Abstract
BACKGROUND: Drug-related memories can hinder abstinence goals in drug addiction. Promoting non-drug memories via ventromedial prefrontal cortex- (vmPFC) and amygdala-guided extinction yields mixed success. Post-retrieval extinction (RE) destabilizes and updates memories during reconsolidation, improving extinction. Supplementing RE, we tested methylphenidate (MPH), a dopamine-agonist that promotes PFC-dependent learning and memory in cocaine use disorder (CUD). In an Early Phase 1 double-blind randomized clinical trial using a within-subjects design, participants received oral MPH (20 mg) or placebo before the retrieval of some of the conditioned stimuli (i.e., reminded CS+ vs. non-reminded CS+) followed by extinction; lab-simulated drug-seeking was measured the following day. RESULTS: Lower vmPFC activity following non-reminded CS+ (standard extinction) under placebo replicated the putative impairments in CUD; separately, RE (trend) and MPH conditions recruited the vmPFC, and RE's vmPFC-reliance correlated with drug-seeking only under placebo. Crucially, MPH-combined RE normalized cortico-limbic processing, bypassing the vmPFC and its amygdala connectivity. CONCLUSIONS: Pharmacologically-enhanced drug memory modulation may inform intervention development for addiction recovery.