Etna J. E. Engeli ^1* Katrin H Preller ¹ Nathalie M Rieser ¹ Johanna Klar ^1,2 Philipp Stämpfli ¹ Lea M Hulka ¹ Matthias Kirschner ^1,3 Erich Seifritz ¹ Marcus Herdener ^1*

• ¹ Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, Zurich, Switzerland
• ² University Children’s Hospital Bern, Bern, Bern, Switzerland
• ³ University Hospitals of Geneva, Geneva, Geneva, Switzerland

Background: Individuals with cocaine use disorder experience increased motivation to pursue rewards tied to cocaine, often triggered by associated cues. Cue reactivity and subsequent craving significantly elevate the risk of substance use. Consequently, there is a pressing need for a treatment that can help alleviate cravings. Still, no pharmaceutical therapies to treat cocaine use disorder have been approved. Preclinical findings reveal dysfunctions in the glutamatergic pathway connecting prefrontal regions with the nucleus accumbens which are correlated with cue-induced substance-seeking behaviour. The reversal of these alterations at both molecular and behavioural levels could be achieved in rodents with N-acetylcysteine, a modulator of glutamatergic signalling. In contrast, the therapeutic potential for humans remains uncertain.Methods: Here, we assessed the impact of a short-term challenge of N-acetylcysteine on neural responses to cocaine cues and cue-induced craving in a randomized, placebo-controlled crossover trial using a fMRI cue reactivity paradigm. Forty-four fMRI cue reactivity scans of twenty-two individuals with cocaine use disorder were recorded, once after the administration of 2400 mg N-acetylcysteine/day on 2 days and once after placebo intake.Results: In the placebo condition, participants showed increased cue reactivity towards cocaine pictures accompanied by significantly higher craving as compared to neutral images. In accordance with recent meta-analyses, cue reactivity was evident in parietal regions such as the posterior cingulate and precuneus, temporal regions like the hippocampus, the bilateral insula, and medial prefrontal regions, namely the inferior, middle, and superior frontal gyrus.The cue-induced activity in the superior frontal gyrus was strongly predicted by individual duration of cocaine use. While N-acetylcysteine showed no impact on subjectively rated cocaine craving, neural cue reactivity in the superior frontal gyrus was significantly decreased under N-acetylcysteine compared to placebo. Conclusions: Our findings show that prefrontal reactivity to cocaine cues can be reduced even by a brief pharmacological challenge with N-acetylcysteine. Since neural drug cue reactivity has been shown to be a precursor of relapse behaviour, N-acetylcysteine's therapeutic potential should be further investigated in future studies by extending treatment periods.