ToxCard: Tianeptine

Authors: Nicholas S. Imperato, DO, MPH (@nickimperato14, Emergency Medicine Resident, Rutgers New Jersey Medical School), Cynthia Santos MD (Associate Professor, Emergency Medicine, Medical Toxicology, Addiction Medicine, Rutgers New Jersey Medical School) // Reviewed by: Ann-Jeannette Geib, MD  (Associate Professor Emergency Medicine, Medical Toxicology, Wake Forest University School of Medicine/Carolinas Medical Center); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 28-year-old male with a history of depression arrives to the ED via EMS after being found somnolent and confused by a friend. According to the patient’s friend, he had recently been purchasing an over-the-counter substance from a convenience store near their apartment, which improved his mood and was used to treat his depression but also had a “euphoric” effect. The friend believed that the substance had “Neptune’s Fix” written on the label. The friend noted that the patient had been continuously increasing his dose over the past few days. On arrival, the patient is bradypneic and hypoxic, has pinpoint pupils, and appears drowsy yet arousable to voice.

Questions:

1. What is tianeptine?
2. How does acute intoxication or withdrawal from tianeptine present?
3. What are the important considerations for management in the ED?

Background:

Tianeptine is an atypical tricyclic antidepressant (Image 1 displays the structure of Tianeptine) primarily used in some European, Asian, and Latin American countries for the treatment of major depressive disorder, and is sold under the name; CoaxilTM or TatinolTM.1 While it has been used across the globe, it is not currently FDA-approved in the United States due to concerns about its potential for abuse, dependence, and misuse, particularly at higher doses where it may produce opioid-like effects. The FDA has not found sufficient evidence supporting its efficacy and safety for treating depression. Additionally, tianeptine has been associated with serious side effects, including withdrawal symptoms and seizures, especially when misused, leading to regulatory restrictions as a controlled substance in several states.2,3

Tianeptine has a complex mechanism of action, believed to modulate glutamatergic neurotransmission and enhance reuptake of serotonin, while also exhibiting partial µ-opioid receptor agonism at higher doses.4 Due to its opioid-like properties, individuals may misuse tianeptine for euphoric effects. Tianeptine is thought to also inhibit sodium channels, which can lead to a prolonged QRS interval or a Brugada pattern on the ECG, similar to tricyclic antidepressants (TCAs).5,6 While its effects on cardiac conduction are less pronounced than TCAs, tianeptine still poses risks for arrhythmias, especially in cases of overdose or misuse. Although tianeptine is not approved in the United States, it is accessible online, in gas stations, or convenience stores, typically sold under the names; “Zaza”, “Pegasus”, “Neptune’s Fix”, or Tianna Red”, raising concerns about overdose, dependence, and withdrawal.7 And because of its increasing availability, paired with its mu-opioid receptor agonism, it has earned the nickname of “gas station heroin”.8

Epidemiology

• Global Variation: Tianeptine has been on the market for decades in various regions; however, data on its misuse are limited and largely come from case reports, poison center calls, and small cohort studies.
• Increasing Awareness: In areas where tianeptine is not approved, online availability has led to increasing reports of recreational use, dependence, and overdose presentations to EDs.9,10 Between 2000 and 2017, there were 218 calls to poison centers across the country for tianeptine exposures. Only 11 of these exposures occurred between 2000-2014.6 And recently, in New Jersey, there was a cluster of 20 tianeptine-related exposures over a 6-month period in 2023.8 
• Under-Recognized: Because tianeptine is not widely known by many health providers and is often absent from routine toxicology panels, many cases of overdose or withdrawal may go undetected or misdiagnosed.

Clinical Presentation:

• Acute Intoxication:
• • Patients may present altered and confused, or resembling opioid toxicity, with respiratory depression, sedation, bradycardia, hypotension, and miosis.6

• Withdrawal:
  • Abrupt cessation after prolonged or high-dose use can lead to opioid-like withdrawal symptoms such as autonomic hyperactivity, anxiety, agitation, insomnia, or diarrhea. In a few cases that have been reported, buprenorphine may offer some utility in the management of acute withdrawal.11,12

Diagnosis

• Clinical Assessment:
  • A high index of suspicion is required in patients with unexplained sedation, respiratory depression, who admit to using medications obtained online, or who may not initially respond to naloxone
• Laboratory Tests:
  • Routine toxicology screens do not typically detect tianeptine
  • Standard workup is often non-specific but necessary to evaluate for other conditions or co-ingestants. Patients should have a routine 12-lead ECG and cardiac monitoring to assess for the development of sodium channel blockade. 
• Collateral Information:
  • History from friends, family, or pill bottles can guide suspicion of tianeptine use.

Management:

• Supportive Care:
  • Airway and Breathing: Monitor for respiratory compromise; provide supplemental oxygen or airway protection if needed
  • Circulation: Administer IV fluids for hypotension and continuously monitor for any changes in hemodynamics. Sodium channel blockade is treated with pushes of sodium bicarbonate. 
• Pharmacological Interventions:
  • Naloxone: Because of tianeptine’s µ-opioid receptor agonism, naloxone may partially reverse respiratory depression and sedation.13
  • Symptomatic Withdrawal Treatment: Benzodiazepines, clonidine, or other supportive medications may be used to address withdrawal symptoms

• Since tianeptine is frequently utilized in Europe, there have been documented cases where prolonged use or withdrawal has been successfully mitigated with buprenorphine.12,14

• Monitoring and Observation:
  • Extended observation in the ED or inpatient setting is warranted to monitor for delayed or rebound toxicity and withdrawal, as well as EKG changes due to its TCA-like effects.
• Psychiatric Evaluation & Addiction Services:
  • While this medication and its misuse may be frequently missed, it is important to connect patients with addiction services and develop a comprehensive discharge plan that can help prevent future relapse.

Case Follow-up:

Over a 24-hour observation period in the ED, the patient’s respiratory status improved with supplemental oxygen and administration of naloxone. He was evaluated by the addiction medicine and psychiatry services, outpatient appointments were scheduled, and he was subsequently discharged.

Clinical Pearls:

• Tianeptine can produce opioid-like effects due to its partial µ-opioid receptor agonism.
• Tianeptine may lead to a prolonged QRS interval or a Brugada pattern on ECG.
• Naloxone may be effective in reversing respiratory depression in acute overdoses.
• Tianeptine withdrawal may mirror opioid withdrawal and can be managed with adjuncts or buprenorphine.
• Consider tianeptine in unexplained sedation or “opioid-like” presentations when standard toxicology screens are negative or naloxone is not effective.

References:

1. Gupta, S., Wallace, R., & Sloshower, J. (2017). Online Sales of Unscheduled Pharmaceutical Agents: A Case Report of Tianeptine Use in the United States. Journal of Addiction Medicine, 11(5), 411. https://doi.org/10.1097/ADM.0000000000000342
2. US Food and Drug Administration. (2022). Tianeptine Products Linked to Serious Harm, Overdoses, Death. FDA. https://www.fda.gov/consumers/consumer-updates/tianeptine-products-linked-serious-harm-overdoses-death
3. Quadir, M., Rine, N. I., Badeti, J., Hays, H. L., Michaels, N. L., Yang, J., & Smith, G. A. (2025). Tianeptine Exposures Reported to United States Poison Centers, 2015-2023. Journal of Medical Toxicology: Official Journal of the American College of Medical Toxicology, 21(1), 30–41. https://doi.org/10.1007/s13181-024-01053-6
4. Dempsey, S. K., Poklis, J. L., Sweat, K., Cumpston, K., & Wolf, C. E. (2017). Acute Toxicity From Intravenous Use of the Tricyclic Antidepressant Tianeptine. Journal of Analytical Toxicology, 41(6), 547–550. https://doi.org/10.1093/jat/bkx034
5. Bayar-Masood, T., Tony-Onugu, N., KHAN, A., Shaikh, S., & Keller, E. (2024). Abstract 4119073: Zaza: A New Etiology of an Acquired Brugada-Pattern ECG. Circulation, 150(Suppl_1), A4119073–A4119073. https://doi.org/10.1161/circ.150.suppl_1.4119073
6. Zahran, T. E. (2018). Characteristics of Tianeptine Exposures Reported to the National Poison Data System—United States, 2000–2017. MMWR. Morbidity and Mortality Weekly Report, 67. https://doi.org/10.15585/mmwr.mm6730a2
7. Edinoff, A. N., Sall, S., Beckman, S. P., Koepnick, A. D., Gold, L. C., Jackson, E. D., Wenger, D. M., Cornett, E. M., Murnane, K. S., Kaye, A. M., & Kaye, A. D. (2023). Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review. Pain and Therapy, 12(5), 1121–1134. https://doi.org/10.1007/s40122-023-00539-5
8. Counts, C. J. (2024). Notes from the Field: Cluster of Severe Illness from Neptune’s Fix Tianeptine Linked to Synthetic Cannabinoids — New Jersey, June–November 2023. MMWR. Morbidity and Mortality Weekly Report, 73. https://doi.org/10.15585/mmwr.mm7304a5
9. Gupta, S., Wallace, R., & Sloshower, J. (2017). Online Sales of Unscheduled Pharmaceutical Agents: A Case Report of Tianeptine Use in the United States. Journal of Addiction Medicine, 11(5), 411. https://doi.org/10.1097/ADM.0000000000000342
10. Hershey, H. L., Onyango, E. M., Durst, K., Korona-Bailey, J., & Mukhopadhyay, S. (2024). Tianeptine-involved emergency department visits, fatal overdoses, and substance seizures in Tennessee, 2021–2023. Drug and Alcohol Dependence Reports, 12, 100272. https://doi.org/10.1016/j.dadr.2024.100272
11. Farsani, A., & Reyes, C. (2024). Tianeptine’s Obscured Withdrawal, Presentation, and Treatment. Cureus. https://doi.org/10.7759/cureus.62554
12. Trowbridge, P., & Walley, A. Y. (2019). Use of Buprenorphine-Naloxone in the Treatment of Tianeptine Use Disorder. Journal of Addiction Medicine, 13(4), 331–333. https://doi.org/10.1097/ADM.0000000000000490
13. Ari, M., Oktar, S., & Duru, M. (2010). Amitriptyline and tianeptine poisoning treated by naloxone. Human & Experimental Toxicology, 29(9), 793–795. https://doi.org/10.1177/0960327110372403
14. Rawal, V. Y., Gallardo, M., Henderson, K., Hall, O. T., Klisovic, N., & Sikic-Klisovic, E. (2025). Severe tianeptine withdrawal symptoms managed with medications for opioid use disorder: A case report. Journal of Addictive Diseases, 43(1), 98–103. https://doi.org/10.1080/10550887.2023.2290139