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

Cannabis Use Disorder (CUD) is associated with significant disability (Hasin et al., 2016) and increased in prevalence from 2.1% in 2002 to 2.6% in 2017 in the United States (Compton et al., 2019). CUD prevalence (Hasin et al., 2016) and chronicity (Khan et al., 2013) is higher in males, but females demonstrate accelerated progression to CUD (i.e., telescoping; Kerridge et al., 2018), worse cannabis withdrawal severity (Sherman et al., 2017), and worse CUD pharmacotherapy outcome (McRae-Clark et al., 2015, 2016). Unfortunately, no FDA-approved medications for CUD exist and psychosocial approaches have modest long-term abstinence rates (Gates et al., 2016). To improve CUD treatments, it is important to understand how biological sex and related variables affect mechanisms implicated in CUD maintenance, which will ultimately inform sex-specific treatment development. Drug cue reactivity is a robust predictor of drug use behavior in substance use disorders, particularly among males (see Vafaie and Kober, 2022 for a meta-analysis). Further, reward-related brain region (i.e., vmPFC, striatum, amygdala) activation to drug cues is often greater in males compared to females across multiple substance use disorders (i.e., alcohol, nicotine, cocaine), whereas cue-induced craving comparisons typically reveal no sex differences or heightened craving in females (Doran, 2014; Dumais et al., 2017; Kaag et al., 2019; Kennedy et al., 2013; Kilts et al., 2004; Petit et al., 2013; Potenza et al., 2012; Robbins et al., 1999; Saladin et al., 2012; Wetherill et al., 2015). As in other substance use disorders, exposure to cannabis cues also activates neural reward-related circuitry (see Sehl et al., 2021 for a meta-analysis) and elicits craving (e.g., Lundahl and Johanson, 2011; McRae-Clark et al., 2011) in CUD. Only four studies to date have examined sex differences in drug cue reactivity in CUD (Henry et al., 2014; Prashad et al., 2020; Lundahl and Johanson, 2011; Wetherill et al., 2015). The three studies that measured neural cannabis cue reactivity found no sex differences (Henry et al., 2014; Prashad et al., 2020; Wetherill et al., 2015), whereas craving results were mixed with two showing no sex differences (Lundahl and Johanson, 2011; Wetherill et al., 2015) and one showing greater craving in females (Prashad et al., 2020). Interestingly, Prashad et al. (2020) found that sex differences in craving were driven by higher craving in the naturally-cycling female subsample in the follicular phase. This finding suggests that sex differences in cannabis cue reactivity may depend on the ovarian hormone milieu in female participants at the time of data collection, which will vary by menstrual cycle phase and hormonal contraceptive use.A large preclinical literature has shown that greater addiction vulnerability in female relative to male animals is dependent on ovarian hormones (see Becker and Koob, 2016 for a review). Estrogen and progesterone typically have opposing effects on drug-seeking (e.g., Maher et al., 2021; Schmoutz et al., 2014). Although multiple mechanisms are likely involved, estrogen and progesterone are thought to influence drug cue reactivity via dopaminergic (exciting drug-seeking) and GABAergic (inhibiting drug-seeking) transmission, respectively (Hudson and Stamp, 2011). Consistent findings have also emerged in humans. For instance, progesterone administration reduced drug cue-induced craving in females with cocaine use disorder (Fox et al., 2013; Milivojevic et al., 2016). Relatedly, greater drug cue-elicited neural activation and craving was found in nicotine-dependent females in the follicular (estrogen > progesterone) vs. luteal (progesterone > estrogen) phase of the menstrual cycle (Franklin et al., 2015; Gray et al., 2010). In a study of regular alcohol-using women, attention bias to alcohol cues increased in the late (high estrogen) vs. early (low estrogen) follicular phase (Griffith et al., 2023). Overall, existing menstrual cycle and drug administration studies suggest that high estrogen/low progesterone may modulate neural drug cue reactivity and craving in females. Hormonal contraceptives (HC) also impact ovarian hormones and are commonly used in the United States (Daniels and Mosher, 2010). HCs suppress endogenous hormones to early follicular phase levels (i.e., low estrogen and progesterone; Hampson, 2020; Sahlberg et al., 1987), but contain synthetic progesterone/estrogen (i.e., progestins/estradiol) that act centrally and are similarly or more potent than their endogenous counterparts (Benagiano et al., 2004; Fishman and Norton, 1977; Gogos et al., 2014). No studies to date have examined drug cue reactivity differences in HC-using vs. naturally-cycling females. Further, most studies on sex differences in drug cue reactivity have used female samples with mixed hormonal status (i.e., HC users and non-users, naturally-cycling at different phases, peri- and post-menopausal) and/or do not present female hormonal status data. Variability in HC use and menstrual cycle phase may underlie mixed findings on sex differences in cannabis cue-induced craving (Lundahl and Johanson, 2011; Prashad et al., 2020; Wetherill et al., 2015), as well as the absence of sex difference in neural cannabis cue reactivity (Henry et al., 2014; Prashad et al., 2020; Wetherill et al., 2015) often found in other substance use disorders. The aim of the present study is to evaluate the roles of HC use and menstrual cycle phase in cannabis cue reactivity sex differences. As part of a larger study (Macatee et al., 2023), young adults reporting frequent cannabis use (89.5% with current DSM-5 CUD diagnosis) were exposed to cannabis-related and neutral images during electroencephalography (EEG) recording. Cannabis craving was measured after cue exposure. Neural drug cue reactivity was assessed using the late positive potential (LPP), an event-related potential typically enhanced to drug cues in substance use disorder compared to control groups (see Webber et al., 2022 for meta-analysis). Further, LPP modulation by drug cues covaries with drug cue-elicited craving (Franklin et al., 2015; Franklin et al., 2015) and other indicators of drug use motivation (e.g., Versace et al., 2023; Dunning et al., 2011; Moeller et al., 2012a, 2012b), underscoring its validity. We hypothesized that male vs. female differences in the cannabis cue LPP and craving would depend on HC status. Because HCs contain only progestin or a high progestin to estradiol ratio, we reasoned that HC users would have reduced craving and cannabis cue LPP amplitude relative to males given the inhibitory effect of progesterone on drug cue reactivity (Fox et al., 2013; Milivojevic et al., 2016). However, HCs also suppress endogenous ovarian hormones to levels observed in the early follicular phase, a phase associated with heightened drug cue reactivity in females with nicotine dependence (Franklin et al., 2015; Gray et al., 2010). Given this ambiguity, our hypothesis was limited to a moderating role of HC status on sex differences in cannabis cue reactivity without specifying directionality. Finally, based on prior menstrual cycle phase findings in CUD (Prashad et al., 2020) and nicotine dependence (Franklin et al., 2015; Gray et al., 2010), as an exploratory analysis we compared cannabis cue LPP amplitude and craving in naturally-cycling females in the follicular vs. luteal phase.

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