Abstract Objective: To study the sex and hormonal effects on cortico-striatal engagement during drug cue-reactivity and its regulation focusing on drug reappraisal. Methods: Forty-nine men (mean age=41.96; SD age=9.71) with heroin use disorder (HUD) and 32 age-matched women (mean age=38.85; SD age=9.84) with HUD (n=16) or cocaine use disorder (CUD; n=16) were scanned using functional MRI, with a subgroup of women scanned twice, during the late-follicular and mid-luteal phases, to examine sex and menstrual phase differences in cortico-striatal drug cue-reactivity and its cognitive reappraisal and their correlations with ovarian hormones and drug craving. 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 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, Δprogesterone/estradiol ratio was positively associated with Δdrug reappraisal in the dlPFC. Conclusions: Compared to men, women with addiction show more cortico-striatal reactivity to drug cue exposure and less PFC activity during drug reappraisal, 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. This study provides insights for developing precisely timed and hormonally informed treatments for women with addiction.

The authors have declared no competing interest.

This work was supported by NIDA grant T32DA053558 to Dr. Ceceli (as trainee), NIMH grant T32MH122394 to Dr. Kronberg (as trainee), and NCCIH grant R01AT010627 and NIDA grant R01DA048301 to Dr. Goldstein.

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The Icahn School of Medicine at Mount Sinai institutional review board approved study procedures, and all participants provided written informed consent.

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The data that support the findings of this study are available from the corresponding author (rita.goldstein@mssm.edu), upon reasonable request.