What is the appropriate acute management for an 18‑30‑year‑old presenting with psychotic symptoms, agitation, and possible serotonin syndrome after high‑dose MDMA (3,4‑methylenedioxymethamphetamine) use?

Acute Management of MDMA-Induced Psychosis with Agitation and Possible Serotonin Syndrome

Benzodiazepines are the first-line pharmacologic treatment for MDMA-induced agitation and psychosis, with antipsychotics reserved only for severe cases refractory to benzodiazepines, because MDMA toxicity primarily involves serotonergic mechanisms that respond to sedation rather than dopamine blockade. 1

Immediate Assessment Priorities

Rule Out Serotonin Syndrome First

• Check for the diagnostic triad: hyperthermia (temperature ≤41.1°C), neuromuscular hyperactivity (clonus, hyperreflexia, rigidity predominantly in lower extremities), and autonomic instability (tachycardia, hypertension, diaphoresis). 1
• Distinguish from neuroleptic malignant syndrome: MDMA-induced serotonin syndrome has rapid onset (minutes to hours, usual 6-24 hours), hyperreflexia with clonus, and lower extremity rigidity greater than upper extremity, versus NMS which develops over days with "lead pipe" rigidity and bradyreflexia. 1
• Assess severity: Temperature >41.1°C, rhabdomyolysis (elevated creatine kinase), metabolic acidosis, elevated aminotransferases, renal failure, seizures, or disseminated intravascular coagulation indicate severe serotonin syndrome requiring ICU-level care. 1, 2

Evaluate for Medical Emergencies

• Obtain vital signs immediately: MDMA causes tachycardia, hypertension, hyperthermia, and tachypnea through massive release of serotonin, dopamine, and norepinephrine. 3, 4
• Check core temperature: Hyperthermia is the most dangerous acute complication and drives mortality through rhabdomyolysis and multi-organ failure. 1
• Assess level of consciousness: Intact awareness distinguishes psychosis from delirium; altered consciousness suggests metabolic emergency or intracranial pathology requiring different management. 5, 6
• Perform focused neurological exam: Look for focal deficits, asterixis, or myoclonus that would indicate structural lesion or metabolic encephalopathy rather than pure drug-induced psychosis. 5

First-Line Pharmacologic Treatment

Benzodiazepines for Agitation and Autonomic Instability

• Lorazepam 1-2 mg IV/IM every 2-4 hours as needed is the preferred agent for MDMA-induced agitation because it treats both the behavioral symptoms and the autonomic hyperactivity of serotonin syndrome. 1
• Midazolam 2.5-5 mg IM/IV may be used for more rapid onset when immediate sedation is required for severe agitation with imminent risk of harm. 1
• Benzodiazepines are first-line because: they reduce muscle rigidity (decreasing heat production and rhabdomyolysis risk), control agitation without worsening hyperthermia, and address the autonomic instability characteristic of serotonin syndrome. 1

When to Add or Switch to Antipsychotics

• Reserve antipsychotics for severe psychotic symptoms (delusions, hallucinations causing dangerous behavior) that persist despite adequate benzodiazepine sedation. 1, 5
• Haloperidol 0.5-1 mg IM/IV (maximum 5 mg/24 hours) is preferred over atypical antipsychotics because it has the most extensive evidence base and lower risk of QTc prolongation compared to alternatives. 1
• Critical warning: Antipsychotics can worsen hyperthermia and lower seizure threshold in MDMA toxicity; use only when psychotic symptoms pose immediate danger and benzodiazepines alone are insufficient. 1

Management of Severe Serotonin Syndrome

Immediate Interventions for Temperature >41.1°C

• Emergency sedation, neuromuscular paralysis, and intubation should be considered for severe hyperthermia to prevent end-organ damage. 1
• Avoid physical restraints: They exacerbate isometric muscle contractions, worsening hyperthermia, lactic acidosis, and mortality. 1
• Active cooling measures: External cooling with ice packs, cooling blankets, and evaporative cooling are essential adjuncts. 1

Supportive Care Essentials

• IV fluid resuscitation: Aggressive hydration to prevent rhabdomyolysis-induced acute kidney injury and to manage autonomic instability. 1
• Monitor for complications: Serial creatine kinase, renal function, liver enzymes, coagulation studies, and arterial blood gas to detect rhabdomyolysis, hepatotoxicity, disseminated intravascular coagulation, and metabolic acidosis. 1, 2
• Cyproheptadine (serotonin2A antagonist): Consider adult dosing for severe serotonin syndrome, though evidence is limited and supportive care remains the mainstay. 1

Management of Psychotic Symptoms

Acute Phase (First 24-72 Hours)

• Most MDMA-induced psychosis resolves within 24-72 hours with abstinence and supportive care alone. 7, 8
• Benzodiazepines provide adequate sedation for the majority of cases without requiring antipsychotic exposure. 1
• If antipsychotic is necessary: Start with low-dose haloperidol 0.5-1 mg, avoiding large initial doses which increase side effects without hastening recovery. 5

Persistent Psychosis Beyond 72 Hours

• Reassess for primary psychotic disorder: MDMA can unmask or trigger persistent psychosis, particularly in individuals with underlying vulnerability. 7, 8
• Continue antipsychotic for 4-6 weeks before determining efficacy if psychotic symptoms persist beyond the acute intoxication phase. 5
• Consider switching agents if symptoms persist after adequate trial, choosing an antipsychotic with different pharmacodynamic profile. 5

Critical Pitfalls to Avoid

• Do not use antipsychotics as first-line: MDMA toxicity is primarily serotonergic, not dopaminergic; benzodiazepines address the core pathophysiology more effectively. 1, 3
• Do not miss delirium: Fluctuating consciousness, disorientation, and inattention distinguish delirium from psychosis and require urgent evaluation for metabolic or infectious causes. 5
• Do not delay cooling measures: Hyperthermia >41.1°C is a medical emergency requiring immediate aggressive cooling and ICU admission. 1
• Do not assume single-substance use: Most MDMA users consume multiple substances; obtain comprehensive toxicology screening and consider polypharmacy effects. 3, 8
• Do not overlook genetic susceptibility: Asian populations (Korean, Chinese, Japanese) have high prevalence of CYP2D6 polymorphisms causing reduced MDMA metabolism, increasing risk of severe toxicity even after single doses. 2

Monitoring and Disposition

• Continuous cardiac monitoring: MDMA causes tachycardia, hypertension, and risk of dysrhythmias. 3, 4
• Serial vital signs every 15-30 minutes until stable, then hourly for first 24 hours. 1
• ICU admission criteria: Temperature >41.1°C, severe rhabdomyolysis (CK >15,000), acute kidney injury, metabolic acidosis, seizures, or disseminated intravascular coagulation. 1, 2
• Psychiatric consultation: For persistent psychotic symptoms beyond 72 hours or if diagnostic uncertainty exists between substance-induced versus primary psychotic disorder. 5, 8