A systematic review of 100 studies investigating pharmacological effects on human aversive memory

Learning to avoid threat is fundamental to human survival, yet maladaptive aversive memories play a central role in anxiety and trauma-related disorders, including post-traumatic stress disorder (PTSD). Pharmacological modulation of aversive memory has therefore attracted sustained interest as a promising avenue for both mechanistic insight and clinical translation. However, evidence in humans remains highly fragmented across neurotransmitter systems, experimental paradigms, and targeted memory stages. The present systematic review [1] addresses the overarching question of how acute pharmacological interventions influence aversive memory processes in healthy humans.

The primary aim of this review was to synthesise evidence systematically on the effects of pharmacological compounds on aversive memory encoding, consolidation, retrieval, extinction learning and consolidation, reconsolidation, and return of fear. Secondary aims were to identify promising interventions for clinical research, and to highlight those that might be promising in the future but currently lack replication, and might thus be prioritised for pre-clinical research.

Following PRISMA-2020 guidelines, we identified 215 candidate compounds spanning 17 neurotransmitter systems and signalling pathways. Comprehensive searches of PubMed, Web of Science, and Scopus were conducted up to June 14, 2024. Randomised, placebo-controlled trials (RCTs) in healthy adults were included if they investigated acute pharmacological interventions on aversive memory and reported behavioural outcomes rather than solely neuroimaging or subjective ratings. Overall, 100 publications investigating 36 compounds across 13 systems met the inclusion criteria. The majority of identified studies focused on the noradrenergic and glucocorticoid systems. Propranolol (N = 19 publications), hydrocortisone (N = 25), and D‑cycloserine (N = 8) were the most frequently examined compounds. Given substantial heterogeneity in paradigms, outcomes, and study designs, a quantitative meta-analysis was not feasible. Instead, we applied a structured evidence-classification framework categorising findings into the following categories based on replication, result consistency, and methodological quality: no evidence, inconsistent, potential, weak, or solid.

Solid evidence emerged for a selective effect of propranolol on aversive memory reconsolidation across both fear conditioning and declarative memory paradigms, as indexed by reduced fear memory retention and attenuated return of fear. In contrast, evidence for propranolol effects on encoding, retrieval, or extinction was inconsistent or weak. D‑cycloserine, 3,4‑methylenedioxymethamphetamine (MDMA), diazepam, and reboxetine showed weak evidence of effects on aversive memory encoding and consolidation, while valproic acid showed weak evidence for facilitating extinction encoding and consolidation. Findings for glucocorticoids, particularly hydrocortisone, were highly inconsistent across memory stages, paradigms, and populations. Notably, 15 compounds demonstrated statistically significant effects in single studies without independent replication, and might be promising for future preclinical research.

In conclusion, robust evidence for pharmacological modulation of aversive memory in healthy humans is currently limited to a small number of compound–memory stage combinations, most notably propranolol targeting memory reconsolidation. The field is characterised by substantial heterogeneity, small sample sizes, and a lack of systematic cross-paradigm replication. Progress towards mechanistic understanding and clinical translation might benefit from standardised experimental protocols, pharmacokinetically informed designs, and conceptual replication across memory models.

References

1. Xia Y, Quednow BB, Bach DR (2026). A systematic review of pharmacological effects on human aversive memory. Neuroscience & Biobehavioral Reviews, 183, 106548.