Tianeptine: Difference between revisions

{{Short description|Atypical antidepressant}}

{{distinguish|Tiagabine|Tiapride}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Use dmy dates|date=July 2019}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 455249171

| IUPAC_name = 7-[(3-Chloro-6-methyl-5,5-dioxo-11''H''-benzo[''c''][2,1]benzothiazepin-11-yl)amino]heptanoic acid

| image = Tianeptine2DACS.svg

| width = 225px

| image2 = File:Tianeptine structure.png

| width2 = 225px

| tradename = Stablon, Coaxil, Tatinol

| Drugs.com = {{drugs.com|international|tianeptine}}

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_status = In general: Rx-only<br />[[United States|US]]: [[Investigational New Drug]] <br />[[Australia|AU]]: [[Standard for the Uniform Scheduling of Medicines and Poisons#Schedule 4: Prescription only medicine|S4]]<ref>{{cite web | url=https://www.legislation.gov.au/Details/F2017L00605 | title=Poisons Standard June 2017 | date=29 May 2017 }}</ref><br />Others: controlled in [[France|FR]], [[Bahrain|BH]], [[Singapore|SG]]

| routes_of_administration = [[Oral administration|By mouth]]

<!--Pharmacokinetic data-->| bioavailability = 99%<ref name="pmid3180120">{{cite journal | vauthors = Royer RJ, Albin H, Barrucand D, Salvadori-Failler C, Kamoun A | title = Pharmacokinetic and metabolic parameters of tianeptine in healthy volunteers and in populations with risk factors | journal = Clinical Neuropharmacology | volume = 11 | issue = Suppl 2 | pages = S90-6 | year = 1988 | pmid = 3180120 }}</ref><ref name = Tian2001>{{cite journal | vauthors = Wagstaff AJ, Ormrod D, Spencer CM | title = Tianeptine: a review of its use in depressive disorders | journal = CNS Drugs | volume = 15 | issue = 3 | pages = 231–59 | date = March 2001 | pmid = 11463130 | doi = 10.2165/00023210-200115030-00006 | s2cid = 37796160 }}</ref>

| protein_bound = 95%<ref name = Tian2001/>

| metabolism = [[Hepatic]]<ref name = Tian2001/> by β-oxidation<ref name="pmid2597170">{{cite journal | pages=3743–3751 | volume=38 | issue=21 | vauthors=Fromenty B, Freneaux E, Labbe G, Deschamps D, Larrey D, Letteron P, Pessayre D | url=https://pubmed.ncbi.nlm.nih.gov/2597170/ | title=Tianeptine, a new tricyclic antidepressant metabolized by beta-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice | doi=10.1016/0006-2952(89)90580-7 | pmid=2597170 | date=Nov 1, 1989 | journal=Biochem Pharmacol}}</ref>

| elimination_half-life = 2.5–3 hours<ref name="pmid3180120" /><ref name = Tian2001/><br />4–9 hours ([[elderly]])<ref name =Tian2001/><ref name="CarlhantLeGarrec1990">{{cite journal | vauthors = Carlhant D, Le Garrec J, Guedes Y, Salvadori C, Mottier D, Riche C |title=Pharmacokinetics and bioavailability of tianeptine in the elderly|journal=Drug Investigation|date=September 1990|volume=2|issue=3|pages=167–172|doi=10.1007/BF03259191 |s2cid=56502717}}</ref>

| excretion = [[Urine]]: 65%<ref name="pmid3180120" /><br />[[Feces]]: 15%<ref name =Tian2001/>

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 72797-41-2

| CAS_supplemental = <br />30123-17-2 ([[sodium]])<br />1224690-84-9 ([[sulfate]])<br /> 2231739-19-6 ([[Oxalic acid|hemioxalate]])

| ATC_prefix = N06

| ATC_suffix = AX14

| PubChem = 68870

| IUPHAR_ligand = 7558

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 62102

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1289110

| ChEBI = 91749

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 0T493YFU8O

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D02575

| synonyms = Tia;<ref>{{cite journal |title=FC13-09 - Antidepressant tianeptine (TIA) action is based on the acceleration of serotonin turnover in the synapse: a hypothesis |url=https://www.cambridge.org/core/journals/european-psychiatry/article/abs/fc1309-antidepressant-tianeptine-tia-action-is-based-on-the-acceleration-of-serotonin-turnover-in-the-synapse-a-hypothesis/556C8D1EDAC950D0FBB8CED6B5651B9A |journal=European Psychiatry |date=2011 |doi=10.1016/S0924-9338(11)73594-5 |access-date=3 December 2023 | vauthors = Uzbekov M |volume=26 |page=1890 |s2cid=143885547 }}</ref> ZaZa;<ref name="Wagner et al 2023">{{cite journal | vauthors = Wagner ML, Pergolizzi J, LeQuang JA, Breve F, Varrassi G | title = From Antidepressant Tianeptine to Street Drug ZaZa: A Narrative Review | journal = Cureus | volume = 15 | issue = 6 | pages = e40688 | date = June 2023 | pmid = 37485121 | pmc = 10359047 | doi = 10.7759/cureus.40688 | doi-access = free }}</ref> S-1574;<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" /> JNJ-39823277; TPI-1062<ref name="AdisInsight" />

<!--Chemical data-->| C = 21

| H = 25

| Cl = 1

| N = 2

| O = 4

| S = 1

| SMILES = Clc1cc2c(cc1)C(c3c(N(C)S2(=O)=O)cccc3)NCCCCCCC(=O)O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C21H24ClN2NaO4S/c1-24-18-9-6-5-8-16(18)21(23-13-7-3-2-4-10-20(25)26)17-12-11-15(22)14-19(17)29(24,27)28/h5-6,8-9,11-12,14,21,23H,2-4,7,10,13H2,1H3,(H,25,26)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = JICJBGPOMZQUBB-UHFFFAOYSA-N

<!-- Definition and medical uses -->

'''Tianeptine''', sold under the brand names '''Stablon''', '''Tatinol''', and '''Coaxil''' among others, is an [[atypical antidepressant|atypical]] [[tricyclic antidepressant]] which is used mainly in the treatment of [[major depressive disorder]], although it may also be used to treat [[anxiety]], [[asthma]], and [[irritable bowel syndrome]].<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1195|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1195–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1024|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=1024–}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/tianeptine.html|title=Tianeptine (International database)|website=Drugs.com}}</ref>

<!-- Side effects and mechanism of action -->

Tianeptine has antidepressant and [[anxiolytic]] effects<ref name="pmid2902922">{{cite journal | vauthors = Defrance R, Marey C, Kamoun A | title = Antidepressant and anxiolytic activities of tianeptine: an overview of clinical trials | journal = Clinical Neuropharmacology | volume = 11 | issue = Suppl 2 | pages = S74-82 | date = 1988 | pmid = 2902922 | url = https://dl.dropboxusercontent.com/u/238511/papers/1988_defrance.pdf | url-status = dead | archive-url = https://web.archive.org/web/20160404140849/https://dl.dropboxusercontent.com/u/238511/papers/1988_defrance.pdf | archive-date = 4 April 2016 }}</ref> with a relative lack of [[sedation|sedative]], [[anticholinergic]], and [[cardiovascular]] [[side effect]]s.<ref name="Tian2001" /><ref name=CNS2008 /> It has been found to act as an atypical [[agonist]] of the [[μ-opioid receptor]] with clinically negligible effects on the [[δ-opioid receptor|δ-]] and [[κ-opioid receptor]]s.<ref name="pmid25026323" /><ref>{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Affective neuroscience of pleasure: reward in humans and animals | journal = Psychopharmacology | volume = 199 | issue = 3 | pages = 457–80 | date = August 2008 | pmid = 18311558 | pmc = 3004012 | doi = 10.1007/s00213-008-1099-6 }}</ref><ref name="pmid30070980">{{cite journal | vauthors = El Zahran T, Schier J, Glidden E, Kieszak S, Law R, Bottei E, Aaron C, King A, Chang A | title = Characteristics of Tianeptine Exposures Reported to the National Poison Data System - United States, 2000-2017 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 67 | issue = 30 | pages = 815–818 | date = August 2018 | pmid = 30070980 | pmc = 6072055 | doi = 10.15585/mmwr.mm6730a2 }}</ref> This may explain part of its antidepressant and anxiolytic effects; however, it is thought that tianeptine also modulates glutamate receptors, and this may also explain tianeptine's antidepressant/anxiolytic effects.

<!-- History and culture -->

Tianeptine was discovered and patented by the French Society of Medical Research in the 1960s. It was introduced for medical use in [[France]] in 1983.<ref name="PharmManuEnc2013">{{cite book | last=Publishing | first=W.A.W.A. | title=Pharmaceutical Manufacturing Encyclopedia | publisher=William Andrew | series=Volumes 1-4 | year=2013 | isbn=978-0-8155-1856-3 | url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA3222 | access-date=10 October 2024 | page=3222}}</ref> Currently, tianeptine is approved in France and manufactured and marketed by Laboratories [[Servier]] SA; it is also marketed in a number of other European countries under the trade name Coaxil as well as in Asia (including [[Singapore]]) and Latin America as Stablon and Tatinol but it is not available in [[Australia]], [[Canada]], [[New Zealand]], or the [[United Kingdom]].<ref name="akiki"/><ref name = MD>{{cite book| chapter = Tianeptine Sodium|date=5 December 2011|access-date=2 December 2013|url=http://www.medicinescomplete.com/mc/martindale/current/17007-n.htm| title = Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|location=London, UK}}</ref>

In the US, it is an unregulated drug sold under several names and some of these products have been found to be adulterated with other [[recreational drugs]]. It is commonly known by the nickname 'gas station heroin'.<ref name=":0" /><ref name="mmwr">{{cite journal | vauthors = Counts CJ, Spadaro AV, Cerbini TA, Krotulski AJ, Greller HA, Nelson LS, Ruck BE, Calello DP | title = Notes from the Field: Cluster of Severe Illness from Neptune's Fix Tianeptine Linked to Synthetic Cannabinoids - New Jersey, June-November 2023 | language = en-us | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 73 | issue = 4 | pages = 89–90 | date = February 2024 | pmid = 38300852 | pmc = 10843069 | doi = 10.15585/mmwr.mm7304a5 | doi-access = free }}</ref>

{{TOC limit|3}}

==Medical uses==

===Depression and anxiety===

Tianeptine shows efficacy against serious depressive episodes ([[major depression]]), comparable to [[amitriptyline]], [[imipramine]] and [[fluoxetine]], but with significantly fewer side effects.<ref name="akiki"/> It was shown to be more effective than [[maprotiline]] in a group of people with co-existing depression and anxiety.<ref name="Tian2001" /> Tianeptine also displays significant [[anxiolytic]] properties and is useful in treating a spectrum of anxiety disorders including [[panic disorder]], as evidenced by a study in which those administered 35% [[carbon dioxide|CO₂]] gas ([[carbogen]]) on [[paroxetine]] or tianeptine therapy showed equivalent panic-blocking effects.<ref name=Schruers_and_Griez_2004>{{cite journal | vauthors = Schruers K, Griez E | title = The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder | journal = Journal of Psychopharmacology | volume = 18 | issue = 4 | pages = 553–8 | date = December 2004 | pmid = 15582922 | doi = 10.1177/0269881104047283 | s2cid = 26981110 }}</ref> Like many antidepressants (including [[bupropion]], the [[selective serotonin reuptake inhibitors]], the [[serotonin-norepinephrine reuptake inhibitors]], [[moclobemide]] and numerous others) it may also have a beneficial effect on cognition in people with [[pseudodementia|depression-induced cognitive dysfunction]].<ref>{{cite journal | vauthors = Baune BT, Renger L | title = Pharmacological and non-pharmacological interventions to improve cognitive dysfunction and functional ability in clinical depression--a systematic review | journal = Psychiatry Research | volume = 219 | issue = 1 | pages = 25–50 | date = September 2014 | pmid = 24863864 | doi = 10.1016/j.psychres.2014.05.013 | s2cid = 23684657 }}</ref>

A 2005 study in Egypt showed tianeptine to be effective in men with depression and [[erectile dysfunction]].<ref name=erectile_dysfunction>{{cite journal | vauthors = El-Shafey H, Atteya A, Abu El-Magd S, Hassanein A, Fathy A, Shamloul R | title = Tianeptine can be effective in men with depression and erectile dysfunction | journal = The Journal of Sexual Medicine | volume = 3 | issue = 5 | pages = 910–917 | date = September 2006 | pmid = 16942535 | doi = 10.1111/j.1743-6109.2005.00141.x }}</ref>

Tianeptine has been found to be effective in depression, in people with [[Parkinson's disease]],<ref>{{cite journal | vauthors = Levin OS | title = Coaxil (tianeptine) in the treatment of depression in Parkinson's disease | journal = Neuroscience and Behavioral Physiology | volume = 37 | issue = 4 | pages = 419–24 | date = May 2007 | pmid = 17457538 | doi = 10.1007/s11055-007-0029-0 | s2cid = 7637174 }}</ref> and with [[post-traumatic stress disorder]]<ref>{{cite journal | vauthors = Aleksandrovskiĭ I, Avedisova AS, Boev IV, Bukhanovkskiĭ AO, Voloshin VM, Tsygankov BD, Shamreĭ BK | title = [Efficacy and tolerability of coaxil (tianeptine) in the therapy of posttraumatic stress disorder] | language = ru | journal = Zhurnal Nevrologii I Psikhiatrii imeni S.S. Korsakova | volume = 105 | issue = 11 | pages = 24–9 | date = 2005 | pmid = 16329631 | script-title = ru:Эффективность и переносимость коаксила (тианептина) при терапии посттравматического стрессового расстройства | trans-title = Efficacy and tolerability of coaxil (tianeptine) in the therapy of posttraumatic stress disorder }}</ref> for which it was as safe and effective as [[fluoxetine]] and [[moclobemide]].<ref>{{cite journal | vauthors = Onder E, Tural U, Aker T | title = A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake | journal = European Psychiatry | volume = 21 | issue = 3 | pages = 174–9 | date = April 2006 | pmid = 15964747 | doi = 10.1016/j.eurpsy.2005.03.007 | s2cid = 21322928 }}</ref>

===Other uses===

A clinical trial comparing its efficacy and tolerability with [[amitriptyline]] in the treatment of [[irritable bowel syndrome]] showed that tianeptine was at least as effective as amitriptyline and produced fewer prominent adverse effects, such as dry mouth and constipation.<ref>{{cite journal | vauthors = Sohn W, Lee OY, Kwon JG, Park KS, Lim YJ, Kim TH, Jung SW, Kim JI | title = Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open-label, non-inferiority, randomized controlled study | journal = Neurogastroenterology and Motility | volume = 24 | issue = 9 | pages = 860–e398 | date = September 2012 | pmid = 22679908 | doi = 10.1111/j.1365-2982.2012.01945.x | s2cid = 2914428 }}</ref>

Tianeptine has been reported to be very effective for [[asthma]]. In August 1998, Dr. Fuad Lechin and colleagues at the [[Central University of Venezuela]] Institute of Experimental Medicine in [[Caracas]] published the results of a 52-week [[randomized controlled trial]] of asthmatic children; the children in the groups who received tianeptine had a sharp decrease in clinical rating and increased lung function.<ref name=By_2004/> Two years earlier, they had found a close, positive association between free serotonin in [[blood plasma|plasma]] and severity of asthma in symptomatic persons.<ref name=By_2004/> As tianeptine was the only agent known to both reduce free serotonin in plasma and enhance uptake in platelets, they decided to use it to see if reducing free serotonin levels in plasma would help.<ref name=By_2004 /> By November 2004, there had been two double-blind placebo-controlled crossover trials and an under-25,000 person open-label study lasting over seven years, both showing effectiveness.<ref name=By_2004>{{cite journal | vauthors = Lechin F, van der Dijs B, Lechin AE | title = Treatment of bronchial asthma with tianeptine | journal = Methods and Findings in Experimental and Clinical Pharmacology | volume = 26 | issue = 9 | pages = 697–701 | date = November 2004 | pmid = 15632955 | doi = 10.1358/mf.2004.26.9.872567 }}</ref>

Tianeptine also has [[anticonvulsant]] and [[analgesic]] effects,<ref name="pmid17826881">{{cite journal | vauthors = Uzbay TI | title = Tianeptine: potential influences on neuroplasticity and novel pharmacological effects | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 32 | issue = 4 | pages = 915–24 | date = May 2008 | pmid = 17826881 | doi = 10.1016/j.pnpbp.2007.08.007 | s2cid = 22365299 }}</ref> and a clinical trial in Spain that ended in January 2007 has shown that tianeptine is effective in treating pain due to [[fibromyalgia]].<ref>{{cite web |url=http://www.controlled-trials.com/ISRCTN16400909/ |title=ISRCTN16400909 – Tianeptine for the treatment of fibromyalgia: a prospective double-blind, randomised, single-centre, placebo-controlled, parallel group study |publisher=Controlled-trials.com |access-date=13 August 2010 |url-status=dead |archive-url=https://web.archive.org/web/20100721093453/http://www.controlled-trials.com/ISRCTN16400909/ |archive-date=21 July 2010}}</ref> Tianeptine has been shown to have efficacy with minimal side effects in the treatment of [[attention-deficit hyperactivity disorder]].<ref name="pmid15034228">{{cite journal | vauthors = Niederhofer H | title = Tianeptine as a slightly effective therapeutic option for attention-deficit hyperactivity disorder | journal = Neuropsychobiology | volume = 49 | issue = 3 | pages = 130–3 | year = 2004 | pmid = 15034228 | doi = 10.1159/000076721 | s2cid = 34300575 }}</ref>

==Contraindications==

Known contraindications include the following:<ref>{{cite web|url=https://www.servier.at/sites/default/files/spc-pil/GI_Stablon_April_2015.pdf|title=Package Insert – Stablon (German)|date=20 August 2012|work=Servier Austria GmbH|access-date=24 February 2020|archive-date=11 August 2016|archive-url=https://web.archive.org/web/20160811122613/http://servier.at/sites/default/files/spc-pil/GI_Stablon_April_2015.pdf|url-status=dead}}</ref>

* Hypersensitivity to tianeptine or any of the tablet's excipients.<ref>{{cite journal | vauthors = Le Bricquir Y, Larrey D, Blanc P, Pageaux GP, Michel H | title = Tianeptine--an instance of drug-induced hepatotoxicity predicted by prospective experimental studies | journal = Journal of Hepatology | volume = 21 | issue = 5 | pages = 771–773 | date = November 1994 | pmid = 7890892 | doi = 10.1016/s0168-8278(94)80237-8 }}</ref>

==Side effects==

Compared to other [[tricyclic antidepressant]]s, it produces significantly fewer cardiovascular, [[anticholinergic]] (like dry mouth or constipation), [[sedative]] and appetite-stimulating effects.<ref name = CNS2008/><ref name="akiki"/> Unlike other tricyclic antidepressants, tianeptine does not affect heart function.<ref>{{cite journal | vauthors = Bril A, Abadie C, Ben Baouali A, Maupoil V, Rochette L | title = Absence of relationship between antiarrhythmic effects of antidepressant drugs and lipid peroxidation | journal = Pharmacology | volume = 46 | issue = 1 | pages = 23–32 | date = 1993 | pmid = 8434029 | doi = 10.1159/000139025 | url = https://pubmed.ncbi.nlm.nih.gov/8434029/ }}</ref>

μ-Opioid receptor agonists can sometimes induce [[euphoria]], as does tianeptine, occasionally, at high doses, well above the normal therapeutic range (see {{section link||Recreational use}} below). Tianeptine can also cause severe withdrawal symptoms after prolonged use at high doses which should prompt extreme caution.<ref name="auto1">{{cite journal | vauthors = Lauhan R, Hsu A, Alam A, Beizai K | title = Tianeptine Abuse and Dependence: Case Report and Literature Review | journal = Psychosomatics | volume = 59 | issue = 6 | pages = 547–553 | date = November 2018 | pmid = 30149933 | doi = 10.1016/j.psym.2018.07.006 | s2cid = 52099752 }}</ref><ref>{{cite journal | vauthors = Vadachkoria D, Gabunia L, Gambashidze K, Pkhaladze N, Kuridze N | title = Addictive potential of Tianeptine - the threatening reality | journal = Georgian Medical News | issue = 174 | pages = 92–4 | date = September 2009 | pmid = 19801742 | url = https://pubmed.ncbi.nlm.nih.gov/19801742/ }}</ref>

===By frequency===

''Sources:''<ref name = Tian2001/><ref name="CNS2008" /><ref>{{cite journal | vauthors = Waintraub L, Septien L, Azoulay P | title = Efficacy and safety of tianeptine in major depression: evidence from a 3-month controlled clinical trial versus paroxetine | journal = CNS Drugs | volume = 16 | issue = 1 | pages = 65–75 | date = January 2002 | pmid = 11772119 | doi = 10.2165/00023210-200216010-00005 | s2cid = 31125177 }}</ref>

;Common (>1% frequency)

{{div col|colwidth=22em}}

* Headache (up to 18%)

* Dizziness (up to 10%)

* Insomnia/nightmares (up to 20%)

* Drowsiness (up to 10%)

* Dry mouth (up to 20%)

* Constipation (up to 15%)

* Nausea

* Abdominal pain

* Weight gain (~3%)

* Agitation

* Anxiety/irritability

{{div col end}}

;Uncommon (0.1–1% frequency)

{{div col|colwidth=22em}}

* [[Bitter taste]]

* Flatulence

* [[Gastralgia]]

* Blurred vision

* [[Myalgia|Muscle aches]]

* [[Premature ventricular contractions]]

* [[Micturition]] disturbances

* [[Palpitations]]

* [[Orthostatic hypotension]]

* [[Hot flushes]]

* [[Tremor]]

{{div col end}}

;Rare (<0.1% frequency)

{{div col|colwidth=18em}}

* [[Hepatitis]]

* [[Hypomania]]<ref name=mania>{{cite journal | vauthors = Gülen Yıldırım S, Başterzi AD, Göka E | year = 2004 | title = Tianeptinin Neden Olduğu Hipomani; Bir Olgu Sunumu | trans-title = Tianeptine Induced Mania: A Case Report | journal = Klinik Psikiyatri Dergisi | volume = 7 | issue = 4 | language = tr | pages = 177–180 | url = http://www.klinikpsikiyatri.org/pdf/4/7/177.pdf | url-status = dead | archive-url = https://web.archive.org/web/20060630014333/http://klinikpsikiyatri.org/pdf/4/7/177.pdf | archive-date = 30 June 2006 | df = dmy-all }}</ref>

* [[Euphoria]]

* ECG changes

* Pruritus/allergic-type skin reactions

* Protracted [[myalgia|muscle aches]]

* General fatigue

{{div col end}}

==Pharmacology==

===Pharmacodynamics===

{{See also|Pharmacology of antidepressants|Tricyclic antidepressant#Binding profiles}}

{| class="wikitable floatright" style="font-size:small;"

|+ Tianeptine<ref name="PDSP">{{cite web | title = PDSP K_i Database | work = Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=tianeptine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref>

|-

! Site !! K_i (nM) !! Species !! Ref

|-

| {{abbrlink|MOR|μ-Opioid receptor}} || 383–768 (K_i)<br />194 ({{abbrlink|EC₅₀|Half-maximal effective concentration}}) || Human || <ref name="pmid25026323" /><ref name="PDSP" /><br /><ref name="pmid25026323" />

|-

| {{abbrlink|DOR|δ-Opioid receptor}} || >10,000 (K_i)<br />37,400 ({{abbr|EC₅₀|Half-maximal effective concentration}}) || Human || <ref name="pmid25026323" /><ref name="PDSP" /><br /><ref name="pmid25026323" />

|-

| {{abbrlink|KOR|κ-Opioid receptor}} || >10,000 (K_i)<br />100,000 ({{abbr|EC₅₀|Half-maximal effective concentration}}) || Human || <ref name="pmid25026323" /><ref name="PDSP" /><br /><ref name="pmid25026323" />

|-

| {{abbrlink|SERT|Serotonin transporter}} || >10,000 || Human || <ref name="PDSP" />

|-

| {{abbrlink|NET|Norepinephrine transporter}} || >10,000 || Human || <ref name="PDSP" />

|-

| {{abbrlink|DAT|Dopamine transporter}} || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT1A receptor|5-HT_1A]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT1B receptor|5-HT_1B]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT1D receptor|5-HT_1D]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT1E receptor|5-HT_1E]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT2A receptor|5-HT_2A]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT2B receptor|5-HT_2B]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT2C receptor|5-HT_2C]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT3 receptor|5-HT₃]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT5A receptor|5-HT_5A]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT6 receptor|5-HT₆]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[5-HT7 receptor|5-HT₇]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Alpha-1A adrenergic receptor|α_1A]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Alpha-1B adrenergic receptor|α_1B]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Alpha-2A adrenergic receptor|α_2A]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Alpha-2B adrenergic receptor|α_2B]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Alpha-2C adrenergic receptor|α_2C]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Beta-1 adrenergic receptor|β₁]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Beta-2 adrenergic receptor|β₂]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[D1 receptor|D₁]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[D2 receptor|D₂]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[D3 receptor|D₃]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[D4 receptor|D₄]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[D5 receptor|D₅]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Histamine H1 receptor|H₁]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Histamine H2 receptor|H₂]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Histamine H3 receptor|H₃]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Histamine H4 receptor|H₄]] || >10,000 || Human || <ref name="PDSP" />

|-

| {{abbrlink|mACh|Muscarinic acetylcholine receptor}} || >10,000 || Human || <ref name="PDSP" />

|-

| [[Sigma-1 receptor|σ₁]] || >10,000 || Guinea pig || <ref name="PDSP" />

|-

| [[Sigma-2 receptor|σ₂]] || >10,000 || Rat || <ref name="PDSP" />

|-

| [[Imidazoline I1 receptor|I₁]] || >10,000 || Human || <ref name="PDSP" />

|-

| [[Adenosine A1 receptor|A₁]] || >10,000 ({{abbr|EC₅₀|Half-maximal effective concentration}}) || Human || <ref name="pmid25026323" />

|-

| {{abbrlink|VDCC|Voltage-dependent calcium channel}} || >10,000 || Human || <ref name="PDSP" />

|- class="sortbottom"

| colspan="4" style="width: 1px;" | Values are K_i (nM), unless otherwise noted. The smaller the value, the more strongly the drug interacts with the site.

|}

====Atypical μ-opioid receptor agonist====

In 2014, tianeptine was found to be a [[μ-opioid receptor]] (MOR) [[full agonist]] using human proteins.<ref name="pmid25026323">{{cite journal | vauthors = Gassaway MM, Rives ML, Kruegel AC, Javitch JA, Sames D | title = The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist | journal = Translational Psychiatry | volume = 4 | issue = 7 | pages = e411 | date = July 2014 | pmid = 25026323 | pmc = 4119213 | doi = 10.1038/tp.2014.30 }}</ref> It was also found to act as a full agonist of the [[δ-opioid receptor]] (DOR), although with approximately 200-fold lower potency.<ref name= "pmid25026323" /> The same researchers subsequently found that the MOR is required for the acute and chronic antidepressant-like behavioral effects of tianeptine in mice and that its primary [[metabolite]] had similar activity as a MOR agonist but with a much longer [[elimination half-life]].<ref name="pmid28303899">{{cite journal | vauthors = Samuels BA, Nautiyal KM, Kruegel AC, Levinstein MR, Magalong VM, Gassaway MM, Grinnell SG, Han J, Ansonoff MA, Pintar JE, Javitch JA, Sames D, Hen R | title = The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor | journal = Neuropsychopharmacology | volume = 42 | issue = 10 | pages = 2052–2063 | date = September 2017 | pmid = 28303899 | pmc = 5561344 | doi = 10.1038/npp.2017.60 }}</ref> Moreover, in mice, although tianeptine produced other [[opioid]]-like behavioral effects such as [[analgesia]] and [[reward system|reward]], it did not result in [[drug tolerance|tolerance]] or [[drug withdrawal|withdrawal]].<ref name="pmid28303899" /> The authors suggested that tianeptine may be acting as a [[biased agonist]] of the MOR and that this may be responsible for its atypical profile as a MOR agonist.<ref name="pmid28303899" /> However, there are reports that suggest that withdrawal effects resembling those of other typical opioid drugs (including but not limited to depression, insomnia, and cold/flu-like symptoms) do manifest following prolonged use at dosages far beyond the medical range.<ref name= "pmid29494783">{{cite journal | vauthors = Springer J, Cubała WJ | title = Tianeptine Abuse and Dependence in Psychiatric Patients: A Review of 18 Case Reports in the Literature | journal = Journal of Psychoactive Drugs | volume = 50 | issue = 3 | pages = 275–280 | date = March 2018 | pmid = 29494783 | doi = 10.1080/02791072.2018.1438687 | s2cid = 3603781 }}</ref><ref name= "pmid29799284">{{cite journal | vauthors = Marraffa JM, Stork CM, Hoffman RS, Su MK | title = Poison control center experience with tianeptine: an unregulated pharmaceutical product with potential for abuse | journal = Clinical Toxicology | volume = 56 | issue = 11 | pages = 1155–1158 | date = November 2018 | pmid = 29799284 | doi = 10.1080/15563650.2018.1476694 | s2cid = 44112801 }}</ref> In addition to its therapeutic effects, activation of the MOR is likely to also be responsible for the [[abuse potential]] of tianeptine at high doses that are well above the normal therapeutic range and efficacy threshold.

In rats, when co-administered with morphine, tianeptine prevents morphine-induced [[respiratory depression]] without impairing analgesia.<ref name= "pmid26068549">{{cite journal | vauthors = Cavalla D, Chianelli F, Korsak A, Hosford PS, Gourine AV, Marina N | title = Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats | journal = European Journal of Pharmacology | volume = 761 | pages = 268–72 | date = August 2015 | pmid = 26068549 | doi = 10.1016/j.ejphar.2015.05.067 }}</ref> In humans, however, tianeptine was found to increase respiratory depression when administered in conjunction with the potent opioid [[remifentanil]].<ref>{{cite journal | vauthors = Algera H, van der Schrier R, Cavalla D, van Velzen M, Roozekrans M, McMorn A, Snape M, Horrigan JP, Evans S, Kiernan B, Sarton E, Olofsen E, Niesters M, Dahan A | title = Respiratory Effects of the Atypical Tricyclic Antidepressant Tianeptine in Human Models of Opioid-induced Respiratory Depression | journal = Anesthesiology | volume = 137 | issue = 4 | pages = 446–458 | date = October 2022 | pmid = 35867853 | doi = 10.1097/ALN.0000000000004324 | s2cid = 250989511 | doi-access = free | hdl = 1887/3572120 | hdl-access = free }}</ref>

====Glutamatergic, neurotrophic, and neuroplastic modulation====

Research suggests that tianeptine produces its antidepressant effects through indirect alteration and inhibition of [[glutamate (neurotransmitter)|glutamate]] receptor activity (i.e., [[AMPA receptor]]s and [[NMDA receptor]]s) and release of {{abbrlink|BDNF|brain-derived neurotrophic factor}}, in turn affecting [[neural plasticity]].<ref name="mp09" /><ref name="pmid15550348" /><ref name="pmid15753957" /><ref name="pmid18221189" /><ref name="CNS2008" /><ref name="akiki" /> Some researchers hypothesize that tianeptine has a protective effect against stress induced [[neuroplasticity|neuronal remodeling]].<ref name=mp09/><ref name=CNS2008 /> There is also action on the [[NMDA receptor|NMDA]] and [[AMPA receptor]]s.<ref name=mp09/><ref name=CNS2008 /> In animal models, tianeptine inhibits the pathological stress-induced changes in glutamatergic neurotransmission in the amygdala and hippocampus. It may also facilitate signal transduction at the CA3 commissural associational synapse by altering the phosphorylation state of glutamate receptors. With the discovery of the rapid and novel antidepressant effects of drugs such as [[ketamine]], many believe the efficacy of antidepressants is related to promotion of [[synaptic plasticity]]. This may be achieved by regulating the excitatory amino acid systems that are responsible for changes in the strength of synaptic connections as well as enhancing [[BDNF]] expression, although these findings are based largely on [[preclinical]] studies.<ref name= "akiki"/>

====Serotonin reuptake enhancer====

Tianeptine is no longer labelled a selective serotonin reuptake enhancer (SSRE) antidepressant.<ref name = mp09>{{cite journal | vauthors = McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E | title = The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation | journal = Molecular Psychiatry | volume = 15 | issue = 3 | pages = 237–49 | date = March 2010 | pmid = 19704408 | pmc = 2902200 | doi = 10.1038/mp.2009.80 }}</ref><ref name="pmid15550348">{{cite journal | vauthors = McEwen BS, Chattarji S | title = Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine | journal = European Neuropsychopharmacology | volume = 14 | issue = Suppl 5 | pages = S497-502 | date = December 2004 | pmid = 15550348 | doi = 10.1016/j.euroneuro.2004.09.008 | s2cid = 21953270 }}</ref><ref name="pmid15753957">{{cite journal | vauthors = McEwen BS, Olié JP | title = Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine | journal = Molecular Psychiatry | volume = 10 | issue = 6 | pages = 525–37 | date = June 2005 | pmid = 15753957 | doi = 10.1038/sj.mp.4001648 | doi-access = free }}</ref><ref name= "pmid18221189">{{cite journal | vauthors = Brink CB, Harvey BH, Brand L | title = Tianeptine: a novel atypical antidepressant that may provide new insights into the biomolecular basis of depression | journal = Recent Patents on CNS Drug Discovery | volume = 1 | issue = 1 | pages = 29–41 | date = January 2006 | pmid = 18221189 | doi = 10.2174/157488906775245327 | url = http://www.bentham-direct.org/pages/content.php?PRN/2006/00000001/00000001/0002PRN.SGM | url-status = dead | archive-url = https://archive.today/20130414074312/http://www.bentham-direct.org/pages/content.php?PRN/2006/00000001/00000001/0002PRN.SGM | archive-date = 2013-04-14 }}</ref><ref name=CNS2008>{{cite journal | vauthors = Kasper S, McEwen BS | title = Neurobiological and clinical effects of the antidepressant tianeptine | journal = CNS Drugs | volume = 22 | issue = 1 | pages = 15–26 | year = 2008 | pmid = 18072812 | doi = 10.2165/00023210-200822010-00002 | s2cid = 30330824 }}</ref><ref name="akiki">{{cite journal |vauthors= Akiki T |title= The etiology of depression and the therapeutic implications |journal= Glob. J. Med. Res. |volume= 13 |issue= 6 |url= http://medicalresearchjournal.org/index.php/GJMR/article/viewFile/465/383 |issn= 2249-4618 |access-date= 26 August 2015 |archive-date= 3 November 2016 |archive-url= https://web.archive.org/web/20161103181307/http://medicalresearchjournal.org/index.php/GJMR/article/viewFile/465/383 |url-status= dead }}</ref>

Tianeptine had been found to bind to the same [[allosteric site]] on the [[serotonin transporter]] (SERT) as conventional TCAs.<ref name= "BaileyAlmatroudi2018">{{cite journal| vauthors = Bailey SJ, Almatroudi A, Kouris A |title=Tianeptine: An Atypical Antidepressant with Multimodal Pharmacology|journal=Current Psychopharmacology|volume=6|issue=2| year=2018|issn=2211-5560 |doi= 10.2174/2211556006666170525154616|s2cid=55965184 |url= http://opus.bath.ac.uk/56181/1/REVISED_Bailey_et_al_Tianeptine_Review_Current_Psychopharmacology_050517_PURE.pdf}}</ref> However, whereas conventional TCAs [[reuptake inhibitor|inhibit]] [[serotonin]] [[reuptake]] by the SERT, tianeptine appeared to enhance it.<ref name="BaileyAlmatroudi2018" /> This seems to be because of the unique C3 [[amine|amino]] [[heptanoic acid]] [[side chain]] of tianeptine, which, in contrast to other TCAs, is thought to lock the SERT in a [[protein conformation|conformation]] that increases [[affinity (pharmacology)|affinity]] for and reuptake ([[Michaelis–Menten kinetics|V_max]]) of serotonin.<ref name= "BaileyAlmatroudi2018" /> As such, tianeptine was thought to act a [[positive allosteric modulator]] of the SERT, or as a "[[serotonin reuptake enhancer]]".<ref name="BaileyAlmatroudi2018" />

Although tianeptine was originally found to have no effect ''in vitro'' on monoamine reuptake, release, or receptor binding, upon acute and repeated administration, tianeptine decreased the extracellular levels of serotonin in rat brain without a decrease in serotonin release, leading to a theory of tianeptine enhancing serotonin reuptake.<ref name= "pmid3437921">{{cite journal | vauthors = Mennini T, Mocaer E, Garattini S | title = Tianeptine, a selective enhancer of serotonin uptake in rat brain | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 336 | issue = 5 | pages = 478–82 | date = November 1987 | pmid = 3437921 | doi = 10.1007/bf00169302 | s2cid = 21499462 }}</ref> The (−)-[[enantiomer]] is more active in this sense than the (+)-enantiomer.<ref>{{cite journal | vauthors = Oluyomi AO, Datla KP, Curzon G | title = Effects of the (+) and (-) enantiomers of the antidepressant drug tianeptine on 5-HTP-induced behaviour | journal = Neuropharmacology | volume = 36 | issue = 3 | pages = 383–7 | date = March 1997 | pmid = 9175617 | doi = 10.1016/s0028-3908(97)00016-6 | s2cid = 11465294 }}</ref> However, more recent studies found that long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of serotonin in rats.<ref name=mp09/> However, coadministration of tianeptine and the [[selective serotonin reuptake inhibitor]] [[fluoxetine]] inhibited the effect of tianeptine on [[long-term potentiation]] in [[hippocampus anatomy|hippocampal CA1 area]]. This is considered an argument for the opposite effects of tianeptine and fluoxetine on serotonin uptake,<ref name="CNS2008" /> although it has been shown that fluoxetine can be partially substituted for tianeptine in animal studies.<ref name= "pmid16292591">{{cite journal | vauthors = Alici T, Kayir H, Aygoren MO, Saglam E, Uzbay IT | title = Discriminative stimulus properties of tianeptine | journal = Psychopharmacology | volume = 183 | issue = 4 | pages = 446–51 | date = January 2006 | pmid = 16292591 | doi = 10.1007/s00213-005-0210-5 | s2cid = 5820336 }}</ref> In any case, the collective research suggests that direct modulation of the serotonin system is unlikely to be the [[mechanism of action]] underlying the antidepressant effects of tianeptine.<ref name= "BaileyAlmatroudi2018" />

====Other actions====

Tianeptine modestly enhances the [[mesolimbic]] release of [[dopamine]]<ref>{{cite journal | vauthors = Invernizzi R, Pozzi L, Garattini S, Samanin R | title = Tianeptine increases the extracellular concentrations of dopamine in the nucleus accumbens by a serotonin-independent mechanism | journal = Neuropharmacology | volume = 31 | issue = 3 | pages = 221–7 | date = March 1992 | pmid = 1630590 | doi = 10.1016/0028-3908(92)90171-K | s2cid = 21610131 }}</ref> and potentiates [[Central nervous system|CNS]] [[Dopamine D2 receptor|D₂]] and [[Dopamine D3 receptor|D₃ receptors]].<ref name="pmid11981225">{{cite journal | vauthors = Dziedzicka-Wasylewska M, Rogoz Z, Skuza G, Dlaboga D, Maj J | title = Effect of repeated treatment with tianeptine and fluoxetine on central dopamine D(2) /D(3) receptors | journal = Behavioural Pharmacology | volume = 13 | issue = 2 | pages = 127–38 | date = March 2002 | pmid = 11981225 | doi = 10.1097/00008877-200203000-00004 | s2cid = 2126834 }}</ref> Tianeptine has no affinity for the [[dopamine transporter]] or the [[dopamine receptor]]s.<ref name=mp09 /> [[CREB]]-TF (CREB, cAMP response element-binding protein)<ref name="ReferenceA">{{cite journal | vauthors = Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ | title = Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein | journal = Cell | volume = 79 | issue = 1 | pages = 59–68 | date = October 1994 | pmid = 7923378 | doi = 10.1016/0092-8674(94)90400-6 | s2cid = 17250247 }}</ref> is a cellular [[transcription factor]]. It binds to certain [[DNA]] sequences called cAMP response elements (CRE), thereby increasing or decreasing the [[Transcription (genetics)|transcription]] of the [[gene]]s.<ref name="Purves">{{cite book|title=Neuroscience|url=https://archive.org/details/neuroscienceissu00purv|url-access=limited| vauthors = Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia AS, McNamara JO, White LE |publisher=Sinauer Associates| year= 2008|isbn=978-0-87893-697-7| edition= 4th| pages=[https://archive.org/details/neuroscienceissu00purv/page/n195 170]–6 }}</ref> CREB has a well-documented role in [[Neuroplasticity|neuronal plasticity]] and [[long-term memory]] formation in the brain. Cocaine- and amphetamine-regulated transcript, also known as [[Cocaine and amphetamine regulated transcript|CART]], is a [[neuropeptide]] [[protein]] that in humans is encoded by the ''CARTPT'' [[gene]].<ref name="pmid8647455">{{cite journal | vauthors = Douglass J, Daoud S | title = Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and amphetamine-regulated transcript | journal = Gene | volume = 169 | issue = 2 | pages = 241–5 | date = March 1996 | pmid = 8647455 | doi = 10.1016/0378-1119(96)88651-3 }}</ref><ref name="pmid9590691">{{cite journal | vauthors = Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S | title = Hypothalamic CART is a new anorectic peptide regulated by leptin | journal = Nature | volume = 393 | issue = 6680 | pages = 72–6 | date = May 1998 | pmid = 9590691 | doi = 10.1038/29993 | bibcode = 1998Natur.393...72K | s2cid = 4427258 }}</ref> CART appears to have roles in reward, feeding, stress,<ref>{{cite journal | vauthors = Zhang M, Han L, Xu Y | title = Roles of cocaine- and amphetamine-regulated transcript in the central nervous system | journal = Clinical and Experimental Pharmacology & Physiology | volume = 39 | issue = 6 | pages = 586–92 | date = June 2012 | pmid = 22077697 | doi = 10.1111/j.1440-1681.2011.05642.x | s2cid = 25134612 }}</ref> and it has the functional properties of an endogenous [[psychostimulant]].<ref name="pmid12147208">{{cite journal | vauthors = Kuhar MJ, Adams S, Dominguez G, Jaworski J, Balkan B | title = CART peptides | journal = Neuropeptides | volume = 36 | issue = 1 | pages = 1–8 | date = February 2002 | pmid = 12147208 | doi = 10.1054/npep.2002.0887 | s2cid = 7079530 }}</ref> Taking into account that CART production is upregulated by CREB,<ref name="pmid19046951">{{cite journal | vauthors = Rogge GA, Jones DC, Green T, Nestler E, Kuhar MJ | title = Regulation of CART peptide expression by CREB in the rat nucleus accumbens in vivo | journal = Brain Research | volume = 1251 | pages = 42–52 | date = January 2009 | pmid = 19046951 | pmc = 2734444 | doi = 10.1016/j.brainres.2008.11.011 }}</ref> it could be hypothesized that due to tianeptine's central role in BDNF and neuronal plasticity, this CREB may be the transcription cascade through which this drug enhances mesolimbic release of dopamine.

Research indicates possible [[anticonvulsant]] (anti-seizure) and [[analgesic]] (painkilling) activity of tianeptine via downstream modulation of [[adenosine]] [[adenosine A1 receptor|A₁ receptors]] (as the effects could be experimentally blocked by [[receptor antagonist|antagonists]] of this receptor).<ref name="pmid17826881"/> Tianpetine is also weak [[histone deacetylase]] inhibitor and analogs with increased potency and selectivity are developed.<ref name="Zhao_2018">{{cite journal | vauthors = Zhao WN, Ghosh B, Tyler M, Lalonde J, Joseph NF, Kosaric N, Fass DM, Tsai LH, Mazitschek R, Haggarty SJ | title = Class I Histone Deacetylase Inhibition by Tianeptinaline Modulates Neuroplasticity and Enhances Memory | journal = ACS Chemical Neuroscience | volume = 9 | issue = 9 | pages = 2262–2273 | date = September 2018 | pmid = 29932631 | doi = 10.1021/acschemneuro.8b00116 | hdl = 1721.1/126372 | s2cid = 49389560 | hdl-access = free }}</ref>

Tianeptine has been shown to be a high-efficacy agonist of [[Peroxisome proliferator-activated receptor delta|PPAR-delta]], a nuclear receptor. <ref>{{cite journal | vauthors = Helmstädter M, Schierle S, Isigkeit L, Proschak E, Marschner JA, Merk D | title = Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists | journal = International Journal of Molecular Sciences | volume = 23 | issue = 17 | pages = 10070 | date = September 2022 | pmid = 36077469 | doi = 10.3390/ijms231710070 | doi-access = free | pmc = 9456086 }}</ref>

===Pharmacokinetics===

The [[bioavailability]] of tianeptine is approximately 99%.<ref name="pmid3180120" /><ref name="Tian2001" /> Its [[plasma protein binding]] is about 95%.<ref name="Tian2001" /> The [[metabolism]] of tianeptine is [[liver|hepatic]], via [[β-oxidation]].<ref name="Tian2001" /> CYP enzymes are not involved, which limits the potential for drug-drug interactions.<ref name = Tian2001/> Maximal concentration is reached in about an hour and the [[elimination half-life]] is 2.5 to 3&nbsp;hours.<ref name="pmid3180120" /><ref name="Tian2001" /> The elimination half-life has been found to be increased to 4 to 9&nbsp;hours in the [[elderly]].<ref name="CarlhantLeGarrec1990" /> Tianeptine is usually packaged as a sodium salt but can also be found as tianeptine sulfate, a slower-releasing formulation patented by [[Janssen Pharmaceuticals|Janssen]] in 2012.<ref>{{Cite web|url=https://patents.google.com/patent/US8198268B2/en|title=Tianeptine sulfate salt forms and methods of making and using the same}}</ref> In 2022 Tonix Pharmaceuticals received permission from the US FDA to conduct phase II clinical trials on tianeptine hemioxalate extended-release tablets designed for once-daily use.<ref>{{cite news | work =Tonix Pharmaceuticals Holding Corp|title=Tonix Pharmaceuticals Announces IND Clearance for TNX-601 ER as a Potential Treatment for Major Depressive Disorder |url=https://www.globenewswire.com/en/news-release/2022/10/03/2526647/28908/en/Tonix-Pharmaceuticals-Announces-IND-Clearance-for-TNX-601-ER-as-a-Potential-Treatment-for-Major-Depressive-Disorder.html |access-date=5 November 2022 | publisher = GlobeNewswire News Room |date=3 October 2022 |language=en}}</ref> The project was discontinued in late 2023 because of disappointing results in [[clinical trial]]s.

Tianeptine has two [[active metabolite]]s, MC5 (a [[pentanoic acid]] derivative of the parent compound) and MC3 (a [[propionic acid]] derivative).<ref>{{cite journal | vauthors = Szafarz M, Wencel A, Pociecha K, Fedak FA, Wlaź P, Wyska E | title = Pharmacokinetic study of tianeptine and its active metabolite MC5 in rats following different routes of administration using a novel liquid chromatography tandem mass spectrometry analytical method | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 391 | issue = 2 | pages = 185–196 | date = February 2018 | pmid = 29230490 | doi = 10.1007/s00210-017-1448-2 | pmc = 5778159 | s2cid = 253742631 }}</ref><ref name = Tian2001/> MC5 has a longer elimination half-life<ref name="pmid28303899" /> of approximately 7.6 hours, and takes about a week to reach steady-state concentration under daily-dosing. MC5 is a mu-opioid agonist but not delta-opioid agonist, with [[EC50]] at the mu-opioid receptor of 0.545 μM (vs 0.194 μM for tianeptine).<ref name="pmid28303899" /> MC3 is a very weak mu-opioid agonist, with an EC50 of 16 μM.<ref name="pmid28303899" /> Tianeptine is [[excretion|excreted]] 65% in the [[urine]] and 15% in [[feces]].<ref name="pmid3180120" /><ref name="Tian2001" />

==Chemistry==

In terms of [[chemical structure]], it is similar to [[tricyclic antidepressants]] (TCAs), but it has significantly different pharmacology and important structural differences, so it is not usually grouped with them.

===Analogues===

Although several related compounds are disclosed in the original patent,<ref>{{cite patent |country=FR |number=2104728 |pubdate=1972-04-21 |title=Nouveaux dérivés tricycliques et leur procédé de préparation [Novel tricyclic derivatives and process for preparing the same] |assign1= Science Union et CIE Societe Francaise de Recherche Medicale |inventor = Malen C, Danrée B, Poignant JC }}

</ref> no activity data are provided and it was unclear whether these share tianeptine's unique pharmacological effects. More recent [[structure-activity relationship]] studies have since been conducted, providing some further insight on μ-opioid, δ-opioid, and [[Pharmacokinetics|pharmacokinetic]] activity.<ref>{{Cite thesis|title=Chemical and Biological Explorations of Novel Opioid Receptor Modulators |publisher=Columbia University|date=2015|doi=10.7916/d8v1242f|language=en| vauthors = Kruegel AC |page=338-358}}</ref><ref>{{cite journal | vauthors = Labrid C, Moleyre J, Poignant JC, Malen C, Mocaër E, Kamoun A | title = Structure-activity relationships of tricyclic antidepressants, with special reference to tianeptine | journal = Clinical Neuropharmacology | volume = 11 | issue = Suppl 2 | pages = S21–S31 | date = 1988 | pmid = 3180115 }}</ref><ref name="pmid12595031">{{cite journal | vauthors = Sánchez-Mateo CC, Darias V, Expósito-Orta MA, Albertos LM | title = Neuropharmacological study of hetero[2,1]benzothiazepine derivatives analogues of tianeptine | journal = Farmaco | publisher = Societa Chimica Italiana | volume = 58 | issue = 1 | pages = 1–10 | date = January 2003 | pmid = 12595031 | doi = 10.1016/S0014-827X(02)00021-6 }}</ref><ref name="pmid12608009">{{cite journal | vauthors = Sánchez-Mateo CC, Darias V, Albertos LM, Expósito-Orta MA | title = Psychopharmacological effects of tianeptine analogous hetero[2,1] benzothiazepine derivatives | journal = Arzneimittel-Forschung | volume = 53 | issue = 1 | pages = 12–20 | date = 2003 | pmid = 12608009 | doi = 10.1055/s-0031-1297064 | s2cid = 23593291 }}</ref><ref name="pmid15344839">{{cite journal | vauthors = Expósito-Orta MA, Albertos LM, Darias V, Sánchez-Mateo CC | title = Behavioural effects of thieno and pyrazolo [2,1] benzothiazepine derivatives in mice | journal = Arzneimittel-Forschung | volume = 54 | issue = 7 | pages = 365–70 | date = 2004 | pmid = 15344839 | doi = 10.1055/s-0031-1296985 | s2cid = 24437547 }}</ref> Derivatives where the aromatic chlorine substituent is replaced by bromine, iodine or methylthio, and/or the heptanoic acid tail is varied in length or replaced with other groups such as 3-methoxypropyl, show similar or increased opioid receptor activity relative to tianeptine itself.<ref>{{cite thesis | url = https://academiccommons.columbia.edu/doi/10.7916/D8V1242F | vauthors = Kruegel AC | title = Chemical and Biological Explorations of Novel Opioid Receptor Modulators | degree = PhD | publisher = Columbia University | date = 2015 | doi = 10.7916/D8V1242F }}</ref><ref>{{cite patent|title=Class of mu-opioid receptor agonists|country=US|number=10183919|pubdate=2019-01-22|assign1=[[Trustees of Columbia University in the City of New York|The Trustees of Columbia University in the City of New York]] | inventor = Kruegel AC, Henke A, Gassaway MM, Rives MM, Javitch JA, Sames D }}</ref><ref>{{cite patent|title=Carboxylic diarylthiazepineamines as mu-opioid receptor agonists |country=WO |number=2017049158 |pubdate=2017-03-23 |assign1=[[Trustees of Columbia University in the City of New York|The Trustees of Columbia University in the City of New York]]| inventor = Kruegel A, Sames D, Gassaway M, Javitch JA }}</ref> [[Amineptine]], the most closely related drug to have been widely studied, is a [[dopamine reuptake inhibitor]] with no significant effect on serotonin levels, nor opioid agonist activity. [[Tianeptinaline]], analog of tianeptine, is a notable class I HDAC inhbitor.<ref name="Zhao_2018" />

==History==

Tianeptine was introduced for medical use in [[France]] under the brand name Stablon in 1983.<ref name="PharmManuEnc2013" />

==Society and culture==

[[Image:StablonBox.jpg|thumb|right|Stablon box and blister pack.]]

===Approval and brand names===

Brand names include:

* Coaxil <small>([[Bulgaria|BG]], [[Croatia|CR]], [[Czech Republic|CZ]], [[Estonia|EE]], [[Hungary|HU]], [[Lithuania|LT]], [[Latvia|LV]], [[Poland|PL]], [[Romania|RO]], [[Russian Federation|RU]], [[Slovakia|SK]] [[Ukraine|UA]])</small>

* Salymbra <small>([[Estonia|EE]])</small>

* Stablon <small>([[Argentina|AR]], [[Austria|AT]], [[Brazil|BR]], [[France|FR]], [[Hong Kong|HK]], [[India|IN]], [[Indonesia|ID]], [[Malaysia|MY]], [[Mexico|MX]], [[Pakistan|PK]], [[Portugal|PT]], [[Singapore|SG]], [[South Korea|SK]], [[Thailand|TH]], [[Trinidad and Tobago|TT]], [[Turkey|TR]], [[Venezuela|VE]])</small>

* Tatinol <small>([[China|CN]])</small>

* Tianeurax <small>([[Germany|DE]])</small>

* Tynept <small>([[India|IN]])</small>

* Zinosal <small>([[Spain|ES]])</small>

* Tianesal <small>([[Poland|PL]])</small>

===Development===

Under the code names JNJ-39823277 and TPI-1062, tianeptine was previously under development for the treatment of major depressive disorder in the [[United States]] and [[Belgium]].<ref name="AdisInsight">{{cite web | title = Tianeptine – AdisInsight | work = AdisInsight | publisher = Springer | url = http://adisinsight.springer.com/drugs/800039841 | access-date = 31 January 2016}}</ref> [[Phases of clinical research#Phase I|Phase I]] [[clinical trial]]s were completed in Belgium and the United States in May and June 2009, respectively.<ref name="AdisInsight" /> For unclear reasons development of tianeptine was discontinued in both countries in January 2012.<ref name="AdisInsight" /> In October 2023, Tonix Pharmaceuticals announced that it had discontinued its development of tianeptine as a monotherapy for [[major depressive disorder]] after disappointing phase-2 clinical trial results.<ref>{{Cite web |date=2023-10-31 |title=Tonix Pharmaceuticals Announces Topline Results from Phase 2 Proof-of-Concept Study of TNX-601 ER for the Treatment of Major Depressive Disorder |url=https://ir.tonixpharma.com/news-events/press-releases/detail/1435/tonix-pharmaceuticals-announces-topline-results-from-phase |access-date=2023-11-02 |website=Tonix Pharmaceuticals Holding Corp. |language=en}}</ref> An ongoing clinical trial, sponsored by the [[New York Psychiatric Institute]], is examining tianeptine's use in [[treatment-resistant depression]].<ref>{{Cite journal |title=Tianeptine for Treatment Resistant Depression |url=https://clinicaltrials.gov/study/NCT04249596 |access-date=2023-11-02 |website=Clinicaltrials.gov|date=15 June 2023 | vauthors = Javitch JA }}</ref>

U.S. [[National Poison Data System]] data on tianeptine showed a nationwide increase in tianeptine exposure calls and calls related to abuse and misuse during 2014–2017.<ref name="pmid30070980" />

===Recreational use===

As a [[μ-opioid]] agonist, tianeptine in large doses has high abuse potential. In 2001, [[Singapore]]'s Ministry of Health restricted tianeptine prescribing to psychiatrists due to its recreational potential.<ref>{{cite web|author=World Health Organization| year=2001 | title=Pharmaceuticals: Restrictions in use and availability, March 2001|url=https://www.who.int/medicinedocs/pdf/s2203e/s2203e.pdf |archive-url=https://web.archive.org/web/20081117023012/http://www.who.int/medicinedocs/pdf/s2203e/s2203e.pdf |url-status=dead |archive-date=17 November 2008 | access-date=24 July 2008 }}</ref>

Between 1989 and 2004, in France 141 cases of recreational use were identified, correlating to an incidence of 1 to 3 cases per 1000 persons treated with tianeptine and 45 between 2006 and 2011. According to Servier, stopping of treatment with tianeptine is difficult, due to the possibility of [[drug withdrawal|withdrawal]] symptoms in a person. The severity of the withdrawal is dependent on the daily dose, with high doses being extremely difficult to quit.<ref>{{cite web | author=APM Health Europe | year=2007 | title=Addiction leads to warning on Servier's antidepressant Stablon | url=http://health.apmnews.com/depechesPublieesDepeches.php?annee=2007&mois=5&jour=21 | access-date=24 July 2008 | url-status=dead | archive-url=https://web.archive.org/web/20110707152046/http://health.apmnews.com/depechesPublieesDepeches.php?annee=2007&mois=5&jour=21 | archive-date=7 July 2011 | df=dmy-all }}</ref>{{better source needed|date=August 2018}}<ref>{{cite web| vauthors = Gibaja V | year= 2006| title= Use, Drug Abuse and Tianeptine (in French)| url= http://www.chu-toulouse.fr/IMG/pdf/Actes_des_Xemes_rencontres_version_finale.pdf| access-date= 24 July 2008| url-status= dead| archive-url= https://web.archive.org/web/20110720211449/http://www.chu-toulouse.fr/IMG/pdf/Actes_des_Xemes_rencontres_version_finale.pdf| archive-date= 20 July 2011| df= dmy-all}}</ref><ref>{{Cite web|url=https://www.prescrire.org/fr/3/31/47483/0/NewsDetails.aspx|title=Tianeptine (Stablon°) dans la dépression : risque trop important de dépendance|website=www.prescrire.org}}</ref> An official [[Drug Enforcement Administration|DEA]] statement<ref>{{Cite web|url=https://www.deadiversion.usdoj.gov/drug_chem_info/tianeptine.pdf|title=Drug Enforcement AdministrationDiversion Control DivisionDrug & Chemical Evaluation Section - Tianeptine}}</ref> states that the withdrawal symptoms in humans typically result in: agitation, nausea, vomiting, tachycardia, hypertension, diarrhea, tremor, and diaphoresis, similar to other opioid drugs.

In 2007, according to [[French Health Products Safety Agency]], tianeptine's manufacturer Servier agreed to modify the drug's label, following problems with dependency.<ref>{{cite web| author=French Health Products Safety Agency (Afssaps)| year=2007| title=Important Information on Drug: Update of the Summary of Product Characteristics Stablon, 16 May 2007 (French)| url=http://agmed.sante.gouv.fr/htm/10/filltrpsc/lp070502.htm| access-date=24 July 2008| url-status=dead| archive-url=https://web.archive.org/web/20080401234439/http://agmed.sante.gouv.fr/htm/10/filltrpsc/lp070502.htm| archive-date=1 April 2008| df=dmy-all}}</ref>

Tianeptine has been intravenously injected by drug users in [[Russia]].<ref name=mrp>{{cite web | vauthors = Ives R |year=2008 |title=Assessment Mission Report for the SCAD V Programme, Component on Prevention and on Media Work |url= http://scadarmenia.org/docs/eng/mission_report_prevention.pdf |access-date=4 November 2008 |url-status=dead |archive-url=https://web.archive.org/web/20101201005404/http://scadarmenia.org/docs/eng/mission_report_prevention.pdf |archive-date=1 December 2010}}</ref><ref name=dt>{{cite web| work=United Nations Office on Drugs and Crime | date=April 2008|title=Illicit Drug Trades in the Russian Federation|url=http://www.unodc.org/documents/regional/central-asia/Illicit%20Drug%20Trends%20Report_Russia.pdf | access-date=16 July 2014}}</ref> This method of administration reportedly causes an [[opioid]]-like effect and is sometimes used in an attempt to lessen [[opioid#Dependence|opioid withdrawal symptoms]].<ref name=mrp /> Tianeptine tablets contain [[Silicon dioxide|silica]] and do not dissolve completely. Often the solution is not filtered well thus particles in the injected fluid block [[Capillary|capillaries]], leading to [[thrombosis]] and then severe [[necrosis]]. Thus, in Russia tianeptine (sold under the brand name "Coaxil") is a schedule III controlled substance in the same list as the majority of [[benzodiazepines]] and [[barbiturates]].<ref name="auto">{{cite web|url = http://base.garant.ru/12112176| title = Decision of the Government of the Russian Federation No. 681 of June 30, 1998 on the Approval of the List of Narcotic Drugs, Psychotropic Substances and Their Precursors That Shall Be Subject to Control in the Russian Federation (with Amendments and Additions) | language = Russian }}</ref>

The [[Centers for Disease Control and Prevention]] (CDC) has expressed concern that tianeptine may be an "emerging public health risk", citing an increase in exposure-related calls to poison control centers in the United States.<ref name="pmid30070980"/> Sold retail as a [[dietary supplement]] and touted as a mood-booster and an aid for concentration, it is colloquially known as "gas-station heroin".<ref>{{Cite news|url=https://www.nytimes.com/2024/01/10/health/gas-station-heroin-tianeptine-addiction.html|title='Gas-Station Heroin' Sold as Dietary Supplement Alarms Health Officials| vauthors = Hoffman J |work=The New York Times |date=10 January 2024|via=NYTimes.com}}</ref> In the US, it is an unregulated drug sold under several product names and has been found to be adulterated with synthetic cannabinoid receptor agonists (SCRAs) or other drugs.<ref name="mmwr"/>

A literature review conducted in 2018 found 25 articles involving 65 patients with tianeptine abuse or dependence.<ref name="auto1"/> Limited data showed that a majority of patients were male and that age ranged from 19 to 67. Routes of intake included oral, intravenous, and insufflation entry. In the 15 cases of overdose, 8 combined ingestion with at least one other substance, of which 3 resulted in death. Six additional deaths are reported involving tianeptine (making it 9 in total). In this report, the amount of tianeptine used ranged from 50&nbsp;mg/day to 10&nbsp;g/day orally.

== Legality ==

In 2003, [[Bahrain]] classified tianeptine a controlled substance due to increasing reports of misuse and recreational use.<ref>{{cite web| author=World Health Organization| year=2003| title=Pharmaceuticals: Restrictions in use and availability, April 2003| url=http://whqlibdoc.who.int/hq/2003/EDM_QSM_2003.5.pdf| access-date=24 July 2008| archive-url=https://web.archive.org/web/20110629182215/http://whqlibdoc.who.int/hq/2003/EDM_QSM_2003.5.pdf| archive-date=29 June 2011| url-status=dead| df=dmy-all}}</ref>

In Russia, tianeptine (sold under the brand name "Coaxil") is a schedule III controlled substance in the same list as the majority of [[benzodiazepines]] and [[barbiturates]].<ref name="auto"/>

On March 13, 2020, with a decree approved by the Minister of Health, [[Italy]] became the first European country to outlaw tianeptine considering it a Class I controlled substance.<ref>{{Cite web|url=https://www.gazzettaufficiale.it/eli/id/2020/03/30/20A01820/sg|title = Gazzetta Ufficiale}}</ref>

===United States===

In the US, tianeptine is not considered by the [[Drug Enforcement Administration]] as a controlled substance or analogue thereof.<ref>{{Cite web |title=Tianeptine |url=https://www.deadiversion.usdoj.gov/drug_chem_info/tianeptine.pdf |access-date=May 25, 2023 |website= deadiversion.usdoj.gov| publisher= [[Drug Enforcement Administration]], US Dept. of Justice }}</ref> However, its use in dietary supplements and food is unlawful.<ref>{{Cite web |date=February 22, 2023 |title=Tianeptine in Dietary Supplements |url=https://www.fda.gov/food/dietary-supplement-ingredient-directory/tianeptine-dietary-supplements |access-date=May 25, 2023 |website= FDA.gov| publisher=Food and Drug Administration }}</ref> The [[Food and Drug Administration]] (FDA) has issued warnings, as recently as January 2024, about the dangers of recreational tianeptine use and the risks posed by adulterated dietary supplements containing undeclared tianeptine.<ref>{{Cite web | vauthors = Musa A |date=2024-01-24 |title=FDA urges consumers not to buy tianeptine products due to serious risks as lawmakers call for "immediate action" |url=https://www.cnn.com/2024/01/24/health/tianeptine-fda-warning/index.html |access-date=2024-01-30 |website=CNN.com |language=en}}</ref>

On 6 April 2018 Michigan became the first US state to outlaw tianeptine sodium, classifying it as a [[Controlled Substances Act#Schedule II controlled substances|schedule II]] [[controlled substance]].<ref>{{cite web | url = https://www.freep.com/story/news/politics/2018/04/06/michigan-ban-antidepressant-tianeptine-sodium/494469002/ | title = Michigan approves ban on antidepressant tianeptine sodium | agency = Associated Press | work = Detroit Free Press }}</ref> The scheduling of tianeptine sodium is effective 4 July 2018.<ref>{{cite web|title= Public Health Code Section 333.7214.amended| url=http://www.legislature.mi.gov/(S(jafo2ceevu4is3cp0fwnb4nb))/mileg.aspx?page=getobject&objectname=mcl-333-7214-amended&query=on&highlight=controlled|website= legislature.mi.gov|publisher= Legislative Council, State of Michigan|access-date=18 May 2018}}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

On March 15, 2021, Alabama outlawed tianeptine, classifying it as a [[Controlled Substances Act#Schedule II controlled substances|schedule II]] [[controlled substance]].

On November 14th, 2021, Alabama outlawed tianepine, classifying it as a [[Controlled Substances Act#Schedule I controlled substances|schedule I]] [[controlled substance]].<ref>{{Cite web | url=https://www.alabamapublichealth.gov/blog/assets/controlledsubstanceslist.pdf | title=Controlled Substances List | website=ww.alabamapublichealth.gov | date=2024-02-22}}</ref> It was previously a [[Controlled Substances Act#Schedule II controlled substances|schedule II]] in Alabama from March 15th, 2021 until November 14th, 2021 when it was moved into schedule I.<ref>{{Cite web |date= 2021-05-25 |title=New crime trend in Giles Co. after Alabama stops selling ZaZa Red, controversial stimulant |url=https://www.wkrn.com/news/crime-tracker/new-crime-trend-in-giles-co-after-alabama-stops-selling-zaza-red-controversial-stimulant/ |access-date=2022-12-14 |website=WKRN.com |language=en-US}}</ref>

On July 1, 2022, Tennessee outlawed tianeptine and adds "any salt, sulfate, free acid, or other preparation of tianeptine, and any salt, sulfate, free acid, compound, derivative, precursor, or preparation thereof that is substantially chemically equivalent or identical with tianeptine", classifying it as a [[Controlled Substances Act#Schedule II controlled substances|schedule II]] [[controlled substance]].<ref>{{cite web | title = HB 2043 by Cochran: Controlled Substances | date = 30 March 2022 | work = Tennessee General Assembly | url = https://wapp.capitol.tn.gov/apps/Billinfo/default.aspx?BillNumber=HB2043&ga=112 | archive-url = https://web.archive.org/web/20220408003936/https://wapp.capitol.tn.gov/apps/Billinfo/default.aspx?BillNumber=HB2043&ga=112 | archive-date = 8 April 2022 }}</ref>

On December 22, 2022, Ohio outlawed tianeptine, classifying it as a [[Controlled Substances Act#Schedule I controlled substances|schedule I]] [[controlled substance]] with Ohio Governor Mike DeWine referencing the widespread availability of the chemical there as "gas-station heroin".<ref>{{Cite web |date=2022-12-23 |title=Governor DeWine Authorizes the State of Ohio Board of Pharmacy to Adopt Emergency Rule to Ban the Sale and Use of Tianeptine|url=https://www.pharmacy.ohio.gov/documents/pubs/newsreleases/2022/governor%20dewine%20authorizes%20the%20state%20of%20ohio%20board%20of%20pharmacy%20to%20adopt%20emergency%20rule%20to%20ban%20the%20sale%20and%20use%20of%20tianeptine.pdf |access-date=2023-01-05 |website=State of Ohio Board of Pharmacy |language=en-US}}</ref>

On March 23, 2023, Kentucky outlawed tianeptine, classifying it as a [[Controlled Substances Act#Schedule I controlled substances|schedule I]] substance by an order of the [[Governor of Kentucky]].<ref>{{cite web | vauthors = Besher A, Friedlander EC | title = Statement of Emergency | work = Government of the State of Kentucky | url = https://governor.ky.gov/attachments/20230323_902-KAR-55-015E.pdf | archive-url = https://web.archive.org/web/20230401115446/https://governor.ky.gov/attachments/20230323_902-KAR-55-015E.pdf | archive-date = 1 April 2023 }}</ref><ref>{{Cite web |title=Growing Danger Of 'Gas Station Heroin': Kentucky Latest State To Ban Tianeptine—Opioid-Like Drug Sold In Groceries |url=https://www.forbes.com/sites/tylerroush/2023/03/24/growing-danger-of-gas-station-heroin-kentucky-latest-state-to-ban-tianeptine-opioid-like-drug-sold-in-groceries/ |access-date=2023-10-26 |website=Forbes |language=en}}</ref>

On September 20, 2023, Florida outlawed tianeptine, classifying it as a [[Controlled Substances Act#Schedule I controlled substances|schedule I]] substance by an administrative edict issued by the [[Florida Attorney General]].<ref>{{cite web | title = Adoption package for Emergency Rule 2ER23-1 | work = Florida Department of State | url = https://www.myfloridalegal.com/sites/default/files/2023-09/2er23-1.pdf}}</ref><ref>{{cite web | url=https://www.myfloridalegal.com/newsrelease/video-attorney-general-moody-outlaws-gas-station-heroin-florida | title=VIDEO: Attorney General Moody Outlaws Gas Station Heroin in Florida &#124; My Florida Legal }}</ref><ref name=":0">{{cite web | url=https://www.vice.com/en/article/m7bpm4/florida-tianeptine-zaza-ban | title=Florida Just Banned 'Gas Station Heroin' | date=25 September 2023 }}</ref>{{Better source needed|date=December 2023}}

* [[Amineptine]]

* [[List of antidepressants]]

* [[List of investigational anxiolytics]]

* [[Tianeptine/naloxone]]

{{Reflist|2}}

* [http://www.tianeptine.com/ Tianeptine – David Pearce – The Good Drug Guide]

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{{Opioid receptor modulators}}

{{Xenobiotic-sensing receptor modulators}}

[[Category:Amines]]

[[Category:Anxiolytics]]

[[Category:Chloroarenes]]

[[Category:Euphoriants]]

[[Category:Laboratoires Servier]]

[[Category:Mu-opioid receptor agonists]]

[[Category:Synthetic opioids]]

[[Category:Tricyclic antidepressants]]

[[Category:Sultams]]

[[Category:Sulfur heterocycles]]

[[Category:Nitrogen heterocycles]]

[[Category:Drugs with unknown mechanisms of action]]