Not just neurons: glial mechanisms driving sex-specific vulnerability to withdrawal and relapse in substance use disorder

• Baseline glial sex differences may underlie male–female divergence in withdrawal. • Prior research favors acute, male-biased symptoms while overlooking glial roles. • Glia–behavior links may explain somatic vs affective withdrawal across sexes. • Sex- and region-specific glial changes may intensify withdrawal and block remission. Sex differences are fundamental determinants of the neurobiology of substance use disorders (SUDs), modulating withdrawal severity, relapse risk, and treatment response. Despite this, prior research has largely studied males and ignored sex differences. Growing bodies of evidence suggests glial cells mediate these sex differences, particularly during withdrawal. In this review, we begin describing baseline sex differences and known glial sex differences at homeostasis. We then examine clinical and preclinical findings describing alterations in glial cells during withdrawal. We describe how glial sex differences are region-specific to areas implicated in reward-induced dysfunction. We conclude with a description of how glial sex differences during withdrawal likely drive sex differences in relapse vulnerability. Our synthesis posits glial cells as key mediators of sex differences in SUD withdrawal. Future investigations focused on glial pathologies could uncover sex-specific, targetable mechanisms to improve treatment and promote sustained remission in both males and females.