Tianeptine is an opioid receptor agonist that is prescribed as an antidepressant in many countries. In the United States, tianeptine is not approved for medical use because of its potential for abuse and addiction. Nonetheless, products containing tianeptine are easily obtainable and are marketed as dietary supplements. There are increasing reports of adverse effects and fatal toxicities resulting from tianeptine use among adolescents and adults. This emerging public health threat could escalate the opioid epidemic and drive increased newborn perinatal exposure. The impact of in utero exposure to tianeptine has not been studied, and to our knowledge, the authors of only 1 report have documented possible neonatal effects. Here, we describe a case of chronic prenatal exposure to tianeptine in the setting of maternal dependence on dietary supplements. This infant developed signs of severe withdrawal shortly after birth that were refractory to treatment with oral phenobarbital but responded to subsequent oral morphine therapy. On further questioning, the mother revealed the use of a tianeptine-containing dietary supplement. We did not perform confirmatory toxicology testing because tianeptine is not assayed by usual urine drug screening tests. For infants with clinical signs of opioid withdrawal without known etiology, we suggest that the maternal interview should inquire about the use of neurotropic over-the-counter drugs.

Tianeptine is an atypical tricyclic antidepressant with anxiolytic properties.1,2  Its effects arise from activation of the μ-opioid receptor.1,2  Tianeptine is used for the treatment of depression and anxiety in 66 countries across Europe, Asia, and Latin America.3,4  In the United States, its medical use is not approved by the Food and Drug Administration (FDA) because of public health concerns regarding adverse effects and fatal overdose.5,6  Nonetheless, dietary supplements containing tianeptine, such as “ZaZa” and “Tianna Red,” remain easily obtainable in gas stations across the United States and online without a prescription.7 

The potential for tianeptine abuse and addiction is well recognized.4  Reports from the National Poison Data System indicate a steady rise in the misuse and intentional abuse of this drug in the United States. Calls to poison control centers about tianeptine exposure increased from 11 over a 13-year period (2000–2013) to 151 in 2020 alone.5  Although tianeptine is an atypical tricyclic antidepressant, its abuse in adults can mimic opioid toxicity and withdrawal.1,2  Its clinical effects have not been specifically studied in newborns; however, tricyclic antidepressants are known to cross the placenta.8 

The only documented case of neonatal abstinence syndrome (NAS) after maternal tianeptine use was recorded in France.9  That case described the early recognition of NAS due to maternal prescription use of tianeptine, with closely monitored dosing throughout her pregnancies.9  Here, we describe the first case reported in the United States. Chronic prenatal exposure of this newborn to tianeptine occurred through maternal use of dietary supplements, and this infant developed NAS. Signs of withdrawal were initially attributed to the use of amphetamine during pregnancy to treat attention-deficit hyperactivity disorder because of a negative urine drug screen result and a lack of information about maternal use of other psychoactive substances. As a result, the infant was unsuccessfully treated with phenobarbital and only demonstrated clinical improvement after the initiation of oral morphine.

We present a case of a 3062g full-term male infant born vaginally at 38 + 3/7 weeks’ gestation to a 22-year-old multiparous Caucasian woman. Prenatal care began late in the second trimester. Significant past medical history included rheumatoid arthritis, fibromyalgia, scoliosis, and attention-deficit hyperactivity disorder, for which Adderall and gabapentin were prescribed. She reported using gabapentin daily. Adderall was taken on 4 to 5 occasions during the pregnancy, only before events she anticipated to be stressful. The mother admitted to smoking at least 3/4 of a pack of cigarettes per day, the occasional use of marijuana, and minimal wine consumption during pregnancy.

Labor and delivery were uncomplicated. Apgar scores were 9 at 1 and 5 minutes of life. At the referring hospital, the infant developed jitteriness, undisturbed tremors, an inconsolable cry, and loose stools at ∼4 hours of life. Because of these evolving clinical signs, a sepsis evaluation was performed, which revealed a normal complete blood count and serum C-reactive protein level. A blood culture was obtained, and ampicillin and gentamicin were started. He was transferred to our NICU at 15 hours of life for suspected NAS.

A physical examination on admission revealed a male infant with a weight appropriate-for-gestational age who had global hypertonia, perineal excoriations, and a weak suck reflex. Shortly afterward, he developed a fever of 38°C (100.4°F) and nonbilious emesis. The initial Finnegan score at 16 hours of life was 24. Urine drug screening test results for both the mother and infant were positive for amphetamines, likely from maternal Adderall use. The initial blood culture was sterile, and antibiotics were discontinued after 48 hours. On the basis of the severity of the initial neurologic signs and the positive drug screening results for amphetamines, we initiated oral phenobarbital therapy. The infant continued to feed poorly. Finnegan scores remained high, ranging from 7 to 12 (Fig 1).

FIGURE 1

Trend of modified Finnegan scores during hospitalization.

FIGURE 1

Trend of modified Finnegan scores during hospitalization.

Close modal

The lack of significant improvement on phenobarbital and the observed clinical signs raised concerns about the possibility of opioid exposure. The infant’s mother was therefore interviewed further. On inquiry, she revealed the use of a dietary supplement, Pegasus Red (Fig 2). She acquired this tianeptine-containing product in a supplement recommended by a friend. She had taken 7 capsules (proprietary blend 700 mg/capsule) daily for the past 2 years, starting 3 months after her last pregnancy. She referred to this medication as an “energy boost” that mitigated her chronic musculoskeletal pains, so she continued use throughout this pregnancy. She expressed feelings of guilt regarding the infant’s clinical condition and admitted dependency on this supplement, detailing multiple failed attempts to discontinue use. After the delivery of this infant, she reported weaning to 2 capsules per day but noticed withdrawal symptoms, such as nausea, vomiting, constipation, abdominal pain, migraines, and the return of her joint pain.

FIGURE 2

A sample of the dietary supplement used by the mother during pregnancy.

FIGURE 2

A sample of the dietary supplement used by the mother during pregnancy.

Close modal

With the discovery of tianeptine exposure, we started oral morphine at 40 hours of life and observed clinical improvement. Finnegan scores and formula feeding improved throughout hospitalization (Fig 1). Phenobarbital was discontinued after 12 days, whereas morphine was tapered over 17 days.

The infant remained clinically stable 48 hours after the discontinuation of morphine. The infant continued tolerating feeds well and had grown appropriately by the time of home discharge on day 19.

Since the enactment of the Dietary Supplement Health and Education Act of 1994, dietary supplement sales have dramatically increased.10  Concomitantly, dietary supplement use in all age groups among US adults has soared.11  More than 75% of pregnant women use dietary supplements.12  Multivitamins, folic acid, and iron-containing supplements are the most common dietary supplements used in this population.12  Under the Dietary Supplement Health and Education Act, dietary supplements are categorized as foods. Therefore, the FDA is not authorized to approve these supplements before marketing, but manufacturers are required to notify the FDA of new dietary ingredients.13,14  The lack of premarketing oversight in the formulation of dietary supplements allows potentially dangerous compounds, such as tianeptine, to be used.14 

Tianeptine (7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid) is a heterocyclic compound with a chemical structure similar to tricyclic antidepressants.15,16  Its precise mechanism of action is yet to be fully elucidated. In plasma, it is bound to albumin and is rapidly eliminated by the kidneys. Its half-life is 2.5 hours.16  Animal studies have revealed μ-opioid receptor agonist activity, as well as modulatory effects on glutaminergic mechanisms that together mediate its antidepressant, anxiolytic, and opioid-like effects.1,2,16 18  Exposure via ingestion, inhalation, and parenteral routes has been reported.19,20  Toxicity produces cardiovascular, neurologic, and gastrointestinal effects mimicking opioid toxicity.20 

Many countries have banned or withdrawn tianeptine from the market because cases of significant adverse effects and fatal intoxication in adults continue to be reported.6,19 22  Tianeptine is not approved by the FDA but is the active ingredient in several dietary supplements and research chemicals sold in gas stations and convenience stores in many states in the United States. It can also be easily purchased online without a prescription.3,5,23  Because of its opioid-like effects, tianeptine is colloquially referred to as “gas station heroin.”23  One-half of all cases of exposures from 2000 to 2017 reported to the National Poison Data System occurred among individuals aged 21 to 40 years, and 12% of cases were noted in users <20 years of age.19  The FDA warns that tianeptine is an unsafe food additive, and its use in dietary supplements constitutes adulteration under the Federal Food, Drug, and Cosmetic Act.14  Currently, tianeptine is banned or restricted in Minnesota, Michigan, Alabama, Tennessee, Georgia, Indiana, and Ohio.5,23 

The effects of tianeptine in neonates have not been studied, and to our knowledge, the authors of only 1 report from France have documented NAS after maternal dependence on tianeptine prescribed for depression.9  In this report, we describe an infant presenting with undisturbed tremors, fever, an inconsolable cry, and gastrointestinal signs consistent with neonatal opioid withdrawal syndrome. In utero tianeptine exposure occurred after chronic maternal prenatal use of dietary supplements and led to the onset of neonatal signs shortly after birth. This patient represents the first case reported in the United States. In this case, possible co-exposure to amphetamines from the occasional maternal use of Adderall and the severity of signs guided the initial decision to start oral phenobarbital. However, the clinical features observed were not typical for amphetamine exposure, prompting further caregiver questioning that revealed tianeptine use. Lethargy, somnolence, and poor feeding in the early newborn period are more common presentations of prenatal amphetamine exposure and typically require minimal support.24  Even with chronic amphetamine exposure at high doses, signs of opioid withdrawal have not been shown to occur.25  The patient’s mother did not report opiate use or dependency in pregnancy, and similarly to the previously reported case, clinical signs improved only when oral morphine was started, suggesting an opioid-receptor-mediated effect.

At present, urine drug testing for tianeptine is unavailable, and blood assays can be obtained only at specialized testing laboratories.26  We urge clinicians to be vigilant for potential cases and to ask about the use of dietary supplements when reviewing medications with patients. Social work risk assessment should be used to facilitate the safe discharge of the infant. Referral to substance abuse and addiction programs may be beneficial.

The adulteration of dietary supplements with tianeptine can result in inadvertent maternal and fetal exposure. The surge in tianeptine exposure among adolescents and young adults is likely producing an increase in perinatal exposure. A stricter premarketing review of dietary supplements will increase consumer safety and should be advocated. Further research is needed to gain more understanding of the neonatal effects of tianeptine.

Dr Ikeri conceptualized and designed the case report and drafted the initial manuscript; Dr Anderson designed the case report and drafted the initial manuscript; Drs Eyal and Whitehurst conceptualized and designed the case report; and all authors reviewed and revised the manuscript for important intellectual content, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

FDA

Food and Drug Administration

NAS

neonatal abstinence syndrome

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