Management of a Kratom and Tianeptine Overdose

Introduction

Kratom (Mitragyna speciosa) is a tropical tree native to Southeast Asia whose leaves contain psychoactive alkaloids, including mitragynine and 7-hydroxymitragynine. ¹ Traditionally used for its stimulant effects at low doses and opioid-like effects at higher doses, kratom has become increasingly popular in Western countries as a “natural” alternative for pain management, mood elevation, and opioid withdrawal. However, unregulated use has been associated with adverse effects, including sedation, respiratory depression, seizures, and death, especially in large doses or combined with other substances. ² Tianeptine, an atypical tricyclic compound marketed under names including TD-Red and Zaza, acts as a mu-opioid receptor agonist at high doses. It is not FDA-approved in the United States but is prescribed in France for Major Depressive Disorder (25-50 mg daily for therapeutic effect). When used recreationally, doses often exceed 3g daily, which results in opioid-like effects, including neurological and respiratory depression. ³ We present a case of combined kratom and tianeptine ingestion that resulted in severe respiratory compromise and encephalopathy.

Case Presentation

A 38-year-old male with a history of polysubstance abuse, including amphetamines, benzodiazepines, and opiates, was found unresponsive by coworkers, who initiated cardiopulmonary resuscitation (CPR) before emergency medical services (EMS) arrived. It was noted that he did have a pulse upon EMS arrival. EMS then administered 2 mg of naloxone intranasally followed by another 2 mg intravenously. On presentation to the emergency department (ED), he was somnolent and hypoxic, saturating 88% on 12 liters via non-rebreather mask with intermittent stridulous respirations.

Laboratory evaluation revealed a creatinine of 1.31 mg/dL, glucose of 150 mg/dL, and white blood cell count of 10.88 ×10³/mcL. Venous blood gas demonstrated a pH of 7.248, pCO₂ of 78.9 mmHg, bicarbonate of 34.5 mmol/L, and oxygen saturation of 29%, consistent with acute respiratory acidosis. Chest radiography showed a right upper lobe infiltrate, and computed tomography (CT) demonstrated additional consolidations in the right upper and bilateral lower lobes, ground-glass opacities in the left upper lobe, and non-displaced fractures of the left 2nd–4th ribs. CT imaging of the head and cervical spine was unremarkable.

History collected from the patient’s wife revealed chronic use of large doses of kratom (approximately twenty-five 500 mg capsules, divided 2-3 times daily) along with an unknown amount of tianeptine. She also reported an active prescription for amphetamine-dextroamphetamine for diagnosed attention deficit hyperactivity disorder. No active prescription for benzodiazepines or opioids were found in the Prescription Drug Monitoring Program. Toxicology screens were positive for amphetamines and benzodiazepines and negative for opiates and fentanyl. Of note, the urine drug screen was obtained approximately 7 hours after the administration of the one-time dose of midazolam 2 mg intravenously for agitation, so it is possible that the positive benzodiazepine screening was due to this.

During ED observation, the patient’s mental status declined. An additional two 2 mg doses of intravenous naloxone were administered with similar effects: transient respiratory improvement followed by opioid withdrawal symptoms including piloerection, mydriasis, tachypnea, and severe agitation. A dexmedetomidine infusion and intermittent midazolam was provided for management of agitation control.

The patient was admitted to the intensive care unit (ICU) on infusions of naloxone at 0.5 mg/hr and dexmedetomidine at 0.2 mcg/kg/hr to maintain respirations and manage agitation. Community-acquired pneumonia coverage with ceftriaxone and doxycycline was initiated based on imaging findings, although a vape-related lung injury was not ruled out by Pulmonology. Aspiration was also suspected. Attempts to wean the naloxone drip within the first 20 hours of presentation were unsuccessful due to rebound respiratory depression.

Naloxone and dexmedetomidine infusions were successfully weaned by 24 hours post-initiation. By hospital day 2, the patient was maintaining oxygen saturation of 98% on room air without supplemental oxygen and showed no ongoing withdrawal symptoms. He was discharged home on hospital day 2 with an oxycodone prescription for management of rib fracture related pain. Per Pulmonology recommendations, the patient continued antibiotics for a total of 7 days following discharge and a levofloxacin 750 mg daily prescription was sent to his outpatient pharmacy.

Discussion

This case demonstrates severe hypoxic respiratory failure following combined kratom and tianeptine ingestion. Tianeptine, acting as a full mu-opioid receptor agonist at recreational doses, and kratom, containing partial opioid agonists like mitragynine, likely produced synergistic respiratory depression. The patient exhibited classic opioid toxidrome, with transient response to naloxone and subsequent acute opioid withdrawal symptoms requiring management of agitation. Aspiration pneumonitis and bystander CPR-related rib fractures further complicated respiratory function. ICU management included naloxone infusion, airway monitoring, empiric antibiotics, and cautious sedation with dexmedetomidine. The use of a continuous naloxone infusion was necessitated by the prolonged duration of action of the ingested agents, requiring sustained opioid receptor antagonism.

Awareness of tianeptine and kratom toxicity is essential, particularly given absence from standard drug screens and the increasing prevalence and availability of these substances. The known half-life of tianeptine is 2.5 hours and is quickly absorbed by the gastrointestinal tract with a low volume of distribution. Metabolites are renally cleared which can lead to prolonged effects in those with kidney disfunction. ⁴ The effects of kratom can typically last 5 to 7 hours with peak effects typically within 2 to 4 hours. The primary metabolite of kratom, mitragynine, does rely on CYP3A4 (and in lesser degree CYP2C19 and CYP2D6) for metabolism, suggesting that kratom could be associated with drug interactions. ⁵ It does appear that the effects of what the patient ingested lasted longer than the assumed half-life of these agents. It is possible a co-ingestion with another substance or benzodiazepine might have occurred or there is an unknown drug interaction that could be prolonging it.

Due to the presence of benzodiazepines on the urine drug screen, it cannot be written off that co-administration of illegally obtained benzodiazepines could have contributed to the patient’s respiratory depression. Unfortunately, this institution does not have the laboratory capability of identifying the offending benzodiazepine(s) and midazolam had been administered in the last 6 hours. Reversal of benzodiazepine efficacy with flumazenil would not have been attempted due to increased risk of seizures in a patient that may have had a long-standing benzodiazepine abuse history. ⁶

Additionally, the patient was discharged with an opioid prescription for broken ribs despite presenting with an acute opioid overdose, underscoring the need for improved prescribing oversight and discharge planning in the context of substance-related admissions. Furthermore, unique overdose cases like this one should warrant an individualized approach to substance abuse counseling prior to discharge as the patient is utilizing agents that are more readily and legally available to the public.

Conclusion

Polysubstance overdose involving kratom and tianeptine can result in profound hypoxemia and acute encephalopathy similar to that of opioids. Clinicians must maintain a high index of suspicion when encountering somnolent, hypoxic patients with known or suspected kratom or tianeptine use, especially considering standard drug screens may not detect these substances. Treatment is often supportive in nature and naloxone should be considered as an antidote to help maintain adequate respirations. Specialized addiction counseling can also be offered to the patient if resources are available.