Sex and drug differences in stress, craving and cortisol response to the trier social stress task

Psychopharmacology (Berl). 2022 Sep;239(9):2819-2827. doi: 10.1007/s00213-022-06163-z. Epub 2022 May 20.


Rationale: The hypothalamic-pituitary-adrenal (HPA) axis is a critical hormonal system involved in stress response. A number of studies have investigated the HPA axis response of drug-dependent individuals to stressors. Stress-induced vulnerabilities in the HPA axis may differ in response to chronic use of different substances, possibly leading to different target therapies. There has not been a direct comparison of HPA axis and subjective response between individuals with different types of substance use disorders following a laboratory stress intervention.

Objectives: The primary goal of the current study was to compare subjective and neuroendocrine response to the Trier Social Stress Task (TSST) across multiple primary types of substance use disorders and investigate differential response between males and females.

Methods: Four hundred participants were drawn from seven studies completed at the Medical University of South Carolina between 2011 and 2021. The TSST was utilized across studies and subjective and neuroendocrine responses measured following completion. Generalized linear mixed effects models and area under the response curve analysis were used to compare both substance type and sex differences.

Results: The study groups involving individuals with cocaine use disorder had blunted stress, craving and cortisol response following the TSST as compared to other substance use groups. Females in the cocaine groups reported higher subjective stress but lower cortisol than males.

Conclusions: The study results indicate that there may be differential effects of substances on the HPA axis, with cocaine using individuals exhibiting more blunting of the HPA axis response as compared to users of other substances.

Keywords: Cannabis; Cocaine; Cortisol; Craving; Nicotine; Opioids; Sex; Stress; Trier Social Stress Task.

MeSH terms

  • Cocaine* / pharmacology
  • Craving
  • Female
  • Humans
  • Hydrocortisone* / pharmacology
  • Hypothalamo-Hypophyseal System
  • Male
  • Pituitary-Adrenal System
  • Saliva
  • Stress, Psychological


  • Cocaine
  • Hydrocortisone