Rates of alcohol use disorder (AUD) have increased in women by 84% over the past ten years relative to a 35% increase in men. This substantive increase in female drinking is alarming given that women experience greater alcohol-related health consequences compared to men. Stress is strongly associated with all phases of alcohol addiction, including drinking initiation, maintenance, and relapse for both women and men, but plays an especially critical role for women. The purpose of the present narrative review is to highlight what is known about sex differences in the relationship between stress and drinking. The critical role stress reactivity and negative affect play in initiating and maintaining alcohol use in women is addressed, and the available evidence for sex differences in drinking for negative reinforcement as it relates to brain stress systems is presented. This review discusses the critical structures and neurotransmitters that may underlie sex differences in stress-related alcohol use (e.g., prefrontal cortex, amygdala, norepinephrine, corticotropin releasing factor, and dynorphin), the involvement of sex and stress in alcohol-induced neurodegeneration, and the role of ovarian hormones in stress-related drinking. Finally, the potential avenues for the development of sex-appropriate pharmacological and behavioral treatments for AUD are identified. Overall, women are generally more likely to drink to regulate negative affect and stress reactivity. Sex differences in the onset and maintenance of alcohol use begin to develop during adolescence, coinciding with exposure to early life stress. These factors continue to affect alcohol use into adulthood, when reduced responsivity to stress, increased affect-related psychiatric comorbidities and alcohol-induced neurodegeneration contribute to chronic and problematic alcohol use, particularly for women. However, current research is limited regarding the examination of sex in the initiation and maintenance of alcohol use. Probing brain stress systems and associated brain regions is an important future direction for developing sex-appropriate treatments to address the role of stress in AUD.

Several theories have proposed that negative affect (NA) plays a large role in the maintenance of substance use behaviors - a phenomenon supported in laboratory-based and clinical studies. It has been demonstrated that mindfulness meditation can improve the regulation of NA, suggesting that mindfulness may be very beneficial in treating problematic substance use behavior. The current study tested whether a brief mindfulness meditation would lower levels of NA, increase willingness to experience NA, lower urges to drink, and increase time to next alcoholic drink in a sample of at-risk college student drinkers (N = 207). Participants were randomized to one of three brief interventions (mindfulness, relaxation, or control) followed by an affect manipulation (negative or neutral stimuli). Affect and urge were measured prior to intervention (Time 1 [T1]), after intervention but prior to affect manipulation (Time 2 [T2]), and immediately after the affect manipulation (Time 3 [T3]). Levels of mindfulness and relaxation were assessed from T1-T3. The additional measures of willingness to continue watching NA images and time to next alcoholic drink were examined at T3. Results indicated that the mindfulness intervention increased state mindfulness and relaxation, and decreased NA immediately following the mindfulness intervention. However, the mindfulness intervention did not influence responses to NA induction on any of the outcome variables at T3. One potential explanation is that the mindfulness intervention was not robust enough to maintain the initial gains made immediately following the intervention.

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Background Cocaine users often report a loss of arousal for nondrug-related stimuli, which may contribute to their response to drug-related rewards. However, little is known about users’ neural reactivity to emotional nondrug-related stimuli and the potential influence of gender. Objectives Test the hypotheses that cocaine-dependent individuals have an attenuated neural response to arousing stimuli relative to controls and that this difference is amplified in women. Methods The brain response to typically arousing positive and negative images as well as neutral images from the International Affective Picture System was measured in 40 individuals (20 non-treatment seeking cocaine-dependent and 20 age- and gender-matched control participants; 50% of whom were women). Images were displayed for 4 s each in blocks of five across two 270-second runs. General linear models assessed within and between group activation differences for the emotional images. Results Cocaine-dependent individuals had a significantly lower response to typically arousing positive and negative images than controls, with attenuated neural activity present in the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). Analyses by gender revealed less mPFC/ACC activation among female users, but not males, for both positive and negative images. Conclusion The dampened neural response to typically arousing stimuli among cocaine-dependent polydrug users suggests decreased salience processing for nondrug stimuli, particularly among female users. This decreased responding is consistent with data from other substance using populations and suggests that this may be a general feature of addiction. Amplifying the neural response to naturally arousing nondrug-related reinforcers may present an opportunity for unique behavioral and brain stimulation therapies.

Objectives: Studies suggest that men and women have different vulnerabilities to a number of substance use disorders (SUDs). We examined whether differences between women and men with opioid use disorder (OUD) are significantly different from those without OUD for selected sociodemographic and health outcomes. Methods: We used a cross-sectional survey design using data from 2012 to 2013 National Epidemiological Survey on Alcohol and Related Conditions Wave III, which surveyed nationally representative samples of non-institutionalized adults (n = 36,309 unweighted). Past-year OUD and other behavioral co-morbidities were defined using DSM-5 criteria. In bivariate analyses, we investigated sex differences in socio-demographic factors, behavioral co-morbidities, pain, and health-related quality of life (HRQOL) between women and men with past-year OUD, and then those without past-year OUD. We further used logistic regression analyses to evaluate interactions between effect of sex and past-year OUD status on behavioral co-morbidities, pain, and HRQOL. Results: When extrapolated, about 2.1 million US adults met diagnostic criteria for past-year OUD. Women with OUD had a higher likelihood of having several past-year psychiatric disorders, and a lower likelihood of having any past-year SUDs compared to male counterparts. However, similar relationships were observed among those without OUD and significant interaction effects were not found on behavioral co-morbidities, pain, and HRQOL, indicating that general sex differences are not specific to OUD. Conclusions: Although sex differences are not specific to OUD, concurrent disorders are not uncommon among women, as well as men, with OUD. There is a need to treat concurrent behavioral health conditions from a multimorbidity perspective in the treatment of OUD in both sexes.

Substance use disorders (SUDs) remain problematic as many individuals are untreated or do not benefit from the currently available interventions. Thus, there is an urgent need to develop novel pharmacological interventions to treat SUDs. Evidence suggests that the female sex hormone, progesterone, attenuates the craving for and the euphoric effects of drugs of abuse. Research to date has demonstrated that progesterone may modulate responses to drugs of abuse and may have utility as a novel treatment for SUDs. A literature search was conducted to identify and examine studies that administered exogenous progesterone. Sixteen publications were identified, exploring the utility of exogenous progesterone or its metabolite, allopregnanolone, among a range of substances, including amphetamines (one study), benzodiazepines (one study), cocaine (nine studies), and tobacco/nicotine (five studies). Results indicated that exogenous progesterone and, its metabolite allopregnanolone, demonstrated preliminary efficacy as a treatment for substance use in both men and women. Notably, progesterone appears to target negative affect and augment cognitive functioning, especially among female substance users. Additional research is needed to explore the potential use of exogenous progesterone and allopregnanolone in the treatment of SUDs, including that associated with alcohol and opioids, but considering the current promising findings, exogenous progesterone and allopregnanolone may have utility as novel pharmacological treatments for SUDs.

E-cigarette users, particularly those who engage in nondaily and dual use, show elevated rates of harmful alcohol use. Heavy drinking may constitute a source of health risk among e-cigarette users.

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