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The neural signature of methylphenidate-enhanced memory disruption in human drug addiction: a randomized clinical trial

Ceceli, A. O.; King, S. G.; Drury, K. R.; McClain, N.; Gray, J.; Dassanayake, P. S.; Newcorn, J. H.; Schiller, D.; Alia-Klein, N.; Goldstein, R. Z.

2025-04-30 addiction medicine
10.1101/2025.04.29.25326658 medRxiv
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BackgroundDrug-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. ResultsLower 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 REs vmPFC-reliance correlated with drug-seeking only under placebo. Crucially, MPH-combined RE normalized cortico-limbic processing, bypassing the vmPFC and its amygdala connectivity. ConclusionsPharmacologically-enhanced drug memory modulation may inform intervention development for addiction recovery.

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