Tianeptine (Ethyl Ester, Hemisulfate Monohydrate (THM), Sodium)
What is Tianeptine?
Tianeptine is a potent synthetic drug which has been used to treat major depressive disorder (MDD). Tianeptine can have beneficial effects for people who are struggling with depression, especially in cases where the disorder has proven difficult to treat with classical anti-depressant drugs. Additionally, tianeptine has been shown to have powerful anxiolytic effects, meaning the drug can be useful for a number of psychiatric disorders.
There are two main forms of tianeptine: tianeptine sodium and tianeptine sulfate. Both drugs act through the same mechanisms and produce similar results. However, tianeptine sodium has a quicker absorption and excretion rate compared to tianeptine sulfate.
Until recently, the tianeptine’s mechanism of action wasn’t fully understood.
Numerous studies have revealed that tianeptine appears to modulate a variety of neurochemical systems. We’ll delve into these in more detail throughout the article. However, according to current animal models, the main mechanisms of action for tianeptine are:
- Direct tianeptine induced activation the mu opioid receptor (MOR).
- Enhanced uptake of serotonin by cells.
- Regulation of the glutamatergic system in a variety of brain regions. This includes the regulation of glutamate receptor activity within the hippocampus and amygdala.
- Modulating glucocorticoid receptors in rodent models of early-life stress.
- Upregulating inhibitory GABA expression in the spinal cord.
- Regulating hypothalamic-pituitary axis (HPA) and prefrontal cortex activity.
- Activating adenosine A1 receptors.
Evidence suggests that tianeptine may also be effective in treating conditions of the peripheral nervous system too, including asthma and irritable bowel syndrome (IBS). This is likely due to the tianeptines ability to modulate the serotoninergic system. Both asthma and IBS are associated with decreased blood-levels of serotonin. Human clinical trials have confirmed tianeptine to be an effective treatment for both of these conditions.
Tianeptine has become controversial due to potentially addictive properties of the compound when taken in large doses.
This primarily suggested due to tianeptine mechanism of action at MOR potentially having similarities with other opioids. Some studies have also reported patients, especially those with a history of substance abuse, experiencing withdrawal and dependence after prolonged use.
However, not all neuropharmacologists agree that tianeptine has a high propensity for addiction and abuse. In fact, there some pharmacologists have expressed that some drugs which are widely prescribed for anxiety at present (such as benzodiazepines) are worse than tianeptine.
There are some animal models which have failed to demonstrate that chronic tianeptine administration leads to tolerance or withdrawal. Additionally, there are many clinical studies which have not reported these addictive effects.
It’s likely that the propensity of the drug to cause addiction may be dependent of the individual. While tianeptine can produce powerful benefits for depression, the compound has now been banned in some regions due to concerns over potential abuse.
Brain Benefits and Mode of Action
Improves Anxiety and Depression
Tianeptine is a powerful anti-depressant and anxiolytic drug. These effects have been shown across a variety of human clinical trials, along with animal and cellular studies.
Clinical trials have shown that tianeptine is as effective as classical anti-depressants at treating major depressive disorder. Tianeptine has a particularly high success rate in patients where previous treatments have been ineffective. Moreover, extended treatment with tianeptine appears to decrease the frequency of relapse or reoccurrence of depression.
Similar results have been found in studies which have investigate the usefulness of tianeptine in the treatment of Parkinson’s disease. Patients with Parkinson’s had a significant decrease in the severity of depression symptoms after tianeptine treatment.
Tianeptine has also been shown to be helpful in the treatment of anxiety-related disorders.
For example, one clinical trial showed that tianeptine was able to block the occurrence of panic attacks. Another trial found that tianeptine significantly improved the symptoms of post-traumatic stress disorder (PSTD) patients. The results from these studies are supported by animal model data. In rodent models of PSTD, tianeptine was able to effectively prevent the effects of psychosocial-related stress.
Human clinical trial and animal studies have highlighted that tianeptine administration can reverse or prevent cognitive, learning and memory deficits which are associated with stress, anxiety and depression.
Mode of Action: Tianeptine modulate numerous neurochemical systems, which makes it difficult to pin down the exact biochemical mechanisms which underlie these positive effects of anxiety and depression. There are a few ways tianeptine may alter brain function to improve mood-related disorders:
- Stabilisation of glutamate levels. Studies have shown that tianeptine can regulate the glutamatergic system in a variety of brain areas. Rodent studies have shown that tianeptine can prevent stress-induced glutamate increase in the amygdala. The amygdala is a structure which is well-known to be involved in the regulation of emotion, reward and fear. Therefore, balancing glutamatergic activity within this structure may play a role in regulating mood. Tianeptine has also been shown to prevent aberrant reorganisation of glutamatergic vesicles at the synapse in the rodent hippocampus. This indicates there tianeptine can actually protect against anatomical pathologies related to stress. Ultimately, the excitatory-inhibitory (glutamate-GABA) balance is vital to health brain function, and dysregulation of these systems are associated with many psychiatric disorders. This glutamatergic regulation may prevent mood disorders such as depression and anxiety.
- Boosts serotonin uptake in cell. Other classical anti-depressants work by modulating the serotonergic system. Serotonin is a molecule that often becomes decreased in depression, leading to the symptoms of low mood. Tianeptine helps neurons to soak up extracellular serotonin, increasing intracellular levels, and potentially balancing any deficit.
- Activating adenosine receptors. Tianeptine can activate the adenosine A1 receptor subunit. This may help with anxiety as activation of this receptors has been shown to reduce heart rate. A reduction to heart rate may lower the physical symptoms associated with anxiety and panic, without masking internal thoughts or emotions completely.
- Restores levels of BDNF after stress. Tianeptine has been shown to aid in the regulation of a vital neuronal growth factor, brain-derived neurotrophic factor (BDNF). BDNF is a well characterised growth factor which has role in neuronal growth, survival and synaptic plasticity. Both cellular and animal studies have shown that acute and chronic stress lowers BDNF levels. However, tianeptine is able to rescue this phenotype. Since BDNF is so critical to synaptic function, plasticity and stabilisation, this may be one mechanism which underlies the improvements seen to learning, memory and cognition after tianeptine treatment.
How to Use
Tianeptine is orally bioavailable and can be taken in capsule or powder form.
When it comes to using powerful drugs such as tianeptine, caution should be exercised with regard to overdosing and drug interactions.
Tianeptine shouldn’t be combined with any other nootropic, pharmacological or natural agents which have an effect on mood.
Since tianeptine can influence so many neurochemical systems, we recommend not stacking this drug with any other powerful nootropic agents (such as the racetam class of drugs). Individuals will often thing combining various nootropic agents will increase their beneficial effects. However, with powerful neurochemical modulators, that is not always the case.
Tianeptine dosage has to be followed carefully, and all potential drug interactions considered before embarking on a tianeptine regime. More details on dose and drug interactions can be found below. As always, you should consult your doctor for the best advice on whether tianeptine is right for you.
Recommended Dose 12.5mg, three times daily
The standard dosage for tianeptine is 12.5mg taken three times daily. It’s advisable to split tianeptine into three separate doses because of the drug has a relatively short half life (2-3 hours). This means that the drug is quickly metabolised and only half as potent after around 2 hours.
Tianeptine can have opioid-like euphoria if used recreationally. Hence, it’s sensible not to use this compound recreationally due to the risk of addiction and abuse.
If you are taking any other kind of medication, or dealing with a complex mental health condition, you must consult your doctor before taking tianeptine.
Tianeptine can worsen depression in some complex psychiatric conditions such as bipolar disorder. Since the drug mimic the effects of opioids, people who have previously struggled with substance abuse disorders should avoid tianeptine.
Pregnant and breast-feeding women should also avoid tianeptine due to these opioid-like effects.
Classification: Mood, Cognition
We’ve classified tianeptine as potent mood stabiliser because of the powerful improvement the drug can have on conditions such as depression and anxiety. We also suggest tianeptine may be able to exert some cognitive enhancement, especially when stress have previously damaged these functions.
However, we don’t recommend taking tianeptine for cognitive benefits alone. There are many other more well-researched and powerful nootropic agents, such as the racetam family of nootropics, which can improve cognition and memory.
- Campbell AM, Park CR, Zoladz PR, Munoz C, Fleshner M, Diamond DM. Pre-training administration of tianeptine, but not propranolol, protects hippocampus-dependent memory from being impaired by predator stress. Eur Neuropsychopharmacol. 2008;18:87–98.
- Campbell, Adam Marc, “The Antidepressant Drug Tianeptine Blocks Working Memory Errors: Pharmacological and Endocrine Manipulations of Stress-Induced Amnesia in Rats” (2004). Graduate Theses and Dissertations.
- Castanon N, Konsman JP, Medina C, Chauvet N, Dantzer R. Chronic treatment with the antidepressant tianeptine attenuates lipopolysaccharide-induced Fos expression in the rat paraventricular nucleus and HPA axis activation. Psychoneuroendocrinology. 2003;28:19–34
- Chamba G, Lemoine P, Flachaire E, Ferry N, Quincy C, Sassard J, Ferber C, Mocaer E, Kamoun A, Renaud B. Increased serotonin platelet uptake after tianeptine administration in depressed patients. Biol Psychiatry. 1991;30:609–617.
- Della, F.P., Abelaira, H.M., Réus, G.Z. et al. Treatment with tianeptine induces antidepressive-like effects and alters the neurotrophin levels, mitochondrial respiratory chain and cycle Krebs enzymes in the brain of maternally deprived adult rats. Metab Brain Dis 28, 93–105 (2013). https://doi.org/10.1007/s11011-012-9375-x
- Delagrange P, Bouyer JJ, Montaron MF, Durand C, Mocaer E, Rougeul A. Action of tianeptine on focalization of attention in cat. Psychopharmacology (Berl) 1990;102:227–233
- Franciela P. Della, Helena M. Abelaira, Gislaine Z. Réus, Altamir R. Antunes, Maria Augusta B. dos Santos, Giovanni Zappelinni, Amanda V. Steckert, Francieli Vuolo, Letícia S. Galant, Felipe Dal-Pizzol, Flávio Kapczinski, João Quevedo (2012) Tianeptine exerts neuroprotective effects in the brain tissue of rats exposed to the chronic stress model, Pharmacology Biochemistry and Behavior, Volume 103, Issue 2, Pages 395-402, ISSN 0091-3057, https://doi.org/10.1016/j.pbb.2012.09.018.
- Godsil, B., Bontempi, B., Mailliet, F. et al. Acute tianeptine treatment selectively modulates neuronal activation in the central nucleus of the amygdala and attenuates fear extinction. Mol Psychiatry 20, 1420–1427 (2015). https://doi.org/10.1038/mp.2014.169
- Invernizzi R, Pozzi L, Garattini S, Samanin R. Tianeptine increases the extracellular concentrations of dopamine in the nucleus accumbens by a serotonin-independent mechanism. Neuropharmacology. 1992;31:221–227.
- Jaffard R, Mocaer E, Poignant JC, Micheau J, Marighetto A, Meunier M, Beracochea D. Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on alcohol-induced alternation deficits in mice. Behav Pharmacol. 1991;2:37–46.
- Kato G, Weitsch AF. Neurochemical profile of tianeptine, a new antidepressant drug. Clin Neuropharmacol. 1988;11 (Suppl 2):S43–S50
- Lee, H., Kim, H. K., Kwon, J. T., Kim, Y. O., Seo, J., Lee, S., Cho, I. H., & Kim, H. J. (2018). Effects of Tianeptine on Adult Rats Following Prenatal Stress. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 16(2), 197–208. https://doi.org/10.9758/cpn.2018.16.2.197
- Samuels, B. A., Nautiyal, K. M., Kruegel, A. C., Levinstein, M. R., Magalong, V. M., Gassaway, M. M., Grinnell, S. G., Han, J., Ansonoff, M. A., Pintar, J. E., Javitch, J. A., Sames, D., & Hen, R. (2017). The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 42(10), 2052–2063. https://doi.org/10.1038/npp.2017.60
- Levin, O.S. Coaxil (tianeptine) in the treatment of depression in Parkinson’s disease. Neurosci Behav Physiol 37, 419–424 (2007). https://doi.org/10.1007/s11055-007-0029-0
- Lucassen PJ, Fuchs E, Czeh B. Antidepressant treatment with tianeptine reduces apoptosis in the hippocampal dentate gyrus and temporal cortex. Biol Psychiatry. 2004;55:789–796.
- Lucassen PJ, Vollmann-Honsdorf GK, Gleisberg M, Czeh B, De Kloet ER, Fuchs E. Chronic psychosocial stress differentially affects apoptosis in hippocampal subregions and cortex of the adult tree shrew. Eur J Neurosci. 2001;14:161–166.
- Marta M. Nowacka, Monika Paul-Samojedny, Anna M. Bielecka, Ewa Obuchowicz (2014) Chronic social instability stress enhances vulnerability of BDNF response to LPS in the limbic structures of female rats: A protective role of antidepressants, Neuroscience Research, Volume 88, Pages 74-83, ISSN 0168-0102, https://doi.org/10.1016/j.neures.2014.08.008.
- Maximino, C., Lima, M.G., Olivera, K.R.M., Picanço‐Diniz, D.L.W. and Herculano, A.M. (2011), Adenosine A1, but not A2, Receptor Blockade Increases Anxiety and Arousal in Zebrafish. Basic & Clinical Pharmacology & Toxicology, 109: 203-207. doi:10.1111/j.1742-7843.2011.00710.x
- McEwen, B. S., Chattarji, S., Diamond, D. M., Jay, T. M., Reagan, L. P., Svenningsson, P., & Fuchs, E. (2010). The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Molecular psychiatry, 15(3), 237–249. https://doi.org/10.1038/mp.2009.80
- Mennini T, Mocaer E, Garattini S. Tianeptine, a selective enhancer of serotonin uptake in rat brain. Naunyn Schmiedebergs Arch Pharmacol. 1987;336:478–482.
- Phillip R. Zoladz, Monika Fleshner, David M. Diamond (2013) Differential effectiveness of tianeptine, clonidine and amitriptyline in blocking traumatic memory expression, anxiety and hypertension in an animal model of PTSD, Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 44, Pages 1-16, ISSN 0278-5846, https://doi.org/10.1016/j.pnpbp.2013.01.001.
- Pineyro G, Deveault L, de Montigny C, Blier P. Effect of prolonged administration of tianeptine on 5-HT neurotransmission: an electrophysiological study in the rat hippocampus and dorsal raphe. Naunyn Schmiedebergs Arch Pharmacol. 1995;351:119–125.
- Plaisant F, Dommergues MA, Spedding M, Cecchelli R, Brillault J, Kato G, Munoz C, Gressens P. Neuroprotective properties of tianeptine: interactions with cytokines. Neuropharmacology. 2003;44:801–809.
- Rogoz Z, Skuza G, Dlaboga D, Maj J, Dziedzicka-Wasylewska M. Effect of repeated treatment with tianeptine and fluoxetine on the central alpha(1)-adrenergic system. Neuropharmacology. 2001;41:360–368.
- Schruers, K., & Griez, E. (2004). The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder. Journal of Psychopharmacology, 18(4), 553–558. https://doi.org/10.1177/0269881104047283
- Sjoukje D. Kuipers, Andrea Trentani, Eddy A. van der Zee, Johan A. den Boer (2013) Chronic stress-induced changes in the rat brain: Role of sex differences and effects of long-term tianeptine treatment, Neuropharmacology, Volume 75, Pages 426-436, ISSN 0028-3908, https://doi.org/10.1016/j.neuropharm.2013.08.018.
- Sohn, W., Lee, O.Y., Kwon, J.G., Park, K.S., Lim, Y.J., Kim, T.H., Jung, S.W. and Kim, J.I. (2012), Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open‐label, non‐inferiority, randomized controlled study. Neurogastroenterology & Motility, 24: 860-e398. doi:10.1111/j.1365-2982.2012.01945.x
- Ślusarczyk, J., Trojan, E., Głombik, K., Piotrowska, A., Budziszewska, B., Kubera, M., Popiołek-Barczyk, K., Lasoń, W., Mika, J., & Basta-Kaim, A. (2018). Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype
- Sevgi Türker-Kaya, Oğuz Mutlu, İpek K. Çelikyurt, Furuzan Akar, Güner Ulak (2016) Tianeptine, olanzapine and fluoxetine show similar restoring effects on stress induced molecular changes in mice brain: An FT-IR study. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy.Volume 161,Pages 178-185, ISSN 1386-1425, https://doi.org/10.1016/j.saa.2016.02.038.
- Wagstaff, A.J., Ormrod, D. & Spencer, C.M. Tianeptine. Mol Diag Ther 15, 231–259 (2001). https://doi.org/10.2165/00023210-200115030-00006
- Whitton PS, Sarna GS, Datla KP, Curzon G. Effects of tianeptine on stress-induced behavioural deficits and 5-HT dependent behaviour. Psychopharmacology (Berl) 1991;104:81–85.
- Zoladz, P. R., Park, C. R., Muñoz, C., Fleshner, M., & Diamond, D. M. (2008). Tianeptine: an antidepressant with memory-protective properties. Current neuropharmacology, 6(4), 311–321. https://doi.org/10.2174/157015908787386096in Lipopolysaccharide-Stimulated Cultures. International journal of molecular sciences, 19(7), 1965. https://doi.org/10.3390/ijms19071965