Tianeptine Review

Tianeptine is a novel antidepressant and anxiolytic (anti-anxiety agent) approved for the treatment of major depressive disorder (MDD) in France. Tianeptine’s legality in the United States is increasingly ambiguous. For the time being, it is sold and marketed as a nootropic (dietary supplement for cognitive health) and for mood enhancement.

Interest in Tianeptine has grown substantially in recent years. Tianeptine is a bestselling item at PowderCity and NootropicsDepot, two reliable nootropics vendors.

In this guide we’ll weigh the benefits of Tianeptine against the risks, discuss the best practices for using Tianeptine, Tianeptine vendors, and finally compare Tianpetine sodium to Tianeptine sulphate (developed by Ceretropic).

Is the Hype About Tianeptine Justified?

Well, it depends. If you’re a perfectly healthy, well-adjusted 18-30 year old with no family history of mental illness, probably not. But if you’ve ever had a mood disorder or struggled with anxiety, Tianeptine is absolutely all it’s cracked up to be.

This reflects a general trend with nootropics: they can iron out wrinkles in your cognitive landscape, but if you’re Richard Feynman, they probably won’t do much for you. In this vein, Adderall and modafinil may enhance cognition in a subset of healthy adults, but do nothing or even impair extremely high-functioning individuals. This stands to reason from an evolutionary standpoint. High-functioning individuals have hit a neurobiological ceiling. There’s just no room for improvement because everything is already optimized, by sequential improvements in fitness with each generation.

What is Tianeptine, Anyway?

Tianeptine is a prescription antidepressant in Europe. It’s a member of the old-school tricyclic class of antidepressants.  Despite its chemical similarity, it shares very little with the tricyclics. It virtually lacks the anticholinergic, serotonergic, and noradrenergic effects of tricyclics.

Tianeptine can be purchased online with no legal repercussions (because it’s marketed as a dietary supplement in the US). No prescription required. It couldn’t be prescribed anyway, since it has never been evaluated, let alone approved, by the FDA.  This does not reflect Tianeptine’s effectiveness as an antidepressant. It has to do with the insurmountable cost and financial risks of the FDA approval process.

What Does Tianeptine Do?

It does a lot of stuff, neurotransmitter-wise. It binds and activates mu-opioid receptors (the same receptors affected by painkillers). It was thought to clear serotonin from the synapse (“selective-serotonin re-uptake enhancement”).  This view has mostly been rescinded. If Tianeptine does promote serotonin clearance at all, this effect is weak and doesn’t contribute to Tianeptine’s efficacy as an antidepressant.

Tianeptine also alters glutamate receptors in the brain. (Specifically, it modifies the phosphorylation state of these receptors, affecting signal transduction). Tianeptine possibly promotes mesolimbic dopamine release and potentiates dopamine receptors.

There’s sparse evidence to support this, but my view is that Tianeptine reproduces the beneficial effects of exercise on cognition. To oversimplify, the “runner’s high” is probably caused by the release of natural opioids, like endorphins (affectionately described as “endogenous morphine”). Since Tianeptine is a full agonist at the mu-opioid receptor, Tianeptine kind of behaves like an endorphin.

There are some other similarities between exercise and Tianeptine. Both “reverse stress-induced synaptic remodeling and impaired neuroplasticity.” There’s some truth there that’s co-mingled with bullshit. Neuroplasticity has become a dirty word:

The latest refrain in popular science is that ‘your brain is plastic’, that experience has the potential to ‘rewire’ your brain, and that many previous mysteries in cognitive science can be explained by ‘neuroplasticity’. What they don’t tell you is that these phrases are virtually meaningless.

Neuroplasticity sounds very technical, but there is no accepted scientific definition for the term and, in its broad sense, it means nothing more than ‘something in the brain has changed’. As your brain is always changing the term is empty on its own.

If endorphins are opiates and exercise-induced endorphin release alleviates depression, then…

Why Aren’t Painkillers Antidepressants?

They are. Opioids like hydrocodone, oxycodone, fentanyl – they’re very robust antidepressants. Opioids have been successfully prescribed to augment antidepressants in patients with treatment-resistant depression. The antidepressant effect of opioids is even retained without dose escalation, in most cases. Obviously, opioids could never be prescribed on a large scale for the treatment of conventional, soccer-mom depression. For obvious reasons.

You’re probably wondering how Tianeptine can be sold as a nutraceutical in the US, like vitamin C, if it’s an opioid.  Doesn’t the government crack down on legal highs? Despite being an opioid, Tianeptine lacks the abuse potential of other opioids. Some Tianeptine users report the development of tolerance, dose escalation, and addiction. Tolerance to the effects of Tianeptine is not uncommon, but Tianeptine addiction is relatively rare.  However, some case reports have emerged characterizing Tianeptine abuse.


Unlike the ubiquitous selective serotonin reuptake inhibitors (SSRIs) which crudely and globally elevate serotonin in the brain, Tianeptine modulates numerous pathways and neurotransmitters, including glutamate, dopamine, serotonin and the opioid system.

Tianeptine is a full agonist at mu-opioid receptors. The endogenous ligand for mu-opioid receptors is enkephalins and beta-endorphins in the brain. These are the same neuropeptides responsible for the mood-elevating effects of exercise (the so-called “runner’s high”).

In other respects, Tianeptine recapitulates the beneficial effects of exercise on cognition. For example, it has been suggested that Tianeptine prevents stress-induced synaptic remodeling in a manner analogous to exercise.

Tianeptine modestly promotes mesolimbic dopamine release and potentiates some subtypes of the dopamine receptor, by an uncharacterized mechanism.

Tianeptine also likely alters the phosphorylation state of glutamate receptors. This modulation of excitatory neurotransmission in the hippocampus and elsewhere may underlie Tianeptine’s neuroprotective effects.

Tianeptine is probably the most novel psychiatric drug currently prescribed for depression (in Europe). Tianeptine affects the opioid system (via mu-opioid agonism), glutamate receptors, and reverses stress-induced impairments in neuroplasticity.

Tianeptine and the Monoamine Hypothesis of Depression

The discovery and characterization of Tianeptine has largely undermined the monoamine theory of depression. It was originally thought that central depletion of the monoaminergic neurotransmitters (serotonin, norepinephrine and dopamine) caused depression. This was the rational for the development of selective serotonin reuptake inhibitors (SSRIs), which would globally increase serotonin in the brain and thereby alleviate depression.

Tianeptine actually has an opposite effect on serotonin signaling. Namely, Tianeptine is a serotonin reuptake enhancer, meaning that it promotes the clearance of serotonin from the synapse (whereas SSRIs inhibit the clearance of serotonin). That Tianeptine both has antidepressant properties while also decreasing serotonergic tone has forced the recognition that many prevailing theories of depression are reductionistic and unlike the brain, not very nuanced.

It is now appreciated that depression is a disorder of impaired neuroplasticity, cellular resilience, and dysfunctional neural circuits. Depression also has a neurodegenerative aspect, since hippocompal atrophy is linked to the duration and severity of depressive episodes.

Tianeptine’s MOA (mechanism of action)

Tianeptine’s mechanism of action remains poorly understood despite decades of research. Most of the studies on Tianeptine are observational, i.e., Tianeptine treatment results in beneficial effects in animal models and in vitro, without the identification of a definitive cellular mechanism underlying these effects.

What is known is that Tianeptine prevents stress-induced neuronal remodeling and hippocampal atrophy. For example, one study which looked at the effect of chronic immobilization stress in rodents found that Tianeptine administration was sufficient to prevent stress-induced patterns in dendritic remodeling. (Dendrites are the short, branched extensions of nerve cells.)

Tianeptine was also reported to reverse the inhibitory effect of severe acute stress on long-term potentiation (LTP). This result is noteworthy because impaired LTP and glutamate neurotransmission is likely a common thread between the cognitive and affective (mood) symptoms of depression. More recently, Vouimbia et. al. reported that Tianeptine abolished stress-induced suppression of primed burst potential in the CA1 region of rat hippocampus. In addition, Tianeptine treatment under non-stress conditions enhanced primed burst potential in the hippocampus and LTP in the amygdala.

Evidence also suggests that Tianeptine increases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and amygdala of rodents. BDNF plays a pivotal role in neuroplasticity and provides trophic support for synapses.

Tianeptine also affects the glutamate system, which has been recently implicated in the pathogenesis of depression. Tianeptine normalized stress-induced changes in the amplitude ratio of NMDA receptor to AMPA/kainate receptor-mediated currents, and facilitated signal transduction at CA3 synapses by modifying the phosphorylation state of glutamate receptors.

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