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Introduction: The use of ECMO, lipid emulsion therapy (LE), and plasma exchange (PLEX) for massive bupropion XL (BUP) overdose has been described in case reports and series focusing on outcomes. However, the impact of combined LE and PLEX on BUP elimination half-life alongside clinical improvement has not been documented. We report a case of BUP overdose treated with LE and PLEX, showing shortened elimination half-life and rapid recovery. Description: A 17 year old female presented after ingestion of 27g of BUP XL and 2.25g of metoprolol XL. She presented comatose with hypotension and sinus bradycardia, with no cough or gag reflex, and non-reactive pupils. She was intubated and started on norepinephrine, epinephrine, and glucagon infusions. She acutely developed a wide complex tachycardia and pulseless cardiac arrest, requiring veno-arterial ECMO rescue. 36 hours into her ECMO course, she remained comatose with no neurologic activity and no native cardiac function. She underwent five daily 1.5-volume PLEX sessions with FFP. Given BUP’s large volume of distribution (20–47 L/kg), LE (intralipids 600 mL over 3 hours) was given before each PLEX to shift drug into the vascular space and reduce its effective volume of distribution. Urine BUP and hydroxybupropion (HBUP) levels were measured pre- and post-PLEX. Prior to the first PLEX, arterial pulse pressure (PP) was 0mmHg and ejection fraction (EF) was 18%. Within hours of the first PLEX, cardiac function improved with EF 33% and PP 20-30mmHg. Her neurological status also improved requiring sedation for purposeful movements and agitation. Following the third PLEX, her EF improved to 50% and she was decannulated from ECMO. She was extubated the day after the fifth PLEX. Discussion: Reported BUP and HBUP half-lives are 14-21 and ~21 hours, respectively. The first PLEX reduced urine levels of BUP and HBUP by 82% and 78%, respectively, reflecting a 4.9 and 5.6 hour half-life over the 12 hour period between samples. Assuming urine concentrations decrease proportionally to serum, this would exceed expected elimination without extracorporeal clearance. This is the first reported case demonstrating LE paired with PLEX can markedly reduce BUP half-life and lead to rapid hemodynamic and neurologic recovery.