RESEARCH ANALYSIS | Reported Adverse Effects, Withdrawal Symptoms, and Misuse Patterns Associated with Non-Prescription Tianeptine Use

Reported Adverse Effects, Withdrawal Symptoms, and Misuse Patterns Associated with Non-Prescription Tianeptine Use

Dante Gilberti, MS

Drexel University College of Medicine

SUMMARY POINTS

• Tianeptine misuse is associated with significant neurologic and cardiovascular adverse effects.

• Withdrawal symptoms from tianeptine resemble opioid withdrawal and frequently require medical treatment, highlighting the drug’s dependence potential.

• Misuse patterns show rapid tolerance and escalating doses, often involving coingestants like kratom, and affecting primarily adults aged 21–40.

ANALYSIS

Background

Tianeptine is an atypical tricyclic antidepressant used in several countries as a treatment for major depressive disorder (1). It is a full mu- and weak delta-opioid receptor agonist capable of triggering dopamine release (2). Despite not being cleared for the market in the United States, tianeptine has been sold commercially as a nootropic and can be bought through online retailers and in convenience stores without a prescription (3). Due to the alarming increases in misuse, in February of 2022, the U.S. Food and Drug Administration (FDA) issued public warnings about the risk of severe side effects and overdose associated with the use of non-prescription tianeptine (4).

Tianeptine exposure calls to U.S. poison control centers increased during 2014-2017, which has led the Centers for Disease Control and Prevention (CDC) to suggest an emerging public health risk (5). Due to its unregulated status and rising misuse, there is an urgent need to better characterize the risks associated with non-prescription tianeptine. This analysis aims to examine the reported adverse effects, withdrawal symptoms, and misuse patterns in those who use non-prescription tianeptine. This analysis will further identify public health concerns and support potential regulatory responses.

Findings

Case studies and reports have documented severe adverse effects from recreational abuse of tianeptine (5). Documented effects include nausea, constipation, abdominal pain, headache, dizziness, and changes in dreaming (6). According to reports by the CDC and various poison control centers, the most frequently reported effects associated with non-prescription tianeptine use were primarily neurologic and cardiovascular (5). Neurologic symptoms occurred in 48.3% of cases and included agitation (21.9%), drowsiness (16.7%), and confusion (13.2%). Cardiovascular effects were reported in 32.5% of cases, with tachycardia being the most common at 25.4%, followed by high blood pressure in 11.4% of individuals. These findings suggest a consistent pattern of central nervous system and autonomic involvement among individuals misusing tianeptine (5).

In a review of 48 cases from May 2019 to March 2020 for acute tianeptine intoxication, 56% of them required hospital admission, and 35% were managed in intensive care units. Naloxone was used in 24% of intoxication cases, indicating the opioid-like effects of tianeptine (7). Benzodiazepines were also frequently administered (7). One case report showed that tianeptine abuse led to an episode of psychosis in one patient (8). Tianeptine has also been reported to cause cardiac and pulmonary failure, leading to death in overdose patients (9, 10). More recent reports have documented severe sedation, miosis, and respiratory depression in overdose patients (11).

Withdrawal symptoms with tianeptine are similar to those observed with opioids (12). Marked euphoria and withdrawal symptoms perpetuate further drug misuse (13). Between 2000 to 2017, poison control centers reported 29 withdrawal-associated calls (5). Among those, tianeptine was reported to be associated with withdrawal in 72.4% of calls. Among these calls, the most frequently reported signs and symptoms were agitation (33.3%), nausea (33.3%), vomiting (19%), tachycardia (19.1%), hypertension (14.3%), diarrhea (9.5%), tremor (9.5%), and diaphoresis (9.5%). The most frequently administered therapies included benzodiazepines (57.1%), fluids (38.1%), and antiemetics (19.1%) (5). Due to tianeptine’s capacity as a mu-opioid receptor agonist at high doses, naloxone is a common intervention used in the treatment of tianeptine toxicity, helping to reverse respiratory depression and sedation (14). The intensity of symptoms and the need for hospitalization highlight the potential for dependence and the significant withdrawal burden associated with tianeptine abuse (7).

Tianeptine is typically used orally, although intravenous use and inhalation have also been reported (5, 15). Recreational doses of tianeptine are typically much higher than those used therapeutically. Progression from the initial dose to a dangerously high supratherapeutic dose can occur rapidly, as therapeutic tolerance to tianeptine develops quickly (3). Because tianeptine’s duration of action is short, frequent repeat dosing is required to prevent withdrawal symptoms (12). Documented misuse patterns include escalation from 12.5 mg/day to 375 mg/day, 100–150 mg taken three to four times daily, 100 mg every two hours, and even 400 mg per dose (15, 16, 17, 18).

CDC reports show that half of all reported exposures occurred among users aged 21–40 years (15). An analysis of ToxIC Core Registry data from 2014 to 2024 by Spyres et al. revealed 12 cases of confirmed tianeptine exposure (19). Most cases (67%) occurred between January 2023 and August 2024. The majority were male (75%) with an average age of 42 years. Co-ingestion with other substances was reported in 42% of cases, most commonly kratom (25%) and phenibut (17%). In one case study, a patient with combined use of tianeptine and kratom experienced agitation, psychosis, hallucinations, and bradycardia. Notably, none of the kratom co-exposed patients received naloxone (19).

Discussion

This analysis highlights the emerging risks of non-prescription tianeptine use, which include neurologic and cardiovascular side effects, opioid-like withdrawal symptoms, and patterns of escalating misuse. The findings support that even in the absence of FDA approval, tianeptine is accessible and capable of producing clinically significant harm. Next steps should aim to develop diagnostic and treatment protocols to address tianeptine misuse. These protocols will better inform toxicologists and clinicians on how to manage both acute toxicity and dependence. Furthermore, there is a need for public health education and consumer awareness to properly address the risks of tianeptine misuse.

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