Tianeptine is an antidepressant, neuroprotective, and anxiolytic drug developed by French researchers Antoine Deslandes and Michael Spedding in the 1980s. It is currently marketed under the trade names Stablon and Coaxil in some European, Asian, and South American countries.
In the United States, Tianeptine is not FDA approved, mainly due to a lack of interest in the drug within the American pharmaceutical sphere. Although it is typically used in a clinical setting to treat depression and related illnesses, it has recently gained favor among nootropic users for its mood and cognition-boosting capabilities. It remains an unscheduled substance in the US, and can be purchased online via several nootropic vendors.
How it Works
Relation to Other Antidepressants
In strict terms of chemical structure, Tianeptine is a tricyclic antidepressant (TCA) and is structurally similar to many prescription TCAs, such as amitriptyline and doxepin. However, Tianeptine’s mechanism of action varies drastically from classical TCAs
Most TCAs work as serotonin-norepinephrine reuptake inhibitors (SNRIs), increasing the levels of extracellular serotonin and norepinephrine. Tianeptine, however, has been found to enhance the reuptake of serotonin, which would consequently decrease serotonin levels in subjects. In addition, Tianeptine does not possess affinity for most neurotransmitter receptors, meaning it has little to no direct impact on norepinephrine and dopamine.
These findings have led some researchers to question what is known as the monoamine hypothesis of depression, which has prevailed in medical circles for around half a century. Monoamines are a group of neurotransmitters that includes dopamine, serotonin, and norepinephrine, the three of which are linked to motivation and mood. The monoamine hypothesis of depression posits that depression is caused by a shortage of monoamine neurotransmitters in the brain.
Most classical antidepressants, (SSRIs, SNRIs, MAOIs, etc.) seek to restore balance to monoamine levels in the brain, thus alleviating symptoms of depression. The fact that Tianeptine has little effect on monoamine levels, yet still alleviates symptoms of depression, has fortified the evidence that depression is much more complex than just an imbalance of monoamine neurotransmitters.
Mechanism of Action
So, then, how exactly does Tianeptine mitigate the symptoms of depression? Some researchers have hypothesized that depression is directly linked to lowered neuroplasticity (the ability of the brain to adapt to new stimuli) and that an increase in neuroplasticity in the human brain will contribute to reducing symptoms of depression. Studies conducted on Tianeptine’s action certainly support this idea.
Essentially, Tianeptine modulates the action of glutamate, the main excitatory neurotransmitter in the brain. Stressful situations tend to augment glutamate’s pathways, either causing too much or too little activity. These fluctuations in glutamatergic action lead to degradation of nerve and brain tissue. 
By keeping glutamatergic pathways under control, Tianeptine inhibits the body’s harmful responses to stress. This leads to increased neuroplasticity, which allows the brain to handle anxiety and depression more readily. The benefits of neuroplasticity also extend into the domain of nootropics by having a positive impact on cognition and working memory. Tianeptine’s positive effects on neuroplasticity suggest that it may treat one of the root cause of severe depression rather than simply treat its symptoms. This would imply that Tianeptine has lasting effects on depression and cognition, even when it is no longer administered.
It was recently discovered in 2014 that Tianeptine works as a µ-opioid receptor agonist, which is believed to contribute to its anxiolytic properties. This could also be linked to the possible euphoric effects of Tianeptine that some users experience at higher (recreational) doses. Although Tianeptine acts on µ-opioid receptors, it does not have the high addictive potential that is associated with many opioid drugs. That said, it is still a good idea to avoid taking Tianeptine for long periods of time without interruptions and/or at higher doses than those used in clinical practice.
Positive Effects of Tianeptine
- Boosting mood and alleviating depression. 
- Reducing anxiety and vulnerability to panic attacks. 
- Improving overall brain health as a neuroprotectant.
- Enhancing cognition, memory, attention, and reaction time. 
Prescription Tianeptine (Stablon) comes packaged in 12.5 mg tablets, which is considered a single dose. Tianeptine sold by nootropics vendors come in powder form, so doses should be measured out with a milligram scale to ensure accuracy.
Because Tianeptine has a relatively short duration of action (about 3-4 hours), three of these doses are taken throughout the day, waiting 3-4 hours between each dose. Tianeptine is administered orally, and there is no evidence that would warrant any other route of administration.
Recently some nootropic vendors have started selling tianeptine sulfate, which, according to them, is longer lasting compared to the regular sodium salt. There doesn’t seem to be any scientific evidence for this statement, however.
Side Effects, Tolerance, and Toxicity
Tianeptine has a similar side effect profile to more traditional antidepressants but does not cause the sexual dysfunction associated with SSRIs. It also does not exhibit anticholinergic effects that are common with TCAs. The most common side effects include nausea, constipation, abdominal pain, headache, and dizziness. However, all of these possible effects only occur in less than 1% of users.
Because Tianeptine is not monoaminergic in its mechanism of action, it is not considered a risk to take it alongside monoaminergic antidepressants. However, it should not be taken with MAOIs to avoid the risk of hypertension and seizures.
Tianeptine is considered safe to take indefinitely, although tolerance can develop over an extended period of use. If you find it necessary to take higher and higher doses to achieve any positive effects, it would be wise to taper off of the substance and take a tolerance break if you still want to use Tianeptine.
Although discontinuation symptoms of Tianeptine are not nearly as severe as with SSRIs and TCAs, it is still not recommended to suddenly stop usage. In addition, Tianeptine can be cycled with other antidepressant nootropics (like selegiline, NSI-189, or moclobemide) to stop tolerance from developing.
The LD50 of Tianeptine is estimated to be 980 mg/kg, so there is a very low chance of consuming a lethal or harmful dose on accident.
Tianeptine stands out among other antidepressants because of its novel modes of action. Rather than temporarily modifying a monoamine imbalance, it aids the brain in healing itself by increasing neuroplasticity.
It is unfortunate that its use has mostly been ignored by the American medical community, but its unscheduled status has opened up opportunities for nootropic usage. Because of its effects on mood, cognition, stress, and neuroplasticity, Tianeptine should definitely be considered by serious users of nootropics.
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