Sex Differences in Neuroendocrine, Sympathetic Nervous System, and Affect Responses to Acute Stress in Cannabis Users

Abstract

Cannabis is the most widely used illicit substance in the United States and is often reportedly used for stress reduction. Indeed, cannabinoids modulate signaling of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. However, the role of biological sex in this interaction between cannabis use and stress is poorly understood, despite sex differences in neurobiological stress responsivity, endocannabinoid signaling, and clinical correlates of cannabis use. Frequent cannabis users (>3x/week, n=48, 52% male) and non-users (n=41, 49% male) participated in an acute psychosocial stress paradigm. Saliva was collected at eight timepoints and analyzed for hypothalamic-pituitary-adrenal (cortisol) and sympathetic (alpha-amylase) indices of stress responsivity, and estradiol at baseline. Subjective ratings of negative affect, including distress, were collected at three timepoints. Cannabis users showed blunted cortisol responsivity and lower alpha-amylase output overall compared to non-users, with no statistical differences between groups on overall negative affect reactivity. Aberrant stress responsivity in cannabis users was driven by females, with significant sex by time interactions for cortisol and alpha-amylase responsivity in cannabis users only. Female cannabis users demonstrated the greatest change in subjective distress across timepoints. Differences in stress responsivity were not explained by estradiol or distress intolerance. Biological sex may moderate multisystem stress responsivity in cannabis users. Paradoxically, female cannabis users showed the least physiological, but greatest subjective, responsivity to the stressor. Further research into sex differences in the effects of cannabis use is warranted to better understand mechanisms and clinical implications.