Tianeptine

The pivotal RCT confirmed no difference between tianeptine and placebo for heart rate or blood pressuresupported

No cardiovascular effects. 0924-9338(96)82332-7

Buprenorphine-naloxone is first-line treatment for tianeptine use disordersupported

Case report: buprenorphine/naloxone successfully used to treat tianeptine use disorder; tianeptine use disorder can follow clinical course consistent with OUD. adm.0000000000000490

Claim in safety — inconclusiveinconclusiveworking →

Naloxone partially or fully reverses these effects.supported

Naloxone partially effective. 15563650.2018.1476694

Death was attributed to combined tianeptine–alcohol intoxicationsupported

Death ruled as intoxication from suicidal tianeptine + alcohol ingestion. pmid:17630235

A 2025 systematic review notes increasing fatal toxicities associated with tianeptine misuse.supported

Systematic review of tianeptine misuse patterns, overdose risk factors with co-administration, and treatment efficacy including naloxone; MOR activity drives opioid crisis contribution. s12889-025-24666-0

A double-blind, placebo-controlled study in 21 healthy volunteers demonstrated no ECG changes and no orthostatic hypotensionsupported

Double-blind, placebo-controlled, crossover study in 21 healthy volunteers; no orthostatic hypotension, no ECG changes, no change in cardiac output or conduction time. pmid:2306747

In clinical populations exceeding 3,300 patients, cardiovascular safety was maintained over up to 1 year of treatment, with fewer cases of orthostatic hypotension than comparator antidepressantssupported

>3,300 patients; no cardiovascular deaths from overdose; fewer cases of orthostatic hypotension vs other antidepressants. pmid:1836619

Claim in safety — inconclusiveinconclusiveworking →

A case of severe neonatal opioid withdrawal syndrome (NOWS) was documented following chronic prenatal maternal tianeptine supplement use; the infant required oral morphine after phenobarbital failuresupported

Case report: severe neonatal withdrawal after maternal tianeptine supplement use; refractory to phenobarbital, responded to oral morphine. peds.2023-062382

Tianeptine is not detected by standard opioid immunoassay urine drug screenssupported

Tianeptine not detected by routine urine screens. peds.2023-062382

Published case reports describe a clinical course consistent with opioid use disorder: compulsive use despite negative consequences, preoccupation with obtaining the substance, and continued use despite physical and psychological deteriorationsupported

Tianeptine use disorder can follow clinical course consistent with OUD. adm.0000000000000490

Claim in safety — not_supportednot supportedworking →

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Animal models demonstrate no analgesic tolerance or withdrawal at clinically relevant doses.supported

No analgesic tolerance or withdrawal at clinical doses. s41386-023-01645-w

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Withdrawal symptoms: Anxiety, agitation, nausea, vomiting, diarrhea, diaphoresis, myalgia, and cravings — identical in character to opioid withdrawalsupported

Withdrawal includes anxiety, agitation, GI distress. 2981699

Clinical course: Consistent with opioid use disordersupported

Tianeptine use disorder can follow clinical course consistent with OUD. adm.0000000000000490

Buprenorphine-naloxone is established as first-line treatment for tianeptine withdrawal and maintenance, with efficacy documented across multiple case reportssupported

Buprenorphine/naloxone successfully used to treat tianeptine use disorder. adm.0000000000000490

Claim in safety — inconclusiveinconclusiveworking →

Buprenorphine-naloxone is established as first-line treatment for tianeptine withdrawal and maintenance, with efficacy documented across multiple case reportssupported

Microdose buprenorphine induction in a tianeptine user; describes low-dose buprenorphine approach to manage tianeptine dependence. adm.0000000000001003

Microdose buprenorphine induction has been describedsupported

Microdose buprenorphine induction in a tianeptine user; describes low-dose buprenorphine approach to manage tianeptine dependence. adm.0000000000001003

Claim in safety — inconclusiveinconclusiveworking →

Methadone has been used in complex casessupported

Case report showing tianeptine used as OTC opiate replacement; buprenorphine-naloxone successfully used to manage tianeptine use disorder alongside methadone treatment. jom.0851

Alcohol reduces tianeptine absorption (~30% lower Cmax and AUC) but the combination is pharmacodynamically potentiating in overdosesupported

Alcohol co-admin decreases absorption ~30%. pmid:2341111

The only confirmed fatal case involved tianeptine plus alcohol (ethanol 0.53 g/L).supported

Fatal case in 26-year-old male; blood tianeptine 5.1 ug/mL with ethanol 0.53 g/L; death ruled as intoxication from suicidal tianeptine + alcohol ingestion. pmid:17630235

A complex case of concurrent methadone and tianeptine use has been documented.supported

Case report showing tianeptine used as OTC opiate replacement; buprenorphine-naloxone successfully used to manage tianeptine use disorder alongside methadone treatment. jom.0851

Concurrent etizolam and tianeptine withdrawal has been documented, highlighting polysubstance complexity.supported

Case of concurrent etizolam and tianeptine withdrawal; highlights polysubstance abuse risk with tianeptine. mhc.2022.12.356

Claim in safety — inconclusiveinconclusiveworking →

CYP450-metabolized drugs: Tianeptine's beta-oxidation metabolism confers lower drug interaction risk than most antidepressantssupported

Tianeptine not primarily CYP450 metabolized (beta-oxidation pathway). pmid:11463130

Tianeptine crosses the placenta and produces severe neonatal opioid withdrawal syndrome requiring opioid-based treatment.supported

Case report: severe neonatal withdrawal after maternal tianeptine supplement use; refractory to phenobarbital, responded to oral morphine. peds.2023-062382

While the pharmacokinetic interaction reduces tianeptine absorption, pharmacodynamic potentiation in overdose and the documented fatality elevate risk, particularly in patients with supratherapeutic use patterns.supported

Fatal case in 26-year-old male; blood tianeptine 5.1 ug/mL with ethanol 0.53 g/L; death ruled as intoxication from suicidal tianeptine + alcohol ingestion. pmid:17630235

Severe renal impairment requires dose reduction due to prolonged t₁/₂supported

Dose adjustment needed in elderly and renal failure. pmid:3180120

Gassaway et al. established this mechanism using radioligand binding assays and BRET-based G-protein activation assays, reporting Ki = 383 ± 183 nM and EC₅₀ = 194 ± 70 nM at human MORsupported

Identified tianeptine as MOR agonist (Ki 383+/-183 nM, EC50 194+/-70 nM). Landmark pharmacology paper. tp.2014.30

Tianeptine is approximately 200-fold less potent at the delta-opioid receptor (DOR; EC₅₀ = 37.4 ± 11.2 µM at human DOR) and is inactive at the kappa-opioid receptor.supported

DOR agonist (EC50 37.4 uM), inactive at KOR. tp.2014.30

Behavioral studies in MOR-knockout mice demonstrate complete loss of antidepressant-like activitysupported

Demonstrated tianeptine antidepressant effects require MOR. npp.2017.60

Cell-type-specific knockout studies localized this requirement to MOR expression on somatostatin-positive GABAergic interneurons in the ventral hippocampus; deletion of MOR from these neurons abolished both acute and chronic antidepressant responsessupported

MOR on somatostatin-positive hippocampal GABAergic neurons required for antidepressant effect; ventral hippocampus implicated. s41386-021-01192-2

Tianeptine does not promote hippocampal neurogenesis — unlike fluoxetine — indicating a mechanistically distinct antidepressant circuit.supported

Different mechanism from fluoxetine; no hippocampal neurogenesis requirement. s41386-021-01192-2

Claim in pharmacology — inconclusiveinconclusiveworking →

The potentiation operates through postsynaptic kinase signaling: activation of CaMKII and PKA via the p38, p42/44 MAPK, and JNK pathways leads to increased GluA1 phosphorylation at Ser831 (CaMKII site) and Ser845 (PKA site), enhancing AMPA receptor conductancesupported

Tianeptine increases AMPA receptor-mediated responses via CaMKII and PKA; increases GluA1 phosphorylation at Ser831 and Ser845; potentiates synaptic plasticity. Postsynaptic site of action. j.neuint.2011.10.008

Tianeptine enhances both AMPA and NMDA currents in hippocampal CA1 pyramidal neurons while paradoxically reducing NMDA currents in the lateral amygdalasupported

Tianeptine reduces NMDA-mediated currents in lateral amygdala but enhances both NMDA and AMPA currents in hippocampal CA1. npp.2012.135

Claim in pharmacology — inconclusiveinconclusiveworking →

Multiple animal studies operated within this frameworksupported

Tianeptine (10 mg/kg/day) prevented stress-induced atrophy of CA3 dendrites and spatial memory impairment; fluoxetine and desipramine failed. pmid:9405958

Multiple animal studies operated within this frameworksupported

Tianeptine (labeled as 5-HT reuptake enhancer) prevented CA3 dendritic atrophy; fluoxetine and fluvoxamine failed. pmid:10357248

Claim in pharmacology — inconclusiveinconclusiveworking →

Claim in pharmacology — inconclusiveinconclusiveworking →

Tianeptine displays near-complete oral bioavailability (~99%) with no significant first-pass hepatic metabolismsupported

Bioavailability ~99%, Tmax 0.94h. pmid:2341111

Tianeptine displays near-complete oral bioavailability (~99%) with no significant first-pass hepatic metabolismsupported

Oral absorption rapid and complete; bioavailability 99%. pmid:3180120

The primary metabolic pathway is mitochondrial beta-oxidation of the heptanoic acid side chain — analogous to fatty acid metabolism — rather than hepatic CYP450 oxidationsupported

Tianeptine not primarily CYP450 metabolized (beta-oxidation pathway). pmid:11463130

The principal active metabolite MC5 (a C5 beta-oxidation product) has a longer half-life of approximately 7.2 ± 5.7 hours and demonstrates behavioral effects in a MOR-dependent fashionsupported

Demonstrated tianeptine antidepressant effects require MOR; metabolite MC5 has longer half-life. npp.2017.60

Chronic restraint stress (21 days) produces measurable CA3 apical dendritic retraction in rodent models; tianeptine at 10 mg/kg/day prevents this atrophy when co-administered with the stressor and reverses already-established atrophy caused by chronic corticosterone treatmentpartially supported

Tianeptine (10 mg/kg/day) prevented stress-induced atrophy of CA3 dendrites and spatial memory impairment; fluoxetine and desipramine failed. pmid:9405958

Chronic restraint stress (21 days) produces measurable CA3 apical dendritic retraction in rodent models; tianeptine at 10 mg/kg/day prevents this atrophy when co-administered with the stressor and reverses already-established atrophy caused by chronic corticosterone treatmentsupported

Tianeptine (labeled as 5-HT reuptake enhancer) prevented CA3 dendritic atrophy; tianeptine reversed established corticosterone-induced atrophy. pmid:10357248

Paradoxically, tianeptine reduces morphine antinociceptive tolerance and physical dependence in animal models, suggesting it modulates opioid receptor signaling cascades in a manner distinct from simple additive agonism.supported

Tianeptine (1-5mg/kg) reduces morphine tolerance development and naloxone-precipitated withdrawal in mice; no antinociception alone. fbp.0b013e32833db7d4

MOR expression on somatostatin-positive GABAergic interneurons in the ventral hippocampus is both necessary and sufficient for antidepressant behavioral effects; cell-type-specific MOR knockout from these neurons abolishes acute and chronic antidepressant-like responses in micepartially supported

MOR on somatostatin-positive hippocampal GABAergic neurons required for antidepressant effect. s41386-021-01192-2

Claim in neuroscience — inconclusiveinconclusiveworking →

The neuroprotective mechanism involves glutamate transporter regulation — tianeptine prevents upregulation of GLT-1 mRNA and protein in hippocampal CA3 under chronic restraint stress, likely reducing excitotoxic glutamate exposurepartially supported

Tianeptine reverses stress-induced GLT-1 upregulation in hippocampus CA3. pmid:14766991

It inhibits TLR4 expression and ERK1/2 phosphorylation, reducing production of IL-1β, IL-18, IL-6, TNF-α, nitric oxide, and reactive oxygen species in LPS-stimulated microgliapartially supported

Suppresses IL-1beta, IL-18, IL-6, TNF-alpha, NO; inhibits TLR4 expression and ERK1/2 phosphorylation. jnc.13452

Tianeptine produces antinociception via increased spinal serotonin and norepinephrine releasesupported

Intrathecal tianeptine shows antiallodynic effect via increased 5-HT and NE in spinal dorsal horn. j.neulet.2014.09.022

The cell-type-specific MOR knockout data establish that MOR activation on somatostatin interneurons gates antidepressant-relevant hippocampal outputsupported

MOR on somatostatin-positive hippocampal GABAergic neurons required for antidepressant effect; ventral hippocampus implicated. s41386-021-01192-2

Tianeptine's prevention of stress-induced dendritic atrophy and promotion of synaptogenesis align with the broader neuroplasticity hypothesis of antidepressant actionsupported

Tianeptine (10 mg/kg/day) prevented stress-induced atrophy of CA3 dendrites and spatial memory impairment. pmid:9405958

Tianeptine's prevention of stress-induced dendritic atrophy and promotion of synaptogenesis align with the broader neuroplasticity hypothesis of antidepressant actionsupported

Tianeptine augments neurite growth and promotes synaptic contacts in cultured hippocampal neurons. pr900799b

The anti-inflammatory effects on microglial polarization position tianeptine within the neuroimmune hypothesis of depression, where chronic neuroinflammation contributes to depressive pathophysiologysupported

Attenuates M1 polarization; decreases CD40, MHC II; reduces IL-1beta, IL-18, IL-6, TNF-alpha, NO, ROS; inhibits NLRP3. ijms19071965

Enantiomeric pharmacology: Differential in vivo effects of R- and S-tianeptine remain uncharacterized beyond albumin binding. This is a significant gap given the potential for enantioselective MOR activity.supported

Chiral separation methods developed; absolute configurations determined by VCD spectroscopy; S-enantiomer has higher affinity for human serum albumin. j.talanta.2025.128197

In 2014, Gassaway, Javitch, and Sames identified it as a full MOR agonist, fundamentally revising the mechanistic understanding and prompting re-evaluation of its abuse liabilitysupported

Identified tianeptine as MOR agonist (Ki 383+/-183 nM, EC50 194+/-70 nM). Landmark pharmacology paper. tp.2014.30

Claim in summary — inconclusiveinconclusiveworking →

Tianeptine binds MOR with moderate affinity (Ki = 383 ± 183 nM; EC₅₀ = 194 ± 70 nM) and is inactive at the kappa-opioid receptorsupported

Identified tianeptine as MOR agonist (Ki 383+/-183 nM, EC50 194+/-70 nM), DOR agonist (EC50 37.4 uM), inactive at KOR. tp.2014.30

Antidepressant effects require MOR expression on somatostatin-positive GABAergic interneurons in the ventral hippocampussupported

MOR on somatostatin-positive hippocampal GABAergic neurons required for antidepressant effect; ventral hippocampus implicated. s41386-021-01192-2

AMPA receptor currents are potentiated indirectly through CaMKII and PKA kinase cascades.supported

Tianeptine increases AMPA receptor-mediated responses via CaMKII and PKA; potentiates synaptic plasticity. j.neuint.2011.10.008

Claim in summary — inconclusiveinconclusiveworking →

Cardiovascular safety at therapeutic doses is well-establishedsupported

No orthostatic hypotension, no ECG changes, no change in cardiac output or conduction time. pmid:2306747

The critical risk is dose-dependent: supratherapeutic use produces rapid opioid-type tolerance, severe physical dependence with withdrawal onset within hours, and respiratory depression reversible by naloxonepartially supported

Opioid withdrawal symptoms; naloxone partially effective; outcomes minor to major. 15563650.2018.1476694

One confirmed fatality involved tianeptine combined with alcoholsupported

Fatal case in 26-year-old male; blood tianeptine 5.1 ug/mL with ethanol 0.53 g/L; death ruled as intoxication from suicidal tianeptine + alcohol ingestion. pmid:17630235

Claim in summary — inconclusiveinconclusiveworking →

Emsley et al. evaluated tianeptine 25–50 mg/day in elderly patients with recurrent major depressive disorder, establishing efficacy and providing dose-finding data for this population.supported

8-week placebo- and escitalopram-controlled study in elderly MDD patients; tianeptine 25-50mg/d evaluated for efficacy and safety. jcp.17m11741

Tianeptine demonstrated antidepressant efficacy significantly superior to placebo, with a safety profile markedly better than imipramine — no difference between tianeptine and placebo was observed for heart rate or blood pressure.supported

Both active drugs superior to placebo on MADRS; tianeptine had significantly fewer anticholinergic side effects; no cardiovascular effects. 0924-9338(96)82332-7

Tianeptine efficacy in maintenance treatment was confirmed in a systematic review and network meta-analysis of antidepressants for MDD.supported

Tianeptine outperformed placebo on 6-month relapse rate in maintenance phase; network meta-analysis of 20 antidepressants. s41380-022-01824-z

Claim in clinical-evidence — inconclusiveinconclusiveworking →

Kauer-Sant'Anna et al. conducted a 24-week randomized, placebo-controlled maintenance trial of adjunctive tianeptine in bipolar disorder (NCT00879372), supporting efficacy as adjunctive treatment.supported

24-week RCT of adjunctive tianeptine for bipolar depression; efficacy and tolerability assessed. 0269881119826602

Onder et al. compared tianeptine, fluoxetine, and moclobemide for PTSD following an earthquake, providing comparative efficacy data across antidepressant classes.supported

Open-label study; fluoxetine, moclobemide, tianeptine compared for PTSD post-earthquake; CAPS and CGI-S outcomes measured. pmid:15964747

The colloquial designation "gas station heroin" emerged by the 2010s as poison control centers documented increasing reports of opioid-like intoxication and withdrawalsupported

9 cases reported to NY PCCs; 5 intentional abuse; abuse doses 5-10g daily; opioid withdrawal symptoms; naloxone partially effective. 15563650.2018.1476694

Claim in history — inconclusiveinconclusiveworking →

Bruce McEwen's group at Rockefeller University demonstrated that tianeptine prevents and reverses stress-induced dendritic atrophy in hippocampal CA3 neurons — effects that fluoxetine and desipramine failed to replicate in the same modelssupported

Tianeptine (10 mg/kg/day) prevented stress-induced atrophy of CA3 dendrites and spatial memory impairment; fluoxetine and desipramine failed. pmid:9405958

The Kasper and McEwen 2008 review synthesized a decade of neurobiological findings, positioning tianeptine as the exemplar compound for stress-related hippocampal plasticity and arguing that its mechanism transcended simple monoamine modulation.supported

Comprehensive review: tianeptine prevents/reverses stress-induced dendritic atrophy in hippocampus, improves neurogenesis, normalizes glutamatergic transmission; effective for mild-to-severe MDD and anxiety. pmid:18072812

In 2014, Gassaway, Javitch, and Sames at Columbia University published the landmark finding that tianeptine is a full agonist at the mu-opioid receptor, with Ki = 383 nM and EC₅₀ = 194 nM at human MORsupported

Identified tianeptine as MOR agonist (Ki 383+/-183 nM, EC50 194+/-70 nM). Landmark pharmacology paper. tp.2014.30

Subsequent cell-type-specific studies refined the circuit mechanism, demonstrating that MOR expression on somatostatin-positive GABAergic interneurons in the ventral hippocampus is required for the antidepressant effect.supported

MOR on somatostatin-positive hippocampal GABAergic neurons required for antidepressant effect; ventral hippocampus implicated. s41386-021-01192-2

Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

Paradoxically, tianeptine reduces morphine antinociceptive tolerance and physical dependence in animal models, suggesting a complex interaction at the MOR signaling level rather than simple additive agonism.supported

Tianeptine (1-5mg/kg) reduces morphine tolerance development and naloxone-precipitated withdrawal in mice; no antinociception alone; comedication may benefit long-term opioid users. fbp.0b013e32833db7d4

Fluoxetine and desipramine failed to prevent CA3 dendritic remodeling in chronic restraint stress models where tianeptine was effective.supported

Tianeptine (10 mg/kg/day) prevented stress-induced atrophy of CA3 dendrites; fluoxetine and desipramine failed. pmid:9405958

Antidepressant efficacy is broadly comparable between tianeptine and SSRIs in clinical trialssupported

Equivalent efficacy to SSRIs and TCAs. pmid:11463130

Tianeptine demonstrated superior neurocognitive outcomes versus escitalopram in the CAMPION trialsupported

Tianeptine 37.5mg/d vs escitalopram 10mg/d for 12 weeks (n=164); tianeptine superior for commission errors and verbal immediate memory. jcp.0000000000000072

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

This pharmacokinetic interaction is paradoxically relevant in overdose contexts, where the tianeptine–alcohol combination appears pharmacodynamically potentiating despite reduced tianeptine absorption — the only confirmed fatal case involved concurrent alcohol (ethanol 0.53 g/L).supported

Fatal case in 26-year-old male; blood tianeptine 5.1 ug/mL with ethanol 0.53 g/L; death ruled as intoxication from suicidal tianeptine + alcohol ingestion. pmid:17630235

Tianeptine is metabolized primarily via mitochondrial beta-oxidation of the heptanoic acid side chain, producing sequential two-carbon truncations analogous to fatty acid catabolismsupported

Tianeptine not primarily CYP450 metabolized (beta-oxidation pathway). pmid:11463130

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

Claim in chemistry — inconclusiveinconclusiveworking →

Enantiomeric separation has been achieved using WhelkoShell and NicoShell chiral HPLC columns, and absolute configurations were assigned by vibrational circular dichroism spectroscopysupported

Chiral separation methods developed; absolute configurations determined by VCD spectroscopy. j.talanta.2025.128197

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

These kinases phosphorylate the GluA1 AMPA receptor subunit at Ser831 (CaMKII) and Ser845 (PKA), increasing receptor conductance and surface expression.supported

Increases GluA1 phosphorylation at Ser831 and Ser845; potentiates synaptic plasticity. j.neuint.2011.10.008

The opioid phenomenology only emerges at doses substantially above the therapeutic range, where the compound's moderate MOR affinity (Ki = 383 nM) produces sufficient receptor occupancy to generate classical opioid effectssupported

Identified tianeptine as MOR agonist (Ki 383+/-183 nM, EC50 194+/-70 nM). Landmark pharmacology paper. tp.2014.30