Abstract
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.
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Data Availability
Data are available from the corresponding author upon reasonable request.
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Acknowledgements
The authors would like to thank Bess Bloomer and Hailey King for their assistance in subject recruitment and data collection.
Funding
This research was supported by the National Institute of Drug Abuse (R01 DA048012 to W. P. H. and B. F. O.), National Institute of Mental Health (T32 MH103213 to W. P. H., A. B. M., and E. R. L.), the Indiana University Faculty Research Support Program (W. P. H., B. F. O., A. B. M., and E. R. L.), Indiana Clinical and Translational Sciences Institute (TL1 TR002531 and UL1 TR002529 to A. B. M.), and additional Indiana University faculty startup to K. M. W.
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Larson, E.R., Moussa-Tooks, A.B., Tullar, R.L. et al. Sex differences in neuroendocrine, sympathetic nervous system, and affect responses to acute stress in cannabis users. Psychopharmacology 240, 1805–1821 (2023). https://doi.org/10.1007/s00213-023-06400-z
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DOI: https://doi.org/10.1007/s00213-023-06400-z