
==== Front
Drug Alcohol Depend Rep
Drug Alcohol Depend Rep
Drug and Alcohol Dependence Reports
2772-7246
Elsevier

S2772-7246(24)00056-8
10.1016/j.dadr.2024.100272
100272
Short Communication
Tianeptine-involved emergency department visits, fatal overdoses, and substance seizures in Tennessee, 2021–2023
Hershey Haley L. haley.hershey@tn.gov
⁎
Onyango Edward M.
Durst Kate
Korona-Bailey Jessica
Mukhopadhyay Sutapa
State of Tennessee - Tennessee Department of Health, Andrew Johnson Tower, 7th Floor, 710 James Robertson Parkway, Nashville, TN 37243, United States
⁎ Corresponding author. haley.hershey@tn.gov
14 8 2024
9 2024
14 8 2024
12 10027222 4 2024
1 8 2024
12 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Tianeptine is an antidepressant that acts as an agonist to the mu-opioid receptor and enhances serotonin reuptake. Tianeptine has been legally sold as an antidepressant in some countries but is not approved for any medical use by the U.S. Food and Drug Administration (FDA). Tianeptine is not a federally controlled substance, but became a schedule II substance in Tennessee on July 1, 2022. This publication aims to describe the prevalence of tianeptine-involved emergency department visits, fatal overdoses, and substance seizures in Tennessee from 2021 to 2023.

Methods

We conducted a study to examine the prevalence of tianeptine-involved emergency department visits and fatal overdoses in Tennessee using data for 2021 to 2023 from the Tennessee Electronic Surveillance System for the Early Notification of Community based Epidemics (ESSENCE) database and the Tennessee State Unintentional Drug Overdose Reporting System (SUDORS). Substance seizure data from National Forensic Laboratory Information System (NFLIS) are included.

Results

Our search of ESSENCE, SUDORS, and NFLIS yielded 50 tianeptine-involved emergency department visits, 6 tianeptine-involved fatal overdoses, and 19 tianeptine substance seizures respectively. Demographic information is provided for the emergency department visits and tianeptine-involved fatal overdoses. Discharge diagnosis and clinical symptomology information are provided for the emergency department visits.

Conclusion

Emergency department visits and fatal overdoses involving tianeptine have occurred in Tennessee despite tianeptine becoming a schedule II substance. Among emergency department visits, tianeptine use is most commonly associated with gastrointestinal and psychological symptoms. All fatal cases where tianeptine was detected involved other substances, suggesting tianeptine plays a role in polysubstance use.

Highlights

• Tianeptine is an illicit substance used for its euphoric effects similar to opioids

• ESSENCE, SUDORS, and NFLIS databases were queried for tianeptine

• Tianeptine is involved in ED visits, fatal overdoses, and substance seizures in Tennessee

• Tianeptine use is associated with gastrointestinal and psychological symptoms

Keywords

Tianeptine
Tennessee
Overdose
Surveillance
SUDORS
ESSENCE
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pmc1 Introduction

Tianeptine, an antidepressant that acts as an agonist to the mu-opioid receptor and enhances serotonin reuptake, is a substance that is used for its euphoric effects similar to other opioids (Counts et al., 2024, U.S. Department of Justice, 2024). Tianeptine is approved in some countries to treat anxiety and depression, but it is not approved for any medical use by the U.S. Food and Drug Administration (FDA) (U.S. Food and Drug Administration, 2024a). Tianeptine is sold in various forms, such as powders, pills, and elixir formulations and is often sold at gas stations, smoke and vape shops, and can even be purchased online (U.S. Department of Justice, 2024; U.S. Food and Drug Administration, 2024a). Tianeptine has been sold under brand names like “ZA ZA”, “Neptune’s Fix”, and “Tianaa” and has been referred to as “gas station heroin” in media reports (Center for Forensic Science Research and Education, 2024). For example, Neptune’s Fix can be purchased online for $29.95 for 20 tablets, each containing 150 mg of tianeptine and Zaza Red can be purchased at $69.99 for 60 capsules, each containing 700 mg of a tianeptine blend (Nootropic Deals, 2024, Allo Supplements, 2024). In the U.S., tianeptine products are often sold using false marketing claims of improving brain function, treating anxiety or depression, or treating pain and opioid use disorder (U.S. Food and Drug Administration, 2024a). Misuse of tianeptine has led to severe adverse health effects like seizure, respiratory depression, loss of consciousness as well as other cardiovascular and neurological effects (U.S. Department of Justice, 2024; U.S. Food and Drug Administration, 2024b). In some cases, the misuse of tianeptine has caused death (U.S. Department of Justice, 2024; U.S. Food and Drug Administration, 2024b). While tianeptine has been prescribed as an effective antidepressant at low doses in foreign countries, the lack of tianeptine regulation in the U.S., the lack of awareness about the harm tianeptine consumption can cause, and the ability for companies to market tianeptine for health purposes, has led to increased incidents of harmful tianeptine use in the U.S. (Wagner et al., 2023).

Tianeptine is not currently controlled under the federal Controlled Substances Act. On January 22, 2024 a bill was introduced in the U.S. House of Representatives to federally control tianeptine as a schedule III substance (HR. 7068, 2024). However, several states have passed legislation to regulate tianeptine (Hargett et al., 2024). In Tennessee, tianeptine became a schedule II substance on July 1, 2022 (SB, 1997, 2024). Due to this change in Tennessee legislation and reporting about the growing threat of tianeptine (U.S. Food and Drug Administration, 2024a, 2024b), the frequency and characteristics of emergency department visits, fatal overdoses, and substance seizures in Tennessee were investigated.

2 Materials and methods

The Tennessee Department of Health (TDH) routinely conducts fatal and nonfatal drug overdose surveillance through the Tennessee Electronic Surveillance System for the Early Notification of Community-based Epidemics (ESSENCE) database and the State Unintentional Drug Overdose Reporting System (SUDORS).

ESSENCE captures details of emergency department visits in Tennessee. A search of the ESSENCE database was conducted for emergency department visits involving tianeptine, from January 1, 2021 to December 31, 2023. Visits were identified with a text-only definition utilizing the following terms: “tianeptine”, “Stablon”, “Coaxil”, “Zaza”, “Tianaa”, “Red Dawn”, “Neptune’s Fix”, and “Pegasus”. TN ESSENCE was queried in the chief complaints-discharge diagnosis (CCDD) and in the Triage Notes fields. Records obtained were inspected and reviewed by two epidemiologists, contributing authors on this paper, to ascertain their inclusion. Encounter details including symptoms of the patient, diagnosis discharge codes, and tianeptine use information were abstracted from the CCDD and Triage Notes fields. Discharge diagnosis codes are from the International-Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Triage notes are an open text field containing encounter notes. The open text Triage Notes field may include information from the patient on their clinical symptoms, their use history with tianeptine, and where they purchased the product. This information is voluntarily provided by the patient and recorded by hospital staff. There is no standardization across hospital systems for what information is provided in either the CCDD or Triage Notes fields. Importantly, other substances or health phenomenon may have affected patients’ encounters but this information may not be captured in ESSENCE.

SUDORS captures details associated with unintentional and undetermined fatal drug overdoses that occur in the state regardless of decedent residence. Details are collected using death certificates, death scene investigation, autopsy reports, and toxicology (Korona-Bailey et al., 2023). Fatal tianeptine-involved overdoses for January 1, 2021 to December 31, 2023 were identified by searching for the word ‘tianeptine’ in toxicology results and cause of death text fields. SUDORS data from July 1, 2023 to December 31, 2023 is provisional.

Once all emergency department visits and fatal tianeptine-involved cases were identified, demographic and geographic trends analyses were completed. Geographic trends are based on the eastern, middle, and western grand divisions outlined in the state statutes (Code, 2024). The grand divisions are legally defined regions that parse Tennessee into thirds and define some state government activities, they were historically created based on the distinct geographic and cultural features of each region (The Tennessee Historical Society, 2024). Additionally, for emergency department visits a trends analysis of encounter details was completed.

A search for tianeptine in law enforcement seizure data was also conducted using the National Forensic Laboratory Information System (NFLIS) for January 1, 2021 to December 31, 2023 due to its public availability and ease of use.

This study was found to not meet the definition of Human Subjects Research per 45 CFR 46.102(e)(1) and was exempted from IRB review by the Tennessee Department of Health Institutional Review Board.

3 Results

Our search of ESSENCE, SUDORS, and NFLIS yielded 50 tianeptine-involved emergency department visits, 6 tianeptine-involved fatal overdoses, and 19 tianeptine substance seizures respectively. Among the 50 tianeptine-involved emergency department visits, most cases were male (58.0 %), white (92.0 %), and not Hispanic or Latino (80.0 %; Table 1). The most frequent age group reported is 35–44 years (30.0 %; Table 1). The largest number of cases were patients with residence status in the middle grand division (52.0 %; Table 1). The temporal distribution of the emergency department cases was 12 (24.0 %) occurring in 2021, 26 (52.0 %) occurring in 2022, and 12 (24.0 %) occurring in 2023. Half of the emergency department visits occurred before July 1, 2022. The three most common discharge diagnosis codes associated with the encounters were mental and behavioral disorders due to psychoactive substances (58.0 %), endocrine, nutritional, and metabolic diseases (24.0 %), and poisoning by, adverse effect of and underdosing of drugs, medicaments, and biological substances (20.0 %; Table 2). The most common symptoms documented were anxiety/paranoia (28.0 %) and nausea/vomiting/diarrhea/abdominal pain (20.0 %; Table 2). There were 17 (34.0 %) patients that mentioned withdrawal from tianeptine and 4 (8.0 %) that mentioned withdrawal from opioids in their encounters (Table 2). The most common tianeptine products documented as consumed were Zaza Red (32.0 %), Pegasus (10.0 %), and Red Dawn (10.0 %; Table 2). When clinicians documented purchasing location information in the Triage Notes, several individuals (18.0 %) reported that they purchased tianeptine products at smoke/vape shops and gas stations.Table 1 Characteristics of Tianeptine-Involved Emergency Department Visits, TN ESSENCE 2021–2023.

Table 1	n=50 n(%)	
Age		
<25	6 (12.0)	
25–34	13 (26.0)	
35–44	15 (30.0)	
45–54	11 (22.0)	
55+	5 (10.0)	
Sex		
Female	21 (42.0)	
Male	29 (58.0)	
Race		
White	46 (92.0)	
Black or African American	1 (2.0)	
All Other	3 (6.0)	
Ethnicity*		
Not Hispanic or Latino	40 (80.0)	
Hispanic or Latino	2 (4.0)	
Grand Division**		
East	13 (26.0)	
Middle	26 (52.0)	
West	5 (10.0)	
⁎ 8 individuals had ethnicity as not reported or null

⁎⁎ Grand division is based on patient’s residence, 6 individuals had residence as other region or state

Table 2 Encounter Details of Tianeptine-Involved Emergency Department Visits, Tennessee ESSENCE 2021–2023.

Table 2		n=50 n(%)	
Discharge Diagnosis codes associated with encounter			
Mental and behavioral disorders due to psychoactive substance use (F10-F19)	29 (58.0)	
Endocrine, nutritional and metabolic diseases (E00-E89)	12 (24.0)	
Poisoning by, adverse effect of and underdosing of drugs, medicaments, and biological substances (T40-T50)	10 (20.0)	
Symptoms and signs involving cognition, perception, emotional state and behavior (R40-R46)	8 (16.0)	
Symptoms and signs involving the digestive system and abdomen (R10-R19)	8 (16.0)	
Symptoms described by patient or observed by provider	Anxiety/paranoia	14 (28.0)	
Nausea/vomiting/diarrhea/abdominal pain	10 (20.0)	
	
Hot/fevered/sweating	7 (14.0)	
Generalized pain/body aches	7 (14.0)	
Insomnia	6 (12.0)	
Chest pain/irregular heartbeat	6 (12.0)	
Lethargy	4 (8.0)	
Withdrawal mentioned in patient's triage notes**	Withdrawal from tianeptine	17 (34.0)	
Withdrawal from opioids	4 (8.0)	
Tianeptine brand name used*	Zaza Red	16 (32.0)	
Pegasus	5 (10.0)	
Red Dawn	5 (10.0)	
Location of tianeptine purchase*	CBD/smoke/vape shops	4 (8.0)	
Gas stations	5 (10.0)	
Frequency of tianeptine use*	Habitual use - patient reported taking tianeptine at a recurring (but not consistent) frequency for a duration of time	15 (30.0)	
Daily use - patient reported taking tianeptine every day for a duration of time	7 (14.0)	
Reason for tianeptine use*	Help with opioid withdrawal	3 (6.0)	
Intentional overdose	2 (4.0)	
Get high	2 (4.0)	
Stay awake at work	1 (2.0)	
For pain	1 (2.0)	
⁎ If documented in triage notes, unknown or not mentioned is not listed

⁎⁎ Not mutually exclusive

We identified 6 tianeptine-involved fatal overdoses from January 1, 2021 to December 31, 2023. All cases were Tennessee residents. In 5 cases, tianeptine was listed as a cause of death along with other substances. Almost all deaths had fentanyl detected (83.3 %) and no deaths were caused by tianeptine alone. Supplemental Table 1 shows the toxicology results of all six decedents. Most decedents were males (83.3 %) and between ages 35–44 years (66.7 %). All decedents were non-Hispanic white. Two-thirds of decedents had a history of substance use disorder (66.7 %). The temporal distribution of the fatal cases was 5 (83.3 %) occurring in 2022 and 1 (16.7 %) occurring in 2023. Four (66.7 %) of the fatalities involving tianeptine occurred before July 1, 2022 and 2 (33.3 %) occurred after.

Tennessee had the highest number of tianeptine substance seizures from any state based on NFLIS data. From January 1, 2021 to December 31, 2023, Tennessee had 19 seizures recorded. The temporal distribution of the substance seizures was 2 (10.5 %) in 2022 and 17 (89.5 %) in 2023. All substance seizures occurred after July 1, 2022.

4 Discussion

This study describes the characteristics of tianeptine-involved emergency department visits, fatal overdoses, and substance seizures in Tennessee from January 1, 2021 to December 31, 2023. During this time frame, there were 50 tianeptine-involved emergency department visits, 6 tianeptine-involved fatal overdoses, and 19 tianeptine substance seizures recorded. Half of the emergency department visits occurred after the July 1, 2022 date when tianeptine became a scheduled substance in Tennessee. The number of fatal overdoses decreased after July 1, 2022 and the number of seizures increased. The similar numbers of emergency department visits before and after July 1, 2022 suggest that individuals are still able to obtain tianeptine despite the scheduling in Tennessee and neighboring states (Hargett et al., 2024).

In comparison to other studies that assessed tianeptine-involved overdoses and exposure, our results were similar. (El Zahran et al., 2018) assessed characteristics of tianeptine exposure in the National Poison Data System in the U.S. between 2000 and 2017. Their study reported 114 tianeptine-only exposure calls, excluding withdrawal associated calls; The most common clinical symptoms reported were neurologic (48.3 %), cardiovascular (32.5 %), and gastrointestinal (10.5 %). Among the 50 tianeptine-involved emergency department visits in our study, there were few neurologic and cardiovascular symptoms reported but several gastrointestinal and psychiatric symptoms, with the most common symptoms reported or observed as anxiety/paranoia (n=14) and nausea/vomiting/diarrhea/abdominal pain (n=10). Comparing the findings of (El Zahran et al., 2018) to our study, there is significant overlap in the type of clinical symptoms experienced. The differences in frequency of type of clinical symptoms between (El Zahran et al., 2018) and our study may represent differences in the severity and type of clinical symptoms experienced by those who call poison control to address their tianeptine exposure versus individuals who report to the emergency department for tianeptine consumption.

Our findings support the FDA’s assertion that tianeptine consumption is associated with serious adverse health outcomes and death (U.S. Food and Drug Administration, 2024c). However, all six deaths involving tianeptine also detected multiple substances with a majority detecting fentanyl in toxicology. This suggests that tianeptine is often used with other substances and may also be used as a cut or buffer product within illicitly sold substances. Further, individuals who were seen in Tennessee emergency departments due to their tianeptine exposure were reported or observed as using tianeptine to address personal health concerns, like addressing withdrawal from opioids or to address pain. The availability of tianeptine products in gas stations, vape shops, and online marketplaces will continue to draw in customers who believe these products are safe to use and effective at treating a multitude of health concerns. It should also be considered that tianeptine may be mixed within the illicit substance supply and individuals not seeking out tianeptine products could be exposed.

Tianeptine, a substance that is not approved for any medical use by the U.S. FDA, has been involved in emergency department visits, fatal overdoses, and substance seizures in Tennessee. Informing individuals about tianeptine products’ lack of safety as well as providing harm reduction materials can increase awareness about tianeptine and how individuals can remain safe in a climate of polysubstance use. As an example of educational materials, the Tennessee Department of Health (Tennessee Department of Health, 2024) created and publicly shared a tianeptine infographic and also directly shared with harm reduction and substance use prevention partners across the state. To understand tianeptine’s impact, public health authorities, public safety entities, and healthcare providers could examine their surveillance data and test for the prevalence of tianeptine to determine how tianeptine has affected their communities.

5 Conclusion

Tianeptine, a substance not currently controlled by the federal Controlled Substances Act, has been involved in emergency department visits, fatal overdoses, and substance seizures in Tennessee between January 1, 2021 and December 31, 2023. Among those who visited the emergency department, discharge diagnosis codes, clinical symptoms, type of products consumed, and frequency of use varied. However, there were commonalities in the types of clinical symptoms among emergency department patients in Tennessee and other national studies, suggesting that tianeptine exposure is frequently associated with a variety of gastrointestinal and psychological clinical symptoms. Additionally, fatalities in which tianeptine was detected on toxicology indicate that tianeptine is another substance that adds to the complexity of polysubstance use. To address tianeptine use in the U.S., we encourage states to examine their surveillance data and provide substance use prevention information that is specific to tianeptine.

Role of Funding Source

This work was supported by a grant from the 10.13039/100000030 Centers for Disease Control and Prevention , Overdose Data to Action [NU17CE924981 ], and Overdose Data to Action in States [NU17CE010208 ]. The funding agency had no role in the design, analysis, or interpretation of the findings for this study. All those making substantial contribution to this study have been listed as authors.

Contributors

All authors were involved in the planning of the publication, literature review, formal analysis of data, interpretation of key findings, and writing the manuscript. Sutapa Mukhopadhyay conceptualized the study. Kate Durst contributed to formal analysis of the triage notes in the ESSENCE data. Jessica Korona-Bailey contributed to formal analysis of the SUDORS and NFLIS data. Edward M Onyango contributed to formal analysis of the ESSENCE data. Haley L Hershey wrote the original manuscript draft.

CRediT authorship contribution statement

Sutapa Mukhopadhyay: Writing – review & editing, Methodology, Conceptualization. Kate Durst: Writing – review & editing, Methodology, Formal analysis. Jessica Korona-Bailey: Writing – review & editing, Formal analysis. Edward M Onyango: Writing – review & editing, Formal analysis. Haley L Hershey: Writing – review & editing, Writing – original draft, Visualization.

Declaration of Competing Interest

The authors declare no financial or personal competing interests that could have influenced the work reported in this publication.

Appendix A Supplementary material

Supplementary material

Acknowledgements

The authors would like to thank the Tennessee SUDORS team for countless hours abstracting and entering data and the Office of the Chief State Medical Examiner for providing autopsy reports to include in analyses.

Appendix A Supplementary data associated with this article can be found in the online version at doi:10.1016/j.dadr.2024.100272.
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