Etifoxine - anyone care to speculate on the mechanism behind any possible hepatotoxicity?

Vastness

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Recently have become interested in etifoxine - brand name "Stresam" in Russia - a non-benzodiazepine anxiolytic, apparently without any significant tolerance, and indeed few negatives at all, except for the unfortunate fact that a very small proportion of patients (30, apparently, since 1995, according to a study from 2012 - https://www.ncbi.nlm.nih.gov/pubmed/22633197) developed hepatitis with a median time of 18 days, varying from 11 to 61 days. At least one of these patients ended up requiring a transplant.

Obviously this is a very small amount of people relative to the total amount of people who have been prescribed this which is probably thousands, but I'm still a little concerned. I am taking it currently, 200mg / day, but plan to take it for no longer than 7 days. I'm also going to get a liver function test shortly after. I mean, I figure that serious liver injury isn't something that would just sneak up on you... right? Surely I should expect to experience some kind of symptoms before it became irreversible?

Anyway, there seems to be precious little information on the actual mechanism behind this effect, so I would be interested to hear if anyone would care to speculate.

I know a lot of substances, even ones widely considered to be "safe" have the odd serious adverse reactions in a very small proportion of the population, like modafinil for example which I also take semi-regularly despite the possible danger of Stephen-Johnson's syndrome... however the apparent seriousness of etifoxine's extreme outlier dangers are a little more concerning, although I don't plan to take it long term.
 

Shadowmeister

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Whoa that's crazy. I ordered a box of this from Russia, I found it to be not very effective, in fact I couldn't definitively say it was beyond placebo, and at the time I was tapering phenibut so I was anxious a lot. Are you finding it effective?
 

Vastness

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I have found it to be effective yeah, although it is definitely "subtle". That said I have taken it before just once or twice rather than for days at a time and did not notice anything significant. This time however I started taking it just after having taken phenibut 6 days in a row, about 1.5-2g each day, and found that I did not experience the negative effects that I would usually expect after a phenibut "binge" - and I can definitely notice "the fade" around 6 hours in when I start feeling a bit less relaxed and wanting to take my next dose. I have also not been tempted to take phenibut like I usually would be.

I've been taking it essentially as if it were prescribed, 100mg twice daily. I have read that higher dosages, 150-300+, for example, can produce more benzodiazepine-like and intoxicating effects but I do not want to risk going into this territory until, firstly I've used it for it's intended purpose (to soften minor phenibut withdrawal) and secondly after this liver function test (obviously if I see any warning signs I'll discontinue use immediately).
 

sekio

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This has calcium channel activity - presumably the effects are similar to gabapentin/pregabalin.

I wonder if the people who experience liver damage are using alcohol concomittantly. There's nothing in the structure that would suggest a direct toxic effect.
 

Vastness

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^ The effects are similar, although definitely of lower magnitude. I don't have much experience with gabapentinoids other than phenibut - but in prescribed dosages etifoxine is probably too subtle to tease out any finer nuances of effect. It feels GABAergic though.

I wondered also if other drugs were a factor, although the study abstract did say "Only cases with suggestive chronological events, no other drug-related or non-drug causes, and sufficient information, were included"... I guess it's hard to say if some cases slipped through though, and for this class of substance it's probably likely a significant proportion of the target user base were self medicating in some way.
 

Shadowmeister

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Strange, I was using it to try to combat phenibut dependence, and it did absolutely nothing for it, or if something, so little as to be essentially worthless. I also took 400mg one time and didn't notice any change in the subtleness of the effects.
 

Vastness

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That is strange indeed. I will have to try a larger dose in a few days time to see if the effects are more in your face.

Honestly I could probably be convinced the effects were placebo. I don't think they are right now, but it wouldn't be the most surprising thing if somehow I found out they were...

Will see if I take a higher dose if I notice any obvious amplification of the effects.
 

Vastness

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So just to report back - I had a bunch of blood tests and everything came back normal, even within optimal ranges - except SHBG, which for some reason in me is sky high, it was even higher this time than a year ago, which may or may not have something to do with etifoxine as it does apparently exert it's effects through some kind of hormonal pathway. I don't know if this is at all relevant to anything but I mention it just for completeness, in case perhaps it is useful information to someone, somewhere...

I've taken 400mg today in 2 doses of 200mg about an hour apart, and while at times I am pretty sure that for me it's not placebo, there is a definite ceiling of how far exactly the anxiolysis can go. There is a report on reddit of someone taking 300mg and having "difficulty forming sentences" which I find very hard to believe, although perhaps I have a low potency fake, I have no idea what quality pharmaceutical regulation is like in Russia but perhaps there is a market for dud medicines to sell to unsuspecting Westerners...

I might take another 200mg in a bit just to see how far this goes, although I suspect not very far. However I did not get a lot of sleep and was quite anxious this morning especially after drinking a big cup of coffee, and I no longer have that sleep deprived anxiety. I noticed the anxiolysis most when I went for a brief walk out into the world to do some things and noticed I was feeling quite relaxed just walking outside... but perhaps it is just a nice day.



Somewhat off-topic but vaguely related and I just want to share - I will note that I have not taken any phenibut for over 2 weeks now, and have taken no armodafinil for 8 days, and am feeling a whole lot better and more stable in general. I really had developed some kind of secret psychological dependence to those 2 compounds over the past couple of years or more where I would be mostly, at least 4/7 days, on them, and if not, always planning when I could take them, and feeling anxious about periods I would be without them... To be honest I had begun to have serious doubts if I was even capable of living and working in the world without at least knowing that I would be able to take one or both of these 2 substances at some point in the future... so it's pretty great to be free of that for the moment. Honestly I haven't really spoken to anyone about my concern of my use of these substances... except in a vague sense to people who would not be too interested or just wouldn't know about them, so it's been kind of a very mild, secret addiction. I am aware that if I was going to pick some substances to develop a psychological dependence on, I could do a lot worse than these ones, but still, it's nice to be off them. I wanted to post this somewhere earlier but felt it was somewhat out of place in Health & Recovery amongst the stories of far more serious addictions... so I'll just share it with you readers of my thread here. :sneaky:



Edit, 3 hours later: Went up to 600mg. I'm actually gonna revise my opinion. I think that what I have been experiencing so far, and indeed, still am, to some extent, is highly likely to be just placebo. I did think I experienced something, but logic dictates otherwise. The placebo effect is a powerful thing.

I would suggest it's probably likely that either -
a) Stresam and probably other anxiolytics which are not widely prescribed outside Russia are helpful only in a certain subset of the population - the lack of research indicating otherwise may be an indicator of bias from the organisations doing the initial research, or perhaps just a factor of the fairly limited amount of research that exists so far, or...
b) Stresam (and probably some other Russian pharmaceuticals) ARE in fact effective in Russia, but widely faked when sold to "unsuspecting Westerners" as I mentioned.

The reason I am leaning towards b) a little is because it's not my first experience with such substances - Bromantane was another that I heard a lot of positives about, but honestly felt next to nothing, not even placebo, when trying it. Admittedly, my life is perhaps less stressful now in some ways than it was when I tried Bromantane / Afabazole, which could account for the fact that the placebo effect was not as significant then.
 
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Shadowmeister

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I had the same experience with bromantane, for what it's worth. Occasionally I thought maybe something but that was it. Same with Afobazole
 
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