Attenuating trauma- and cocaine-related intrusions by blocking memory reconsolidation with minocycline: protocol for a transdiagnostic randomized controlled trial.

Background: Post-traumatic stress disorder (PTSD) and substance use disorders frequently co-occur, with their comorbidity linked to poorer treatment outcomes. Beyond this epidemiological overlap, PTSD and, in particular, cocaine use disorder (CUD) have also been conceptually linked, as maladaptive memory processes are thought to play a central role in both of their etiopathogeneses. PTSD and CUD are each characterized by intrusive memories - either trauma or cocaine related - that sustain distress and craving, respectively. These parallels have motivated transdiagnostic mechanistic research targeting memory reconsolidation. Matrix metalloproteinase-9 (MMP-9) is critically involved in synaptic plasticity and memory updating, and has been suggested as a pharmacological entry point for modulating reconsolidation-related processes.Objective: This study examines whether pharmacological interference with reconsolidation via MMP-9 inhibition by minocycline modulates trauma- and cocaine-related intrusive memories and their neurobiological correlates in PTSD and CUD.Method: In this monocentric, randomized, double-blind, placebo-controlled trial (NCT05902819), individuals with PTSD (n = 60) or CUD (n = 60) receive a single dose of minocycline - a tetracycline inhibiting MMP-9 - or placebo prior to an individualized, imagery-based reactivation of their most salient intrusive memory. Intrusive memories in day-to-day life are assessed using event-based ecological momentary assessment and pre-post intrusion questionnaires. Neurobiological correlates of maladaptive memory processing are indexed through functional magnetic resonance imaging and magnetic resonance spectroscopy, and peripheral biomarkers are obtained from blood, urine, and hair samples. Diagnostic status and comorbid symptoms are characterized using clinical interviews and standardized self-report measures.Conclusions: This trial adopts a mechanistic framework to investigate whether minocycline-augmented memory reactivation modulates intrusions and associated neurobiological markers in PTSD and CUD. By directly targeting candidate memory mechanisms shared by both disorders, it evaluates a transdiagnostic reconsolidation-based approach and is expected to inform models of intrusive memory persistence and updating. The findings may guide future development of memory-focused interventions in trauma- and addiction-related disorders.