Sex‐dependent prefrontal cortex activation in regular cocaine users: A working memory functional magnetic resonance imaging study

Although two thirds of patients with a cocaine use disorder (CUD) are female, little is known about sex differences in the (neuro)pathology of CUD. The aim of this explorative study was to investigate sex‐dependent differences in prefrontal cortex (PFC) functioning during a working memory (WM) functional magnetic resonance imaging (fMRI) task in regular cocaine users (CUs), as PFC deficits are implicated in the shift from recreational cocaine use to CUD. Neural activation was measured using fMRI during a standard WM task (n‐back task) in 27 male and 28 female CUs and in 26 male and 28 female non‐cocaine users (non‐CUs). Although there were no main or interaction effects of sex and group on n‐back task performance, WM‐related (2‐back > 0‐back) PFC functioning was significantly moderated by sex and group: female compared with male CUs displayed higher WM‐related activation of the middle frontal gyrus (MFG), whereas female compared with male non‐CUs displayed lower WM‐related MFG activation. Additionally, WM‐related activation of the inferior frontal gyrus, insula, and putamen was negatively associated with cocaine use severity in female but not male CUs. These data support the hypothesis of sex‐dependent PFC differences in CUs and speculatively suggest that PFC deficits may be more strongly implicated in the development, continuation, and possibly treatment of CUD in females. Most importantly, the current data stress the importance of studying both males and females in psychiatry research as not doing so could greatly bias our knowledge of CUD and other psychiatric disorders.