In addition to differences in alcohol sensitivity, reward circuitry, and neurobiological processes of learning and memory, there are also gender differences in development that may differentially influence males’ and females’ risk for BD. For example, females undergo many neurobiological changes earlier than males, and this is in part related to the earlier onset of puberty in females (111, 112). According to the dual systems model, although the striatum matures more quickly than the prefrontal cortex (PFC) in females, it is also suggested that females undergo more extensive maturation in the PFC compared to the striatum in both humans (49, 113) and animals (48, 114). This sex-specific trajectory highlights how females develop greater levels of inhibitory control and lower peak levels of sensation seeking compared to males (53).

In addition to gender differences related to inhibitory control and sensation seeking, the triadic model hypothesizes that there are also gender differences in the development of the amygdala (AMY) as well as differences in connectivity between the PFC and AMY, which influence emotional control (115). In particular, the triadic model posits that development in the AMY and connectivity between the AMY and the PFC may have a greater influence on emotional functioning in females compared to males (33, 50, 51). While, to date, few studies have longitudinally examined the effects of these preclinically assessed neurobiological processes on later risk for BD, we do know that emotion regulation, inhibitory control, and sensation seeking have been linked to BD (54). Thus, these unique neurobiological trajectories in development may manifest as different risk paths to BD among males and females. In the next section, we review literature on the link between psychiatric issues and BD, in particular highlighting distinct risk phenotypes across adolescent males and females.

The link between externalizing symptoms (including behavioral disinhibition, impulsivity, sensation seeking, and defiant behaviors) and substance use has been well documented in the literature (21, 122). As discussed previously, males consistently exhibit higher levels of sensation seeking and behavioral disinhibition throughout development, while females show greater inhibitory control (53). Thus, this externalizing risk phenotype for substance use appears to be more prominent in adolescent boys compared to girls (21). For example, in a recent study of college students, male binge drinkers were characterized by their higher scores on impulsivity and sensation seeking compared to non-BD males, and this pattern was not seen in females (54). Another study also found stronger associations between delinquency and BD in males only (55). Adolescent males are also more likely to report drinking for positive reinforcing effects as well as sensation and risk seeking (26, 56).

There is also evidence that environmental and genetic origins underlying associations between externalizing symptoms and substance use differ by gender. For example, one study found externalizing symptoms mediated the relationship between problematic alcohol use and parental alcoholism in males, but not in females (57). In another study of children of alcoholics, early BD was related to externalizing disorders in boys, but not in girls (13). In another similar study examining children of alcoholics, genetic factors associated with disinhibition and externalizing symptoms were predictive of early drinking for boys only; for girls in the study, environmental risk factors were more closely linked to alcohol initiation (58). Thus, given adolescent males’ higher levels of sensation seeking and lower inhibitory control, and evidence for males’ unique vulnerability to genetic factors underlying the link between externalizing symptoms and BD, it is not surprising that this externalizing risk phenotype for BD and other problem alcohol use is more prominent in males.

Internalizing symptoms, including depression and anxiety, have also been linked to BD (54). As explained above, there are important gender differences in risk for developing internalizing disorders that occur with pubertal development, with girls being twice as likely to develop anxiety and depression compared to boys (117). In addition to the higher rates of internalizing disorders in females, females are also more vulnerable to stress compared to boys (120). Even in animal studies, adolescent female rats exhibited depressive-like behavior following stress, while male rats did not experience depressive-like symptoms (52).

As such, in contrast to males, females’ substance use risk profile is better characterized by internalizing symptoms, such as anxiety, depression, stress vulnerability, and other negative mood symptoms. For example, among a study of college students, female binge drinkers were characterized by higher scores on neuroticism-anxiety compared to non-BD females, while male binge drinkers were better categorized by traits related to sensation seeking and impulse control (54). In addition to females’ heightened vulnerability to stress, females are even more likely to engage in BD in response to stress (123). For example, one Swedish study found that peer bullying and other risk factors had a greater effect on drinking in females than in males (59). Similarly, adolescent girls who abuse alcohol are more likely to have experienced a high level of stressful life events and exhibit post-traumatic stress symptoms, but this is not seen in boys (26).

Females’ higher vulnerability for internalizing disorders also increases their risk for addiction, in part, due to self-medicating tendencies (28). For example, one study found that among females only, greater increases in depression symptoms were also linked to greater increases in problem alcohol use and BD over time (60). Similarly, other studies have shown longitudinal bidirectional relationships between BD and depressive symptoms across adolescence that are particularly strong for females (61). Moreover, among females who began drinking in adolescence, those who continued drinking in adulthood showed high levels of depression during adolescence relative to those who stopped abusing alcohol (31). In addition to females’ greater vulnerability to stress and internalizing symptoms, females may also be more prone to BD following trauma.

Exposure to potentially traumatic events—such as physical assault or abuse, sexual assault or abuse, and witnessed violence in the home or community—is common in adolescence, with approximately two-thirds of youth reporting exposure to one or more events (124, 125). Trauma exposure has been linked to increased risk of BD and problematic alcohol use, with evidence indicating higher rates of BD among adolescents exposed to childhood maltreatment (126) and greater risk for problematic alcohol use among adolescents exposed to assault and other forms of violence (127). In addition, adolescents exposed to multiple types of victimization are more likely to experience more alcohol abuse (128) than peers who experience fewer victimization types. Hazardous drinking can also increase risk for future trauma and victimization (129, 130). BD also can co-occur with traumatic experiences, in particular, sexual victimization (i.e., drug/alcohol-facilitated and incapacitated sexual assault).

While both male and female adolescents experience sexual victimization, adolescent girls are at heightened vulnerability to sexual assault (131). A recent study of adolescent girls aged 12–17 found that girls who reported drug/alcohol-facilitated and incapacitated sexual assault were more likely to report past-year alcohol abuse than girls with other types of assault or no assault (132). Similarly, sexual victimization predicted acute increases in BD in a national sample of adolescent girls, although victimization did not predict overall escalation of BD over time (62).

Evidence suggests that girls may also be more likely to engage in BD and experience more negative psychological sequelae as a result of trauma experience compared to boys (63). There is evidence that child abuse and neglect predicts later problem drinking for girls, but not boys (133), and that girls (but not boys) who start abusing alcohol during adolescence are more likely to have experienced early traumatic stress (31). Taken together, in addition to females’ increased vulnerability to stress and increased likelihood of BD in response to acute stress, females are also more vulnerable to binge drink in response to more prolonged stress as a result of trauma.

Taken together, this recent research suggests that male and female adolescents exhibit unique BD risk phenotypes: while boys exhibit the traditional externalizing risk phenotype, girls’ risk phenotype is characterized by “internalizing” symptoms, such as high stress reactivity, and the presence of mood disorders and internalizing symptoms (54). These gender differences are related to gender differences in adolescent neural development and are also consistent with findings that adolescent males drink to enhance positive mood states while females drink to avoid negative mood states (134). These findings also highlight the importance of considering trauma in BD, and furthermore, gender differences in males and females’ vulnerability to BD following trauma and stress. Given girls’ increased vulnerability to stress and higher stress reactivity, it is not surprising that the link between trauma exposure and BD is particularly salient in girls.

Despite advances in tailoring treatments to address comorbid psychiatric and substance use issues (34), less research has focused on developing gender-specific treatment approaches or identifying gender differences in evidence-based treatments for substance use (176, 177). Over the past few decades, there have been efforts to develop gender-specific treatment programs and focus on issues among adult women; however, less research has focused on adolescent girls in particular (177, 178). Furthermore, many studies do not assess for or report on gender differences in treatment effectiveness (177, 178), and as noted previously, few studies focus intervention for BD specifically. Thus, in the following section, we highlight findings from literature on adolescent substance use treatment more broadly and discuss the potential utility of these findings to inform treatment considerations for BD.

There have been some substance use programs developed to target female adolescents in particular, and these gender-specific programs have been based on social learning and behavior theories (165, 177), which is consistent with the previous discussion that adolescent girls may be more vulnerable to social influences on BD (24). For example, programs focused on social skills training, including teaching assertiveness skills and refusal skills to combat peer pressure, how to develop positive peer networks, and challenge perceptions of the prevalence of alcohol use among peers (e.g., “everyone’s doing it”), are most effective in reducing adolescent girls’ problem alcohol use (166, 177). Furthermore, small group settings may be particularly beneficial for girls, as girls may benefit more from sharing experiences and expressing opinions with others (179). In addition, given girls’ proneness to internalizing symptoms and heightened sensitivity to stress, programs focusing on teaching coping skills and stress and tension reduction techniques may be particularly beneficial (167). For example, the coping skills component of CBT-based treatments are likely particularly beneficial for girls as this may help them to learn healthy and adaptive coping skills to manage stress, negative mood, and other internalizing symptoms that trigger BD.

For boys, given their externalizing risk phenotype, they may benefit more from contingency management techniques that reinforce and reward prosocial behaviors as well as expectancy challenge techniques that challenge their beliefs about the positive effects of drinking (168). Furthermore, the personalized feedback component of MET may be particularly beneficial for boys, given that adolescent boys may be more likely to be “in competition” with or trying to keep up with male peers, given that heavy drinking is seen as more socially acceptable for males and sometimes encouraged, such as in college settings (147). Adolescent boys are more prone to overestimate their peers’ drinking and, thus, challenging these perceptions, such as using personalized feedback, could influence males’ behavior (155). In addition, although gender differences in medication treatment effectiveness among adolescents are unknown (180), among adults, men have better treatment outcomes to pharmacologic treatment for alcohol use than women (181–183). Thus, if these gender differences are similar in adolescents, adolescent males may particularly benefit from pharmacological treatment compared to females.

With respect to gender and parental involvement in treatment, findings are mixed, with some evidence showing more effectiveness of parent involvement in treatment for girls (167) and others showing more effectiveness in boys (169). Among adolescents in residential treatment for substance use, parental involvement in treatment had a significant effect on abstinence at 6-month post-treatment status among boys only; however, treatment characteristics were unknown (169). It may be that the type of parental involvement and family support targeted in treatment should be gender-specific. For example, addressing discipline and rewarding and reinforcing prosocial behaviors may be important for boys given their externalizing risk profile, while for girls, better communication and emotional understanding and support might better target their internalizing risk profile.

There are also important gender differences in treatment seeking. In 2008, only 30% of adolescents who sought substance use treatment were girls (35); however, one study found that girls reported higher intentions to seek treatment for alcohol-related problems (170). One reason for this could be related to treatment referrals. Among adolescents, many substance use treatment referrals come from the juvenile justice system (171). Importantly, boys are more likely to get referred for substance use treatment due to a legal issue (171, 172) or to enter treatment under criminal justice supervision (171, 173). Thus, girls are often not identified as early as boys for needing treatment since the criminal justice system is more likely to identify boys. Girls may be more likely to get referred for treatment or identified from another issue in which BD may be secondary. For example, females seeking substance use treatment in general are twice as likely to be diagnosed with depression (174). Still, girls entering treatment have more severe alcohol problems and higher rates of mental health problems, sexual abuse (171), general health problems (63) and family-related stress (169), while males have more school and legal problems [see Ref. (175) for discussion]. Therefore, girls may also have more severe problems before being identified for treatment which could be detrimental to treatment success. In addition, while not studied in adolescents, among adults, women are less likely to seek treatment due to social stigma, and thus, girls may be less likely to seek treatment due to social stigma as well (28). Due to these differences, further work may need to be done to train and educate health care providers to more effectively screen for and identify BD and other substance use problems in adolescents (184).

There have been mixed findings on treatment outcomes for alcohol and substance use treatment among adolescents. There is some evidence that boys were more likely to become non-drinkers compared to girls following non-specific alcohol use treatment (185), but another study found that girls were more likely to become non-drinkers compared to boys (171). However, one limitation is that these results are based on non-specific treatment across multiple treatment sites (171), thus limiting understanding of specific factors influencing results. One study using data from multiple treatment sites implementing adolescent community reinforcement approach (175) showed similar change rates in substance use problems across boys and girls in treatment but unique course of treatment. Specifically, boys showed quicker improvement in mental health symptoms while girls had more abstinent days from alcohol and were more likely to be in recovery at 6-month follow-up (175). There is also evidence that girls are more likely to utilize social resources and attend after-care and self-help groups such as Alcoholics Anonymous (186), which may lead to better long-term treatment outcomes (169). One consistent finding is that across all adolescents, peer affiliation, school engagement, and parental supervision influence successful treatment in changing adolescents in treatment from binge drinkers to non-binge drinkers (175). Taken together, these mixed findings emphasize the need for further research to determine treatment components that contribute to potential gender differences in outcomes (24, 25). Furthermore, these findings do not address BD in particular, and thus, it is unknown whether these considerations also apply in BD treatment.

Based on the literature review, it is clear that adolescents are a unique, vulnerable population at risk for BD, and that there are important gender differences to consider in treatment. While literature on risk factors and consequences of BD in particular has increased, there is still a gap in the literature on unique considerations in prevention and intervention techniques for BD, as well as in how to effectively target unique differences in psychiatric comorbidity and risks across girls and boy in treatment.