What is tianeptine, and are there recommendations for managing tianeptine misuse/withdrawal in the medical setting?
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Background
Tianeptine is marketed as a prescription drug in Europe, Latin America, and Asia, where it has been used to treat depression, anxiety, and irritable bowel syndrome.1,2 Although it is not approved for medical use in the United States, it can be found in a variety of products sold online and in convenience stores or gas stations under brand names such as ZaZa Red, Tianaa/Tianna/Tianna Red, Pegasus, Red Dawn, and Neptune’s Fix.1-4 Tianeptine products are commonly marketed as supplements to improve brain function or treat a variety of conditions, including anxiety, depression, pain, and opioid use disorder.3 However, the U.S. Food and Drug Administration classifies tianeptine as an “unsafe food additive” and warns that users may become addicted to it.5 In November 2023, the U.S. Food and Drug Administration (FDA) advised consumers to avoid purchasing or using products that contain tianeptine.3 This warning was issued in response to reports of severe adverse events occurring after tianeptine consumption, including seizures and loss of consciousness leading to hospitalization and/or death. Although several states have banned tianeptine (including Alabama, Florida, Georgia, Indiana, Kentucky, Michigan, Mississippi, Ohio, and Tennessee), tianeptine products remain available in other areas of the United States.4
What is Tianeptine?
Tianeptine was initially developed in the 1980s as a treatment for depression; it is currently classified as an atypical tricyclic antidepressant, due to its unique molecular structure and mechanism of action.2 Initially, tianeptine was thought to work by enhancing serotonin reuptake in the synaptic cleft. However, more recent studies have shown that it has a low affinity for serotonin transporters and does not significantly impact serotonin neurotransmission. Instead, tianeptine’s antidepressant effects are the result of glutamate modulation. Tianeptine stabilizes glutaminergic signaling and exerts opposing effects on N-methyl-D-aspartate (NMDA) and aminomethylphosphonic acid (AMPA) receptors. Tianeptine also acts as a full agonist at mu opioid receptors and a weak agonist at delta opioid receptors. Mu opioid receptor activation leads to downstream stimulation of the glutaminergic pathway, thereby enhancing the therapeutic effects of tianeptine. When taken at high doses, tianeptine’s actions at mu opioid receptors can also trigger dopamine release and produce an opioid-like euphoric high. Tianeptine’s opioid-like effects give it significant potential for misuse and have earned it the nickname “gas station heroin.”
When used medically, the dose of tianeptine typically ranges from 25 to 50 mg/day.2,6 However, doses used for recreational purposes may be more than 100-fold higher, exceeding 4000 mg/day; mean recreational doses have been reported between 1645 and 1924 mg/day.7,8 It is typically used via the oral route, although intravenous use and inhalation of tianeptine have also been reported.8,9 Tianeptine is quickly absorbed when taken orally, and highly protein bound once it reaches the bloodstream.2 It is metabolized by beta-oxidation in the liver to two major metabolites, MC3 and MC5; MC5 is an active metabolite with similar activity to the parent drug.10 Tianeptine is renally cleared, and has a half-life of only 2.5 hours.2
Epidemiology and Potential Consequences of Tianeptine Misuse
Although data on tianeptine misuse and abuse in the United States are limited, information from poison centers seems to indicate that tianeptine exposure has become more common in recent years.9,11 Tianeptine exposures reported to poison centers rose from 11 total cases between 2000 and 2013 to 151 cases in 2020 alone. Several reports using poison center data have described the symptoms associated with tianeptine ingestions, as well as current measures employed in the management of such ingestions.9,12,13 Although none of the poison center studies reported deaths due to tianeptine intoxication, separate reports have documented fatal tianeptine overdoses, including 2 deaths that occurred in the United States.14
The Centers for Disease Control and Prevention (CDC) analyzed data from the National Poison Data System (NPDS) between 2000 to 2017 and reported on 114 cases of tianeptine exposure that occurred during this time period.9 Tianeptine exposure was commonly associated with neurologic, cardiovascular and gastrointestinal effects. Cardiovascular effects included tachycardia (25.4%), hypertension (11.4%), and conduction delays (4.4%). Neurologic effects included agitation (21.9%), drowsiness (16.7%), confusion (13.2%), and coma (4.4%). Gastrointestinal effects included nausea (7.9%), vomiting (4.4%), and diarrhea (2.6%). Respiratory depression was reported in 5.3% of patients. While no deaths were reported, 24% of patients were admitted to a critical care unit, and 4.4% required ventilator support. Patients were most commonly treated with fluids, benzodiazepines, oxygen, and/or naloxone.
Between January 1, 2015 and March 15, 2020, 48 cases of tianeptine intoxication or withdrawal were reported to the Alabama Poison Information Center; 77% of these cases were reported between May 2019 and March 2020.12 Seventeen cases of acute tianeptine intoxication were identified in this series, with 11 involving tianeptine as the sole agent ingested. The most common symptoms of tianeptine-only intoxication were lethargy (7 patients) and hypertension (4 patients). Agitation and tachycardia were reported in 3 patients each; other symptoms included myoclonic symptoms, gastrointestinal distress, and hallucinations. The majority of patients (55%) were admitted to the intensive care unit for management and monitoring. The most common treatments for tianeptine-only intoxication were naloxone (3 patients), benzodiazepines (2 patients), and antipsychotics (2 patients); one patient also received antimuscarinics.
A sharp increase in cases of tianeptine ingestion was reported in New Jersey between June and November 2023.13 During this time period, 17 patients aged 28 to 69 years presented with serious adverse effects after ingesting tianeptine, including altered mental status, tachycardia, hypotension, seizure, prolonged QT interval, prolonged QRS duration, and cardiac arrest. Fourteen of the 17 patients ingested tianeptine in the form of Neptune’s Fix, which contains tianeptine and kavain; in some cases, the products were adulterated with other substances (including synthetic cannabinoid receptor agonists), highlighting the risks associated with these unregulated formulations. While no patients died, 13 required admission to the intensive care unit, and 7 underwent endotracheal intubation. Nine of these patients had used tianeptine previously, and 6 reported co-ingestion of other substances, including alprazolam, kratom, tramadol, trazodone, and gabapentin.
Risk factors for tianeptine abuse are not well-characterized. Data from the NPDS indicate that most tianeptine exposures occur in patients aged 21 to 40 years.9 Patients with a history of other drug or alcohol use disorders may be at increased risk, as well as those with a history of treatment for mood or personality disorders.15 In many cases, tianeptine is taken with other substances, sometimes with the intent of mitigating the effects of other drugs or alcohol.6 Commonly reported reasons for using tianeptine include improving mood, increasing mental sharpness, and self-medicating pain or symptoms of mental health disorders. Patients may also try to use tianeptine to self-manage withdrawals from other substances (eg, opioids); unfortunately, this can inadvertently lead them to become addicted to tianeptine itself.5,6
Tianeptine Withdrawal Symptoms and Management
As mentioned above, recreational doses of tianeptine are typically much higher than those used therapeutically.6 Progression from the initial dose to a dangerously high supratherapeutic dose can occur rapidly, as tolerance to tianeptine develops quickly. Because tianeptine’s duration of action is short, frequent repeat doses are required to prevent withdrawal symptoms.15 Withdrawal symptoms with tianeptine are similar to those observed with opioid withdrawal.15 Patients may experience myalgia, chills, anxiety, nausea, vomiting, tremor, mood changes, insomnia, rhinorrhea, diarrhea, cravings, agitation, myoclonic jerking, tachycardia, hypertension, and diaphoresis.
There is no consensus on the best intervention(s) to manage tianeptine use disorder and tianeptine withdrawal; evidence is currently limited to case reports and poison center data.1,8,9,12,16-21 The analysis of NPDS data from 2000 to 2017 identified 21 cases of tianeptine withdrawal; the most frequently administered therapies in these cases included benzodiazepines (57.1%), fluids (38.1%), and antiemetics (19.1%).9 The most common symptoms of tianeptine withdrawal in this analysis were agitation, nausea, vomiting, tachycardia, hypertension, diarrhea, tremor, and diaphoresis. In the report from the Alabama Poison Information Center, 31 cases of tianeptine withdrawal were documented, with 27 of these cases withdrawing from tianeptine only.12 Common symptoms of tianeptine-only withdrawal included anxiety (12 patients), gastrointestinal distress (9 patients), agitation (8 patients), hypertension (8 patients), and tachycardia (7 patients); some patients also reported myalgias, myoclonic symptoms, and hallucinations. Treatments administered included benzodiazepines in 10 patients, opioids in 6 patients, alpha-2 agonists in 5 patients, antipsychotics in 5 patients, and antimuscarinics in 5 patients. Some patients also received barbiturates, buprenorphine, and/or gabapentin. Withdrawal generally improved within 24 to 48 hours. Details from individual case reports are summarized in the Table below.1,8,16-21 In general, patients were managed with medications that are used to treat opioid use disorder, including methadone and buprenorphine; other successful interventions included bupropion plus topiramate, clonidine plus diphenhydramine, and benzodiazepines plus gabapentin. Selection of a course of treatment may depend on factors such as other substance use history and withdrawal symptom severity.
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| Table. Case Reports of Tianeptine Use Disorder and Withdrawal Management.1,8,16-21 | ||||
|---|---|---|---|---|
| Study Citation | Key Patient Characteristics | Withdrawal Symptoms | Treatments Administered | Outcome |
| Velagapudi 202416 | Male aged 33 years with history of OUD, ADHD, and GAD presenting to outpatient addiction clinic Patient has long history of opioid use; most recently, patient reported use of a few M30 (counterfeit oxycodone) tablets per day (last use, 3 to 4 days before presentation) and heroin (last use, 2 to 3 weeks before presentation) Patient had been using tianeptine when unable to obtain M30 tablets; dosage increased over the course of a year to approximately 45 capsules per day | Anxiety, temperature intolerance, and cravings between tianeptine doses | Methadone 30 mg with scheduled increases of 5 mg every 2 days based on cravings and withdrawal symptoms using COWS; over the course of treatment, methadone dose was up-titrated to 128 mg | After 10 days, patient had reduced tianeptine usage by half without significant adverse effects; by day 28, patient was able to stop using tianeptine with no cravings or withdrawal symptoms; patient was continued on methadone replacement therapy due to duration of tianeptine use, difficulties with tianeptine cessation, and history of OUD |
| Rawal 202317 | Male aged 38 years presenting to the ED; history of anxiety disorder and OUD Patient had been using tianeptine 8 to 20 g daily; patient also reported ingesting hand sanitizer and cough syrup, huffing keyboard cleaner and body spray, drinking mouthwash, and smoking delta-8 tetrahydrocannabinol Concomitant medications: duloxetine 20 mg daily (noncompliant) | Patient was pale, cyanotic, tachycardic, and hypotensive on presentation and admitted to the ICU Patient reported that ingestions were attempts to control tianeptine withdrawal symptoms, which consisted of anxiety, dysphoria, depression, headaches, diffuse myalgias, restless legs, hot flashes, sweating, chills, abdominal discomfort, nausea, diarrhea, and vomiting | Buprenorphine/naloxone 4 mg/1 mg SL twice daily initially, with buprenorphine/naloxone 2 mg/0.5 mg every 2 hours as needed and buprenorphine 0.15 mg IV every 6 hours Patient was stabilized and discharged from the ICU but experienced ongoing withdrawal symptoms on the medical floor; anxiety symptoms managed with hydroxyzine 25 mg every 6 hours as needed After consultation with addiction medicine, buprenorphine/naloxone was discontinued and patient was started on methadone 5 mg daily; additional 5 mg doses were provided as needed for ongoing withdrawal symptoms and in the absence of sedation, up to a maximum of 15 mg/day; additional medications included clonidine 0.1 mg/24 hour patch as needed for withdrawal symptoms and ropinirole 0.5 mg by mouth 3 times daily as needed for restless leg syndrome | Withdrawal symptoms improved by day 3 of admission after initiation of methadone; to expedite discharge, patient was switched to buprenorphine/naloxone 8 mg/2 mg SL twice daily and referred for outpatient follow-up |
| Chawla 202218 | Male aged 32 years prescribed tianeptine 12.5 mg/day for depression; patient had independently increased dose to 375 mg/day over a period of 6 months to treat persistent depression symptoms Concomitant medications were diazepam 5 mg/day, imipramine 25 mg/day, and propranolol 20 mg/day | Cravings, anxiety, low mood, headache, insomnia, and irritability when tianeptine doses were delayed | Bupropion (up to 300 mg/day) and topiramate 50 mg/day | Tianeptine was tapered (25% dose reduction every 2 weeks) to a dose of 25 mg/day; patient was stable on this dose for 4 weeks |
| Markovic 202219 | Male aged 32 years presenting to the ED after being found unconscious; history of insomnia and benzodiazepine use disorder Patient had been taking liquid etizolam 20 to 30 mg daily for 1.5 years and tianeptine (up to 50 mg) daily for 2 years | Patient initially presented with overdose; the day after admission, he began experiencing withdrawal symptoms, including dilated pupils, shivering, insomnia, diarrhea, myalgia, anxiety, and irritability; patient also reported tingling/numbness of the lower extremities and auditory and visual hallucinations | Methadone 5 mg twice daily for opioid withdrawal and chlordiazepoxide 25 mg every 6 hours for benzodiazepine withdrawal initially After consultation with addiction medicine, patient received oral diazepam 20 mg 4 times daily (with additional doses of diazepam 20 mg every 6 hours as needed for breakthrough symptoms), gabapentin 300 mg 3 times daily, and other supportive medications (trazodone, clonidine, ibuprofen, loperamide, ondansetron); patient was tapered off methadone and referred for outpatient buprenorphine maintenance treatment | Patient was discharged on day 6 on diazepam 40 mg twice daily and gabapentin 300 mg 3 times daily; patient was referred for outpatient addiction treatment (planned to initiate a prolonged diazepam taper and OUD medication) |
| Szczesniak 202220 | Middle-aged male presenting to an outpatient addiction clinic; had been taking tianeptine for 3 years with a gradual increase to almost 10g daily History of heroin use (stopped 3 years ago, after starting tianeptine) | Patient had attempted to taper tianeptine doses by approximately 25 to 50 mg every 3 to 4 days; attempts to reduce dose below 2000 mg daily were unsuccessful, causing withdrawal symptoms of fatigue, diaphoresis, emesis, and myalgia | Patient was instructed to taper dosage of tianeptine over the course of several months; in the first 2 weeks, tianeptine dosage was decreased to 1800 mg daily, but withdrawal symptoms became unbearable Buprenorphine SL film was initiated with a microdose induction (dose gradually increased from 0.25 mg to 24 mg daily over 8 days) | On day 7 of buprenorphine treatment, the patient discontinued tianeptine usage; patient continued on buprenorphine 8 mg 3 times daily with no symptoms of withdrawal, anxiety, depression, or cravings on 2-month follow-up |
| Trowbridge 201921 | Male aged 24 years presenting to an outpatient addiction clinic; had been taking tianeptine for 2.5 years to self-medicate anxiety, with doses eventually escalating to 100 mg every 2 hours | Itching, poor sleep, night sweats, depression, and anxiety between doses; attempts to decrease daily dosage led to whole body pain, lack of motivation, and crippling anxiety | Mirtazapine and clonidine started; patient attempted to taper tianeptine, but was only able to taper to 50 mg every 4 to 5 hours due to labile mood and worsening anhedonia/lack of motivation Increased mirtazapine dose and addition of risperidone allowed for further reduction of tianeptine dose to 25 mg every 2 to 3 hours; however, patient continued to experience increased body pains, diaphoresis, and nausea on the lower tianeptine dose Patient attempted tianeptine cessation, but reported severe anxiety, insomnia, restless legs, congestion, runny nose, diaphoresis, profound depression, nausea, abdominal cramping, diarrhea, and suicidal ideation; patient relapsed to tianeptine use after less than 1 week of abstinence Patient abstained from tianeptine use for 24 hours, then started on buprenorphine/naloxone at 2 mg/0.5 mg; at a dose of 2 mg/0.5 mg twice daily, the patient’s symptoms disappeared, with the exception of mild anxiety | Patient remained abstinent after starting buprenorphine/naloxone; treatment with buprenorphine/naloxone was continued, given the duration of prior tianeptine use, escalation of use, and difficulties observed with cessation |
| Lauhan 20188 | Male aged 44 years taking tianeptine for approximately 1 year, with doses increased up to 100 to 150 mg 3 to 4 times daily to manage stress; history of GAD and other substance use disorders; patient presented to the ED with suicidal ideation Concomitant medication: mirtazapine 30 mg daily Also reported drinking 36 to 48 oz of beer per week; urine drug screen was positive for barbiturates, though patient denied use (may have been adulterant in tianeptine formulation) | Worsening depression, emotional lability, anxiety, diaphoresis, temperature intolerance, and cravings between doses; additional symptoms during admission were nausea, chills, and fatigue | Lorazepam 0.5 mg given initially for anxiety; withdrawal managed with oral diazepam using the Minnesota Detoxification Scale (a symptom-driven alcohol withdrawal protocol); patient received a total of 30 mg diazepam over 2 days in the hospital and was discharged on gabapentin to cover for potential protracted withdrawal | Withdrawal symptoms improved and patient was discharged on gabapentin |
| Gupta 20171 | Male aged 36 years taking tianeptine to manage persistent depression symptoms on sertraline 150 mg/day; tianeptine use began with 12.5 mg three times daily and escalated to over 400 mg/dose within 3 months | Marked restlessness and anxiety between doses | Loperamide plus cimetidine (patient-initiated) Clonidine 3 times daily plus as-needed diphenhydramine (medically supervised) | Loperamide plus cimetidine was ineffective; patient was able to stop tianeptine use completely within 3 months using clonidine plus diphenhydramine |
| Abbreviations: ADHD=attention deficit hyperactivity disorder; COWS=clinical opioid withdrawal scale; ED=emergency department; GAD=generalized anxiety disorder; ICU=intensive care unit; IV=intravenous; OUD=opioid use disorder; SL=sublingual. | ||||
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Conclusion
Tianeptine is an atypical tricyclic antidepressant that is not approved for medical use in the United States. Supplements containing tianeptine can be easily purchased without a prescription online or at small retail locations such as gas stations. Tianeptine misuse has become more common in the United States in recent years. Patients who seek out tianeptine for its effects on brain function, anxiety, depression, pain, or opioid use disorder may inadvertently find themselves addicted to it, requiring escalating doses of the drug to avoid symptoms of withdrawal. Evidence pertaining to the treatment of tianeptine misuse and withdrawal is limited; however, case reports and data from poison centers suggest that treatment of tianeptine use disorder/withdrawal is similar to that of opioid use disorder/withdrawal. Further data are needed before a specific course of treatment can be recommended.
References
1. Gupta S, Wallace R, Sloshower J. Online sales of unscheduled pharmaceutical agents: a case report of tianeptine use in the united states. J Addict Med. 2017;11(5):411-412. doi:10.1097/adm.0000000000000342
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3. FDA warns consumers not to purchase or use Neptune’s Fix or any tianeptine product due to serious risks. U.S. Food and Drug Administration. Published November 21, 2023. Updated February 16, 2024. Accessed May 16, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-neptunes-fix-or-any-tianeptine-product-due-serious-risks
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8. Lauhan R, Hsu A, Alam A, Beizai K. Tianeptine abuse and dependence: case report and literature review. Psychosomatics. 2018;59(6):547-553. doi:10.1016/j.psym.2018.07.006
9. El Zahran T, Schier J, Glidden E, et al. Characteristics of tianeptine exposures reported to the National Poison Data System – United States, 2000-2017. MMWR Morb Mortal Wkly Rep. 2018;67(30):815-818. doi:10.15585/mmwr.mm6730a2
10. Szafarz M, Wencel A, Pociecha K, Fedak FA, Wlaź P, Wyska E. Pharmacokinetic study of tianeptine and its active metabolite MC5 in rats following different routes of administration using a novel liquid chromatography tandem mass spectrometry analytical method. Naunyn Schmiedebergs Arch Pharmacol. 2018;391(2):185-196. doi:10.1007/s00210-017-1448-2
11. Tianeptine products linked to serious harm, overdoses, death. U.S. Food and Drug Administration. Updated February 10, 2022. Accessed May 17, 2024. https://www.fda.gov/consumers/consumer-updates/tianeptine-products-linked-serious-harm-overdoses-death
12. Rushton W, Whitworth B, Brown J, Kurz M, Rivera J. Characteristics of tianeptine effects reported to a poison control center: a growing threat to public health. Clin Toxicol (Phila). 2021;59(2):152-157. doi:10.1080/15563650.2020.1781151
13. Counts CJ, Spadaro AV, Cerbini TA, et al. Notes from the field: cluster of severe illness from Neptune’s Fix tianeptine linked to synthetic cannabinoids – New Jersey, June-November 2023. MMWR Morb Mortal Wkly Rep. 2024;73(4):89-90. doi:10.15585/mmwr.mm7304a5
14. Bakota EL, Samms WC, Gray TR, Oleske DA, Hines MO. Case reports of fatalities involving tianeptine in the United States. J Anal Toxicol. 2018;42(7):503-509. doi:10.1093/jat/bky023
15. Hargett JL, Lowry PF, Lee KN. Nursing implications for tianeptine use and misuse. J Addict Nurs. 2023;34(2):158-161. doi:10.1097/jan.0000000000000535
16. Velagapudi V, Calabrese J, Sethi R. Tianeptine as an opiate replacement in a patient on methadone treatment: A case report. J Opioid Manag. 2024;20(1):87-91. doi:10.5055/jom.0851
17. Rawal VY, Gallardo M, Henderson K, Hall OT, Klisovic N, Sikic-Klisovic E. Severe tianeptine withdrawal symptoms managed with medications for opioid use disorder: a case report. J Addict Dis. 2023:1-6. doi:10.1080/10550887.2023.2290139
18. Chawla K, Kar SK. Use of bupropion and topiramate in management of tianeptine abuse in a young male with dysthymia. Ann Indian Psych. 2022;6(1):111. doi:10.4103/aip.aip_131_21
19. Markovic M, Niwash D. Ment Health Clin. In. Treatment of concurrent etizolam and tianeptine withdrawal following accidental overdose. Vol 12. © 2022 AAPP. The Mental Health Clinician is a publication of the American Association of Psychiatric Pharmacists.; 2022:356-359.
20. Szczesniak L, Sullivan R. Microdose induction of buprenorphine in a patient using tianeptine. J Addict Med. 2022;16(6):736-738. doi:10.1097/adm.0000000000001003
21. Trowbridge P, Walley AY. Use of buprenorphine-naloxone in the treatment of tianeptine use disorder. J Addict Med. 2019;13(4):331-333. doi:10.1097/adm.0000000000000490
Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
June 2024
The information presented is current as of May 16, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.