Time Course of Serum Dextromethorphan Concentrations in a Case of Serotonin Syndrome After Massive Overdose

Introduction

Dextromethorphan (DXM), known for its antagonistic effect on N-methyl-d-aspartate receptors, is widely included in over-the-counter antitussive and cold medications. However, at high doses, it can induce euphoria and hallucinations, leading to concerns about abuse among younger individuals [1]. Notably, when ingested in large quantities, DXM inhibits serotonin reuptake, triggering serotonin syndrome [2]. Serotonin syndrome is a potentially life-threatening adverse drug reaction associated with excess activation of central and peripheral serotonin postsynaptic receptors [2,3], and involves mental status changes, neuromuscular hyperactivity, and autonomic instability. Symptoms range from mild tremors and agitation to severe hyperthermia, rigidity, and organ failure. The diagnosis is primarily clinical, based on patient history and symptoms, and a differential diagnosis is important to distinguish it from other conditions. The key treatment is supportive care [2].

Despite the existence of a few reports on serotonin syndrome after DXM overdose, no case report has provided a detailed analysis of serial blood DXM levels along with the clinical course. Analyzing blood concentrations in conjunction with clinical symptoms is essential for the appropriate management of toxicological cases. Herein, we present a case in which serial measurement of blood DXM levels was obtained over time. Written informed consent was obtained from the patient for the publication of this case report.

Case Report

A 24-year-old man (height, 175 cm; weight, 65 kg) was receiving pharmacotherapy with trazodone and methylphenidate for bipolar disorder and attention-deficit/hyperactivity disorder. He ingested an excessive dose of an over-the-counter cough suppressant containing DXM (300 mg; equivalent to 4.6 mg/kg). Approximately 10 h after ingestion, he was transported to our emergency department with impaired consciousness, presenting with agitation and confusion.

His vital signs were as follows: blood pressure, 157/96 mmHg; heart rate, 139 bpm; respiratory rate, 24 breaths/min; oxygen saturation, 97% on room air; body temperature, 37.5°C; and Glasgow Coma Scale score, 11 (E4V3M4). His pupillary diameter was 7 mm. Urine drug screening was positive for oxycodone, 3,4-methylenedioxymethamphetamine, and phencyclidine. Thus, he was diagnosed with a DXM overdose and admitted to the intensive care unit.

At 13 h after ingestion (at hospital admission), the DXM blood concentration was 398 ng/mL, while the trazodone and methylphenidate levels were both below 1 ng/mL. After admission, his condition deteriorated. He developed worsening signs of serotonin syndrome, including clonus, muscle rigidity, tachycardia, hypertension, mydriasis, diaphoresis, and hyperthermia. Spontaneous clonus appeared, leading to a diagnosis of serotonin syndrome based on the Hunter criteria [4]. His symptoms worsened, resulting in generalized tonic-clonic seizures. Intravenous diazepam (5 mg) was administered, which successfully terminated the seizures. Continuous sedation, intubation, and mechanical ventilation were required due to persistent psychomotor agitation.

On hospital day 2, his spontaneous clonus improved, and the hypertension, tachycardia, mydriasis, and hyperthermia gradually abated. On hospital day 3, the DXM blood concentration had decreased to 26 ng/mL. On hospital day 4, the DXM level dropped to 2 ng/mL, and the patient’s agitation had lessened, allowing for extubation. However, although his autonomic symptoms improved, neuropsychiatric manifestations such as hallucinations and delusions persisted despite the significant drop in DXM levels. On hospital day 5, the DXM level had fallen below the detectable limit, yet neuropsychiatric symptoms persisted. Table 1 summarizes blood DXM levels and the clinical course of serotonin syndrome.

On hospital day 9, after the resolution of autonomic symptoms, he was diagnosed with an acute and transient psychotic disorder and transferred to the psychiatric department. On hospital day 33, his condition improved with oral therapy and modified electroconvulsive therapy. The final diagnosis was substance/medication-induced psychotic disorder, and he was discharged with a plan for outpatient follow-up.

Discussion

We present a case in which serial measurements of blood DMX levels were obtained over time along with the clinical course of serotonin syndrome. Incorporating accurate blood concentration levels enables a thorough consideration of serotonin syndrome, potentially leading to a more accurate clinical assessment.

Serotonin syndrome develops from excessive serotonin receptor stimulation by drugs that increase synaptic serotonin levels. Its clinical manifestations are characterized by central nervous system and autonomic excitation and altered mental status, ranging from mild symptoms such as diaphoresis and tremors to life-threatening conditions including hyperthermia, seizures, and impaired consciousness [4,5]. The causative agents include psychiatric medications, antiepileptics, and opioids. Typically, serotonin syndrome is associated with the initiation or dose increases of these medications, developing within several to 24 h following exposure [5]. Reports indicate that high doses of DXM can lead to serotonin syndrome. Furthermore, even at lower doses, DXM can induce serotonin syndrome through interactions with other medications [2].

Despite some reports, detailed analyses examining the relationship between blood levels of these drugs and serotonin syndrome symptoms are scarce. Consequently, the exact relationship between blood levels, their fluctuations, and drug interactions remains unclear. Five cases of serotonin syndrome associated with raised DXM blood levels have been reported [6–9]. Table 2 summarizes the dosage, blood levels, timing of measurements, and any co-administered interacting drugs for these cases.

In healthy individuals, a single 20-mg DXM oral dose resulted in a blood level of 1.8 ng/mL approximately 2.5 h after administration [10]. Schwartz et al reported the clinical course of DXM toxicity in patients with elevated blood levels [6]. In the first case, a 20-year-old man presented with serotonin syndrome after ingesting a DXM-containing cough suppressant. His initial DXM level was 950 ng/mL, accompanied by an elevated chlorpheniramine level of 430 ng/mL. The initial clinical manifestations were confusion, fever (38.4°C), tachycardia (168 bpm), and pronounced neurological findings such as hyperreflexia and clonus. In the second case, a 6-year-old boy exhibited DXM toxicity after ingesting approximately 40 mg/kg; the peak blood level was 2820 ng/mL. Symptoms included lethargy, confusion, lower-extremity rigidity, clonus, dilated pupils, and diaphoresis.

Ganetsky et al reported a case of an 18-year-old man who presented with agitation, neuromuscular hyperactivity, and autonomic instability. His blood DXM level was 930 ng/mL; the exact ingested dose was not determined. Co-administered drugs were deemed non-contributory [7]. Tanaka et al reported a case of a 64-year-old man on peritoneal dialysis who presented with myoclonus, tremors, agitation, slurred speech, and diaphoresis. Upon evaluation, his DXM blood level was found to be 2.68 ng/mL, approximately 60 h after ingesting a 30-mg dose. Serum levels of the co-administered drugs were clinically insignificant; however, the report suggested the potential role of prolonged dosing effects or drug interactions in the clinical presentation [8]. Monte et al reported a case of a 19-year-old man with borderline personality disorder who presented with agitation, delirium, mydriasis, and autonomic instability (blood pressure, 177/113 mmHg; heart rate, 128 bpm; temperature, 38.5°C) 12 h after ingesting 1440 mg of DXM. His blood DXM level was 250 ng/mL 12 h after ingestion, which decreased to 38 ng/mL at 38 h. Symptoms resolved with supportive care as DXM levels declined, suggesting that symptom improvement was correlated with a reduction in DXM levels [9].

Our patient presented with an altered level of consciousness 13 h after the DXM overdose (300 mg [4.6 mg/kg]); the initial DXM blood level was 398 ng/mL. His symptoms progressed to serotonin syndrome, characterized by clonus and autonomic instability, which persisted even as the serum DXM levels gradually declined. By the third hospital day, his DXM level had dropped to 26 ng/mL, reaching 2 ng/mL by the fourth day, and became undetectable by the fifth day; concurrent drug levels remained below detectable thresholds. Serotonin syndrome symptoms persisted alongside declining DXM levels, with improvement noted as the levels approached undetectable limits. This case underscores the potential for serotonin syndrome to manifest across a range of serum DXM levels, suggesting that symptom-focused monitoring may be crucial in managing DXM overdose.

Compared with previously reported cases, this case is unique in that serial blood level measurements were performed, allowing for a clearer understanding of the temporal relationship between DXM levels and symptom progression. Further research with larger datasets is needed to elucidate the pathophysiology of this condition.

Conclusions

Our case report demonstrates in detail the time course of blood DXM concentrations with the clinical course in a patient with serotonin syndrome following an acute overdose. The result of the serial measurements of blood DXM levels would support the importance of symptom-focused monitoring in guiding treatment decisions.