Neuroimaging as the 'missing link' for preclinical to clinical translation: an example using N-acetylcysteine among individuals with cocaine- and opioid-use disorders receiving methadone treatment.

RATIONALE: Cocaine use disorder (CUD) remains a major public health problem, particularly among individuals receiving medications for opioid use disorder (mOUD), where ongoing cocaine use is associated with poorer treatment outcomes and elevated overdose risk. N-acetylcysteine (NAC) is a promising adjunctive candidate that reduces cocaine-seeking in preclinical models and shows mixed efficacy in humans, but its functional neural mechanisms in individuals with CUD-especially within mOUD settings-remain poorly understood.

OBJECTIVES

The present study uses functional magnetic resonance imaging (fMRI) to determine whether short-term NAC administration modulates brain activity in regions associated with inhibitory control and affective processing in people with CUD receiving medications for opioid use disorder (mOUD).

METHODS

In this double-blind, placebo-controlled, crossover study, 21 individuals with CUD enrolled in an mOUD program were randomized to receive NAC or placebo for 7 days and participated in fMRI scanning on the 7th day of this period. Following a fourteen-day washout period, participants were crossed over to receive the other condition for another 7-day period. Participants received a second fMRI scan on the 7th day of this period. Participants completed a go/no-go (GNG) and emotion-regulation task (ERT) during each scan.

RESULTS

Compared to placebo, active NAC did not significantly affect brain activity during either the GNG task or the ERT.

CONCLUSIONS

Overall, short-term NAC did not robustly modulate neural circuits supporting inhibitory control or emotion regulation in individuals with comorbid CUD and OUD receiving mOUD, consistent with prior trials reporting limited efficacy of NAC for CUD. These findings underscore the value of incorporating neuroimaging into early-phase treatment trials to evaluate target engagement in humans.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02994875, registered 2016-12-16.