Sex differences in stress reactivity after intranasal oxytocin in recreational cannabis users

Cannabis is the most widely used illicit drugs and the changing legal, political and cultural climate will likely increase cannabis use further. One factor that may underlie the transition from recreational use to problematic use is stress. The hormone oxytocin (OXT) modulates stress and may have therapeutic efficacy for substance use disorders, but few studies have examined OXT in cannabis users. Another factor is sex; although more men smoke cannabis, the transition from recreational to problematic use is faster in women. Using a within-subjects design, the effects of intranasal (i.n.) oxytocin (OXT; 40 IU) administration on stress reactivity (using the Trier Social Stress Test; TSST) and cannabis (5.6% THC) self-administration was assessed in recreational cannabis using men (n = 31) and women (n = 32) relative to i.n. placebo (PBO) and no-stress (NST) conditions. The TSST produced expected subjective and cardiovascular effects compared to the NST. However, in the i.n. OXT-TSST condition, positive subjective effects were lower and negative subjective effects were higher in women compared to PBO administration and compared to men. Further, latency to self-administer cannabis was longer in women than men and women self-administered less cannabis than men regardless of stress condition. There were no differences in cannabis craving as a function of sex, stress, or medication. These results suggest that OXT administration may lead to greater stress reactivity in recreational cannabis users, particularly women, and support growing evidence that sex differences should be carefully considered when examining the therapeutic potential of OXT.