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The nootropics spaces online (notably /r/nootropics, among others) contain references to compounds like semax or noopept which seem to have unclear support from the literature, or in the case of semax have hundreds of studies from russian labs, and only a single one from a western lab (https://pubs.acs.org/doi/10.1021/acschemneuro.1c00707).
After having little success with the headache meds my doctors have been prescribing me, I was thinking of trying some of these compounds. I was curious what your guys' thoughts are on these compounds. Is there a good reason they haven't been studied much in the west yet, or is it just inertia?
Open to any thoughts.
Thanks.
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Notes -
Hi TIRM,
I believe most "incurable" diseases have their best treatment (not necessarily a complete cure but better than existing) already found 30 years ago but since then completely ignored.
It is fascinating how self victimizing (sorry for the offense but it morally needs to be said) victims of chronic disease are. They just simply believe it is a fatality and trust so called "experts" practitioners that are pubmed illiterate and don't actually give a fuck about your condition.
A victim of a chronic disease should for him and for others systematically try most of the treatment candidates and especially all the treatment that have a negligible rate of serious non-transient side effects.
A disease being considered incurable generally simply means epistemologically that nobody has yet attempted said systematic experimentation.
In many cases nobody will for the centuries to come.
So IIRC from my meta research, for tinnitus the best thing to do is indeed to prevent it, e.g. by taking NAC.
Once the damage is done, NAC does not help. However if your tinnitus is degenerative, NAC will probably reduce the long term worsening.
Now about treatments for someone that already has a (stable) chronic tinnitus:
Firstly about the palliatives:
People use benzos/gabaergics for tinnitus AKA gaba-A subtypes.
I would consider experimenting with Etifoxine (+TUDCA and look at CYP interactions) instead as an alternative with apparently less tolerance building.
Note that a benzo addiction reversal can be accelerated with (Imidazenil or flumazenil? Don't recall) but that process is possibly neurotoxic and ironically ototoxic.
Now about the real treatments:
Unfortunately for you I have forgotten about many things regarding this condition.
Tinnitus is in essence of special form of excitotoxicity.
Therefore the use or gabaergics is probably not only palliative but also to some extent therapeutic as the excitotoxicity possibility drive a worsening over time.
Unfortunately gaba A and B are subject to relatively quick tolerance.
As I said optimality in tolerance reversal and in tolerance building is to fine tune, e.g. Etifoxine.
One could also alternate between gaba A and B or between A subtypes via biased agonism. This might however not necessarily work well and induce cross tolerances although I do believe alternating A and B is not absurd.
GABA also has other receptors which is the point of Etifoxine since it target the mitochondria gaba receptor (although its upregulation of neurosteroids do agonise gaba A and (B?) IIRC)
As said playing with the half life might alter the speed of tolerance building.
There exist other GABA receptors, IIRC tofisopam partially potentiate GABA Y and without tolerance but how useful that is is an unknown.
Tofisopam while having questionable effectivenes as a gabaergic has studies showing it as useful being a potentiator, an augmentation to benzos effectiveness while allowing to reduce tolerance increase.
Also there are alternative ways to induce gabaergy, e.g releasing agent, reuptake agent, prodrug, catabolize inhibitor, etc
However the main salient thing is to look at other beyond gabaergy is the other complementary ways to reduce excitotoxicity.
The #1 to try IMHO (not by potenty but by likelyhood of being useful) would be an NMDA antagonist such as Memantine.
Then maybe concomitantly a calcium blocker.
I have no knowledge in AMPA blockers/negative allosteric modulators.
Kainate and glurs would probably be toxic.
I haven't looked into it but Glycine 4g sounds helpful since it is inhibitory.
You could also play with the secondary messenger inositol at megadoses (unsure about side effect profile), that is an atypical effective anxyolitic and possibility an atypical promising tinnitus treatment.
You could play with vasodilation e.g. Cialis.
Finally you could play with synaptotrophics such as magnesium l threonate.
However of all of that, except for GABAERGY, NMDA antagonism and maybe vasodilation, I don't know empirical studies about those on tinnitus. I conjecture those would be useful based on my expertise. Especially curious about inositol or maybe sigmaergics like opipramol or lthreonate or Etifoxine.
Synaptotrophics are the only really potentially dangerous class, which they are usually not but tinnitus is special so..
The japaneses have however beyond conjectures, empirically found ones that apparently works.
Wether those results reproduce is something you should confirm us.
I would try first Bifemelane
https://www.jstage.jst.go.jp/article/jibirin1925/86/12/86_12_1799/_article
This drug is very interesting, it is a RIMA so the best class of antidepressants, with very minor side effects contrary to MAOIs, see e.g moclobemide or pirazidol.
I don't know any online seller of it.
So you best chance is a trip to Japan for a month or to convince Vanuatu international pharma to get it (good luck..) or to find a cooperative Japanese guy or to ask a japan e-pharma to get it, e.g. contact
https://bio-japan.net/
I think it is the most interesting tinnitus treatment candidate.
I don't think that another RIMA would work though, there is probably something special about bifemelane. But maybe you could try if you have nothing else to try, moclobemide.
Then we have very ironically tofisopam, with a very high efficacy score
https://www.jstage.jst.go.jp/article/jibirin1925/82/1/82_1_133/_article
You should definitely try it. I doubt it reproduce but I mean the efficacy score is record high, the side effect profile and cost negligible and the action mechanism (special PDE inhibition and GABA Y) is actually unique in the world.
Titrate dose slowly up to the study dose and if no results above up to the max dose (300 IIRC?)
Wait for 5 weeks before concluding about no efficacy.
And then report back.
I would recommend getting the official brand OTC e.g. on rupharma dot com
Then after trying tofisopam I would try the many other compounds that have positive efficacy results albeit milders
E.g. IIRC pge1
https://www.jstage.jst.go.jp/result/global/-char/en?globalSearchKey=Treatment+of+Tinnitus
And also not just pharmacology but behaviours such as
https://www.jstage.jst.go.jp/article/audiology1968/44/3/44_3_163/_article/-char/en
Edit:
There's also atypical non drug based pharmacological actions,
Such as tVNS
https://www.researchgate.net/publication/233912804_Transcutaneous_vagus_nerve_stimulation_in_tinnitus_A_pilot_study
And
tDCS
https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-018-0467-3
BTW not a treatment but an underused palliative for sleep would be ASMR
https://www.tinnitustalk.com/threads/asmrs-autonomous-sensory-meridian-response-effect-on-tinnitus.44581/
Then if nothing of all tolerable treatments that have been empirically found over the last decades does bot work for you then I would consider actively joining clinical trials or preclinical trials or to ask for the
https://en.wikipedia.org/wiki/Right-to-try_law
You could also become an expert and conjecture yourself an priori optimal polypharmacology like I did but better than I did since I haven't studied the precise nature of the excitotoxicity/long term potentiation.
E.g if it was epigenetic then one would consider e.g. HDAC inhibitors
EDIT
this action mechanism seems potent
https://pubmed.ncbi.nlm.nih.gov/17221143/
EDIT additional treatments:
for pge1
"Misoprostol"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136369/#:
:text=treatments%20(217).-,Misoprostol,-Misoprostol%20(Cytotec%C2%AE)%20is"However, the combination of sulpiride plus melatonin, which interacts with dopamine receptors, reduced tinnitus visual analog scale scores significantly more than placebo (275–277). In a single-blind, placebo-controlled study, sulpiride plus hydroxyzine, an antihistamine and anxiolytic, was significantly more effective in reducing tinnitus visual analog scale and tinnitus perception scores than placebo or sulpiride alone (278)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136369/#::text=produced%20by%20placebo.-,However,-%2C%20the%20combination%20of
Edit:
Potassium channel modulators looks interesting
Vigabatrin too despite possibly permanent side effect profile
Gacyclidine could be better than Memantine
Same for neramexane and AM-101
I guess one should try all tolerable nmda antagonists to find the one that works best on him
It's possible that nmda antagonists take time to show effectiveness
See e.g this atypical one
Acamprosate had no beneficial effects after 30 days of treatment, a modest benefit at 60 days and a significant effect at 90 days.
Nice resource btw
https://github.com/aioue/tinnitus-treatments/blob/master/to-be-sorted.md
"2.2.5. Primidone"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235102/#:
:text=day%20%5B33%5D.-,2.2.5.%20Primidone,-Primidone%20is%20an"Furosemide"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235102/#::text=2.7.%20Diuretics-,Furosemide,-is%20a%20loop
"Intratympanic Steroid Injection"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235102/#:
:text=2.12.9.%20Steroids%3A-,Intratympanic%20Steroid%20Injection,-Intratympanically%20injected%20steroids"2.12.10. Trimetazidine HCl https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235102/#::text=2.12.10.%20Trimetazidine%20HCl%20Trimetazidine%20HCl%20inhibits%20the%20generation%20of%20free%20radicals%20noxious%20to%20cells%20by%20directly%20preventing%20acidification%20in%20ischemic%20cells%20and%20promoting%20the%20generation%20of%20ATP%2C%20a%20source%20of%20energy
With so many treatments and the obvious potent synergies between them, I strongly believe you can strongly reduce your tinnitus.
TL;DR
Start with tofisopam, Etifoxine and pge1.
Etifoxine must be taken with TUDCA and ideally liver enzymes should be monitored although optional.
Verify about the cyp interaction iirc tofisopam and Etifoxine inhibit the
Thanks for the surprisingly detailed writeup. I'll read quite a bit more before attempting DYI pharmacology.
Update: I serendipitely stumbled upon betahistidine and it seems like a no-brainer low hanging fruit from a quick glance, acting as an ear selective vasodilator https://en.wikipedia.org/wiki/Betahistine#:~:text=Primarily%2C%20it%20is%20a%20weak%20agonist%20on%20the%20H1%20receptors%20located%20on%20blood%20vessels%20in%20the%20inner%20ear.%20This%20gives%20rise%20to%20local%20vasodilation%20and%20increased%20permeability%2C%20which%20helps%20to%20reverse%20the%20underlying%20problem%20of%20endolymphatic%20hydrops.
edit doesn't seem very effective but good to have in a polyphamacotherapy
maybe synergetyc with pge2
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All the drugs I mentioned above the "EDIT" have benign side effects, are non-dangerous, cheap and available OTC.
The only thing you need to check is the CYP interaction between inhibiting a CYP enzyme and a CYP substrate, especially for etifoxine.
You also need to be aware that benzos and GABA B tolerance and addictions are real, you need to dose responsibly and cycle, google about it.
rupharma is the best legit epharma online. For more choice although less reputable, there is indiamart.
btw Misoprostol is the most likely to help IMHO
also the Intratympanic Steroid Injection are extremely interesting, if they work for you, that would mean you could solve your tinnitus via an immunosuppressant/modulator, maybe thymosin alpha 1.
I would also try the atypical protectant and gaba potentiator emoxypine.
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