The effect of oxytocin, gender, and ovarian hormones on stress reactivity in individuals with cocaine use disorder

Psychopharmacology (Berl). 2020 Jul;237(7):2031-2042. doi: 10.1007/s00213-020-05516-w. Epub 2020 May 9.


Rationale: Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction.

Objectives: To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response.

Methods: One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min.

Results: Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033).

Conclusions: Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.

Keywords: Cocaine; Cocaine use disorder; Cortisol; Cue-reactivity; Gender; Oxytocin; Sex; Stress.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Intranasal
  • Adult
  • Cocaine-Related Disorders / blood
  • Cocaine-Related Disorders / drug therapy*
  • Double-Blind Method
  • Estradiol / blood
  • Female
  • Gonadal Steroid Hormones / blood*
  • Humans
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism
  • Male
  • Middle Aged
  • Ovary / drug effects
  • Ovary / metabolism*
  • Oxytocin / administration & dosage*
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / metabolism
  • Progesterone / blood
  • Sex Characteristics*
  • Stress, Psychological / blood
  • Stress, Psychological / drug therapy*
  • Treatment Outcome
  • Young Adult


  • Gonadal Steroid Hormones
  • Progesterone
  • Estradiol
  • Oxytocin
  • Hydrocortisone