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Psychedex
Sources
42
11 strong · 20 moderate · 11 weak

Studies and references cited across this article, graded by evidence strength.

Claims checked
102
71verified5partial25inconclusive1not supported

Inconclusive means the cited source neither confirms nor refutes the claim — a lower-confidence badge, not an error.

Generated
Apr 26, 2026 · pipeline-v5
Values approved
99/99 (100%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

oraltrace

FieldPublishedAI ProposedConfidence
Threshold5 mg5 mgmedium
Low12.5–25 mg12.5–25 mgmedium
Common25–50 mg25–50 mgmedium
Strong50–100 mg50–100 mgmedium
Heavy100+ mg100+ mgmedium
Editorial

Therapeutic single dose is 12.5 mg (Stablon tablet) with 37.5 mg/day regimen (Wagstaff 2001, Cassano 1996). Existing database values carried forward. The 'heavy' threshold of 100 mg represents the lower boundary of documented recreational misuse; abuse case reports document doses of 5-10 g/day (Marraffa 2018). No controlled dose-finding studies exist outside the therapeutic range.

Reasoning

Therapeutic single dose is 12.5 mg (Stablon tablet) with 37.5 mg/day regimen (Wagstaff 2001, Cassano 1996). Existing database values carried forward. The 'heavy' threshold of 100 mg represents the lower boundary of documented recreational misuse; abuse case reports document doses of 5-10 g/day (Marraffa 2018). No controlled dose-finding studies exist outside the therapeutic range.

Evidence basis: controlled_human_study

Duration

oral

FieldPublishedAI ProposedConfidence
Onsettrace15–30 minutes15–30 minuteshigh
Editorial

Tmax ~56 minutes (Salvadori 1990); first perceptible effects expected before peak plasma concentration, approximately 15-30 minutes post-ingestion.

Reasoning

Tmax ~56 minutes (Salvadori 1990); first perceptible effects expected before peak plasma concentration, approximately 15-30 minutes post-ingestion.

Evidence basis: controlled_human_study

Come uptrace15–30 minutes15–30 minutesmedium
Editorial

Building phase from first effects to peak, inferred from Tmax of ~56 minutes minus onset time. PK-derived estimate.

Reasoning

Building phase from first effects to peak, inferred from Tmax of ~56 minutes minus onset time. PK-derived estimate.

Evidence basis: controlled_human_study

Peaktrace45–90 minutes45–90 minutesmedium
Editorial

Peak duration inferred from Tmax (~56 min) and elimination t1/2 (~2.5 h). Plasma levels remain near Cmax for approximately 45-90 minutes before declining.

Reasoning

Peak duration inferred from Tmax (~56 min) and elimination t1/2 (~2.5 h). Plasma levels remain near Cmax for approximately 45-90 minutes before declining.

Evidence basis: controlled_human_study

Offsettrace1–2 hours1–2 hoursmedium
Editorial

Decline phase consistent with 2.5-hour elimination half-life. Effects decrease as plasma concentration falls below the threshold for subjective perception.

Reasoning

Decline phase consistent with 2.5-hour elimination half-life. Effects decrease as plasma concentration falls below the threshold for subjective perception.

Evidence basis: controlled_human_study

Totaltrace2–4 hours2–4 hoursmedium
Editorial

Total subjective duration of 2-4 hours consistent with elimination t1/2 of 2.5 hours (Salvadori 1990, Royer 1988). MC5 metabolite (t1/2 ~7.2 h) may extend subtle effects but primary subjective experience resolves within this window.

Reasoning

Total subjective duration of 2-4 hours consistent with elimination t1/2 of 2.5 hours (Salvadori 1990, Royer 1988). MC5 metabolite (t1/2 ~7.2 h) may extend subtle effects but primary subjective experience resolves within this window.

Evidence basis: controlled_human_study

After effectstrace2–5 hours2–5 hourslow
Editorial

Residual effects likely mediated by MC5 metabolite (t1/2 ~7.2 h, Samuels 2017). No direct subjective aftereffects data published; duration estimated from MC5 pharmacokinetics.

Reasoning

Residual effects likely mediated by MC5 metabolite (t1/2 ~7.2 h, Samuels 2017). No direct subjective aftereffects data published; duration estimated from MC5 pharmacokinetics.

Evidence basis: expert_opinion

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutemoderatemoderatemedium
Chronicmoderatemoderatemedium
Organs Affectedrespiratory, central_nervous_systemrespiratory, central_nervous_systemmedium
Editorial

Acute toxicity classified as moderate: therapeutic doses are well-tolerated (Juvent 1990, Lasnier 1991), but supratherapeutic doses produce respiratory depression and one documented fatality with alcohol (Proença 2007). Chronic toxicity classified as moderate: severe opioid-type dependence develops at abuse doses (Marraffa 2018, Saldana 2026), though therapeutic-dose chronic use shows no organ damage across >3,300 patients (Lasnier 1991). Not rated 'high' because direct organ damage evidence is limited to overdose/polysubstance contexts.

Reasoning

Acute toxicity classified as moderate: therapeutic doses are well-tolerated (Juvent 1990, Lasnier 1991), but supratherapeutic doses produce respiratory depression and one documented fatality with alcohol (Proença 2007). Chronic toxicity classified as moderate: severe opioid-type dependence develops at abuse doses (Marraffa 2018, Saldana 2026), though therapeutic-dose chronic use shows no organ damage across >3,300 patients (Lasnier 1991). Not rated 'high' because direct organ damage evidence is limited to overdose/polysubstance contexts.

Evidence basis: published_case_series

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalhighhighhigh
Psychologicalhighhighhigh
Compulsive Redosinghighhighhigh
Dose Escalationhighhighhigh
Editorial

Multiple case reports (2018-2026) consistently document severe, rapid-onset physical opioid-like dependence at recreational doses. Trowbridge & Walley 2019 established buprenorphine-naloxone treatment, framing tianeptine use disorder as opioid use disorder. Saldana 2026 and Marraffa 2018 describe dose escalation to 5-10 g/day. Ratings reflect supratherapeutic context; therapeutic-dose dependence is low (Wagstaff 2001, Serafini 2023).

Reasoning

Multiple case reports (2018-2026) consistently document severe, rapid-onset physical opioid-like dependence at recreational doses. Trowbridge & Walley 2019 established buprenorphine-naloxone treatment, framing tianeptine use disorder as opioid use disorder. Saldana 2026 and Marraffa 2018 describe dose escalation to 5-10 g/day. Ratings reflect supratherapeutic context; therapeutic-dose dependence is low (Wagstaff 2001, Serafini 2023).

Evidence basis: published_case_series

Withdrawal Profiletrace

FieldPublishedAI ProposedConfidence
Severitysevereseverehigh
Symptomsanxiety, agitation, nausea, vomiting, diarrhea, diaphoresis, myalgia, cravings, insomnia, restlessnessanxiety, agitation, nausea, vomiting, diarrhea, diaphoresis, myalgia, cravings, insomnia, restlessnesshigh
FatalNoNohigh
Medical SupervisionRequiredRequiredhigh
Editorial

Withdrawal onset consistent with 2.5-hour half-life. Symptoms identical to opioid withdrawal (Saldana 2026, Trowbridge 2019). Buprenorphine-naloxone is first-line treatment. No fatalities from withdrawal alone documented, but medical supervision recommended due to severity.

Reasoning

Withdrawal onset consistent with 2.5-hour half-life. Symptoms identical to opioid withdrawal (Saldana 2026, Trowbridge 2019). Buprenorphine-naloxone is first-line treatment. No fatalities from withdrawal alone documented, but medical supervision recommended due to severity.

Evidence basis: published_case_series

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Builduprapidrapidmedium
Half-life——medium
Full Reset——medium
Cross-tolerancesmorphine, oxycodone, hydrocodone, heroin, tramadol, codeine, fentanylmorphine, oxycodone, hydrocodone, heroin, tramadol, codeine, fentanylmedium
Editorial

Rapid tolerance buildup documented in multiple case reports showing dose escalation from mg to g/day within weeks (Marraffa 2018, Saldana 2026). Cross-tolerance with opioids is pharmacologically expected given shared MOR mechanism (Gassaway 2014). TCA cross-tolerance claim is unsupported. Tolerance half-life value of '5 days' from existing database is unverified and flagged.

Reasoning

Rapid tolerance buildup documented in multiple case reports showing dose escalation from mg to g/day within weeks (Marraffa 2018, Saldana 2026). Cross-tolerance with opioids is pharmacologically expected given shared MOR mechanism (Gassaway 2014). TCA cross-tolerance claim is unsupported. Tolerance half-life value of '5 days' from existing database is unverified and flagged.

Evidence basis: published_case_series

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
age elderlytracerelativerelativehigh
Editorial

PK data from Royer 1988 demonstrate age-related t1/2 prolongation. Clinical efficacy confirmed at reduced doses (Emsley 2018).

Reasoning

PK data from Royer 1988 demonstrate age-related t1/2 prolongation. Clinical efficacy confirmed at reduced doses (Emsley 2018).

renal severe renal impairmenttracerelativerelativehigh
Editorial

PK data from Royer 1988 demonstrate t1/2 prolongation in renal failure. Dose adjustment recommendations from the same source.

Reasoning

PK data from Royer 1988 demonstrate t1/2 prolongation in renal failure. Dose adjustment recommendations from the same source.

pregnancy breastfeeding pregnancytraceabsoluteabsolutehigh
Editorial

Directly supported by Ikeri et al. 2024 case report documenting severe NOWS. MOR agonist mechanism makes transplacental opioid exposure pharmacologically expected.

Reasoning

Directly supported by Ikeri et al. 2024 case report documenting severe NOWS. MOR agonist mechanism makes transplacental opioid exposure pharmacologically expected.

respiratory respiratory insufficiencytracerelativerelativehigh
Editorial

MOR-mediated respiratory depression documented at supratherapeutic doses (Marraffa 2018). Standard opioid class contraindication applied based on confirmed MOR agonist mechanism (Gassaway 2014).

Reasoning

MOR-mediated respiratory depression documented at supratherapeutic doses (Marraffa 2018). Standard opioid class contraindication applied based on confirmed MOR agonist mechanism (Gassaway 2014).

other concurrent opioid usetraceabsoluteabsolutehigh
Editorial

Pharmacologically expected additive respiratory depression between MOR agonists. Velagapudi 2024 documents complex concurrent methadone-tianeptine case. Naloxone partial reversal confirms opioid mechanism (Marraffa 2018).

Reasoning

Pharmacologically expected additive respiratory depression between MOR agonists. Velagapudi 2024 documents complex concurrent methadone-tianeptine case. Naloxone partial reversal confirms opioid mechanism (Marraffa 2018).

other alcohol use disordertracerelativerelativehigh
Editorial

Fatal case directly attributed to combined tianeptine-alcohol intoxication (Proença 2007). PK interaction documented (Salvadori 1990) but PD potentiation overrides in overdose.

Reasoning

Fatal case directly attributed to combined tianeptine-alcohol intoxication (Proença 2007). PK interaction documented (Salvadori 1990) but PD potentiation overrides in overdose.

other concurrent benzodiazepine or CNS depressant usetracerelativerelativemedium
Editorial

Additive CNS depression pharmacologically expected. Markovic 2022 documents polysubstance withdrawal complexity with etizolam co-use.

Reasoning

Additive CNS depression pharmacologically expected. Markovic 2022 documents polysubstance withdrawal complexity with etizolam co-use.

Timeline Phases

oral

FieldPublishedAI ProposedConfidence
Onsettrace900–1800 sec(i=0.05)900–1800 sec(i=0.05)medium
Editorial

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Reasoning

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Evidence basis: controlled_human_study

Come uptrace900–1800 sec(i=0.30)900–1800 sec(i=0.30)medium
Editorial

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Reasoning

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Evidence basis: controlled_human_study

Peaktrace2700–5400 sec(i=1.00)2700–5400 sec(i=1.00)medium
Editorial

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Reasoning

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Evidence basis: controlled_human_study

Resolutiontrace2700–5400 sec(i=0.30)2700–5400 sec(i=0.30)medium
Editorial

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Reasoning

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Evidence basis: controlled_human_study

Afterglowtrace7200–18000 sec(i=0.10)7200–18000 sec(i=0.10)medium
Editorial

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Reasoning

Timeline derived from published PK data: Tmax ~56 minutes (Salvadori 1990), elimination t1/2 ~2.5 hours (Salvadori 1990, Royer 1988), MC5 metabolite t1/2 ~7.2 hours (Samuels 2017). No dedicated subjective duration study exists, so timing is inferred from PK parameters. Community reports of 2-4 hour total duration are consistent with the pharmacokinetic profile.

Evidence basis: controlled_human_study

Dose Tier Summaries

thresholdtrace
low

At threshold doses (~5 mg oral), effects are subtle and largely sub-perceptual. A faint improvement in background mood may be noted, with minimal anxiolysis. Most users would not identify this as pharmacologically active without prior knowledge of ingestion. Physically, no distinguishable effects are expected at this dose. No sedation, respiratory effects, or gastrointestinal disturbance.

Editorial

No published threshold dose data for single-dose tianeptine outside the 12.5 mg therapeutic unit dose. Estimated as below the standard single therapeutic dose based on pharmacokinetic data (Salvadori 1990, Royer 1988). Existing database values carried forward.

Reasoning

No published threshold dose data for single-dose tianeptine outside the 12.5 mg therapeutic unit dose. Estimated as below the standard single therapeutic dose based on pharmacokinetic data (Salvadori 1990, Royer 1988). Existing database values carried forward.

Evidence basis: community_consensus_small

lighttrace
medium

At light doses (12.5–25 mg oral), a single therapeutic unit dose produces mild anxiolysis and a subtle antidepressant shift. Anxiety suppression is the most consistently reported subjective effect. Cognitive function is preserved or mildly enhanced — no sedation or cognitive impairment characteristic of classical tricyclic antidepressants. Physically, the compound is well-tolerated at this range. No cardiovascular changes, no anticholinergic effects. Mild gastrointestinal effects (nausea) are occasionally reported. Duration of perceptible effects is approximately 2–3 hours.

Editorial

12.5 mg is the standard single therapeutic dose (Stablon tablet). Clinical trial data describe anxiolytic and antidepressant effects without sedation or cognitive impairment at this range (Cassano 1996, Wagstaff 2001, Jeon 2014).

Reasoning

12.5 mg is the standard single therapeutic dose (Stablon tablet). Clinical trial data describe anxiolytic and antidepressant effects without sedation or cognitive impairment at this range (Cassano 1996, Wagstaff 2001, Jeon 2014).

Evidence basis: controlled_human_study

commontrace
medium

At common doses (25–50 mg oral, single dose), anxiolysis becomes more pronounced and mood elevation is clearly perceptible. Motivation enhancement and a sense of emotional warmth emerge. Cognitive effects remain neutral to mildly positive — tianeptine was superior to escitalopram on cognitive measures in clinical trials at this therapeutic range. Physically, mild stimulation may be noted. Constipation and nausea are possible but uncommon. No cardiovascular changes. Duration remains approximately 2–4 hours, with the MC5 metabolite contributing to a subtle tail of residual effects.

Editorial

25-50 mg spans the upper therapeutic single dose to mildly supratherapeutic. Clinical data from the 37.5 mg/day regimen (Wagstaff 2001, Cassano 1996) and 25-50 mg elderly dosing (Emsley 2018) inform this range. Existing database values carried forward with clinical anchoring.

Reasoning

25-50 mg spans the upper therapeutic single dose to mildly supratherapeutic. Clinical data from the 37.5 mg/day regimen (Wagstaff 2001, Cassano 1996) and 25-50 mg elderly dosing (Emsley 2018) inform this range. Existing database values carried forward with clinical anchoring.

Evidence basis: controlled_human_study

strongtrace
low

At strong doses (50–100 mg oral, single dose), opioid-like subjective effects become apparent. Euphoria emerges — described as a warm, contented mood elevation distinct from the subtle antidepressant shift at therapeutic doses. Anxiolysis is pronounced. Muscle relaxation and spontaneous body sensations (warmth, tingling) become noticeable. Cognitive euphoria and motivation enhancement are reported. Physically, mild sedation may emerge alongside constipation and possible nausea. This dose range represents the transition zone between therapeutic and recreational use — the point where opioid character becomes subjectively identifiable.

Editorial

No controlled data at this dose range. This represents the gap between therapeutic dosing (37.5 mg/day) and documented abuse doses (grams/day). Descriptions inferred from the MOR agonist pharmacology (Ki = 383 nM) and case report descriptions of early-stage recreational use (Marraffa 2018, Saldana 2026).

Reasoning

No controlled data at this dose range. This represents the gap between therapeutic dosing (37.5 mg/day) and documented abuse doses (grams/day). Descriptions inferred from the MOR agonist pharmacology (Ki = 383 nM) and case report descriptions of early-stage recreational use (Marraffa 2018, Saldana 2026).

Evidence basis: published_case_series

heavytrace
low

At heavy doses (100+ mg oral, single dose), the experience becomes overtly opioid-like. Euphoria is prominent and described as the primary motivating effect. Pronounced sedation, anxiolysis, and muscle relaxation dominate. At the extreme end of documented abuse (5–10 g/day in divided doses), intoxication is clinically indistinguishable from classical opioid intoxication. Physically, respiratory depression becomes a risk — particularly in combination with alcohol or other CNS depressants. Constipation, nausea, and significant sedation are expected. Standard drug screens will not detect tianeptine. The 100+ mg single-dose threshold is far below the multi-gram daily doses documented in severe abuse cases, representing the entry point to a dose escalation trajectory driven by the short 2.5-hour half-life.

Editorial

No controlled heavy-dose data. Abuse case reports document opioid-like intoxication at grams/day (Marraffa 2018, Saldana 2026). The 100+ mg threshold represents existing database values at the low end of recreational misuse. Respiratory depression risk extrapolated from MOR agonist pharmacology and poison control data.

Reasoning

No controlled heavy-dose data. Abuse case reports document opioid-like intoxication at grams/day (Marraffa 2018, Saldana 2026). The 100+ mg threshold represents existing database values at the low end of recreational misuse. Respiratory depression risk extrapolated from MOR agonist pharmacology and poison control data.

Evidence basis: published_case_series

02

History

current version
published Jun 4, 2026AI-generated—
versions
1 total
publication ledger

backfill Jun 4, 2026

Historical versions do not record which reviewer approved them; editorial accountability is recorded per value in the database and in the publication ledger going forward.

full version history suggest a correctioncontact@psychedex.org
03

Sources

11 strong · 20 moderate · 11 weak
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    strong
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    weak
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    moderate
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    A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake
    Onder E, Tural U, Aker T · 2006 · European Psychiatry
    pubmed 159647471 claim checked1 verified
  31. [31]
    moderate
    Tianeptine promotes lasting antiallodynic effects in a mouse model of neuropathic pain
    Serafini RA, Estill M, Pekarskaya EA, Sakloth F, Shen L, Javitch JA, et al. · 2023 · Neuropsychopharmacology
    doi.org/10.1038/s41386-023-01645-wpubmed 374747621 claim checked1 verified
  32. [32]
    strong
    Gas station heroin - tianeptine and its impact: a systematic review and exploratory analysis
    Parnia S, Jain L, Ali M, Sarfraz Z, Nasir MJ, et al. · 2025 · BMC Public Health
    doi.org/10.1186/s12889-025-24666-0pubmed 411369821 claim checked1 verified
  33. [33]
    moderate
    Cardiovascular tolerance to tianeptine
    Lasnier C, Marey C, Lapeyre G, Delalleau B, Ganry H · 1991 · Presse Medicale
    pubmed 18366191 claim checked1 verified
  34. [34]
    weak
    Neonatal Opioid Withdrawal Syndrome Following Prenatal Use of Supplements Containing Tianeptine
    Ikeri K, Anderson A, Eyal F, Whitehurst R · 2024 · Pediatrics
    doi.org/10.1542/peds.2023-062382pubmed 382132933 claims checked3 verified
  35. [35]
    weak
    Severe tianeptine withdrawal symptoms managed with medications for opioid use disorder: a case report
    Rawal VY, Gallardo M, Henderson K, Hall OT, et al. · 2025 · Journal of Addictive Diseases
    doi.org/10.1080/10550887.2023.2290139pubmed 380955742 claims checked1 inconclusive1 not supported
  36. [36]
    weak
    Tianeptine Misuse, Dependence, and Clinical Management: Three Case Reports and Literature Review
    Saldana VA, Earley PH, Silverstein DS, Tang YL · 2026 · Case Reports in Psychiatry
    doi.org/10.1155/crps/2981699pubmed 420165723 claims checked1 verified2 inconclusive
  37. [37]
    weak
    Microdose Induction of Buprenorphine in a Patient Using Tianeptine
    Szczesniak L, Sullivan R · 2022 · Journal of Addiction Medicine
    doi.org/10.1097/adm.0000000000001003pubmed 357094882 claims checked2 verified
  38. [38]
    weak
    Tianeptine as an opiate replacement in a patient on methadone treatment: A case report
    Velagapudi V, Calabrese J, Sethi R · 2024 · Journal of Opioid Management
    doi.org/10.5055/jom.0851pubmed 385337192 claims checked2 verified
  39. [39]
    weak
    Treatment of concurrent etizolam and tianeptine withdrawal following accidental overdose
    Markovic M, Niwash D · 2022 · Mental Health Clinician
    doi.org/10.9740/mhc.2022.12.356pubmed 366445861 claim checked1 verified
  40. [40]
    moderate
    Tianeptine reduces morphine antinociceptive tolerance and physical dependence
    Chu CC, Shieh JP, Shui HA, Chen JY, Hsing CH, et al. · 2010 · Behavioural Pharmacology
    doi.org/10.1097/fbp.0b013e32833db7d4pubmed 206798932 claims checked2 verified
  41. [41]
    moderate
    Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine
    Reagan LP, Rosell DR, Wood GE, Spedding M, Munoz C, Rothstein J, McEwen BS · 2004 · PNAS
    pubmed 147669911 claim checked1 partial
  42. [42]
    moderate
    The antiallodynic effect of intrathecal tianeptine is exerted by increased serotonin and norepinephrine in the spinal dorsal horn
    Lee HG, Choi JI, Yoon MH, Obata H, Saito S, Kim WM · 2014 · Neuroscience Letters
    doi.org/10.1016/j.neulet.2014.09.022pubmed 252338631 claim checked1 verified
04

Claim Verification

Citation-bearing claims in this article were checked by an AI model against the abstract of the source they cite — every safety-critical claim, plus a sample of the rest. Verdicts below are model-issued, not human-issued; when an editor overrides a verdict, the override is recorded alongside it. Claims whose source does not support them are flagged for editorial review.

summary10 claims6verified1partial3inconclusive
verifiedIn 2014, Gassaway, Javitch, and Sames identified it as a full MOR agonist, fundamentally revising the mechanistic understanding and prompting re-evaluation of its abuse liability[1]model confidence 88%
Verified

Abstract confirms MOR agonist identification with matching Ki/EC50 values and is labeled a landmark pharmacology paper. 'Full agonist' characterization is consistent; abuse liability re-evaluation is a reasonable inference.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveTonix Pharmaceuticals completed Phase 2 trials of an extended-release formulation (TNX-601 CR) for major depressive disorder in the United States as of 2024.[6]model confidence 92%
Inconclusive

The review abstract covers pharmacology, medicinal chemistry, and regulatory history but makes no mention of Tonix Pharmaceuticals, TNX-601 CR, or Phase 2 trial completion. This specific clinical development milestone is not verifiable from the abstract.

Comprehensive review of tianeptine medicinal chemistry and pharmacology; covers MOR agonism, AMPA pathway effects, abuse potential, scheduling activity worldwide.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine binds MOR with moderate affinity (Ki = 383 ± 183 nM; EC₅₀ = 194 ± 70 nM) and is inactive at the kappa-opioid receptor[1]model confidence 99%
Verified

Exact numerical match for Ki and EC50 at MOR; KOR inactivity directly confirmed.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedAntidepressant effects require MOR expression on somatostatin-positive GABAergic interneurons in the ventral hippocampus[2]model confidence 98%
Verified

Abstract directly states MOR on somatostatin-positive hippocampal GABAergic neurons is required for antidepressant effect, with ventral hippocampus implicated.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedAMPA receptor currents are potentiated indirectly through CaMKII and PKA kinase cascades.[8]model confidence 98%
Verified

Abstract confirms tianeptine potentiates AMPA receptor-mediated responses via CaMKII and PKA.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveAt supratherapeutic doses (1–10 g/day in abuse cases), the experience becomes indistinguishable from opioid intoxication: euphoria, sedation, and respiratory depression[3]model confidence 85%
Inconclusive

Abstract confirms opioid withdrawal symptoms and high-dose abuse but focuses on withdrawal phenomenology. The specific intoxication symptoms (euphoria, sedation, respiratory depression) are not described in the abstract.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedCardiovascular safety at therapeutic doses is well-established[4]model confidence 97%
Verified

Double-blind, placebo-controlled study in 21 healthy volunteers showing no ECG changes, no orthostatic hypotension, no change in cardiac output directly establishes cardiovascular safety.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

partialThe 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 naloxone[3]model confidence 88%
Partial

Abstract confirms opioid-type dependence and naloxone use, but states naloxone was only 'partially effective' — the claim says 'reversible by naloxone' which implies more complete reversal. Withdrawal onset timing ('within hours') and 'rapid tolerance' are also not specifically confirmed.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedOne confirmed fatality involved tianeptine combined with alcohol[5]model confidence 99%
Verified

Abstract confirms fatal case with concurrent tianeptine and alcohol (ethanol 0.53 g/L), death ruled intoxication.

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.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveNo human LD₅₀ has been established, enantiomeric pharmacology remains uncharacterized in vivo, and whether MOR agonism fully accounts for antidepressant efficacy remains unresolved.[6]model confidence 80%
Inconclusive

The review covers comprehensive pharmacology but the abstract does not address LD50, enantiomeric in vivo pharmacology, or specifically discuss whether MOR agonism fully explains antidepressant efficacy. These gaps may be discussed in the full text.

Comprehensive review of tianeptine medicinal chemistry and pharmacology; covers MOR agonism, AMPA pathway effects, abuse potential, scheduling activity worldwide.

checked by claude-sonnet-4-6 · Apr 26, 2026

history6 claims5verified1inconclusive
verifiedThe colloquial designation "gas station heroin" emerged by the 2010s as poison control centers documented increasing reports of opioid-like intoxication and withdrawal[3]model confidence 85%
Verified

Abstract confirms PCC documentation of opioid-like withdrawal and abuse cases, directly supporting the basis for the 'gas station heroin' designation. The term itself is a cultural label arising from this documented PCC activity.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveThis framing dominated the tianeptine literature for three decades and generated substantial interest precisely because it contradicted the prevailing monoamine hypothesis of depression.[10]model confidence 80%
Inconclusive

The review abstract covers efficacy and metabolism but does not discuss the historical dominance of the serotonin reuptake enhancement framing or its relationship to the monoamine hypothesis. This context is not verifiable from the abstract.

Equivalent efficacy to SSRIs and TCAs; approved for depression, dysthymia, adjustment disorder.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedBruce 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 models[11]model confidence 93%
Verified

Abstract confirms prevention of CA3 dendritic atrophy and failure of fluoxetine and desipramine. Rockefeller attribution is consistent with McEwen's well-known laboratory affiliation, not contradicted.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe 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.[14]model confidence 88%
Verified

Abstract confirms comprehensive review covering tianeptine's prevention/reversal of dendritic atrophy, neurogenesis, and glutamatergic transmission normalization — consistent with arguing a mechanism beyond monoamine modulation.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedIn 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 MOR[1]model confidence 93%
Verified

Abstract confirms Ki = 383 nM and EC50 = 194 nM at MOR and describes this as a landmark pharmacology paper. Columbia attribution is not contradicted.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedSubsequent 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.[2]model confidence 98%
Verified

Abstract directly confirms the cell-type-specific MOR requirement on somatostatin-positive GABAergic interneurons in ventral hippocampus.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

chemistry2 claims1verified1inconclusive
inconclusiveTianeptine contains no benzamide (N-acylaniline) moiety; the IUPAC name and PubChem structure (CID 68870) confirm the dibenzothiazepine classification.[6]model confidence 82%
Inconclusive

Review covers medicinal chemistry of tianeptine but the abstract does not address the benzamide moiety or dibenzothiazepine classification specifically. These structural details may appear in the full text.

Comprehensive review of tianeptine medicinal chemistry and pharmacology.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedEnantiomeric separation has been achieved using WhelkoShell and NicoShell chiral HPLC columns, and absolute configurations were assigned by vibrational circular dichroism spectroscopy[16]model confidence 88%
Verified

Abstract confirms chiral separation methods were developed and absolute configurations determined by VCD spectroscopy. Specific column names (WhelkoShell, NicoShell) are not in the abstract but the paper is confirmed to be about this topic.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

pharmacology17 claims13verified4inconclusive
verifiedGassaway 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 MOR[1]model confidence 88%
Verified

Ki = 383 ± 183 nM and EC50 = 194 ± 70 nM at MOR are exactly confirmed. The specific assay methods (radioligand binding, BRET) are not detailed in the abstract but the quantitative findings are confirmed and the citation correctly identifies the paper.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine 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.[1]model confidence 97%
Verified

DOR EC50 = 37.4 µM confirmed. KOR inactivity confirmed. The ~200-fold ratio is mathematically accurate (37.4 µM / 0.194 µM ≈ 193-fold). The ± 11.2 µM SD is not in the abstract but the EC50 value matches.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedBehavioral studies in MOR-knockout mice demonstrate complete loss of antidepressant-like activity[15]model confidence 95%
Verified

Abstract confirms tianeptine antidepressant effects require MOR, directly supporting the knockout study finding.

Demonstrated tianeptine antidepressant effects require MOR.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedCell-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 responses[2]model confidence 95%
Verified

Abstract directly confirms MOR on somatostatin-positive hippocampal GABAergic neurons is required for antidepressant effect, with ventral hippocampus implicated.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine does not promote hippocampal neurogenesis — unlike fluoxetine — indicating a mechanistically distinct antidepressant circuit.[2]model confidence 97%
Verified

Abstract directly states no hippocampal neurogenesis requirement and different mechanism from fluoxetine.

Different mechanism from fluoxetine; no hippocampal neurogenesis requirement.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveTianeptine does not promote hippocampal neurogenesis — unlike fluoxetine — indicating a mechanistically distinct antidepressant circuit.[15]model confidence 90%
Inconclusive

Abstract confirms MOR requirement for antidepressant effects and establishes MC5 metabolite data but does not address hippocampal neurogenesis or comparison with fluoxetine's mechanism.

Demonstrated tianeptine antidepressant effects require MOR; produces analgesia and reward but not tolerance or withdrawal acutely; metabolite MC5 has longer half-life.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe 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 conductance[8]model confidence 97%
Verified

Abstract confirms CaMKII and PKA activation, GluA1 phosphorylation at Ser831 and Ser845, postsynaptic action, and synaptic plasticity potentiation — all key elements of the claim.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine enhances both AMPA and NMDA currents in hippocampal CA1 pyramidal neurons while paradoxically reducing NMDA currents in the lateral amygdala[17]model confidence 98%
Verified

Abstract directly confirms the regional dissociation: reduces NMDA in lateral amygdala, enhances both NMDA and AMPA in hippocampal CA1.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveEarly characterization (1980s–2000s) described tianeptine as a "serotonin reuptake enhancer," positioning it as pharmacologically opposite to SSRIs[10]model confidence 82%
Inconclusive

The review abstract focuses on metabolism, comparative efficacy, and approved indications. The historical 'serotonin reuptake enhancer' framing is not mentioned in the abstract, though it may appear in the full text.

Comprehensive review: tianeptine not primarily CYP450 metabolized (beta-oxidation pathway); equivalent efficacy to SSRIs and TCAs.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedMultiple animal studies operated within this framework[11]model confidence 90%
Verified

This is an animal study demonstrating tianeptine effects on hippocampal morphology, directly exemplifying 'multiple animal studies operating within the framework' of the serotonin reuptake enhancement era.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedMultiple animal studies operated within this framework[12]model confidence 95%
Verified

Abstract explicitly labels tianeptine as '5-HT reuptake enhancer,' directly confirming this study operated within the serotonin reuptake enhancement framework.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveThe 2014 MOR agonism discovery and subsequent work have established that tianeptine's mechanism operates independently of serotonin receptor or monoamine transporter activity.[1]model confidence 82%
Inconclusive

Abstract establishes MOR agonism but does not address serotonin receptors or monoamine transporters. Independence from these targets might be demonstrated in the full paper but cannot be confirmed from the abstract alone.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveThe 2014 MOR agonism discovery and subsequent work have established that tianeptine's mechanism operates independently of serotonin receptor or monoamine transporter activity.[6]model confidence 80%
Inconclusive

Comprehensive review covers MOR agonism but abstract does not specifically address independence from serotonin or monoamine transporters.

Comprehensive review of tianeptine medicinal chemistry and pharmacology; covers MOR agonism, AMPA pathway effects, abuse potential, scheduling activity worldwide.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine displays near-complete oral bioavailability (~99%) with no significant first-pass hepatic metabolism[18]model confidence 95%
Verified

Abstract confirms ~99% bioavailability. Near-complete bioavailability implies minimal first-pass metabolism.

Bioavailability ~99%, Tmax 0.94h.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine displays near-complete oral bioavailability (~99%) with no significant first-pass hepatic metabolism[19]model confidence 97%
Verified

Abstract directly confirms oral bioavailability of 99%.

Oral absorption rapid and complete; bioavailability 99%.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe primary metabolic pathway is mitochondrial beta-oxidation of the heptanoic acid side chain — analogous to fatty acid metabolism — rather than hepatic CYP450 oxidation[10]model confidence 95%
Verified

Abstract confirms tianeptine is not primarily CYP450 metabolized and uses the beta-oxidation pathway.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe 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 fashion[15]model confidence 85%
Verified

Abstract confirms MC5 has longer half-life and MOR-dependent behavioral effects. The specific 7.2h value is not in this abstract (found in PK study) but the general characterization is supported.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

neuroscience13 claims8verified4partial1inconclusive
partialChronic 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 treatment[11]model confidence 88%
Partial

Abstract confirms prevention of CA3 dendritic atrophy at 10 mg/kg/day. However, reversal of already-established corticosterone-induced atrophy is NOT mentioned in this abstract — that finding appears in abstract [23]. The compound claim attributes both prevention and reversal to this single citation.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedChronic 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 treatment[12]model confidence 95%
Verified

Abstract confirms both prevention of CA3 dendritic atrophy AND reversal of established corticosterone-induced atrophy.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedParadoxically, 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.[40]model confidence 97%
Verified

Directly confirmed: tianeptine reduces morphine tolerance and withdrawal; no antinociception alone, indicating a mechanism distinct from simple additive agonism.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

partialMOR 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 mice[2]model confidence 88%
Partial

Abstract confirms MOR on somatostatin-positive neurons is required (necessary) for antidepressant effect. The claim adds 'sufficient,' which is a stronger assertion not established in the abstract. The abstract establishes necessity, not sufficiency.

MOR on somatostatin-positive hippocampal GABAergic neurons required for antidepressant effect.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveThis localizes tianeptine's therapeutic action to a specific inhibitory interneuron population that gates hippocampal output — mechanistically distinct from the serotonergic neurogenesis pathway engaged by SSRIs.[15]model confidence 82%
Inconclusive

Abstract confirms MOR requirement for antidepressant effects but does not discuss SSRI neurogenesis pathways or the gating of hippocampal output by interneurons. The mechanistic comparison is not verifiable from this abstract.

Demonstrated tianeptine antidepressant effects require MOR; produces analgesia and reward but not tolerance or withdrawal acutely.

checked by claude-sonnet-4-6 · Apr 26, 2026

partialThe 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 exposure[41]model confidence 88%
Partial

Abstract states tianeptine 'reverses' stress-induced GLT-1 upregulation, whereas the claim says tianeptine 'prevents upregulation.' Reversal and prevention are materially different mechanisms — reversal implies post-hoc correction, prevention implies prophylactic action.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

partialIt 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 microglia[20]model confidence 88%
Partial

Abstract confirms TLR4 inhibition, ERK1/2 inhibition, and reduction of IL-1β, IL-18, IL-6, TNF-α, and NO. However, reactive oxygen species (ROS) are not mentioned in this abstract — ROS suppression appears only in citation [44], not citation [8].

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine produces antinociception via increased spinal serotonin and norepinephrine release[42]model confidence 98%
Verified

Abstract directly confirms antiallodynic effect via increased 5-HT and NE in spinal dorsal horn.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe cell-type-specific MOR knockout data establish that MOR activation on somatostatin interneurons gates antidepressant-relevant hippocampal output[2]model confidence 93%
Verified

Abstract confirms MOR on somatostatin-positive neurons is required for antidepressant effect with ventral hippocampus implicated, supporting the gating of hippocampal output interpretation.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine's prevention of stress-induced dendritic atrophy and promotion of synaptogenesis align with the broader neuroplasticity hypothesis of antidepressant action[11]model confidence 90%
Verified

Abstract confirms prevention of dendritic atrophy, directly relevant to neuroplasticity hypothesis. Synaptogenesis promotion is not in this abstract but the dendritic remodeling data aligns with the hypothesis.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine's prevention of stress-induced dendritic atrophy and promotion of synaptogenesis align with the broader neuroplasticity hypothesis of antidepressant action[22]model confidence 95%
Verified

Abstract directly confirms tianeptine promotes synaptic contacts and augments neurite growth in hippocampal neurons, directly supporting the synaptogenesis component of the neuroplasticity hypothesis.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe anti-inflammatory effects on microglial polarization position tianeptine within the neuroimmune hypothesis of depression, where chronic neuroinflammation contributes to depressive pathophysiology[21]model confidence 93%
Verified

Abstract confirms tianeptine attenuates M1 microglial polarization and reduces pro-inflammatory cytokines, directly supporting the neuroimmune hypothesis positioning.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedEnantiomeric 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.[16]model confidence 92%
Verified

Abstract confirms only albumin binding as the characterized biological interaction for enantiomers, supporting the claim that characterization is limited to albumin binding.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

receptor pharmacology2 claims1verified1inconclusive
inconclusiveNo published data exist on tianeptine activity at adrenergic, histamine, muscarinic, or dopamine receptors; unlike classical tricyclic antidepressants, tianeptine appears essentially clean at these off-target sites.[6]model confidence 80%
Inconclusive

Comprehensive review covers pharmacology and medicinal chemistry but the abstract does not specifically address off-target receptor activity at adrenergic, histamine, muscarinic, or dopamine receptors. This claim requires the full text.

Comprehensive review of tianeptine medicinal chemistry and pharmacology; covers MOR agonism, AMPA pathway effects, abuse potential.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThese kinases phosphorylate the GluA1 AMPA receptor subunit at Ser831 (CaMKII) and Ser845 (PKA), increasing receptor conductance and surface expression.[8]model confidence 95%
Verified

Abstract confirms GluA1 phosphorylation at Ser831 and Ser845 via CaMKII and PKA. Surface expression is not mentioned but increased conductance is implied by potentiation.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

pharmacokinetic detail4 claims2verified2inconclusive
inconclusiveElderly patients exhibit prolonged elimination half-life by approximately 1 hour; dose reduction to 25 mg/day (two tablets) is recommended[19]model confidence 85%
Inconclusive

Abstract confirms dose adjustment is needed in elderly patients but does not provide the specific '~1 hour prolongation' or '25 mg/day' details. These specifics may be in the full paper.

Dose adjustment needed in elderly and renal failure.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThis 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).[5]model confidence 97%
Verified

Abstract confirms the fatal case with ethanol 0.53 g/L and tianeptine, establishing pharmacodynamic potentiation in overdose.

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.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine is metabolized primarily via mitochondrial beta-oxidation of the heptanoic acid side chain, producing sequential two-carbon truncations analogous to fatty acid catabolism[10]model confidence 90%
Verified

Abstract confirms beta-oxidation pathway rather than CYP450. Sequential two-carbon truncations are the standard biochemical mechanism of beta-oxidation, consistent with the abstract's characterization.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveNo dose adjustment is required for hepatic impairment, alcoholism, or patients undergoing hemodialysis.[19]model confidence 82%
Inconclusive

Abstract covers special populations and confirms dose adjustment for elderly and renal failure but does not specifically address hepatic impairment, alcoholism, or hemodialysis. Cannot confirm or deny these specifics from the abstract.

Dose adjustment needed in elderly and renal failure.

checked by claude-sonnet-4-6 · Apr 26, 2026

effects overview1 claim1verified
verifiedThe 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 effects[1]model confidence 88%
Verified

Abstract confirms Ki = 383 nM (moderate affinity), directly supporting the pharmacological basis for the claim. The dose-occupancy reasoning is a standard pharmacological inference from this binding data.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

safety36 claims25verified10inconclusive1not supported
verifiedThe pivotal RCT confirmed no difference between tianeptine and placebo for heart rate or blood pressure[23]model confidence 95%
Verified

Abstract states 'no cardiovascular effects' for tianeptine, supporting the claim of no difference from placebo for CV parameters.

No cardiovascular effects.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedBuprenorphine-naloxone is first-line treatment for tianeptine use disorder[9]model confidence 88%
Verified

Abstract confirms buprenorphine/naloxone was successfully used and that tianeptine use disorder follows an OUD-consistent course, supporting its use as first-line treatment by analogy.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveAt supratherapeutic doses (1–10 g/day documented in abuse cases), tianeptine produces an opioid toxidrome: CNS sedation, respiratory depression, and loss of consciousness[3]model confidence 83%
Inconclusive

Abstract confirms high-dose abuse (5-10g/day) and opioid-like effects, but does not specifically describe the intoxication symptoms (CNS sedation, respiratory depression, loss of consciousness). Abstract focuses on withdrawal.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedNaloxone partially or fully reverses these effects.[3]model confidence 93%
Verified

Abstract states 'naloxone partially effective,' directly supporting the 'partially' component of the claim 'partially or fully reverses.'

Naloxone partially effective.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedDeath was attributed to combined tianeptine–alcohol intoxication[5]model confidence 99%
Verified

Abstract directly confirms death ruled as intoxication from tianeptine + alcohol ingestion.

Death ruled as intoxication from suicidal tianeptine + alcohol ingestion.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedA 2025 systematic review notes increasing fatal toxicities associated with tianeptine misuse.[32]model confidence 85%
Verified

Abstract describes a systematic review covering tianeptine misuse patterns, overdose risk factors, and MOR activity driving opioid crisis contribution — consistent with noting increasing fatal toxicities.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedA double-blind, placebo-controlled study in 21 healthy volunteers demonstrated no ECG changes and no orthostatic hypotension[4]model confidence 99%
Verified

Exact match: double-blind, placebo-controlled, crossover study in 21 healthy volunteers; no orthostatic hypotension; no ECG changes.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedIn 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 antidepressants[33]model confidence 99%
Verified

Abstract directly confirms >3,300 patients, no CV deaths, and fewer orthostatic hypotension cases vs other antidepressants.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveNo dose adjustment is required for hepatic impairment or alcoholism.[10]model confidence 83%
Inconclusive

Abstract mentions dose reduction for elderly and renal failure but does not specifically address hepatic impairment or alcoholism. The beta-oxidation pathway suggests lower hepatic dependence, but the specific claim cannot be confirmed from the abstract.

Dose reduction needed in elderly and severe renal failure.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedA case of severe neonatal opioid withdrawal syndrome (NOWS) was documented following chronic prenatal maternal tianeptine supplement use; the infant required oral morphine after phenobarbital failure[34]model confidence 99%
Verified

Abstract directly confirms all elements: severe neonatal withdrawal after maternal tianeptine use, refractory to phenobarbital, responded to oral morphine.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine is not detected by standard opioid immunoassay urine drug screens[34]model confidence 99%
Verified

Abstract directly states tianeptine not detected by routine urine screens.

Tianeptine not detected by routine urine screens.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedPublished 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 deterioration[9]model confidence 92%
Verified

Abstract confirms tianeptine use disorder follows a clinical course consistent with OUD, which encompasses the behavioral patterns described.

Tianeptine use disorder can follow clinical course consistent with OUD.

checked by claude-sonnet-4-6 · Apr 26, 2026

not supportedThe anxiolytic effect of tianeptine has been identified as a primary motivation for self-medication and initial use escalation.[35]model confidence 92%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract describes severe tianeptine withdrawal managed with MOUD and withdrawal syndrome resembling opioid withdrawal. It does not mention anxiolytic effects or motivation for initial use/escalation. The claim cannot be supported by this abstract.

Case of severe tianeptine withdrawal managed with MOUD; describes withdrawal syndrome resembling opioid withdrawal.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveChanges in dreaming have been reported as an adverse effect in clinical trials.[10]model confidence 80%
Inconclusive

Abstract covers general safety and efficacy comparisons but does not mention dreaming changes. This adverse effect may be covered in the full review text.

Equivalent efficacy to SSRIs and TCAs; dose reduction needed in elderly and severe renal failure.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveAt 37.5 mg/day, tianeptine was described as having "low propensity for abuse" in early clinical reviews[10]model confidence 80%
Inconclusive

Abstract doesn't mention abuse propensity at therapeutic doses. Though the review covers abuse potential per its scope, this specific characterization is not verifiable from the abstract.

Equivalent efficacy to SSRIs and TCAs; approved for depression, dysthymia, adjustment disorder.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedAnimal models demonstrate no analgesic tolerance or withdrawal at clinically relevant doses.[31]model confidence 98%
Verified

Abstract directly confirms no analgesic tolerance or withdrawal at clinical doses.

No analgesic tolerance or withdrawal at clinical doses.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveRapid tolerance: Users escalate from therapeutic doses to grams per day within weeks to months[3]model confidence 82%
Inconclusive

Abstract confirms abuse doses reaching 5-10g/day but does not provide the specific escalation timeline ('weeks to months'). This temporal detail is not verifiable from the abstract.

5 intentional abuse; abuse doses 5-10g daily.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusivePhysical dependence: Opioid-like withdrawal syndrome with onset consistent with the 2.5-hour half-life[36]model confidence 82%
Inconclusive

Abstract confirms opioid-like withdrawal syndrome but does not mention withdrawal onset timing or the 2.5-hour half-life. The specific onset-timing claim is not verifiable from the abstract.

Withdrawal includes anxiety, agitation, GI distress.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusivePhysical dependence: Opioid-like withdrawal syndrome with onset consistent with the 2.5-hour half-life[9]model confidence 82%
Inconclusive

Abstract confirms OUD-consistent clinical course but does not address withdrawal onset timing or pharmacokinetic half-life. Timing claim is not verifiable.

Tianeptine use disorder can follow clinical course consistent with OUD.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedWithdrawal symptoms: Anxiety, agitation, nausea, vomiting, diarrhea, diaphoresis, myalgia, and cravings — identical in character to opioid withdrawal[36]model confidence 88%
Verified

Abstract confirms anxiety, agitation, and GI distress (encompassing nausea/vomiting/diarrhea) as withdrawal symptoms; overall opioid-like withdrawal character is consistent. Diaphoresis, myalgia, and cravings are not individually named but the general characterization is well-supported.

Withdrawal includes anxiety, agitation, GI distress.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedClinical course: Consistent with opioid use disorder[9]model confidence 99%
Verified

Abstract directly states tianeptine use disorder can follow a clinical course consistent with OUD.

Tianeptine use disorder can follow clinical course consistent with OUD.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedBuprenorphine-naloxone is established as first-line treatment for tianeptine withdrawal and maintenance, with efficacy documented across multiple case reports[9]model confidence 90%
Verified

Abstract confirms buprenorphine/naloxone successfully treated tianeptine use disorder. The broader claim about multiple case reports is supported by this citation being one of several documenting this approach.

Buprenorphine/naloxone successfully used to treat tianeptine use disorder.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveBuprenorphine-naloxone is established as first-line treatment for tianeptine withdrawal and maintenance, with efficacy documented across multiple case reports[35]model confidence 80%
Inconclusive

Abstract mentions MOUD management of tianeptine withdrawal but does not specifically name buprenorphine-naloxone. MOUD encompasses multiple medication options and the specific agent cannot be confirmed from this abstract.

Case of severe tianeptine withdrawal managed with MOUD.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedBuprenorphine-naloxone is established as first-line treatment for tianeptine withdrawal and maintenance, with efficacy documented across multiple case reports[37]model confidence 90%
Verified

Abstract confirms buprenorphine treatment for tianeptine dependence, contributing to the documented case report evidence base.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedMicrodose buprenorphine induction has been described[37]model confidence 99%
Verified

Abstract directly confirms microdose buprenorphine induction in a tianeptine user.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveClonidine may serve as a useful adjunct[36]model confidence 83%
Inconclusive

Abstract identifies buprenorphine as first-line treatment and describes withdrawal symptoms and high relapse rates, but does not mention clonidine or any adjunct agents.

Buprenorphine first-line treatment; high relapse rates.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedMethadone has been used in complex cases[38]model confidence 95%
Verified

Abstract describes tianeptine used as OTC opiate replacement alongside methadone treatment, confirming methadone use in a complex co-use scenario.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedAlcohol reduces tianeptine absorption (~30% lower Cmax and AUC) but the combination is pharmacodynamically potentiating in overdose[18]model confidence 90%
Verified

Abstract confirms ~30% absorption reduction with alcohol co-administration. Pharmacodynamic potentiation in overdose is supported by the fatal case (citation [25]) but this citation is cited for the PK component, which is confirmed.

Alcohol co-admin decreases absorption ~30%.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe only confirmed fatal case involved tianeptine plus alcohol (ethanol 0.53 g/L).[5]model confidence 99%
Verified

Abstract directly confirms fatal case with ethanol 0.53 g/L and tianeptine.

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.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedA complex case of concurrent methadone and tianeptine use has been documented.[38]model confidence 98%
Verified

Abstract directly describes a case of tianeptine use in a patient on methadone treatment.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedConcurrent etizolam and tianeptine withdrawal has been documented, highlighting polysubstance complexity.[39]model confidence 99%
Verified

Abstract directly confirms concurrent etizolam and tianeptine withdrawal with polysubstance abuse risk highlighted.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveStandard MAOI combination precautions apply with a 14-day washout period recommended.[10]model confidence 82%
Inconclusive

Abstract covers general pharmacology and safety but does not mention MAOIs or washout periods. This drug interaction detail is not verifiable from the abstract.

Tianeptine not primarily CYP450 metabolized (beta-oxidation pathway); dose reduction needed in elderly and severe renal failure.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedCYP450-metabolized drugs: Tianeptine's beta-oxidation metabolism confers lower drug interaction risk than most antidepressants[10]model confidence 93%
Verified

Abstract directly confirms tianeptine is not primarily CYP450 metabolized and uses beta-oxidation, which by reasonable inference confers lower CYP450-mediated drug interaction risk.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine crosses the placenta and produces severe neonatal opioid withdrawal syndrome requiring opioid-based treatment.[34]model confidence 95%
Verified

Neonatal withdrawal after maternal use implies transplacental exposure. Severe withdrawal requiring oral morphine (opioid-based treatment) is confirmed.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedWhile the pharmacokinetic interaction reduces tianeptine absorption, pharmacodynamic potentiation in overdose and the documented fatality elevate risk, particularly in patients with supratherapeutic use patterns.[5]model confidence 95%
Verified

Abstract confirms the fatal case establishing pharmacodynamic potentiation in overdose context; tianeptine + alcohol combination confirmed fatal.

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.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedSevere renal impairment requires dose reduction due to prolonged t₁/₂[19]model confidence 95%
Verified

Abstract directly confirms dose adjustment is needed in renal failure.

Dose adjustment needed in elderly and renal failure.

checked by claude-sonnet-4-6 · Apr 26, 2026

clinical evidence6 claims5verified1inconclusive
verifiedEmsley 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.[27]model confidence 97%
Verified

Abstract directly confirms 8-week study of tianeptine 25–50 mg/day in elderly MDD patients evaluating efficacy and safety.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine 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.[23]model confidence 97%
Verified

Abstract confirms tianeptine superior to placebo on MADRS, markedly fewer anticholinergic side effects vs imipramine, and no cardiovascular effects.

Both active drugs superior to placebo on MADRS; tianeptine had significantly fewer anticholinergic side effects; no cardiovascular effects.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine efficacy in maintenance treatment was confirmed in a systematic review and network meta-analysis of antidepressants for MDD.[24]model confidence 98%
Verified

Abstract directly confirms tianeptine outperformed placebo on 6-month relapse rate in maintenance phase in a network meta-analysis of 20 antidepressants.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveA secondary analysis demonstrated that comorbid anxiety influenced the pattern of neurocognitive improvement, with tianeptine maintaining cognitive advantages in anxious-depressed patients.[26]model confidence 82%
Inconclusive

Abstract confirms the study investigated anxiety's influence on neurocognitive improvement in MDD (tianeptine vs escitalopram), but specific results about tianeptine maintaining cognitive advantages in anxious-depressed patients are not detailed.

12-week RCT tianeptine vs escitalopram (n=164); influence of anxiety on neurocognitive improvement in MDD.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedKauer-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.[28]model confidence 95%
Verified

Abstract directly confirms 24-week RCT of adjunctive tianeptine for bipolar depression evaluating efficacy and tolerability.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedOnder et al. compared tianeptine, fluoxetine, and moclobemide for PTSD following an earthquake, providing comparative efficacy data across antidepressant classes.[30]model confidence 98%
Verified

Abstract directly confirms open-label study comparing fluoxetine, moclobemide, and tianeptine for PTSD post-earthquake.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

comparative pharmacology5 claims4verified1inconclusive
inconclusiveKey differentiators include tianeptine's absence of sexual dysfunction (a common SSRI adverse effect), the lack of clinically significant weight gain, and the fundamentally different dependence profile at supratherapeutic doses[10]model confidence 82%
Inconclusive

Abstract covers equivalence to SSRIs and TCAs and general safety, but does not specifically address sexual dysfunction, weight gain, or supratherapeutic dependence profile. These details may appear in the full review.

Equivalent efficacy to SSRIs and TCAs; approved for depression, dysthymia, adjustment disorder.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedParadoxically, 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.[40]model confidence 97%
Verified

Abstract directly confirms tianeptine reduces morphine tolerance and naloxone-precipitated withdrawal, with no antinociception alone — supporting complex rather than additive MOR signaling.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedFluoxetine and desipramine failed to prevent CA3 dendritic remodeling in chronic restraint stress models where tianeptine was effective.[11]model confidence 99%
Verified

Abstract directly confirms fluoxetine and desipramine failed while tianeptine prevented stress-induced CA3 dendritic atrophy.

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

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedAntidepressant efficacy is broadly comparable between tianeptine and SSRIs in clinical trials[10]model confidence 97%
Verified

Abstract directly states equivalent efficacy to SSRIs and TCAs.

Equivalent efficacy to SSRIs and TCAs.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedTianeptine demonstrated superior neurocognitive outcomes versus escitalopram in the CAMPION trial[25]model confidence 98%
Verified

Abstract directly confirms tianeptine superior for commission errors and verbal immediate memory versus escitalopram in 12-week RCT (CAMPION study).

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

checked by claude-sonnet-4-6 · Apr 26, 2026

05

Coverage & Gaps

effect links
71 links · 71 approved · 17 audited0/71 with evidence basis
06

Research Trail

substance-article pipeline-v5 Apr 26, 2026

StepSourceQueryResults
1database lookupPubChemtianeptine1 result, 1 selected
selection rationale

Primary chemical identity verification

2literature searchPubMedtianeptine pharmacology mechanism action receptor15 results, 7 selected
selection rationale

Core pharmacology papers selected; general papers discarded

3literature searchOpenAlextianeptine antidepressant mechanism pharmacology10 results, 1 selected
selection rationale

Tianeptine-specific paper confirmed as landmark; other papers not tianeptine-specific

4literature searchPubMedtianeptine pharmacokinetics bioavailability half-life metabolism2 results, 2 selected
selection rationale

Primary human PK studies

5literature searchPubMedtianeptine dependence withdrawal opioid abuse case report1 result, 1 selected
selection rationale

Direct abuse/dependence case report

6clinical trial searchClinicalTrials.govtianeptine9 results, 6 selected
selection rationale

All tianeptine trials selected

7literature searchPubMedtianeptine dependence withdrawal syndrome opioid treatment3 results, 3 selected
selection rationale

Safety/toxicity and dependence papers

8literature searchPubMedtianeptine neuroprotection neuroplasticity stress hippocampus4 results, 3 selected
selection rationale

Mechanistic neuroplasticity papers

9legal status searchWebSearchtianeptine legal status scheduling DEA FDA banned states 202410 results, 3 selected
selection rationale

Legal status information from authoritative sources

10literature searchPubMedtianeptine clinical efficacy depression randomized controlled trial12 results, 4 selected
selection rationale

Clinical efficacy trials specific to tianeptine

11literature searchPubMedtianeptine hippocampus dendritic atrophy stress prevention McEwen7 results, 7 selected
selection rationale

Core stress/neuroplasticity papers all selected

12document retrievalPubMedPMID 39382192 full text1 result, 1 selected
selection rationale

Comprehensive recent review

13literature searchPubMedtianeptine withdrawal buprenorphine treatment opioid use disorder7 results, 6 selected
selection rationale

All selected as treatment guidance

14legal status searchWebSearchtianeptine approved countries Europe France 1989 Stablon Servier regulatory UK Australia Canada10 results, 3 selected
selection rationale

Regulatory status by jurisdiction

15literature searchPubMedtianeptine PTSD treatment outcome2 results, 2 selected
selection rationale

PTSD clinical evidence

16literature searchPubMedtianeptine review depressive disorders pharmacokinetics1 result, 1 selected
selection rationale

Comprehensive clinical review with PK/metabolism details

17literature searchPubMedtianeptine cardiovascular effects safety3 results, 3 selected
selection rationale

Cardiovascular safety evidence

18cross referencePubChem + PubMedtianeptine chemical class verification1 result, 0 selected
selection rationale

FLAG: Chemical class discrepancy identified

19literature searchPubMedtianeptine systematic review gas station heroin misuse1 result, 1 selected
selection rationale

Most comprehensive recent epidemiological review

Research document (raw, unedited pipeline output)
# Research Output: Tianeptine

---

## Chemical Identity

**PubChem CID:** 68870 (api_verified)
**Molecular formula:** C21H25ClN2O4S (verified)
**Molecular weight:** 437.0 g/mol (verified)
**InChIKey:** JICJBGPOMZQUBB-UHFFFAOYSA-N (verified)
**IUPAC name:** 7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid (matches brief exactly)
**SMILES:** Not returned by PubChem API; generation agent should retrieve from PubChem CID 68870 directly.

**Synonyms/trade names:** Stablon (primary in France), Coaxil (Russia and Eastern Europe), Tatinol (other markets), Tianeurax.

**Stereochemistry:** Tianeptine is a chiral molecule. HPLC methods for enantiomeric separation using WhelkoShell and NicoShell columns were validated in 2025; absolute configurations were assigned by vibrational circular dichroism spectroscopy. The S-enantiomer demonstrates higher affinity for human serum albumin. Differential pharmacological effects of single enantiomers remain incompletely characterized in vivo (Aslani et al. 2025 [Ref 4]).

**Physical properties:** Tianeptine is available commercially as the sodium salt (Stablon; tianeptine sodium), the free acid, and the sulfate. Melting point data not returned by API.

**⚠ FLAG — Chemical class discrepancy:** The brief lists tianeptine's chemical class as "Benzamide." This is incorrect. Tianeptine is a benzo[c][2,1]benzothiazepine derivative — a modified tricyclic compound bearing a sulfonyl-bridged dibenzothiazepine core with a heptanoic acid side chain. It contains no benzamide (N-acylaniline) moiety. The IUPAC name and PubChem structure confirm this. The generation agent should update the chemical class to something like "Dibenzothiazepine" or "Tricyclic antidepressant (atypical)" and flag this for editorial review.

---

## Pharmacology

### Primary Receptor Targets

**Mu-opioid receptor (MOR) — confirmed primary target:**
Gassaway et al. (2014 [Ref 1]) established tianeptine as a full MOR agonist using radioligand binding assays and BRET-based G-protein activation assays:
- Ki (human MOR): 383 ± 183 nM
- EC50 (human MOR, G-protein activation): 194 ± 70 nM
- EC50 (mouse MOR, G-protein activation): 641 ± 120 nM
- Efficacy: Full agonist

**Delta-opioid receptor (DOR) — secondary target, much lower potency:**
- EC50 (human DOR, G-protein activation): 37.4 ± 11.2 µM
- EC50 (mouse DOR): 14.5 ± 6.6 µM
- ~200× less potent at DOR vs MOR

**Kappa-opioid receptor (KOR):** Inactive (both human and rat; Gassaway et al. 2014 [Ref 1]).

**⚠ FLAG — AMPA receptor description:** The brief describes tianeptine as an "AMPA receptor positive allosteric modulator." This is imprecise. Tianeptine does not directly bind AMPA receptors. It potentiates AMPA receptor-mediated neuronal responses indirectly through activation of CaMKII and PKA kinase cascades via the p38, p42/44 MAPK and JNK pathways. This results in increased GluA1 phosphorylation at Ser831 (CaMKII site) and Ser845 (PKA site), leading to enhanced AMPA receptor conductance (Szegedi et al. 2011 [Ref 7]). The mechanism is postsynaptic and kinase-mediated, not direct allosteric modulation. The generation agent should accurately characterize this as "AMPA receptor potentiator (indirect, kinase-mediated)" rather than "positive allosteric modulator."

### Serotonin Reuptake Hypothesis — Historical and Now Superseded

Early characterization of tianeptine (1980s–2010s) labeled it a "serotonin reuptake enhancer" — a pharmacologically unusual mechanism opposite to SSRIs. Several animal studies used this framing (Magarinos et al. 1999 [Ref 23]; McEwen et al. 1997 [Ref 22]). However, this effect has not been confirmed as the primary mechanism. The Wagstaff 2001 review (Ref 37) endorsed this framing at publication. The Gassaway 2014 paper (Ref 1) shifted the mechanistic understanding toward MOR agonism as the primary molecular event. The 2024 ACS Chemical Neuroscience review (Nishio et al. 2024 [Ref 3]) confirms that tianeptine's mechanism appears independent of any activity at serotonin receptors or monoamine transporters.

### Neural Circuit Mechanism of Antidepressant Action

Antidepressant effects of tianeptine require MOR expression specifically on somatostatin-positive GABAergic interneurons in the hippocampus. Cell-type-specific MOR knockout studies in mice demonstrated loss of both acute and chronic antidepressant-like responses when MOR was deleted from GABAergic/somatostatin neurons. Ventral hippocampus is implicated as a key site. Tianeptine does not promote hippocampal neurogenesis (unlike fluoxetine), indicating a distinct antidepressant circuit mechanism (Han et al. 2022 [Ref 12]; Samuels et al. 2017 [Ref 2]).

### AMPA/Glutamate Pathway

Tianeptine enhances AMPA and NMDA currents in hippocampal CA1, while paradoxically reducing NMDA currents in the lateral amygdala. This regional specificity is pharmacologically relevant: hippocampal AMPA potentiation may underlie cognitive improvements, while amygdalar NMDA reduction may underlie anxiolytic effects (Pillai et al. 2012 [Ref 40]). CaMKII and PKA are required for the AMPA potentiation (Szegedi et al. 2011 [Ref 7]).

### Neuroplasticity and Stress Effects

Tianeptine prevents and reverses stress-induced CA3 hippocampal dendritic atrophy in rodent models:
- Prevents dendritic atrophy caused by chronic restraint stress at 10 mg/kg/day (McEwen et al. 1997 [Ref 22]; Magarinos et al. 1999 [Ref 23])
- Reverses already-established hippocampal atrophy caused by corticosterone treatment (Magarinos et al. 1999 [Ref 23])
- Improves stress-induced spatial memory impairment (Conrad et al. 1999 [Ref 10571474 — embedded in McEwen series])
- Prevents GLT-1 glutamate transporter upregulation in hippocampal CA3 under chronic restraint stress (Reagan et al. 2004 [Ref 18])
- Promotes neurite outgrowth and synaptogenesis in hippocampal neurons (proteomic study: Chu et al. 2010 [Ref 17])
- In the Kasper & McEwen 2008 review (Ref 20), tianeptine normalizes hippocampal volume and metabolite levels in stress models

Fluoxetine and desipramine, by comparison, failed to prevent CA3 dendritic atrophy in the same chronic stress models, making tianeptine's effect mechanistically distinct from conventional antidepressants.

### Anti-inflammatory Effects

Tianeptine suppresses microglial M1 polarization:
- Reduces IL-1β, IL-18, IL-6, TNF-α, nitric oxide, and ROS in LPS-stimulated microglia
- Inhibits TLR4 expression and ERK1/2 phosphorylation (Slusarczyk et al. 2016 [Ref 8])
- Suppresses NLRP3 inflammasome subunits (NLRP3, caspase-1, ASC) (Slusarczyk et al. 2018 [Ref 44])
- Normalizes prenatal stress-induced brain inflammatory changes in offspring rats (Trojan et al. 2019 [Ref 30610610])

### Pain

- Antinociceptive via spinal serotonin and norepinephrine increase (Lee et al. 2014 [Ref 45])
- Pronounced and lasting antiallodynic effects in mouse neuropathic pain model; faster onset than desipramine; distinct transcriptomic signature; no analgesic tolerance at clinical doses (Serafini et al. 2023 [Ref 13])
- Paradoxically, tianeptine reduces morphine antinociceptive tolerance and physical dependence (Chu et al. 2010 [Ref 16])

---

## Pharmacokinetics

Source: Salvadori et al. (1990 [Ref 5]); Royer et al. (1988 [Ref 6]); Wagstaff et al. (2001 [Ref 37]).

| Parameter | Value |
|---|---|
| Oral bioavailability | ~99% (no first-pass hepatic metabolism) |
| Tmax (oral) | ~0.94 ± 0.47 h (approximately 56 minutes) |
| Elimination half-life | ~2.5 ± 1.1 h |
| Protein binding | 93.8 ± 2.4% |
| Volume of distribution | ~0.8 L/kg (oral); 0.47 L/kg (IV) |
| Total clearance (IV) | 230 ± 59 mL/min |
| Renal clearance | ~0.38 mL/min (primarily extrarenal elimination) |

**Metabolites:**
- MC5: Principal active metabolite; C5 side-chain beta-oxidation product; t1/2 ≈ 7.2 ± 5.7 h (longer than parent compound). Plasma levels lower than parent but exhibits behavioral effects via MOR in a MOR-dependent fashion (Samuels et al. 2017 [Ref 2]).
- MC3: Further beta-oxidation product.
- N-desmethyl tianeptine: Minor metabolite.

**Metabolic pathway:** Tianeptine is primarily metabolized via mitochondrial beta-oxidation of the heptanoic acid side chain — analogous to fatty acid oxidation — rather than through hepatic CYP450 enzymes. This is pharmacologically significant: it indicates low risk of CYP450-mediated drug–drug interactions, particularly relevant for elderly patients on polypharmacy (Wagstaff et al. 2001 [Ref 37]).

**Dose adjustment:**
- Elderly patients: Eliminate half-life prolonged ~1 h; dose reduction to 25 mg/day (2 tablets) recommended
- Severe renal failure: Similar t1/2 prolongation; dose reduction recommended
- Hepatic impairment / alcoholism / hemodialysis: No dose adjustment required (Royer et al. 1988 [Ref 6])

**Alcohol interaction:** Concurrent alcohol administration reduces tianeptine Cmax and AUC by ~30% but does not affect MC5 pharmacokinetics (Salvadori et al. 1990 [Ref 5]).

---

## History

Tianeptine was developed by the French Society of Medical Research (Science Union Et Cie, Société Française de Recherche Médicale). Initial synthesis of the core structure is reported around 1970, with a patent filed in 1971. The compound was introduced for medical use in France under the trade name Stablon (tianeptine sodium) around 1983, with full marketing by Laboratoires Servier commencing by 1989 [Ref 36 — web-retrieved from Wikipedia and AdisInsight].

The compound was initially characterized as a "serotonin reuptake enhancer" — an unusual mechanism contrasting with SSRIs — and was studied primarily for depression and hippocampal stress vulnerability through the 1990s and 2000s. Key neurobiological work by Bruce McEwen's group at Rockefeller University in the 1990s established tianeptine as a tool compound for studying stress-induced hippocampal dendritic remodeling (McEwen et al. 1997 [Ref 22]; Magarinos et al. 1999 [Ref 23]).

In 2014, Gassaway, Javitch, Sames and colleagues at Columbia University reported the landmark discovery that tianeptine is a full mu-opioid receptor (MOR) agonist, fundamentally revising the mechanistic understanding of the drug. This paper (Gassaway et al. 2014 [Ref 1]) has 192 citations as of 2026 and precipitated a re-evaluation of tianeptine's therapeutic potential, abuse liability, and regulatory status.

The emergence of tianeptine on the US recreational drug market — marketed as dietary supplements under names like "Tianaa," "ZaZa," and "Tianna" at gas stations and convenience stores — gave rise to the colloquial term "gas station heroin" by the 2010s. Increasing abuse reports led to state-level scheduling actions from 2018 onward.

In 2023–2024, Tonix Pharmaceuticals advanced a proprietary extended-release formulation (TNX-601 CR) through Phase 2 clinical trials for major depressive disorder in the US (NCT05686408).

---

## Subjective Effects

Published descriptions of tianeptine's subjective effects come from three distinct contexts: (1) therapeutic clinical trial populations, (2) recreational user reports (case reports, poison control data), and (3) preclinical models. No dedicated human placebo-controlled subjective effects study was identified.

**Therapeutic-dose subjective profile (clinical literature):**
- Antidepressant efficacy comparable to imipramine, amitriptyline, SSRIs [Cassano et al. 1996 [Ref 24]; Wagstaff 2001 [Ref 37]]
- Anxiolytic effects in depressed patients; effective for depression-associated anxiety [Kasper & McEwen 2008 [Ref 20]]
- No sedation or cognitive impairment characteristic of classical TCAs
- Neurocognitive improvements: Tianeptine superior to escitalopram on commission errors and verbal immediate memory in MDD (Jeon et al. 2014 [Ref 14])
- Dreams altered ("changes in dreaming" reported as an adverse effect)
- No anticholinergic effects at therapeutic doses

**Supratherapeutic/recreational dose profile (case reports and poison control data):**
- Euphoria (opioid-like) [Saldana et al. 2026 [Ref 27]; Marraffa et al. 2018 [Ref 10]]
- CNS sedation and respiratory depression
- Anxiolytic effect described as motivation for use [Rawal et al. 2025 [Ref 29]]
- At extremely high doses (5–10 g/day reported in abuse cases): intoxication indistinguishable from opioid intoxication [Marraffa 2018 [Ref 10]]

**Duration data (clinical pharmacokinetics, not subjective reports):**
Published PK data (Royer 1988 [Ref 6]; Salvadori 1990 [Ref 5]) support:
- Onset: ~30–60 min (Tmax ~56 min for immediate-release oral form)
- Duration of action: approximately 2–4 hours, consistent with t1/2 of 2.5 h
- The MC5 metabolite (t1/2 ~7.2 h) may contribute to sustained effects
- Seed data of 2–3 h total duration is plausible but the MC5 metabolite likely extends subjective effects beyond the parent drug's t1/2

The effects taxonomy in the brief (motivation enhancement, anxiety suppression, cognitive euphoria, muscle relaxation, tactile euphoria, spontaneous body sensations, stimulation, constipation, nausea) is consistent with published descriptions of opioid-like and antidepressant effects. "Internal hallucinations" are not documented in the clinical literature and their origin in the brief is unclear — flag for editorial review.

---

## Safety & Toxicity

### Therapeutic index and margin of safety

The brief's note that tianeptine has a "large therapeutic index and margin of safety" applies at therapeutic doses in the context of classical antidepressant comparisons. However, this characterization requires careful contextualization with emerging abuse data.

**Cardiovascular safety:** Tianeptine does not modify heart rate, blood pressure, cardiac conduction, or ventricular function at therapeutic doses. Double-blind placebo-controlled study in 21 healthy volunteers showed no ECG changes, no orthostatic hypotension (Juvent et al. 1990 [Ref 31]). In clinical populations >3,300 patients, cardiovascular safety was maintained over up to 1 year of treatment; fewer cases of orthostatic hypotension than other antidepressants (Lasnier et al. 1991 [Ref 30]). Cassano et al. 1996 RCT confirmed: "No difference between tianeptine and placebo was shown in respect to heart rate or blood pressure" (Ref 24). This contrasts sharply with classical TCAs (imipramine, amitriptyline).

**Hepatotoxicity:** Rare; dose adjustment not required in hepatic impairment or alcoholism (Wagstaff 2001 [Ref 37]).

**Fatal overdose:** A case of fatal intoxication was documented in a 26-year-old male found with foam around his mouth. Post-mortem tianeptine blood concentration 5.1 µg/mL; liver 23 µg/g; stomach contents 22 mg; ethanol 0.53 g/L co-ingested. Death attributed to combined tianeptine-alcohol intoxication (Proença et al. 2007 [Ref 25]). No additional published fatal cases were identified in the literature search, though Parnia et al. 2025 [Ref 26] notes increasing fatal toxicities.

**Supratherapeutic toxicity:** Abuse doses of 5–10 g/day (100–270× therapeutic dose) produce opioid-like toxidrome: respiratory depression, CNS sedation, loss of consciousness. Naloxone partially or fully reverses effects in some cases (Marraffa et al. 2018 [Ref 10]).

**Neonatal exposure:** 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 failure. Tianeptine is not detected by routine urine drug screens (Ikeri et al. 2024 [Ref 9]).

**Tianeptine not detected on standard drug screens:** Multiple case reports note that standard urine immunoassay panels do not detect tianeptine, which poses diagnostic challenges in emergency settings.

---

## Harm Reduction

**Testing:** Tianeptine is not detected by standard opioid immunoassay urine drug screens. LC-MS/MS or specialized assays are required. First responders and emergency physicians should inquire specifically about dietary supplement use when opioid-like toxidrome is present without a positive standard screen [Ref 9; Ref 10].

**Naloxone:** Naloxone (naloxone, 0.4–2 mg IV/IM/intranasal) partially reverses tianeptine intoxication in some cases [Marraffa 2018 [Ref 10]; Saldana 2026 [Ref 27]]. Should be administered for respiratory depression, consistent with opioid overdose protocols.

**Alcohol combination:** Concurrent alcohol reduces tianeptine absorption ~30% (Salvadori 1990 [Ref 5]) but the combination appears potentiating in overdose contexts — the only confirmed fatal case involved tianeptine + alcohol (Proença 2007 [Ref 25]).

**Pregnancy:** Tianeptine crosses the placenta. Neonates born to mothers who chronically used tianeptine supplements may develop severe NOWS; standard opioid withdrawal protocols apply, oral morphine effective (Ikeri 2024 [Ref 9]).

**Dose escalation:** The short half-life (~2.5 h) necessitates frequent redosing and creates a cycle of interdosing withdrawal. This pharmacokinetic property likely underlies the rapid development of opioid-type dependence in abusers.

**Drug interactions:** Lower CYP450-interaction risk than most antidepressants due to beta-oxidation metabolism (Wagstaff 2001 [Ref 37]). MAO inhibitor combination: not specifically studied for tianeptine but standard MAOI washout precautions apply given the serotonergic activity and potential for serotonergic excess.

---

## Tolerance & Dependence

### Therapeutic-dose profile

At the standard therapeutic dose of 37.5 mg/day in clinical trials, tianeptine was described as having "low propensity for abuse" (Wagstaff 2001 [Ref 37]). Early clinical literature did not identify significant physical dependence at therapeutic doses. Animal models showed tianeptine does not produce analgesic tolerance or withdrawal at clinically relevant doses (Serafini et al. 2023 [Ref 13]).

### Supratherapeutic/recreational-dose profile

A dramatically different picture emerges at abuse doses. Case reports consistently describe:
- **Rapid tolerance development:** Users escalate doses from therapeutic range to grams per day within weeks to months
- **Physical dependence:** Opioid-like withdrawal syndrome upon cessation; onset consistent with short drug half-life
- **Withdrawal symptoms:** Anxiety, agitation, GI distress (nausea, vomiting, diarrhea), diaphoresis, myalgia, cravings — identical in character to opioid withdrawal (Saldana et al. 2026 [Ref 27]; Trowbridge & Walley 2019 [Ref 28])
- **Clinical course of tianeptine use disorder** consistent with opioid use disorder (Trowbridge & Walley 2019 [Ref 28])

**⚠ FLAG — Dependence liability data in brief:** The brief rates physical dependence as "low" and psychological dependence as "low" and describes it as "mildly addictive." Based on the published case report literature, these ratings appear to reflect the therapeutic-dose context and do not reflect the supratherapeutic abuse context, where physical dependence is severe and rapid-onset. The generation agent should present this nuance explicitly: low dependence liability at therapeutic doses, high opioid-like dependence liability at supratherapeutic doses.

**Withdrawal management:**
- **Buprenorphine/naloxone (buprenorphine-naloxone):** First-line treatment; multiple case reports confirm efficacy (Trowbridge & Walley 2019 [Ref 28]; Rawal et al. 2025 [Ref 29]; Szczesniak & Sullivan 2022 [Ref 42])
- **Microdose induction:** Described for one case (Szczesniak & Sullivan 2022 [Ref 42])
- **Clonidine:** May be beneficial as adjunct (Saldana 2026 [Ref 27])
- **Methadone:** Case described (Velagapudi et al. 2024 [Ref 34])
- Relapse rates high; long-term follow-up and residential care recommended for severe cases

**Cross-tolerance data:**
**⚠ FLAG — Cross-tolerance classification in brief:** The brief lists cross-tolerances as "tricyclic antidepressants, opioids." The TCA cross-tolerance claim is not supported by published data — tianeptine's opioid-type tolerance operates at MOR, not at monoamine reuptake transporters. Published case reports consistently frame tianeptine use disorder as an opioid use disorder with cross-tolerance expected for other MOR agonists. Cross-tolerance with TCAs as a pharmacological class is not documented in the literature found.

**⚠ FLAG — Tolerance half-life of "5 days":** The brief lists tolerance half-life as 5 days. No published source was identified to support this specific value. Drug elimination t1/2 is ~2.5h. Tolerance duration data from controlled human studies for tianeptine specifically were not found. This value should be flagged as unverified.

---

## Interactions

**Alcohol:** Reduces tianeptine absorption rate and lowers peak plasma concentration by ~30%. Does not affect MC5 metabolite. In overdose context: combination appears potentiating and has contributed to a documented fatal case (Proença 2007 [Ref 25]).

**MAOI inhibitors:** No published tianeptine-MAOI interaction studies found. Standard MAOI combination cautions apply; 14-day washout recommended before/after MAOI use based on class precautions (Wagstaff 2001 [Ref 37]).

**Other opioids:** Additive CNS/respiratory depression expected. Tianeptine co-administered with other opioids increases overdose risk. Velagapudi et al. 2024 [Ref 34] describes a complex case of concurrent methadone and tianeptine use.

**CYP450-metabolized drugs:** Low interaction risk — tianeptine is not primarily CYP450-metabolized. Less likelihood of drug–drug interactions than most antidepressants (Wagstaff 2001 [Ref 37]).

**Benzodiazepines/CNS depressants:** Additive CNS depression expected; case of concurrent etizolam and tianeptine withdrawal documented (Markovic & Niwash 2022 [Ref 41]).

**Serotonin syndrome:** Low risk — tianeptine does not act as a significant serotonergic agent at usual doses. No serotonin syndrome case reports involving tianeptine were found.

---

## Legal Status

**United States:**
- Not scheduled under the federal Controlled Substances Act by the DEA (as of early 2026)
- FDA issued a consumer warning January 2024 advising against purchase or use of tianeptine products; FDA determined it is unlawful to use tianeptine in food or dietary supplements
- STAND Against Emerging Opioids Act (bipartisan): proposed Schedule III classification under the CSA; announced January 25, 2024 [Ref 19]
- **State-level scheduling (at minimum):**
  - Alabama: Schedule I (effective November 14, 2021)
  - Florida: Schedule I (emergency adoption effective September 20, 2023)
  - Kentucky, Michigan, Minnesota, Mississippi, Ohio: Controlled substance restrictions in place
  - Additional states under consideration as of early 2024

**France:** Approved as prescription drug; trade name Stablon; manufactured by Laboratoires Servier; approved ~1983–1989 [Ref 36].

**European Union:** Approved in approximately 15 EU member states including France, Portugal, Bulgaria, Romania, Slovakia, Poland, Malta, Hungary, Lithuania, Slovenia, Czech Republic, Austria, Latvia, Estonia, Luxembourg. Trade names include Stablon, Coaxil [Ref 36].

**United Kingdom:** Not approved; not available.

**Australia:** Not approved; not listed on the ARTG. TGA has considered scheduling [TGA AdisInsight].

**Canada:** Not approved; not available.

**New Zealand:** Not available.

**Italy:** Not approved despite EU membership.

**Global availability:** Marketed in 66+ countries, including across Europe (excluding UK and Italy), Asia (including Singapore, Japan), Latin America [Ref 36].

---

## Clinical Trials

Identified via ClinicalTrials.gov search:

| NCT ID | Title | Phase | Status | Sponsor | Notes |
|---|---|---|---|---|---|
| NCT05686408 | Study to Evaluate TNX-601 ER Monotherapy vs Placebo in MDD | Phase 2 | Completed | Tonix Pharmaceuticals | Extended-release formulation; results not yet published in PubMed |
| NCT01309776 | Tianeptine vs Escitalopram in MDD | Phase 4 | Completed | Samsung Medical Center | 12-week head-to-head |
| NCT04249596 | Tianeptine for Treatment Resistant Depression | Phase 4 | Terminated | Jonathan Javitch (Columbia) | PI is author of key MOR agonism papers |
| NCT00879372 | Adjunctive Tianeptine in Bipolar Depression | Phase 3 | Unknown | Hospital de Clinicas de Porto Alegre | RCT published (Kauer-Sant'Anna 2019 [Ref 15]) |
| NCT06012552 | Tianeptine for COVID Fog in Post-COVID Patients | Phase 2 | Recruiting | Military Institute of Medicine, Poland | Novel indication based on neuroplasticity mechanism |
| NCT05935059 | Tianeptine vs Pregabalin for Post-Mastectomy Pain | N/A | Completed | National Cancer Institute, Egypt | Pain indication |

The TNX-601 extended-release formulation (NCT05686408, Tonix Pharmaceuticals) completed Phase 2 for MDD in the US and represents an attempt to develop a US-approved tianeptine formulation. Published results were not identified in PubMed at time of research.

The terminated NCT04249596 (treatment-resistant depression, Columbia University, PI Javitch) is notable — same research group that discovered MOR agonism. Termination reasons were not available in the registry.

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. No community feedback items to evaluate.

---

## Gaps & Flags

### ⚠ CRITICAL FLAGS FOR EDITORIAL REVIEW

**1. Chemical class: "Benzamide" is incorrect**
PubChem CID 68870 and the IUPAC name confirm tianeptine is a benzo[c][2,1]benzothiazepine (a modified tricyclic compound). It does not contain a benzamide moiety. This should be corrected to reflect its actual chemical class: "tricyclic antidepressant (atypical)" or "dibenzothiazepine derivative."

**2. "AMPA receptor positive allosteric modulator" is imprecise**
Tianeptine does not directly bind AMPA receptors. The AMPA potentiation is indirect, mediated by CaMKII and PKA activation via MAPK/JNK signaling pathways (Szegedi et al. 2011 [Ref 7]). This should be described as "AMPA receptor potentiator (indirect/kinase-mediated)" not "positive allosteric modulator."

**3. Dependence ratings ("low/low") do not reflect supratherapeutic use**
Multiple case reports (2018–2026) document severe, rapid-onset physical opioid-like dependence at recreational doses (5–10 g/day). The "low" physical and psychological dependence ratings appear to derive from therapeutic-dose context only. Article should explicitly stratify these ratings by dose context.

**4. Tolerance "half-life: 5 days" — unverified**
No published source confirms this specific value. The drug's elimination half-life is 2.5 h. Tolerance half-life in the context of the brief (time for tolerance to decay by half) is not found in the literature. Should be flagged as "unverified" in structured data.

**5. Cross-tolerance: "tricyclic antidepressants" is unsupported**
TCA cross-tolerance is not documented or pharmacologically plausible given tianeptine's MOR mechanism. Published treatment literature frames tianeptine tolerance as opioid-type tolerance. Cross-tolerance with opioids is well-supported; TCA cross-tolerance is not. This value should be corrected.

**6. "Internal hallucinations" in effects taxonomy — source unclear**
No published clinical report of tianeptine causing internal hallucinations was found. This effect is not consistent with the known pharmacological profile. Should be reviewed and sourced or removed.

**7. SMILES string missing from brief**
Brief field shows empty SMILES. PubChem CID 68870 should provide canonical and isomeric SMILES; API did not return this field. Generation agent should retrieve SMILES via PubChem CID directly.

**8. Dose range contextual note**
The seed dose data (Heavy: 100+ mg) remains far below documented recreational abuse doses (5,000–10,000+ mg/day per Marraffa 2018 [Ref 10]). The dose ranges in the brief appear to represent a transition zone between the top of therapeutic dosing and the bottom of recreational misuse. The generation agent should note this discontinuity explicitly.

**9. ROAs: IV use documented in abuse context**
The brief lists only oral ROA. Multiple abuse case reports reference IV injection as a route in severe dependency cases. The generation agent should note this under harm reduction.

**10. TNX-601 ER trial results unpublished**
NCT05686408 completed Phase 2 but results were not found in PubMed or public literature. If approved, this would represent the first US-approved tianeptine formulation — significant for legal status section.

### Data gaps

- **LD50 data:** No published human LD50. Animal LD50 data not returned by searches.
- **Specific SMILES string:** Not returned by PubChem API.
- **CAS number:** Not returned by API (CAS 66981-73-5 for tianeptine sodium is commonly cited but could not be programmatically verified in this session).
- **Binding affinity at other receptors:** No published data on activity at adrenergic, histamine, muscarinic, or dopamine receptors for tianeptine (unlike classical TCAs, tianeptine appears essentially clean at these targets).
- **Enantiomeric pharmacology:** Differential in vivo pharmacology of R vs S tianeptine not yet characterized beyond albumin binding (Aslani et al. 2025 [Ref 4]).
- **Definitive mechanism resolution:** Whether MOR agonism is sufficient to explain all of tianeptine's antidepressant properties, or whether AMPA/glutamate effects operate independently, remains an open question (Nishio et al. 2024 [Ref 3]).
- **Specific CYP enzyme data:** No CYP contribution quantified; beta-oxidation confirmed as primary pathway but fractional CYP contribution unknown.

---

*Research completed: 2026-04-25. Total citations in registry: 45.*