Tianeptine for tolerance reversal? Thoughts please?

[VelocideX]

In lieu of having read this thread it occurred to me that tianeptine could serve as a tolerance-reducing agent.

Barring neurotoxicity, much of the theorisation around MDMA-induced tolerance relates to receptor downregulation. Serotonin can be replaced intraneuronally by tryptophan/5-HTP, but receptor re-regulation seems to occur over much longer timescales.

Even upon cessation of SSRI administration, it usually takes users some weeks to get back to the point where they can feel the MDMA high, and even then it's not usually back to full strengh for some months, or perhaps never again.

Many users on here successfully report taking seroquel or another DA-antagonist to reduce amphetamine tolerance... the theory being that lower DA levels will force the receptors to upregulate. I am not sure whether there is literature backing this, but if you accept this, then my argument logically follows. I will repeat: this is the key step in my argument, and I am not sure of its veracity.


I have always thought that a serotonin antagonist could be used for this purpose, but since no-one really seems to suffer from excess serotonin (bar people with serotonin sydrome) (i.e. there is no analogy to schizophrenia in the serotonin system to my knowledge), they aren't publically available.

Why not target the entire reuptake system with tianeptine, a reuptake-enhancer? It could speed up reregulation?

Hell you don't even have to worry about the potential of ensuing depression: tianeptine is an antidepressant. Some research shows that tianeptine aids memory formation:
Meneses A. "Tianeptine: 5-HT uptake sites and 5-HT(1-7) receptors modulate memory formation in an autoshaping Pavlovian/instrumental task" Neurosci Biobehav Rev 2002 May;26(3):309-19

The aforementioned thread seems to report significant success from one user.
Another thread suggesting potentiation, possibly through upregulation (user had one month of treatment)

Mysteriously this journal article seems to imply that transporter sites are decreased, despite reuptake enhancement... i'm not entirely sure how this would occur
thoughts?

 

[MazDan]

Mate I am happy to be a guinea pig..............where do ya get it??

 

[David]

Seems to me like it just accelerates the rate of re-uptake at the cost of burning out the transporter sites. It's similar to the effects of MDMA, but it only causes the accelerated re-uptake? No actual release. Interesting, but what are the known side-effects?




Here's what is said about the known side-effects, or lack thereof.

 

[BilZ0r]

I big fat HRMMMMMMMMMM on this one.
What can I say. Regulation of transporter protein action is a funny one.
God, too many competing thoughts.

Well for one, I'd like to thank you for bringing that drug to my attention, I'd never heard of it!

Two, is there any evidence (apart from common sense) that MDMA causes 5-HT-R downregulation? Well lets go look!

Half and hour later: Yeah, mixed evidence, some subtypes up, some down, and conflicting reports. But, okay, lets assume theres generally downregulation (not a small assumption).
[1, 2]

And so we're assuming that 5-HT content could come back quickly right (again not the smallest assumption), and that theres no such think as neurotoxicity (this is starting to get tenuous).

And we're also assuming antagonists cause upregulation

45 minutes later. Well yeah, it seems likely, Initially I was focusing on the adrenergic system, because I geussed the research would have been done there, and I was right, and adrenergic antagonists don't cause upregulation. But it seems that 5-HT2 antagonists (at least) cause upregulation.

[3, 4, 5]

Also, you've forgotten than most atypical antipsychotics are primarily 5-HT2(a/b/c) antagonists.

So what is tianeptine actaully doing? Do I actaully believe its increasing 5-HT uptake? Well I don't have a fucking clue, because initially I thought, "it must be dephosphorylating the SERT, which leads to increased reuptake" but then if it was doing that, it would cause decreased SERT internalization, which is doesn't seem to do, infact it seems to increase internalization.

Well I've seen evidence that tianeptine increases the phosphorylation of AMPA channels, now correct me if I'm wrong, but thats PKC mediated right? And so is the Phospho-ing of SERTs. Now Phosphoing SERTs is possibley a mechanism of amphetamines... see where I'm going? Sounds like a likely "antidepressant" a bit more now?

[6, 7]

Eureka... well of sorts, check it
The effect of the novel antidepressant tianeptine on the concentration of 5-hydroxytryptamine in rat hippocampal dialysates in vivo. and Effects of acute and chronic tianeptine administration on serotonin outflow in rats: comparison with paroxetine by using in vivo microdialysis. It seems that our old friend tianeptine doesn't fuck with 5-HT uptake very much in vivo (just as I suspected)

*shrug* I've thought too much. Where does that leave us now bro?

p.s. I've referenced this quickly, not to be wanky, but for furture arguements, and for my own personal record.
[1] Neuropsychopharmacology. 2002 Mar;26(3):387-96. The acute and chronic effects of MDMA ("ecstasy") on cortical 5-HT2A receptors in rat and human brain. Reneman L, Endert E, de Bruin K, Lavalaye J, Feenstra MG, de Wolff FA, Booij J.
[2] Neuropharmacology. 1992 Sep;31(9):881-93. Repeated administration of MDMA causes transient down-regulation of serotonin 5-HT2 receptors. Scheffel U, Lever JR, Stathis M, Ricaurte GA.
[3] FEBS Lett. 1996 Dec 9;399(1-2):108-12. Up-regulation of a constitutively active form of the beta2-adrenoceptor by sustained treatment with inverse agonists but not antagonists. MacEwan DJ, Milligan G.
[4] Fundam Clin Pharmacol. 1995;9(6):522-30.Propranolol therapy in experimental heart failure in rabbits improves cardiac response to catecholamines without beta-adrenoceptor up-regulation. Xiong L, Bouanani NE, Su JB, Crozatier B.
[5] Mol Pharmacol. 1993 Jan;43(1):84-9. Repeated administration of SR 46349B, a selective 5-hydroxytryptamine2 antagonist, up-regulates 5-hydroxytryptamine2 receptors in mouse brain. Rinaldi-Carmona M, Congy C, Simiand J, Oury-Donat F, Soubrie P, Breliere JC, Le Fur G.
[6] Science. 1999 Jul 30;285(5428):763-6. Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Ramamoorthy S, Blakely RD.
[7] Eur J Neurosci. 2002 Sep;16(5):807-16. The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. Kole MH, Swan L, Fuchs E.

 

[VelocideX]

I agree with much of what you've said Bilz0r... I'm just curious as to how it can accelerate the reuptake of serotonin whilst decreasing transporter sites... that doesn't seem sustainable, but it appears to be.

 

[Brian Oblivion]

I'm in a hurry right now, but briefly and from memory...

Tianeptine was developed by a France pharmaceutical company a few years ago. It is a novel drug which has been shown to accelerate serotonin reuptake. An interesting feature of tianeptine is that they have found that it arrests neurotissue loss that result from acute depression.

It has been established that clinical depression produces neurotissue loss - this was well documented a few years ago in an issue of JAMA (Journal of the American Medical Association) along with PET images to support the finding. If I remember correctly, tianeptine was also cited in that report as showing a decrease in this tissue loss, and that it was currently (two years ago) the only drug which produced this effect in patients suffering from acute depression. (SSRIs, although effective in many cases in treating clinical depression, do not halt tissue loss.)

There have been reports of problems when taking tianeptine concurrently with adrafinil (Provigil) and modafinil (adrafinil is a modafinil metabolite), which is an alpha 1 adrenoceptor agonist.


I'll post more later.

Brilliant postulate VelocideX. This definitely merits investigation, IMO.

 

[VelocideX]

^^ I don't have references handy, but I believe the alpha 1 adrenoreceptor idea has been disproven; recent studies on medline indicate other methods of action:
The histamine system appears to be involved: see here

Noradrenaline reuptake in sleep-related neurons seems to be affected: see here

Unfortunately I don't know enougha bout receptor reregulation other than to provide my postulate.

As I said, the few anecdotal reports around on bluelight appear to be relatively positive.

The main problem is whether there are not just antagonists for 5-HT receptors but inverse agonists... and also whether low extracellular serotonin levels may upregulate receptors?

 

[BilZ0r]

Well I did some whole article research on ol' tianeptine. Its one hell of a weird drug. It decreases SERT mRNA, which is probably its mechanism for decreased SERT density, and so we might geuss that's its mechanism for being an antidepressant.

That's right, I saw something else in my readings, that tianeptine increase the 5-HT releasing ability of phenfluramine or one of its metabolites in completely naive animals. God, I've read so much today I'm trying to sort it all out.

Hmm, well a similar idea I had is kinda like this. PKC phosphorylates SERTs, making them unable to take up neurotransmitters. Now when a SERT is occupied, by either an SSRI or 5-HT, this stops the phosphorylation, presumabley because its deformed the transporter, so now PKC can't bind. So that means that 5-HT and SSRIs kinda inhance uptake, by blocking this negative phosphorylation, but of course, SSRIs actaully block the uptake physically, and 5-HT doesn't really count. But perhaps tianeptine binds to the SERT, and causes it to deform, so PKC can't bind, but without blocking the action of the SERT, so it can still take up 5-HT.

 

[Brian Oblivion]

Adrafinil and Modafinil

^^ I don't have references handy, but I believe the alpha 1 adrenoreceptor idea has been disproven; recent studies on medline indicate other methods of action:
The histamine system appears to be involved: see here

Noradrenaline reuptake in sleep-related neurons seems to be affected: see here

BTW, I got this ass backwards:
"adrafinil (Provigil) and modafinil (adrafinil is a modafinil metabolite)"

should read:

"adrafinil and modafinil (Provigil) (modafinil is an adrafinil metabolite)"

That's interesting regarding modafinil's involvement on the histaminergic system. My last reading on adrafinil and modafinil is few years old now. At the time adrafinil was (and may still be) unregulated in the US, so importing it without having a physician involved was not a problem.

Both adrafinil (Olmifon is its commercial name in Europe) and modafinil were developed at Louis Lafon Laboratories in France (modafinil being the result of the "next generation" of this drug class). One reason for the improvement was that adrafinil can compromise the liver if the patient is lacking a specific enzyme (I forget which one). And the patient needs to have a liver enzyme study performed at 6 month intervals after starting it (but it's only a problem for some people).

Modafinil had a higher effect to dosage ratio and did not adversely impact the liver (eliminating the routine liver evaluations). Then an American company gave Lafon a helaous amount of money with royalties, and pursued the steps to qualify approval by the FDA in the US. Lafon initially intended adrafinil and modafinil for use by aged patients to establish improved mental clarity and "vigilance" (their description). But modafinil is primarily being marketed in the US for treating sleep disorders.


I actually tried adrafinil for a few months in 2001, and I was rather impressed with the increased mental clarity it produced. I naturally wake up feeling a bit foggy for a while. But while I was taking the adrafinil, I was immediately awake and alert as soon as I woke up (no ass dragging :D ). But it has absolutely no recreational value as one needs to remain on the drug for about a week before it begins producing any beneficial effects.

 

[Brian Oblivion]

Tianeptine (Stablon)

Regarding Tianeptine, I last remember it not being regulated in the US but that it failing FDA approval. I seem to remember that it made it through the trials just fine, and that there was some other reason for FDA rejection.

In terms of being a treatment for depression, from what I read, it was not as effective as the SSRI route of treatment. Which makes me wonder why given the appearent protective qualities that it has in halting cell death in depressed patients.

Unfortunately I don't know enougha bout receptor reregulation other than to provide my postulate.

As I said, the few anecdotal reports around on bluelight appear to be relatively positive.

The main problem is whether there are not just antagonists for 5-HT receptors but inverse agonists... and also whether low extracellular serotonin levels may upregulate receptors?

I think that your postulate definitely warrents some kind of evaluation. If Tianeptine (Stablon) is still unregulated in the US it could be imported legally in (3 month supply max). I'm not sure how difficult it is to obtain in Europe or Australia. I know that it is a precription drug in Europe, but I don't know what the restrictions are in the EU.

 

[BilZ0r]

Inverse agonists are going to be the most effective in inhibiting internalization of GPCRs. In the case of serotonin receptors at least, seeing as I think both the 5-HT2a and the 5-HT1b receptor are constitutively active.

Though, I think the 5-HT2a receptor undergoes arrestin independed internalization...

...and when I think about it some more, 5-HT2a is internalized by antagonists... isn't it...
Yup, it is. At least some of them. Oh, I see, those are all in vitro studies... In vivo we have:

Neuroscience. 1999;91(2):599-606.
Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo.
Willins DL, Berry SA, Alsayegh L, Backstrom JR, Sanders-Bush E, Friedman L, Roth BL.

Which tells us, as I was originally reporting "We discovered that clozapine, olanzapine, risperidone and the putative atypical antipsychotic drug MDL 100,907 all induced 5-hydroxytryptamine-2A receptor internalization in fibroblasts stably expressing the 5-hydroxytryptamine-2A receptor in vitro."

But then "Treatment of rats for seven days with clozapine induced an increase in intracellular 5-hydroxytryptamine-2A receptor-like immunoreactivity in pyramidal neurons, while causing a decrease in labeling of apical dendrites in the medial prefrontal cortex. This redistribution of 5-hydroxytryptamine-2A receptors in pyramidal neurons was also seen when rats were chronically treated with another atypical antipsychotic drug, olanzapine."

I just wish they had used a SPECIFIC 5-HT2a ligand! Though they report that typical antipsychotics don't have that effect, so we could concluded that its because of the 5-HT2a effect of atypical antipsychs, that they have this effect.

There's quite a fun review in:
Brain Res Bull. 2001 Nov 15;56(5):441-51.
Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists.
Gray JA, Roth BL


There are some fun reviews on the subject of internalization in general:

Prog Neurobiol. 2002 Feb;66(2):61-79.
Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and beta-arrestin proteins.
Claing A, Laporte SA, Caron MG, Lefkowitz RJ

and a review by the same group which talks more about the roles arrestin has APART from internalization

Biochem J. 2003 Nov 1;375(Pt 3):503-15.
Multifaceted roles of beta-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling.
Shenoy SK, Lefkowitz RJ.

 

[VelocideX]

Neither the PBS nor MIMS in Australia lists tianeptine, and so I can only guess it has not been approved and therefore could be imported legally under the TGA's Personal Importation Scheme.

 

[VelocideX]

Bilzor - I'm not familiar enough with neuropharmacology and neurochemistry to know what all that means.... Can you give a rough summary as to the implications for tianeptine for tolerance reversal?

 

[David]

Bilzor - I'm not familiar enough with neuropharmacology and neurochemistry to know what all that means.... Can you give a rough summary as to the implications for tianeptine for tolerance reversal?

Yes, please. I second this motion.:D

 

[BilZ0r]

From my readings, and understandings, this is a classic case of sciences favorite sentance "...but more research is needed".

If we had some solid axioms we could perhaps make some conclusions. The biggest problem is what causes tolerance? Some people argue receptor downregulation, some people say neurotransmitter loss, some toxicity. My personal favorite is transporter downregulation.

If we were to argue transporter downregulation, then tianeptine isn't going to help, because it also causes that.
If we were going to argue toxicity or neurotransmitter loss, then it's not going to help again.

But, if we argue receptor downregulation, then on the surface tianeptine might help, BUT, coupled with tianeptine-mediated transporter downregulation, its probably going to be giving with one hand, and taking away with the other.

 

[VelocideX]

In the end I think the best we can do is look at the anecodotal reports, of which there are a few... and they seem promising, though they could be merely statistical fluctuations or idiosyncracies of some sort.

 

[BilZ0r]

It's placebo effect that I find more likely.

 

[Brian Oblivion]

In the end I think the best we can do is look at the anecodotal reports, of which there are a few... and they seem promising, though they could be merely statistical fluctuations or idiosyncracies of some sort.

I still think it is worth investigating.

If it were solely a placebo effect, then there would be other "stuff" that folks would be reporting "worked." But we haven't been seeing people announce that other substances work.

I mean, heaven forbid that something would be found which brings the MDMA joy back to those who've lost it. The powers that be would just piss all over themselves. 8)

:D

 

[streetsurfer]

Bump

Has anyone had any experiences with this drug, importing it to oz, reducing their tolerence or treating depression?

 

[J_B_Wild]

Tianeptin / Coaxil / Stablon

Hello all,

I was lucky enough to find this sight at the beginning of my explorations and thus attribute it to my current solid health. I have always been tentative to post anything, partly from being paraniod of big brother, but mainly because so much is allready covered here, I would just feel redundent.
I do actually have "a friend" that has some experience with Tianaptine that I will be glad to share:

History of mdma usage: approx. 4 yrs, sometimes escalating, 2 weeks apart at the extreme, usually a month to three months though. (A couple 6 month breaks as well as 3 regrettable times with only one week in between.)
Few times with Molly @ approx. 220mg for a night, but normally 2 - 2.5 beans maybe totalling 150mg, never can tell though. (It was actually only 1 bean for the first 2 years.)

The magic never was lost, but certainly at times, diminished. One thing that has almost always remained consistent is the duration (usually 4-6 hours solid) as well as the attitude going in to never expect anything and just take it for what it was.

Minimal alcohol usage, (couple glasses of wine or some whiskey with dinner) some ganja, but never in excess. No other drugs of any kind, ever. (Other then the unknown that comes in the beans of course.)

With tianiptine, the reccomended dosage is 3 per day. Below is what has been found to be a success. This is not a fact, nor is it based on any research. Just an experience from one person. I will describe "success" at the end of this.

2 days after dropping: single dose htp5 once a day for 2 days, Piracetam, choline, along with the usual daily vitamins and antioxidants. Raw fruits and vege's as well are fantastic. Lots of water.

Tianaptine 1 dose for a few days after, working up to the reccomended 3 a day for about 3 days. Then back down to once or twice a day for a couple days. During this time, Piracetam and some kind of choline supplement is taken with this. (My humble opinion is not to mix 5htp with tianaptine or take it very often in any case.)

Next time rolling: couple glasses of grapefruit juice, (no pre-load with 5htp), nice dose of Piracetam about an hour before (never tried it with tianaptine the day of either, don't know if that would be safe)

The rolls are fantastic, very intense, less is needed. More of a ROLLING effect then noticed before. Really baseline then suddenly flying. Comedowns are almost non-existent. Recovering, what used to take over a week to feel, attitude wise and motivation wise, takes maybe a couple days now.

From experience, tianaptine really helps get back into the swing of things and just feels right. The recommended dosage for longer then a few days, (at least for my friend) begins to feel like to much. I would not dismiss the Piracetam in this mix. Piracetam makes the rolls more intense and no question, the comedowns less of a bummer. It also seems to completely negate any sort of headache, throbbing, whatever you would normally get from partying all night, lack of sleep, etc...

In short, it does seem that the dose needed is back down to what it was in the beginning. 2.5 beans is really intense, but tolerable. 1 to 1.5 certainly would be satisfying for a night, however. Weather this can be attributed soley to Tainaptine, or more likely the combo with Piracetam is unknown.

One thing is for sure; No matter what you supplement with, if you abuse MDMA, nothing will help. Take those 3 - 6 month breaks. Try to wait a couple months minimum. Don't take to much in one night. Stay hydrated, but don't overdrink and generally, don't be a dumb ass. Just pay attention to your body and health.

I hope this helps a little and will eagerly watch this thread to glean any more insights on how tianaptine has effected others.