Biological sex and hormonal contraceptive associations with drug cue reactivity in cannabis use disorder.

Biological sex differences in Cannabis Use Disorder (CUD) progression, cannabis withdrawal severity, and pharmacotherapy response have been reported, suggesting that CUD mechanisms may differ by sex. Drug cue reactivity is an established predictor of drug use behavior, but the literature on sex differences in drug cue reactivity is mixed, including in CUD. One possible moderator of sex differences in drug cue reactivity is hormonal contraceptive (HC) use. The aim of the present study was to test whether sex differences in neural cannabis cue reactivity and craving varied by female HC use in a CUD sample. As part of a larger study, 152 adults reporting frequent cannabis use completed a drug cue reactivity task during electrocenphalogram recording. Late positive potential (LPP) amplitude modulation by cannabis cues was used to measure neural cue reactivity. Craving after the cue reactivity task was also assessed. Males (n = 74) and naturally-cycling females (n = 26), who did not differ from each other, showed significantly greater LPP enhancement to cannabis vs. neutral cues compared to HC-using females (n = 52), an effect mostly driven by neutral cues. Craving was significantly higher in naturally-cycling but not HC-using females compared to males, but only in covariate-unadjusted analyses. Exploratory analyses of HC and menstrual phase characteristics indicate a progesterone-related mechanism may underlie HC effects on cannabis cue reactivity. The present study's results suggest that mixed findings on drug cue reactivity sex differences may be due to variability in HC use, which has implications for sex-specific models of CUD progression and treatment.