Abstract

Background: The underlying cortico-striatal mechanisms of sex and hormonal effects in addiction are unknown, limiting the development of personalized treatments. Methods: Thirty-two women (age=38.85±9.84) with heroin or cocaine use disorder (HUD=16; CUD=16) and 49 age-matched men (age=41.96±9.71) with HUD were scanned using functional MRI, with a subgroup of women (HUD=3; CUD=13) scanned twice, during the late-follicular and mid-luteal phases. Results: Women showed higher medial prefrontal cortex (PFC) drug cue-reactivity while men showed higher frontal eye field (FEF)/dorsolateral PFC (dlPFC) drug reappraisal as associated with lower cue-induced drug craving. In the women, drug cue-reactivity was higher during the follicular phase in the FEF/dlPFC, whereas drug reappraisal was higher during the luteal phase in the anterior PFC/orbitofrontal cortex. The more the estradiol during the follicular vs. luteal phase (Δ), the higher the Δdrug cue-reactivity in the ventromedial PFC (vmPFC), which also correlated with higher Δdrug craving (observed also in the inferior frontal gyrus). The more this Δestradiol, the lower the Δdrug reappraisal in the vmPFC, anterior PFC and striatum. Conversely, during the luteal vs. follicular phase, Δprogesterone/estradiol ratio was positively associated with Δdrug reappraisal in the dlPFC. Conclusions: Compared to men with HUD, women with HUD/CUD show more cortico-striatal drug cue-reactivity and less PFC drug reappraisal activity, driven by the follicular compared to luteal phase and directly related to craving and fluctuations in estrogen and progesterone with the former constituting a vulnerability and the latter a protective factor; providing insights for developing precisely timed and hormonally informed treatments for women with HUD/CUD.