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.

J.H.N.: consultant/advisory board for AGB Pharma, Cingulate Therapeutics, Hippo T&C, Lumos, Medice, Mentavi Health, MindTension, Otsuka, Signant Health and Supernus; research support from Cingulate, MindTension, and Supernus; honoraria for disease state lectures from Apsen and Otsuka, and served as a consultant for the US National Football League. The other authors declare no competing interests.

NCT05978167

We thank Yui Ying Wong and Maggie Boros for their assistance in recruitment and data collection. This work was supported by grant no. T32DA053558 to A.O.C. as trainee, and grant no. R21DA054281 to R.Z.G. The funders had no role in the design and conduct of the study, the collection, management, analysis and interpretation of the data, the preparation, review or approval of the manuscript, and the decision to submit the manuscript for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Icahn School of Medicine at Mount Sinai Institutional Review Board approved all study procedures. All participants provided written informed consent prior to participating in the study and were compensated after study completion.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors