Estradiol and Social Withdrawal in Addiction: A Sex-Specific Neuroendocrine Perspective

Abstract Addiction models have traditionally emphasized drug rewards while often underestimating the role of social processes in relapse vulnerability. Converging evidence from preclinical and clinical studies suggests that social withdrawal during substance use and abstinence may weaken access to social reinforcement, increase perceived stress, and heighten vulnerability to relapse. This brief perspective proposes that estradiol-sensitive signaling shapes, rather than determines, neural systems governing social motivation, stress responsivity, and affective regulation. Across hormonal states, fluctuations or reductions in estradiol signaling may alter the salience of social and stress-related cues, potentially increasing vulnerability to withdrawal-related negative affect. These effects may be further compounded by structural stressors that disproportionately burden Black women, amplifying relapse risk through combined biological and social pathways. Recognizing social withdrawal as a hormonally sensitive and structurally embedded process may help refine addiction models and inform more precise and equitable translational research strategies.