Sex differences in neuroendocrine, sympathetic nervous system, and affect responses to acute stress in cannabis users

Rationale Cannabis is the most widely used illicit substance in the USA 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. Objective The study aims to examine the role of biological sex in multisystem stress responsivity in cannabis users. Methods Frequent cannabis users (> 3 times/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 basal estradiol. Subjective ratings of negative affect, including distress, were collected at three timepoints. Results Cannabis users showed blunted pre-to-post-stress cortisol reactivity. Female cannabis users demonstrated greater blunted cortisol reactivity than their male counterparts. Sex moderated the effect of cannabis use on alpha-amylase responsivity over time, wherein female cannabis users showed flattened alpha-amylase responses across the stressor compared to male cannabis users and both non-user groups. Qualitatively, female cannabis users demonstrated the greatest pre-to-post-stress change in subjective distress. Differences in stress responding were not explained by estradiol or distress intolerance. Conclusions Biological sex impacts multisystem stress responding in cannabis users. Paradoxically, female cannabis users showed the least physiological, but greatest subjective, responses to the stressor. Further research into sex differences in the effects of cannabis use is warranted to better understand mechanisms and clinical implications.