Since tianeptine is not FDA-approved, tianeptine products are not regulated, so there is no knowing how much tianeptine is in a particular product, or if there are contaminants in the product. Because tianeptine is not well-studied, we have a limited understanding of potential drug-drug interactions. Tianeptine is not considered a controlled substance by the Drug Enforcement Agency at this time. Researchers have also hypothesized that depression involves a disruption of long-term synaptic plasticity 36,121. Extensive work has shown that stress impairs the induction of LTP in the hippocampus and prefrontal cortex, while facilitating its induction in the amygdala 37,39,41,85.

Although reports in the literature of fatal tianeptine overdose are rare, a tianeptine products linked to serious harm, overdoses, death review of two cases of fatal tianeptine intoxication in the U.S. was published in early 2018 9. In both cases, the authors found post-mortem serum concentration of tianeptine different than in previously reported non-fatal intoxication. In the first case, serum tianeptine concentration was measured at 2.0 mg/l, less than in previously reported fatal intoxication 25. However, significant levels of the tianeptine metabolite MC5 were identified using the time-of-flight spectrum, indicating the possibility of a much higher serum tianeptine concentration at one point during intoxication. The authors also noted the potential drug tolerance for affecting this and previously reported cases, potentially obscuring results. In the second case, serum levels were reported at 8.4 mg/l, in line with other cases of fatal intoxication.

Information for health care providers

As part of our response to this outbreak, we published a report of our preliminary investigation based on the first 20 calls we received that led to the identification of tianeptine products adulterated with natural and synthetic cannabinoids 7. The aim of this case series was to follow up the outbreak with additional clinical information, including an additional 21 exposures and analytical test results. First, reporting to poison centers is voluntary, and our reported cases likely under-represent the number of cases of acute toxicity and withdrawal that occurred during this period. The completeness and accuracy of the clinical data collected is dependent on the reporting of the caller, completeness of the information available to them, and the poison specialist and/or toxicologist receiving the call. For example, co-ingested substances that were not known or reported may have been present in some cases. Second, we were able to obtain confirmatory analytic testing on only a small number of the total cases, and contents identified in these product samples may not be generalizable to all patients in the outbreak.

Calls regarding tianeptine to US poison centers increased from 11 total between 2000 and 2013 to 151 in 2020, and individual poison centers have observed increasing reports over a similar period 3, 5, 6. The New Jersey Poison Information and Education System (NJPIES) typically receives two or fewer calls per year regarding tianeptine exposure. From June 2023– February 2024, NJPIES received 41 calls regarding tianeptine exposure, the majority of which were about patients who became ill shortly after ingesting purported tianeptine-containing products.

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Although the mechanisms responsible for tianeptine’s clinical efficacy have only recently been elucidated, its basic pharmacokinetics have been established through decades of preclinical studies. With a half-life of only 2.5 h, tianeptine is quickly absorbed in the gastrointestinal tract. It becomes highly bound to albumin once in the bloodstream, thus having a low volume of distribution 4, 8. It is hepatically metabolized into MC3 and the biologically active MC5, which functions similarly to its parent compound 4, 7, 8. Since tianeptine is really cleared, its half-life is markedly increased in elderly patients and those with kidney disease.

Study Population and Data Collection

The investigation was approved by the Rutgers University Institutional Review Board with a waiver of informed consent for research that involves minimal risk. NJPIES is the sole poison center for the state of New Jersey, serving a population of approximately 9 million. Each call to NJPIES is entered into Toxicall® by a Certified Specialist in Poison Information, producing an electronic record that captures demographic and clinical information, as well as free text descriptions of the exposure history. This information is coded to produce an entry that can be retrieved when the database is queried based on the exposure of interest or other relevant variables. All cases involving tianeptine exposure reported to NJPIES from June 2023– February 2024 were included. Individual records were reviewed for exposure history, demographic and clinical data.

Medical journals and reports to the FDA suggest that bad effects may occur when tianeptine is taken at doses higher than those prescribed in the countries where the drug has been approved. These reports describe U.S. consumers taking daily doses between 1.3 and 250 times the daily tianeptine dose typically recommended in products approved in other countries. Tianeptine is a non-prescription antidepressant that has become a popular method of getting high in the US in the past decade. It’s even been found in powder form in counterfeit pills of hydrocodone and oxycodone. Some products market dietary supplements containing tianeptine under the brand names Tianaa, Tianna Green, Tianna Red, Tianna White, and ZaZa.

Nevertheless, tianeptine is being marketed as a “research chemical,” a “nootropic” cognitive enhancer, or a dietary supplement. Major depressive disorder (MDD) is one of the most pervasive psychiatric diagnoses in the United States 1. Worldwide, it is responsible for the most significant proportion of disease burden related to disability, measured as years lost to disability (YLD) 2. Despite its immense prevalence and decades of research dedicated to understanding its etiologies, MDD remains controversial in public health, psychology, and medicine. First-line pharmacotherapies for MDD include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and serotonin modulators (SMs), among others 3.

• These substances may be produced commercially by drug manufacturers or in clandestine laboratories to mimic the effects of more well-known illicit/controlled substances such as marijuana, cocaine, opioids, etc.
• However, he continued to experience anxiety along with depression and recurrent withdrawal symptoms, relapsing less than a week later.
• In both cases, the patients reported large daily ingestions of tianeptine (7 g and 13.5 g total).

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• Nevertheless, tianeptine products with brands names such as ZaZa, Pegasus, Tianna, and Neptune’s Fix are readily purchased online, at headshops or smoke shops, and at gas stations 3, 4.
• The authors noted the difficulty in recovering tianeptine because it comprises both active acidic and basic groups.
• Support for this hypothesis was based on the incidental finding that efficacious antidepressants, such as monoamine oxidase inhibitors and tricyclics, increased monoamine neurotransmitter levels 127.
• The Sunshine State recently joined eight other US states (Alabama, Georgia, Indiana, Kentucky, Michigan, Mississippi, Ohio, and Tennessee) in forbidding sales of the over the counter pill, citing concerns for its high potential of abuse and addictive properties.

But about a dozen states have passed laws prohibiting or restricting tianeptine, including Alabama, Georgia, Michigan, Minnesota, Ohio and Tennessee. While tianeptine is not an opioid, the drug binds to some of the same receptors in the brain, which can temporarily produce effects akin to oxycodone and other opioids. Tianeptine also carries some of the same physiological risks of opioids, including the potential to dangerously depress breathing. Overseas, tianeptine was reclassified in France in 2012 as a narcotic after an analysis determined that the benefits of using the drug for depression did not outweigh the risks.

I want the public to be especially aware of this dangerous product and the serious and continuing risk it poses to America’s youth. While the FDA is closely following the distribution and sale of these products, it is critical that you appreciate the magnitude of the underlying danger of these products, and disseminate information about it. We analyzed cases involving tianeptine reported to the National Poison Data System from 2015 to 2023.

It can also be obtained online from independent vendors without a prescription 9. Tianeptine’s unregulated production and distribution have made it difficult to monitor. However, using online forums like Reddit, Smith et al. were able to use social media posts to gather information on current, former, and prospective tianeptine users via personal blog posts 10. They found that tianeptine users were more likely to be polydrug users, and tianeptine is often co-ingested with other drugs marketed online as “cognitive enhancers” or dietary supplements 10. A novel finding from this study is that recreational tianeptine users overwhelmingly conceptualized the drug as an opioid and were motivated to use tianeptine related to additional perceived benefits 10. It is important for members of the public and health care professionals to be aware that readily purchased tianeptine products might be adulterated with synthetic cannabinoid receptor agonists or other drugs and can produce severe adverse effects.

The authors classified cases as acute exposure if the patient developed signs or symptoms shortly after a single ingestion of a tianeptine product. Cases were classified as chronic exposures if they were reported as such by the patient or the patient’s healthcare provider. “Withdrawal” was defined as the development of signs or symptoms in the setting of discontinuation or decreased dose of tianeptine in patients who self-identified as chronic tianeptine users.

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Depression is a common mental disorder for which effective pharmacological treatments are lacking. Investigators have utilized animal models of depression to develop a better understanding of the neurobiological basis of this disorder, which could ultimately produce improved treatment options for the patient. We have reviewed the findings of preclinical research demonstrating that tianeptine prevents the deleterious effects of stress on physiology and behavior. Tianeptine prevents chronic stress-induced morphological changes in the hippocampus and amygdala and blocks the effects of acute stress on synaptic plasticity in the hippocampus and prefrontal cortex. We have also reviewed findings demonstrating that tianeptine has memory-protective properties, in which tianeptine-treated rats exhibited intact hippocampus-dependent memory despite their being exposed to powerful fear-provoking stressors. Tianeptine’s prevention of the adverse effects of stress on brain and behavior is likely to contribute to its effectiveness as a treatment for people suffering from major depressive disorder.