In substance use research, most clinical and pre-clinical studies have used only male subjects (Becker and Koob, 2016), and sex as a biological factor has not been considered in a great many studies, even though it is an influencing factor in many drug taking behaviors. Males have been the primary focus in studying drugs of abuse perhaps to avoid the impact of the menstrual cycle (or estrous cycle in rodent models), with fluctuating sex hormones potentially affecting drug intake and associated behaviors (Simpson et al., 2012). Major research entities such as the National Institutes of Health recognize the importance of studying both sexes, and have instituted guidelines to require the consideration of sex as a biological factor. Thus, much work needs to be done to address gaps in the literature that have resulted from the historical use of only male subjects. These investigations will continue to increase our understanding of physiological and behavioral mechanisms in females and will examine if these responses differ in quality or magnitude from those previously observed in males.

Substance use disorder (SUD) is a chronic, complex, relapsing condition that has many facets that have been studied extensively in clinical and preclinical models. Prevailing theoretical frameworks of the cycle of addiction describe a three stage process including binge intoxication, withdrawal/negative affect, and preoccupation/craving (Koob and Le Moal, 2008). The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) includes diagnostic criteria that fall into categories of preoccupation and persistent use, lack of control over intake, intake despite negative consequences, and tolerance/withdrawal. Here, we will focus on the aspect of compulsive drug use, which is described by the DSM-5 as continued use of a drug despite negative consequences leading to the inability to control or limit drug intake (DSM-5). In humans, these consequences can be broken down into social and physical issues (Table 1). When individuals become resistant to these aversive effects, it can lead to continued drug use and the potential for substance dependence (SAMHSA).

In preclinical models, compulsive-like drug use is studied in models that introduce an aversive stimulus along with drug intake to reduce seeking behavior. When intake persists in the face of these negative stimuli, this is known as aversion-resistance (Hopf and Lesscher, 2014). For rodents, there are two primary stimuli that are delivered along with the reinforcer to produce an aversion-induced reduction in intake: contingent footshock and bitter tastants (quinine). Findings using these core models are outlined in detail in this review. Many groups have examined this behavior in males, and only a handful of groups have examined the female perspective on aversion or aversion-resistant behaviors. This review will serve to summarize key findings in aversion-related intake of alcohol, psychostimulants, and opioids in females by examining studies that have used only female subjects, or that have included both sexes.