A systematic review of pharmacological effects on human aversive memory

A large body of work has investigated the effect of various pharmacological compounds on aversive memory formation, retrieval, and modification in humans. A broad overview across signalling pathways and memory models is currently lacking. Here, we systematically review publications that tested the impact of acute pharmacological interventions on aversive memory in healthy humans, following PRISMA-2020. We identified 215 candidate compounds from 17 systems and searched PubMed, Web of Science and Scopus, until 14 June 2024. We identified 100 publications with 36 compounds targeting 13 systems. Three compounds were used by the majority of studies: hydrocortisone (n = 25), propranolol (n = 19), and D-cycloserine (n = 8), while many of the remaining 33 compounds were investigated in single studies only. We summarise the effect of each investigated compound across memory models, according to the targeted memory stage. Solid evidence emerges for an impact of propranolol on reconsolidation, and weak evidence for an impact of propranolol, 3,4-methylenedioxymethamphetamine (MDMA), benzodiazepines, yohimbine, reboxetine, and D-cycloserine on aversive memory encoding/consolidation, and valproic acid on extinction encoding/consolidation. Furthermore, 15 compounds showed significant effects in individual studies with no published replication attempts to date. We discuss potential research directions and suggest steps for greater comparability of findings between compounds, memory models, and laboratories.