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Reversing a strange Tianeptine tolerance

^

The combination of tianeptine with morphine significantly reduced the development of morphine antinociceptive tolerance and suppressed the incidence of naloxone-precipitated withdrawal symptoms.
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Interesting. Why?
 
seep im not to sure why. i assume you know what antinociceptive means.
Tianeptine was considered an SSRE but some information says otherwise.
its role thought to be played on dopamine
Tiapentine enhances the extracellular concentration of dopamine in the nucleus accumbens[4] and modulates the D2 and D3 dopamine receptors,[5] but this effect is modest and almost certainly indirect.[2] There is also action on the NMDA and AMPA receptors. Recent reviews point to this pathway as a hypothesized mechanism of action, based on tianeptine's effect of reducing stress-associated neuroplasticity

In contrast to SSRIs and tricyclic antidepressants, tianeptine modestly enhances the mesolimbic release of dopamine, but it is also unclear how this occurs because tiapentine itself has no effect on dopamine transporters, nor does it affect D1, D2, D3, D4 and D5 receptors.

Perhaps the most studied hypothesis is that Tianeptine has a protective effect against stress induced neuronal remodeling. This is all based largely on preclinical studies



im thinking it has to do with the way it acts on these receptors protecting them.
ill research more on antinociceptive tolerance. and the supposed mechanics behind why one would be more sensitive to pain stimuli after extended morphine
 
here is another article talking about antinociceptive tolerance.

http://journals.lww.com/anesthesiol...f_Morphine_induced_Antinociception_in.32.aspx

The classic models of explaining the development of opioid tolerance have mostly focused on changes in neurons themselves. The changes caused by repeated administration of opioids and consequent receptor activation may involve adaptive changes in the neurons, such as internalization of opioid receptors,4 up-regulation of N-methyl-d-aspartate receptor function,5,6 production of nitric oxide, or down-regulation of glutamate transporters.7 Also, a counter-regulatory antiopioid system could be involved, including neuromodulators such as cholecystokinin or dynorphin

Recent studies suggest that opioid administration induces tolerance also via mechanisms other than those involving neurons. The glial cells of the central nervous system have previously been considered neuroimmune cells that mainly provide support and nutrition for the neurons. New data indicate that activated glial cells may modulate the activity of the nociceptive neurons in the central nervous system9–11 and actively oppose the analgesic action of opioids on pain-transmission neurons....

after repeated administration of opioids, various proinflammatory neuromodulatory substances, such as substance P, fractalkine, nitric oxide, interleukin (IL)-1, and tumor necrosis factor α, are released in the central nervous system. These pronociceptive substances may attenuate opioid analgesia. The role of glial activation in this process still needs to be clarified. However, glial activation has also been suggested to be involved in the pathophysiology of neuropathic pain which is less responsive to opioids than nociceptive pain.
 
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blessedamines said:
There is also action on the NMDA and AMPA receptors. Recent reviews point to this pathway as a hypothesized mechanism of action, based on tianeptine's effect of reducing stress-associated neuroplasticity

Perhaps the most studied hypothesis is that Tianeptine has a protective effect against stress induced neuronal remodeling. This is all based largely on preclinical studies

im thinking it has to do with the way it acts on these receptors protecting them.
ill research more on antinociceptive tolerance. and the supposed mechanics behind why one would be more sensitive to pain stimuli after extended morphine
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This dovetails into the discussion in the other thread about glutamate receptor ligands and drug tolerance. Interestingly, tianeptine is reported to cause irreversible tolerance that persists even after discontinuation. In that other thread, posters are wondering why the same phenomenon (irreversible tolerance) is sometimes seen with ketamine.
 
My guess is that because Tianeptine decreases Serotonin levels in the brain, 5-HT2c receptors are not as active in the VTA so less GABA is released on to Dopamine neurons, so you get a bit more Dopamine release.
 
Dr. Beat. can you explain and verify on how GABA is released onto dopamine neurons? and what specific ones? D1, D2, etc...?
what exactly are you refering to when you say Tianeptine decreases serotonin levels in the brain?
 
Kudos said:
I acquired tianeptine while outside of north america and began taking a daily regimen of it. The first pill I took produced immediate, full-fledged anti-depressant effects in a way which seemed impossible to that point. This included the oft-referenced stimulating sensation of the drug, which seemed quite key to its symptom-relief.

I took it for 4 months, with narry a side-effect and that stimulating sensation maintained the way through. Tianeptine seemed to push my brain into an absolutely perfect state of balance. I felt a return to a state of mind I had not experienced in eons and was suddenly adverse to muddling it with any other recreational drugs. Alcohol depressed the effects; adding nicotine to the stimulus became overbearing to the point of nausea; caffeine seemed to have no effect whatsoever.

But then I ran out. Back in north america, where it is not available at market. I was forced into withdrawal as I waited for a supply solution. The withdrawal was punctuated by constant headaches which felt best described as my brain shriveling down to a dead state. I acquired a small supply off the internet. It didn't work, or at least it was severely muffled from before. I put a tremendous amount of hope and stock in the fact that the package seemed to indicate it was expired, or that perhaps it sat in the Turkish sun for too long and degraded.

However, four months later, I have now acquired unexpired medication through perfectly legitimate means, from western Europe, and I am devestated to find no difference. There is no stimulating sensation, and there is a negligible change in mindset. Mostly it just induces fatigue after it's apparent peak and fall in my bloodstream.

My question is what happened? And how can I reverse it? It seems that a tolerance to it developed in its absence, which is awfully counter-intuitive. I am willing to try anything to get its original effects back and I have access to anything prescribe-able should a mix of something else be the solution.
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I think I can offer a possible explanation for the OP. I had a similar experience with selegiline years ago. After an initital honeymoon phase, I ran out after 2 months and quit cold-turkey. No problem. The day I took my last pill, I had exhibited no signs of tolerance AT ALL. Based on this, I figured I could get back into it at some other time with absolutely no tolerance issues as the last pill hit me just as hard as my first.

Sadly, that was not to be the case. One year later, a new supply from the same manufacturer had absolutely zero effect, not even a placebo-type buzz. Several subsequent attempts spaced many months apart from different manufacturers still had no effect whatsoever. Much brain picking ensued.

The fact that some people's brains are extremely drug resilient and will produce long-term tolerance with short term administration is pretty obvious. I am, unfortunately, one of those people. But there is more at work here than meets the eye.

I now believe that the initial administration of selegiline sent me into a mild hypomanic episode that persisted for the time I was on the drug. You do not need a previous diagnosis of bipolar to have a drug-induced hypomanic episode. I did not have that diagnosis (and still don't), and I have never suffered from a bout of depression or have had another episode since. This would explain your weird reactions to psychoactive drugs (most drugs have little effect or negative effects on manic people, especially psychostimulants). Throughout my hypomanic episode, my tolerance to selegiline fully developed but was masked by the aforementioned episode. When I came down, and subsequently retried selegiline, well... you know the rest.

That's my hypothesis anyways. What you should really be asking yourself is, during your honeymoon period with tianeptine, did you suffer from the classical hypomanic symptoms such as insomnia, poor appetite, mood elevation, irritability, etc.?
 
@alpha.... interesting post. When i first took fluoxetine it gave me hypomania for months on end... so much so that i stopped it as I thought i don't need it. And I crashed majorly. Went back on it... to no avail . . . .. anotherssri i tried then also wouldnt do it and when that one made me sick i went back on fluoxetine and it still wouldnt work properly like it diid that first time where i felt quite simply marvellous...

selegiline seems not to do much for me at all i have to say. I use it sublingually and after a few days of feeling quite stimulated when i first used it I seem to get no effect at all beynd a a very mild stimulation that does not last long. Coffee is more euphoric for me, perhaps because i don't use it daily, but even that is hit&miss.

tianeptine I have just started and after a few initial 50mg+ attack doses I am down to the recommended low dose of 12.5mg now and it seems to help some. Hope it won't make me hypomanic (I am prone to that!) so I can use it long-term but only sporadically as the need arises. I had a terrible day today, lost in regrets about the past etc, and when I finally took my dose around 8pm I started feeling fine. now, 4 hours later, I still feel fine. But I have been posting on BL a LOT today, which i haven't done in ages. I really must make sure it won't make me hypomanic.
 
Kudos said:
I acquired tianeptine while outside of north america and began taking a daily regimen of it. The first pill I took produced immediate, full-fledged anti-depressant effects in a way which seemed impossible to that point. This included the oft-referenced stimulating sensation of the drug, which seemed quite key to its symptom-relief.

I took it for 4 months, with narry a side-effect and that stimulating sensation maintained the way through. Tianeptine seemed to push my brain into an absolutely perfect state of balance. I felt a return to a state of mind I had not experienced in eons and was suddenly adverse to muddling it with any other recreational drugs. Alcohol depressed the effects; adding nicotine to the stimulus became overbearing to the point of nausea; caffeine seemed to have no effect whatsoever.

But then I ran out. Back in north america, where it is not available at market. I was forced into withdrawal as I waited for a supply solution. The withdrawal was punctuated by constant headaches which felt best described as my brain shriveling down to a dead state. I acquired a small supply off the internet. It didn't work, or at least it was severely muffled from before. I put a tremendous amount of hope and stock in the fact that the package seemed to indicate it was expired, or that perhaps it sat in the Turkish sun for too long and degraded.

However, four months later, I have now acquired unexpired medication through perfectly legitimate means, from western Europe, and I am devestated to find no difference. There is no stimulating sensation, and there is a negligible change in mindset. Mostly it just induces fatigue after it's apparent peak and fall in my bloodstream.

My question is what happened? And how can I reverse it? It seems that a tolerance to it developed in its absence, which is awfully counter-intuitive. I am willing to try anything to get its original effects back and I have access to anything prescribe-able should a mix of something else be the solution.
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How long did you give the tianeptine to work the subsequent time? Did you give it enough time to take its full action? Below is my experience going on and off then back on Tianeptine. Perhaps comparison of different experiences can help us deduce some things.

My experience w tianeptine consists of 2 separate stints:

THE FIRST STINT: was for almost 3 months. I never got a direct response from each dose, however in the beginning i started to feel better by the 3rd or 4th day. In retrospect, i strongly feel this was placebo. As i got near the 2 week point i started getting morbidly depressed and had strong urges to be self destructive. I didn't know what the hell was happening, I thought that that was it. It was over, the med didn't work, and now i was far worse than i had even been prior to the medication. but i stuck with it. It lasted about 4 days in which i might even have offed myself had i not had a loving and understanding wife and/or if i had access to an easy painless way to do it. I am very glad I made it through those 4 days (which seem so short in retrospect but an eternity whilst on depression's terms) and I'm lucky that my wife is my best friend and was there to help me through. On the second day of that pit of despair (a little over 2 weeks on the drug) i remembered how most antidepressants warn against this exact situation. For some reason i had thought myself exempt from such side effects; wrong. I'm gaining wisdom with my age, i just hope most of my lessons won't be so hard earned.

HOWEVER: After that miserabley dysphoric and mentally agonizing 4 days, my condition improved drastically and by 3 or 4 days later i felt great! More motivated, a generally increased energy level (again, no direct dose-response), I finally felt like there I had some of myself to give instead of feeling like i had been picked apart to the bones. The medication was working, without any doubt. NOTE: my dose was started at 1 tab 3x/day and was raised to 4x during the 1st month, regretfully i cannot remember exactly when i added 1 tab.

TAPER:The positive effects plateaued and remained fairly constant for the next few months until i realized that my next order would not be making it to the U.S. in time for me to continue uninterupted. I tapered from 4/day to 3/day for 4 days, then 2/day for 3 days, then 1/day for 1 day, then none. I had minimal discomfort. I think i had 1 or 2 moderately anxious days when i switched from 3 to 2 tabs/day but that was all. No noticed effect when i went from 1 tab to none.

I went about 8 days without the med, during which i stayed fairly even and stable. Perhaps i subtly lost maybe 20% of the wind from my sails, yet i remained measurably better than before i had began the med.

THE SECOND STINT ON THE DRUG: began about 8 days after i had run out the first time. I really didn't think that such a short time frame would have a major effect, but it did. I first tried a day of attack doses totalling about 80-90 mgs for the day, then resumed 3-4 tabs/day. I was not as strict with my dosing this time around for some reason and i would sometiimes forget 1 or 2 tabs/day. I did not feel any difference from the drug yet on this second run.

ABOUT A WEEK IN: to the second stint, my mood started to tank again. 2 or 3 days later and i was once again morbidly depressed. This time it was accompanied by what felt like horrible opiate-esque hot flashes and sweats constantly and an inability to eat much of anything. They were heavily exacerbated by any stress or emotional arousal. Although i have had a rather lengthy opiate problem in the past, i was on the same 1-3mg suboxone dose that i had been on during the first stint and variation of the suboxone dose did nothing for the depression or the serious physical discomfort. I still have no idea why i was visited by the sweat fairy and her flame thrower during that time, but, ONCE AGAIN, after about 4 days it all lifted, leaving me feeling empowered and good again.

I AM NOW A MONTH into the second stint and all is well.

IN SUMMARY: I didn't expect a period of such strong suicidal ideation as i have never gotten it like that from any other antidepressants i've taken (3 others), and i hadn't heard it reported by any other users, but for 4 days at a time it sure kicked my ass. So Pls be warned that it COULD happen and have someone keep an eye on you if you are going to start this medication. I DO recommend this med, of course it effects everyone differently, but for me it works, and now that the second 4 day hell ride is over again and i'm really feeling GOOD for the first sustained time in a while, i feel it was worth it.

I was expecting a drug that would be felt after each dose and then wear off in a few hours, genrally improving mood. It was not like that at all for me. I have taken 10 at a time with no noticeable effects. For my body it seems Tianeptine has to run a certain course with a few distinct sequential phases. But overall it is helping me, and as an added bonus, i have definately noticed that i no longer crave other drugs and have drastically cut down on my usage of them.
 
Upon reading a little more about antidepresent induced suicidal ideation, i see the warnings are for children and young adults. I am 31, but I sure as hell experienced this. Am i still considered a young adult or might this effect reach beyond the terms of the warnings?
 
I would assume that the withdrawal effects of tianeptine described in this thread could be due to upregulation of serotonin receptors.. Overactivation of 5-HT is never a good thing.. Downregulation of 5-HT receptors might explain schizophrenic-like withdrawal reactions.
 
Some research indicates that tianeptine's enhancement of reuptake might be of limited relevance. Oddly enough, the drug doesn't reduce concentrations of intersynaptic 5ht a great deal. It seems that tianeptine's immediate hedonistic effects and anti-depressant action are driven by other mechanisms.

ebola
 
One of the theory behind tianeptine efficiency is the NMDA pathway, where, if memory servers me well, tianeptine works as an NMDA modulator or antagonist. Jamshyd has written quite a few posts about it. I must have a brain similar to Jamshyd's "exotic" brain because it does work very well for me, although it pooped out on me after three months the first time I tried it. So I stopped taking it. Two years later another go at it and boom, it's honey moon all over again. 30 to 60 minutes after intake, all the anxiety is swept away and the effect lasts for at least 2 to 3 hours. Physically the symptoms are that I feel all warm and fuzzy (my hands do get really warm), and breathing becomes more pleasurable do to some broncho-dilatation. No wonder tianeptine is currently being investigated as a drug for asthma. In all regards, tianeptine feels like what I'd think a low (sub-roll, not so recreational) dose of mdma would feel.

And one last thing: I did it only once (and that was today) but high-dose magnesium (1000 mg Mg Mg citrate) seems to have mightily potentiated tianeptine: I felt like being on a not so low dose of mdma. I'll have to give it another try. That might also help for tianeptine tolerance...
 
I must have a brain similar to Jamshyd's "exotic" brain because it does work very well for me, although it pooped out on me after three months the first time I tried it.
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The medication works well for a lot of people...
 
Tianeptine use when Histamine blocks serotonin release

Having tried nearly everything.... SSRIs give me serotonin syndrome immediately( within 30 min flu symptoms).... I have used most TCAs for sleep aid... after violent assault with head injury I had PTSD... and hence the beginning of the sleep disturbances...

I had used Tianeptine( just a few times) in the past ..but noticed no real effect... I also suffer from severe allergies... have been taking or giving allergy shots for nearly 20 years.... and have developed significant fragrance allergies... so where I live the pollen situation is severe...and after a recent sinus infection... steroid shot, antibiotics, nasal steroids, nasal antihistamines... I was still having a 'reaction' my sense of smell was magnified to extreme.... I remembered some discussion with two previous allergy doctors and the discussion of serotonin and that nearly all people with severe allergies have depression... ( one doctor suggested lexapro and the other doctor prescribes sublingual liquid serotonin in place of antihistamines) my recent mental state was certainly one of depression... I was not getting out of bed... couldnt go outside because of the allergy response...etc... I knew there must be some other interaction taking place.... so I tried Tianeptine.... not only did my mood immediately improve...my allergy symptoms vastly improved... I could go outside and not even smell the plants and mold ... I was astounded..... the mood lift only lasts a few hours... and the reduction of histamine response lasts for hours..... I just wanted to report this.... I am able to get enough result with just one 12.5 pill.... I dont want to develop tollerance.... as I feel 'normal' and not depressed.... there certainly needs to be more research in the area... now I am wondering if I should report my findings to the psychiatrist and the allergy doctors? I dont think that I have low serotonin... I believe that the extreme histamine my body releases is blocking the release of serotonin... there is recent research about this... Histamine H1 H2 H3 H4 receptors..... again I am thanking the heavens I have some relief from the depression and allergy response...
 
It is said that Lithium can have such an effect. That one takes it and after discontiunuing doesn't have that effect again. It is not clear where the point of action of tianeptine is, but much points towards an effect on kinase networks, like lithium.
 
FWIW, this is a known though clinically overlooked phenomenon. As referenced earlier there are many anecdotes from people who have good responses to a medication, discontinue it, restart and find they are resistant to the therapeutic effects.

See: http://www.ncbi.nlm.nih.gov/pubmed/12633120

'A number of reported clinical findings point to the following possibilities: very unfavorable long-term outcome of major depression treated by pharmacologic means, paradoxical (depression-inducing) effects of antidepressant drugs in some patients with mood and anxiety disturbances, antidepressant-induced switching and cycle acceleration in bipolar disorder, occurrence of tolerance to the effects of antidepressants during long-term treatment, onset of resistance upon rechallenge with the same antidepressant drug in a few patients, and withdrawal syndromes following discontinuation of mood-elevating drugs.'
 
There are tons of reports of drugs with this kind of "internet rep" having fakes with completely different actives in them. My thoughts are that you ended up with some sort of cheap RC stimulant in the first batch, and the second batch was the real stuff.

Granted it could also be a unfortunate effect as described above.
 
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