Opioid Resource Center

Opioid Resource Center

Disclosures: Konkel and Radin report no relevant financial disclosures.
December 01, 2020
5 min read

Tianeptine use: Another dangerous substance emerges during opioid crisis

Disclosures: Konkel and Radin report no relevant financial disclosures.
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As part of its public health mission, FDA has been monitoring for adverse effects from opioids and opioid-like substances for years. Two recent examples of concern are loperamide and kratom.

Loperamide, an over-the-counter antidiarrheal and a peripherally acting opioid, has been used in higher than recommended doses, resulting in serious heart problems or death. Kratom, also known as Mitragyna speciosa, has opioid-like properties that expose users to the risks of addiction, abuse and dependence. More recently, tianeptine has emerged as another substance being sought for its opioid-like qualities. FDA is seeing signals that suggest tianeptine use may be increasing in the United States and that a growing number of people are experiencing associated significant adverse events.

Nonmedical use of tianeptine

Tianeptine’s pharmacology

Tianeptine is an atypical antidepressant. Although it is approved in several other countries to treat depression and anxiety, it is not approved in the U.S. Tianeptine is structurally similar to tricyclic antidepressants. However, among other actions, the drug activates the mu and delta opioid receptors and may increase dopamine release. This mechanism is hypothesized to influence tianeptine’s antidepressant qualities but could also create a euphoric effect similar to other drugs with potential for abuse.

Tianeptine’s regulatory status

Photo of Karen Konkel 
Karen Konkel
Photo of Rose Radin 
Rose Radin

Several countries that initially approved tianeptine have since either removed it from sale or restricted its use due to concerns about risks for abuse. In 2005, France modified the labeling of tianeptine to warn of potential addiction, particularly in patients with a history of substance use disorders. Since 2012, it has been subject to France’s narcotics regulations, which place restrictions on prescribing and dispensing. Russia, Armenia, Ukraine and Turkey have classified tianeptine as a controlled substance. In 2010, the country of Georgia withdrew the drug from the market. In the U.S., in response to a series of tianeptine overdoses, Michigan recently placed the drug on its list of controlled dangerous substances. Similar legislation is being considered in Alabama, Minnesota and New York.

Tianeptine sources

Although it is not an FDA-approved product, tianeptine is sold in the U.S. via online merchants and in convenience stores, and it is typically supplied in capsule, tablet or powder forms. It is among a variety of substances being marketed as a “nootropic.” Increasingly popular, nootropics — or “smart drugs” — refer to dietary supplements that purportedly have cognitive-enhancing qualities.

FDA sends warning letters

In 2018, based on findings from the FDA’s Center for Food Safety and Nutrition (CFSAN), the agency sent warning letters to two companies illegally marketing tianeptine-containing products labeled as dietary supplements claiming to treat opioid use disorder, pain and anxiety, among other unlawful and unproven claims. Also, in 2018, the CDC published a study that, among other findings, showed that calls about tianeptine exposure to U.S. poison control centers increased between 2014 and 2017, suggesting a possible emerging public health risk. Reported adverse effects included neurologic, cardiovascular and gastrointestinal signs and symptoms, with some effects mimicking opioid toxicity and withdrawal.

What the evidence says about tianeptine

Prompted by this CDC study, FDA recently reviewed and analyzed cases of adverse events that were reported with tianeptine use. Consistent with the CDC findings, FDA has found that tianeptine use in the U.S. may be increasing and is associated with death and other serious adverse events that may be attributed to its opioid-like properties.

FDA researchers evaluated 59 case reports of tianeptine-related adverse events suggestive of abuse, misuse, tolerance, dependence and withdrawal. The researchers gathered case-level information from the FDA Adverse Event Reporting System, the CFSAN Adverse Event Reporting System and the medical literature. These cases are from several countries, including some where tianeptine is legally prescribed and sold.

FDA found that the number of reports increased between 2013 and 2018 (from 16 to 42). Thirty-two (54%) of the 59 cases occurred in the U.S. There was also a rapid growth in literature case reports in 2018, which may reflect growing use and interest in the drug.

Among the 59 case reports, the majority were young men. The most commonly reported reasons for tianeptine use were to treat depression or anxiety, or to achieve a euphoric effect. When reported, the internet was the most frequently cited source for obtaining tianeptine.

All the U.S. cases reported tianeptine use with other drugs, including 24 reports that described concurrent use with other psychotropics, including other antidepressants, benzodiazepines, cocaine and alcohol.

The reported cases suggest that tianeptine is typically supplied in tablet or powder form. Oral and IV injection were the most commonly reported routes of administration. In all 27 cases that reported a specific daily dose, that amount far exceeded the usual antidepressant prescription dose of 12.5 mg three times daily, with an average daily dose of 2,900 mg.

Because we were interested in determining if there was evidence of tianeptine-related abuse, misuse, dependence, tolerance and withdrawal, we searched for the adverse events commonly reported following opioid abuse. These included drug withdrawal syndrome, drug dependence, drug abuse, tolerance, anxiety, intentional product misuse, loss of consciousness, respiratory depression or arrest, and toxicity to various agents. Six deaths were described in the literature. Of these, three deaths occurred in the U.S. Further, there were six life-threatening events reported in the U.S., including four cases of respiratory depression, three of which responded to naloxone, a case of possible withdrawal leading to the need for intensive care, and a case of serotonin syndrome that also required intensive care.

Expanding on the prior CDC analysis of U.S. poison control center calls for tianeptine exposure with more recent years of data, FDA found a 24-fold increase in cases involving tianeptine misuse, abuse or withdrawal from 2014 (n = 3) to 2019 (n = 74).

An in-depth analysis of the 162 tianeptine misuse, abuse or withdrawal cases from U.S. poison control center calls from 2014 to 2018 found that, in contrast to the case reports described earlier, just 36% of cases were polysubstance exposures. For cases of tianeptine misuse or abuse with one or more other substances, frequent co-exposures included phenibut (another nootropic), benzodiazepines, ethanol and prescription opioids.

What health care professionals can do

The opioid crisis continues to evolve, and people continue to seek opioid-like effects from the misuse of novel agents. Evidence suggests that there is increasing misuse of tianeptine in the U.S., a concerning substance with opioid-like qualities. Like other drugs with these properties, tianeptine may expose users to significant risks, including addiction and dependence. FDA advises health care professionals to be aware that products containing tianeptine have not been evaluated by FDA for either efficacy or safety, and to consider the possibility of tianeptine use when evaluating a patient with clinical evidence of opioid use. FDA will continue to monitor these trends and communicate to practitioners.

Editor’s note: Nonmedical use comprises two categories defined by the American Association of Poison Control Centers: intentional misuse (“an exposure resulting from the intentional improper or incorrect use of a substance for reasons other than the pursuit of a psychotropic effect”) and abuse (“an exposure resulting from the intentional improper or incorrect use of a substance where the victim was likely attempting to gain a high, euphoric effect or some other psychotropic effect”).


El Zahran T, et al. MMWR Morb Mortal Wkly Rep. 2018;doi:10.15585/mmwr.mm6730a2.