Collateral Damage: Neurological Correlates of Non-Fatal Overdose in the Era of Fentanyl-Xylazine

Non-fatal opioid overdoses are associated with significant morbidity. Hypoxic brain injury caused by opioid-induced respiratory depression is a key mechanism of such morbidity. For example, reports describe an amnestic syndrome in opioid users associated with acute injury to the hippocampus, a brain region that is highly susceptible to hypoxic injury. In our recent study we investigated the effects of non-fatal opioid overdose on the hippocampal volume in a well-characterized sample of opioid use disorder (OUD) patients with a history of overdose (OD) compared to those with no prior overdose (NOD). Using structural magnetic resonance imaging (MRI) and voxel-based morphometry, we observed lower hippocampal volume in patients with a history OD than in the NOD group. These findings support an association between non-fatal opioid overdose and hippocampal injury, which we hypothesize contributes to recently reported cases of OUD related amnestic syndrome. Here we review our study findings and the potential pathophysiological mechanisms underlying the acute and delayed hippocampal injury in nonfatal opioid overdose. We also discuss the implications for the risk of overdose and brain injury with the increased prevalence of fentanyl and xylazine contamination of the illicit opioid supply. Lastly, we highlight considerations for clinical management of the underappreciated neurological injury and cognitive dysfunction in OUD patients.