… but especially this trial.

Some interesting information on the cinnarizine component, from the Meniere’s Society UK:

Cinnarizine has two pharmacological actions. It is a calcium antagonist, though not a powerful one. This acts mainly on the blood vessels and prevents constriction on these vessels. In theory it therefore improves the micro circulation of the ear. At the same time it has a mild antihistaminic effect.

Remember to subscribe to the email newsletter for updates related to this cinnarizine/bitter almond combination therapy (and news about other experimental tinnitus treatments in development).

References

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