Case Presentation: A 43-year-old male with anxiety and chronic back pain presented to the emergency department with altered mental status. He was found by family exhibiting incoherent vocalizations and agitated behavior, despite acting normally the previous day. Vitals revealed a fever of 100.5 F and heart rate of 127 BPM. On exam, he was diaphoretic, in acute distress, with tremors and generalized muscular rigidity with spontaneous and inducible clonus in the lower extremities. He was disoriented and unable to provide any history. Labs were notable for a mild leukocytosis (14.7) and a negative urine drug screen. Diagnostic workup excluded metabolic, infectious, and structural etiologies of acute encephalopathy, raising suspicion for toxicologic cause. The clinical presentation was consistent with serotonin syndrome, and this was reinforced by patient’s electronic medication records, which confirmed a current paroxetine prescription. He was treated with benzodiazepines, cyproheptadine, and supportive care, resulting in marked clinical improvement over 48 hours. With clinical improvement, the patient reported adherence to his prescribed paroxetine without missed or extra doses. No other causative medications were identified during medication reconciliation; however, he disclosed concurrent daily use of Kratom for chronic back pain. It was ultimately determined that the serotonin syndrome was the result of Kratom use in combination with paroxetine. The patient met DSM-5 criteria for substance use disorder secondary to Kratom use, and he was discharged on buprenorphine.
Discussion: Kratom (Mitragyna speciosa) is an unregulated botanical containing psychoactive alkaloids with dose-dependent effects – stimulant-like at low doses and opioid-like at higher doses (4). Despite its increasing use for self-management of pain, anxiety, and opioid withdrawal, Kratom remains unapproved by the FDA and lacks robust evidence supporting safety or efficacy (3,4). Kratom-associated risks include hepatotoxicity, cardiotoxicity, respiratory depression, seizure, neonatal abstinence syndrome, hypothyroidism, overdose toxidrome, and fatalities (4). Emerging literature has documented serotonin syndrome resulting from Kratom in conjunction with serotonergic medications (1, 2). These interactions are hypothesized to stem from Kratom’s inhibition of cytochrome P450 isozymes 3A4, 2C9, 2D6, and 1A2 (2) that are involved in the metabolism of many psychotropic agents, including paroxetine which is extensively metabolized via CYP2D6 (5). Inhibition of these pathways can lead to elevated levels of serotonin and in extreme cases, serotonin syndrome.
Conclusions: It is important for the hospitalist to thoroughly investigate supplement use, specifically Kratom use, in cases of unexplained serotonin syndrome. We encourage clinicians to maintain a high index of suspicion for herbal-drug interactions and Kratom-associated adverse events as Kratom use increases nationally.