Sex and Hormonal Effects on Drug Cue Reactivity and Its Regulation in Human Addiction

Background The underlying corticostriatal 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 years) with heroin use disorder (HUD) or cocaine use disorder (CUD) (HUD = 16; CUD = 16) and 49 age-matched men (age = 41.96 ± 9.71 years) with HUD were scanned using functional magnetic resonance imaging (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 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 versus 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 the Δestradiol, the lower the Δdrug reappraisal in the vmPFC, anterior PFC, and striatum. Conversely, during the luteal versus follicular phase, the Δprogesterone/estradiol ratio was positively associated with Δdrug reappraisal in the dlPFC. Conclusions Compared with men with HUD, women with HUD/CUD show more corticostriatal drug cue reactivity and less PFC drug reappraisal activity, an effect driven by the follicular compared with the 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.