Opioid-Associated Hippocampal Injury: Past, Present, and Future Directions

Abstract

Three of the great public health challenges of our time converge at the hippocampus. The first, dementia, most commonly in the form of Alzheimer's disease, is well known to cause progressive hippocampal damage, resulting in the memory loss associated with the illness. The second, COVID-19 infection, has thus far been linked to hippocampal alterations across multiple studies. Lastly, the third, opioids—especially in the setting of misuse—have been associated with acute and persistent hippocampal injury; this review focuses on the collection of pre-clinical, clinical, and epidemiologic observations supporting this final relationship. Basic science work dating back decades has demonstrated a hypermetabolic response to opioids and associated damage to the hippocampus. The earliest cases recognized as opioid-associated amnestic syndrome (OAS) were subsequently identified in 2012 and reported as part of larger case series several years later. In 2019, a related but more fulminant syndrome involving cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) was first described. From these investigations, a growing body of data has since emerged to suggest that regular opioid use, particularly at higher doses or potency, may be connected to a reduction in hippocampal volume and greater risk of dementia. This review begins with a synthesis of data supporting the underlying pathological mechanisms of opioid-associated hippocampal injury (OAHI), then covers the clinical spectrum of this phenomenon. Lastly, we will close with implications of OAHI that warrant further study, including the future epidemiologic impact on related cognitive disorders in the wake of the opioid epidemic and potential therapeutic applications of opioid antagonism for mild cognitive impairment.