Forget GABA for a While... Think Glutamate?!

[Fish]

Louise - every person is unique and each individual reaction to meds might be different. One of my relatives has been occasionally using xanax for about 20 years now and it still works for him. It's important to use it only when really necessary. Talk to your doctor about it, maybe it is ok to use clonazepam when your T is at it's worst? If clonazepam helps you, perhaps your T is stress-related?

Still I am glad to hear you have found something that works for you so well. You were having a really hard time and you definitely deserve some relief!

 

[Karl]

Louise -
I think that clonezepam is calming the efferent nerve that is causing the tinnitus. They call this "neural inhibition".

This is actually sort of the topic of this thread started by mock turtle, "Forget GABA for a while...think glutamate!?". Mock turtle and others (Joe, Markku) understand this brain chemistry thing very well, I think. (Me, I'm more of a nuts and bolts guy.)

It's my understanding that neurons transmit signals using neurotransmitter chemicals. These chemicals are held in little pockets at the axion end of the neurons. When a neuron "fires", the pocket of chemicals is released, and the chemicals are binded on the dendrite end of the next neuron. Glutamate and gaba are chemicals that play a key role in this process. One excites neurons while the other inhibits neurons.

It would be great to find a drug that targets just the nerves that are causing tinnitus. The trick is finding a drug that will be selectively absorbed by just those efferent nerves that are too excited. Benzos like clonazepam and Xanax seem to calm down those nerves - however, they calm down a whole lot of other nerves in the process.

For those of us who take anti-anxiety drugs, let's not get confused that we're taking them for anxiety; we're taking them to calm the nerves that cause tinnitus.

 

[DezDog]

Get some facts about the tolerance issues instead of trying to predict them. You'd think people become tolerant to Prozac, but it doesn't work like that. You're kind of scaring yourself with future predictions and that is one of the CBT/anxiety "no-nos".

You never know; also, they could help you while you become habituated. They also might be all you need to "unclench" and release the anxiety ratchet.

Keep your chin up L.

 

[DezDog]

> For those of us who take anti-anxiety drugs, let's not get confused that we're taking them for anxiety;
> we're taking them to calm the nerves that cause tinnitus.

Ultimately, you're taking them in both cases for anxiety. When you don't care about T, T isn't a problem.

 

[Louise]

Thanks Fish, I did ask my doctor if I could use it 'ad-hoc' and he said it should be ok.

DD - I am going to get the facts about tolerance (somehow) and then decide if I should take it regularly.

Karl - this is exactly my take on why its worked. Its inhibitted the neurotransmitters in the auditory cortex (or auditory nerve or whatever) and thats why the sound has dropped.

Yes, its also relieved the anxiety and panic but the noise level has gone down due to the effect on the neurons in the auditory system. The noise really did go down and it went right down as well.

Over excited neurons are my problem then. Is that the case for all T sufferers?

I need to do some research proper into this area now I know that is the cause. If the other guys you have mentioned who are experts in this area could post something I'd be grateful.

Thanks all for your replies.

 

[Louise]

As an aside, I emailed Merz yesterday about Neramexane testing and Memantine. Its probably been covered already but here's what I got back..........

"The development program for the treatment of subjective tinnitus has not confirmed our objectives for the most recent Phase III trial.

We have comprehensively analyzed the data in this respect in cooperation with our Japanese development partner Kyorin.
Based on the findings from this analysis, Kyorin initiated a Phase II trial in October 2011 in Japan which should be concluded in 2014.

We will then evaluate the new data thoroughly in cooperation with Kyorin and take our next steps – e.g. further clinical trials in Europe and also indication of tinnitus due to sudden hearing loss – on the basis of the Japanese results.

Memantine is approved in Europe for moderate to severe Alzheimer disease. There were / are no trials with Memantine in tinnitus indication going on."

 

[erik]

Memantine an Neramexane have been in studies since about 2009 (what's taking so long) but reduced chronic tinnitus in rats -Study. Glad to see that companies are doing more research in this area.

More about Neramexane-

Neramexane is expected to improve the patients' psychological
suffering and difficulties in their life associated with tinnitus by inhibiting the excessive
excitation in the auditory pathway from the inner ear to nerve and cerebral cortex via mainly
its two pharmacological properties.

1) Neramexane inhibits the excessive nerve excitation in the auditory pathway between the
inner ear and cerebral cortex via NMDA antagonistic activity.
2) Neramexane inhibits the nerve excitation in the inner ear via nicotinic acetylcholine
receptor antagonistic activity.
Expected Indications: Alleviation of the psychological suffering and difficulties in the life
associated with tinnitus in patients suffering from moderate to severe tinnitus
* About NMDA antagonist: "NMDA receptor" is a receptor that receives glutamic acid in
the nerve system which transmits signals between the nerves via glutamic acid, a kind of
amino acid. NMDA antagonist inhibits the excessive excitation of brain cells and nerve
variation.

About nicotinic acetylcholine receptor antagonist: "Nicotinic receptor" is one of two
receptors which acetylcholine binds to. It is known that a lot of nicotinic receptors
categorized α9 and α10 exist in the inner ear. Nicotinic acetylcholine receptor antagonist
inhibits the nerve excitation mainly in the inner ear.

 

[Louise]

Neramexane is just what we need. Like you say, what are they dawdling about for? So the Japanese testing will be completed by 2014 then they have to do some more in Europe? Is there a set number of phases something has to be tested for?

 

[Karl]

Erik -
Excellent information.

...Like you say, what are they dawdling about for?...

Good one! I am very happy you are finding relief. It may get less and less...wouldn't that be great?

Yes, I agree there is associated anxiety with tinnitus. However, not to "put the cart before the horse", clonezapam actually reduces tinnitus (for most cases), based on ATA's studies. It's not just an indirect psychologic fix, via a reduction in anxiety.

I admit that in my past, I had a bout with depression - long before I had tinnitus. Tinnitus is something entirely different, which can make you depressed. Anti-anxiety drugs seem to reduce tinnitus for a lot of people who aren't even anxious or depressed.

I'm not sure if there is such a thing as "building up a tolerance" , but taking too much for a really long time isn't good. There are people who can abuse this type of thing and take handfuls.

 

[DezDog]

> However, not to "put the cart before the horse", clonezapam actually reduces tinnitus (for most cases),
> based on ATA's studies.

It is comforting to know there is at least this kind of back-stop available.

 

[Karl]

Sorry to say that Markku and Joe were closely following Neramexane clinical trials last year, with not-so-good results:
https://www.tinnitustalk.com/threads/tinnitus-research-initiative.4/#post-1223

 

[Louise]

Yes the Clonazepam did reduce the T, substantially. But, I got it for the panic attacks I was having from T in the hope that it would also reduce T. So, I did get it for both reasons but the drug actually does reduce T noise, like you say Karl, that reduction isnt coming from just the reduction of anxiety.

I'm not taking it though not yet as I cant handle the 'back to normal' feeling, the way life used to be all night and then the crushing blow of reality in the morning when its there again. Its not a long-term strategy and even in my current bad state I recognise that. Somehow I have to habituate it. Or come to terms with it or learn to live with it. Somehow.

I've read the Neramexane posts Karl, so disappointing. However, I wonder if we do have to give up on it as the Japan tests are still going on, they haven't axed them. On the email Merz sent to me the lady said their objectives for Phase III werent met, I asked what she meant. I found her reply sad as we can all identify with it. Here's the response....

"Health authorities usually require studies, to see that a drug works better than a placebo (=drug with no active ingredient, "sugar pill") or existing therapies. Studies can be conducted in different ways, with different scales, durations, and patient groups – this is called the study design.
In tinnitus, patients all over the world do currently not have any therapies which heals them – and as some of them suffer a lot, they are searching for relief for years. You can imagine the feeling of relief if those patients are then meeting the requirements of the study and are selected to participate in a study; the pure participation give them a lot relief as they feel they can now do something against their disease. As this effect exists in all patient groups (regardless whether they get placebo or drug), it can happen that the results of the study are not very clear and studies need to be repeated in a different design – this is currently the case."

 

[Louise]

She replied again with this site English for the Japanese company that are doing the testing and said I could check the results from tome to time. She also said Kyorin wouldnt be wasting their money if they didnt believe in the compound. Maybe we dont have to give up hope in this stuff quite yet?

http://www.kyorin-pharm.co.jp/en/news/

 

[Karl]

Louise -

My mind can run wild thinking of ways to fix tinnitus. Trouble is, I'm not a doctor! The best that we can do is try to influence the ATA, the BTA and individual researchers to explore approaches that we would like them to pursue. I have written quite a few letters to people involved in auditory system research, and, to my amazement, I have gotten replies from everyone I have written. Of course there is always the possibility they are just being polite to me!

I think people on this forum fall into two camps: Those who try to figure things out, those who don't. We are all looking to each other for advice. I'm a lot like you, in the way we are both trying to understand the physical science behind tinnitus. I have convinced myself it is feedback in a neural circuit. Now I'm trying to get the ATA to establish Step 1 (what is going wrong) and get on with Step 2 (a fix).

Aside from understanding what it is and trying medicines, we also have another way to deal with tinnitus: TRT therapy. I've been having a private converstation with someone on this forum who has successfully habituated after having 18 months of TRT. He wrote some profound words about his success:

When I was told that the generators would not eliminate tinnitus but make it easier to live with I was disappointed, but now I understand that it can be done. On this forum we read about the fight/flight syndrome. One of the principles of TRT is to live with the generated sound and through monthly counseling sessions understand that the sound is not threatening at which time it is not alarming to the brain - just another meaningless everyday sound. For me, it is still present but I rarely think about it and when I do there is no alarm whatsoever. There is one interesting thing told to me by the audiologist that would be unbelievable to most, or all, members of this forum. That is: the sound of tinnitus does not increase or decrease, only the perception of it

He recommended a book by Jastreboff, which I just purchased. I'm trying to cover all the bases.

 

[erik]

TRT has, for the past 20+ years, been the standard when it comes to treatment for T. Some I talked to swear by it as the one thing that helped them get through it all and others have said it offered little to no help. One of the difficulties is that there are very few certified TRT clinicians in world. Every Audiologist you talk to boasts about TRT with the use of hearing aids or noise generators, but this in fact is only one part of actual complete TRT. The part that most Audiologists fail to mention is just as important, if not more important than using noise generators. That is the CBT (Cognitive Behavior Therapy) component as Karl has mentioned above in the Jastreboff book above. This teaches you all about T and the concepts/strategies which help make the T a non-issue in your life. The most successful TRT employs both the CBT side and the use of hearing aids/noise generators. Audiologists are not equipped or trained to do both.

 

[Karl]

...One of the difficulties is that there are very few certified TRT clinicians in world. ...Audiologists are not equipped or trained to do both.

Very good points.

As I said, I started a private conversation with someone here who has successfully gone through the TRT therapy. He has his head together about this stuff, and he recommended this book.

The only potential issue that I may have is viewing tinnitus as a psychological thing. I think of a lot of us, myself included, are searching for what is the neurological cause of tinnitus, which is a valid question. Psychology deals with higher brain functions (thoughts), which we can train ourselves to ignore.

 

[Karl]

Louise -
I found something very interesting in a book I've been reading , "Principles of Neural Science". At 1700+ pages, this book is as big as a phone book.

Neurons can be either excitatory or inhibitory:
Excitatory synapses are glutmatergic. These types of synapses excite nerves.
Inhibitory synapses are GABAergic. These types of synapses calm down nerves.

The knee-jerk reflex is an example of how one set of nerves excite the muscles and how another set of nerves inhibit (stop) the process. These form sort of a closed loop with the muscles in the leg. All nerves systems seem to form a closed loops, including the nerve system in the auditory system.

About drugs like clonazepam which is a benzodiazepene (derived from benzene): "Benzodiazepines facilitate the opening of GABA receptor-channels through a binding site separate from that for GABA."

So, it would appear that by taking clonazepam, it is causing neural inhibition through GABA receptor -channels.

I subscribe to the theory that tinnitus is due to an overexcited efferent nerve that leads back to the cochlea. If true, then clonazepam may be calming down that nerve.

 

[mock turtle]

karl...me too

im thinking the auditory system is trying to boost the signal from the damaged stereo cilia (hearing hair cells) from the "dead" frequencies by sending a signal back to the ear...efferent pathway

and as most here know the outer hair cells arent there to sense sound....they are there to boost the signal. ..the outer hair cells "make" sound

it would be an interesting experiment.....if we could wipe out the outer hair cells corresponding to the inner hair cells that have been completely destroyed

 

[Louise]

Louise -
I found something very interesting in a book I've been reading , "Principles of Neural Science". At 1700+ pages, this book is as big as a phone book.

Neurons can be either excitatory or inhibitory:
Excitatory synapses are glutmatergic. These types of synapses excite nerves.
Inhibitory synapses are GABAergic. These types of synapses calm down nerves.

The knee-jerk reflex is an example of how one set of nerves excite the muscles and how another set of nerves inhibit (stop) the process. These form sort of a closed loop with the muscles in the leg. All nerves systems seem to form a closed loops, including the nerve system in the auditory system.

About drugs like clonazepam which is a benzodiazepene (derived from benzene): "Benzodiazepines facilitate the opening of GABA receptor-channels through a binding site separate from that for GABA."

So, it would appear that by taking clonazepam, it is causing neural inhibition through GABA receptor -channels.

I subscribe to the theory that tinnitus is due to an overexcited efferent nerve that leads back to the cochlea. If true, then clonazepam may be calming down that nerve.

Thanks for the info Karl. I keep missing posts, only just seen this one. From another thread there's an AntiD called Tianeptine which I think reduces Glutamate activity so that's attacking the problem from the other end it seems. Its a French drug though and it isnt available in the UK. Typical.

 

[mock turtle]

hello all

way back at the beginnign of this thread i proposed a little trial, and im ready to "report in"

for 6 weeks ive been experimenting with a form of vitamin b-12 called methyl cobalamin and taking at the same time magnesium as both are known to be glutamate antagonists

i struggled to try and measure what if any improvement ive experienced but this has been difficult because my tinnitus fluctuates on an hourly and daily basis

i tried to match my tinnitus with similar sounds at different levels (volume) i can make with my keyboard (electronic musical instrument) and masking with tracks of white noise played back at various levels

it appears that methyl cobalamin and magnesium has been of limited value

initially i was taking 1000mcgs of methyl cobalamin (micrograms) and 1000mg of magnesium

at that dose i realized no change after a week so i doubled the dose of each for a period of two weeks and still was not able to measure significant improvement

i continued at these doses for another week...no change and then boosted the methyl b-12 to 3000mcgs the max level that was cautioned against going beyond by a medical professional

and at this level i found a modest improvement especially on days and during hours when i was experiencing a spike but this improvement i would characterize as minimal...like maybe 10% and im struggling to figure out if any of this is just due to wishful thinking and or randomness

at this point im considering trying to find an additional or alternative glutamate antagonist, or wondering if i should press the limits an "up" the dose of methyyl b-12...hmmm....... thinking

another thought has occurred to me...strangely...gaba is manufactured by the body from glutamate ! ! ...yes i know it sounds crazy, the excitement neurotransmitter is the precursor to the calming neurotransmitter...ah nature plays its little jokes on us

but indeed, an enzyme called GAD (glutamic acid decarboxilase) is responsible for making gaba out of glutamic acid

so

if i did indeed reduce or antagonize glutamate...maybe i also diminished my levels of gaba?

speculation....i will be conjuring up another "experiment" but alas i have to confess my foray into trying to suppress my bodies level of glutamate has met with little or no success

amazingly i sure know how to almost double my tinnitus...a half teaspoon of mono sodium glutamate will always do the trick and of course the sugar substitute aspartame also makes my ears ring off the hook

if i could only find the negative ...or is it the inverse of these two

best wishes
mock turtle

 

[Louise]

Interesting stuff Mock Turtle. What do you think of Tianeptine as a glutamate antagonist? I wish I oculd get some to try it.

 

[mock turtle]

louise

it reads like a wonder drug...anti depresssant and anti anxiety, and more.... but it appears to be neither a SSRI nor a gaba agonist if what ive read is correct

and on top of it all even after 40 years of approved use in europe it is unavailable in the usa...(our opharma doesnt like competition?)

yeah, id like to try it...id try anything that was either FDA or EU approved and didnt represent a clear and present danger

best wishes
mock turtle

 

[Louise]

I thought I read it is an SSRE, it actually sucks up serotonin, working the opposite to SSRIs. And I thought I'd read its a Glutamate antagonist. Its French and that has something to do with why its not available in other countries. Some political/economic thing.

 

[mock turtle]

yes..ssre

wow you just said the magic words for me...glutamate antagonist

 

[Andy]

Hi M.T I find you posts very interesting over the past months and with all the experiments you do you must hit oil sometime however
I would like your opinion if you don't mind on Resveratrol you may have covered in the past and I've mist it i read it can help to reduce T what do you think ? Thanks

 

[mock turtle]

hi andy

thanks for the complement

i could never make up my mind on resveratrol

like NAC it seems that if taken before carcinogenisis then it can extend your life but after, it may acccelerate the proliferation of cancer...very strange...may have something to do with telomeres and cell immortality...which is what cancer cells are..immortal (that is they defy apoptosis), im just not sure

and the dose thing for effectiveness...wow.... youve got to drink a lot of wine or eat a lot of peanuts to get a therapeutic" level of resveratrol..or take pills. but one thing has always caught my eye.... that many of the good things in fruits an vegies are synergistic...taken by themselves it takes a lot to do good but if you combine all the good things in tomatoes, blueberries, turmeric, ginger garlic broccoli and grapes, you get this big multiplication effect that does a body a lot of good...very complex

a lot of these things are so complex i just cant get my mind to understand whats going on...i struggle

so dont take anything ive said above as reliable

but heres something you can take to the bank...eat lots of colorful fruits, examples, including red grapes (for resveratrol) and veggies (tomatoes for lycopene) and blueberries, and you will be way ahead of the game

best wishes
mt