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TissueReligion  1yr ago (slatestarcodex.com)   2022 thread views

Thoughts 8 years later on the SSC article on russian psychopharmacology?

slatestarcodex.com

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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Throwaway to share that I'm currently trying out bromantane (9mg nasal). I was hoping for the anxiolytic effect but haven't gotten much out of it yet, positive or negative. 9mg is small, probably time to try bumping it.

Will share results on ACX when I'm through testing.

Keep an eye on you’re blood pressure, I liked bromantane but it spiked mine so I quit using it

Unless you can read Russian fluently and have good general medical knowledge, I wouldn't risk it regardless of how well the idea is in theory. There is a reason that medications require prescriptions.

I have read over 1000 Russian/USSR studies in pharmacology.

The Russian medical research is not the only one to be an isolated island, this apply also to Japanese research for example, see e.g their research on tinnitus.

While it is true that Russian research in pharmacology is understudied by the west, because of criminal mediocrity, there are many counter examples of Russian counpounds that have a decent amount of international research.

See e.g the biggest discovery in medecine of the century: skq1.

IIRC for Russian pharmaceuticals, the international researchers I "often see" study them are Indian or Brazilian. Maybe German too.

As for Nootropics or geroprotectors, they are generally markedly more ignored by the international "community" because of systemic failures, since nootropics/cognition enhancement are not considered a legitimate drug target and therefore is underfunded. Except for the niche research on mitigating fragile X syndrome, autism, the negative symptoms of schizophrenia, social anxiety, etc.

Since USSR and to some extent Russian research is public funded they are almost the only one in the world to afford fundamental research at scale of targets that have no commercial value in the prescription drug market.

As for geroprotectors the same apply, Ageing is generally not considered a disease, nor something that should be treated by taking pharmacology because we live in a very infantile/stockholmised world.

Even though geroprotectors often have partial efficacy against a wide range of lucrative diseases, the extreme inertia and cost of clinical trials combined to the extreme aversion of doctors for polypharmacology, partial drugs and simply keeping up with medical advance when it is evolitive instead of being disruptive explain that they are underresearched by the west and never prescribed.

The Russian also afford something revolutionary, they study the pharmacological application of drug that are plant/animal derived or that are endogenously produced in the human body (e.g. Peptides).

Those entire class of pharmacologicals, which have a billion of year of existence and bidirectional fine tuning, and ideal side effects profile are in general not patentable and since mostly only corporations fund clinical trials, the main class of medecine is in practice, non-existent because of broken incentives.

Because the Russian bypass those attractors/repulsors that plague the medical research, they can and do make revolutionary discoveries in most fields of medicine.

As i said, many Russian counpounds do have multiple international research that reproduce and corroborate the potency of their results.

However it is true that there is a concern of fraud/amplifying the potency of the effect of a pharmaceutical.

In my experience such fraud is rare but is possible.

The main candidate I have is the atypical anxiolytic Tofisopam.

Not Russian though, but from an ex USSR European state.

I have read the 300s studies about it.

There is IIRC a lot of corroborating studies from around the world, Including recent studies.

Tofisopam is an atypical anxiolytic, antidepressant, non addictive gabaergic, dopaminergic and generally excitatory drug as is is an atypical selective PDE inhibitor.

It is the only drug in the world to have this pharmacological profile and can be expected to have widespread, unique effects.

The body of studies for its action mechanisms are many and are very convincing in principle.

I am not rejecting the research on the nature of its effects.

Tofisopam is extremely interesting and that is not a fraud per se.

However I am rejecting the extreme amount of studies showing very potent effects on depression, anxiety, schizophrenia and other psychological conditions.

While the effect is real and tofisopam might be used for those conditions, how can there be so many studies corroborating very potent results while the actual reported effect online is very mild/inconsistent is a mystery for me.

Even though the online reports are rare and it might be that tofisopam truly is a wonder drug, IMHO I doubt it.

How can it be fraud when there is so much research from different teams and decade, even international one ?

Just look at how potent tofisopam is supposed to be https://fr.scribd.com/presentation/328205226/Tofisopam-Medical-2014-REVISED

A fraud at this scale can't be explained.

It would be too risky to synchronize such a massive amount of fraudulent researchers. Among the 300s studies not a single one significantly dismiss the rest of the research.

But if the reported potency of tofisopam is really a fraud then that is horrific for the rest of the medical research, nothing could be trusted as even a compound with so many studies, over decades and many international teams, for so many conditions would not be immune to consistent, systematic international fraud.

Japanese research for example, see e.g their research on tinnitus.

Do they have any treatments for tinnitus that you know of?

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

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.

n = 1, but tofisopam did nothing for me.

I have studied all anxyolitics, there are many effective alternative with no/low tolerance.

Based on the scientific evidence, I would strongly recommend opipramol or Etifoxine + TUDCA (beware CYP interactions, can be lethal)

Note: I haven't tried many anxiolytics myself but I have used glycine for sleep and I must say it makes me feel calm and nice/soft.

So about tofisopam, I have tried it on myself for 2 weeks (a bit too short, the studies show peak results at 3-4 weeks iirc)

Firstly I am not depressed. I can have mild social anxiety with some people. I can be a bit hypoactive or have slightly chronic fatigue or high sensitivity to sleep deprivation.

I am not anhedonic but I am less hedonic than I wish to be.

I have ADHD PI untreated.

I don't know what I hoped out of tofisopam, I'm not the main audience, especially for depression.

For the social anxiety it might have helped me but not enough experience with it at parties. If it helped it was inconsistent or ambiguous because I sometimes mixed it with bromantane (another dopaminergic and anxyolitic).

So what did it do?

the first day I felt a slight increase in heart contractility which is consistent with theoretical models

I didn't felt it the other days, probably homeostasis doing its work

at the upper range of the daily dose it felt slightly weird

Like I knew I was on something.

Subtle but a bit dirty.

Less dirty than high dose bromantane though.

At low-mid dose I didn't felt it.

That's notable since few drugs can be felt.

It might have helped me with ADHD in theory (dopa) but I did not feel an improvement. Nothing like e.g. 2fma

It might have had a Nootropic effect, lots of promising research on PDEs about this however I did not feel smarter however I consider myself a very high performer and did not design a benchmark.

It might have helped me with SAD (the most likely) but not enough data yet, I'll try again one day eventually. Especially as a potential augmentation to stimulants.

Yeah my personal report is quite useless but I hope it allows to bring some nuance that tofisopam does not do nothing per se, as in it is not homeopathy.

One theory I have to explain the reported discrepancy online would be that most of the lab rat(ionalist)s do not actually suffer from clinical GAD or depression.

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