There has been a growing awareness in recent years of the importance of gender in medical treatment and research. While much past research in addiction focused on men, there is now recognition that biologic and psychosocial differences between men and women influence the prevalence, presentation, comorbidity, and treatment of substance use disorders. For instance, Greenfield and colleagues1 conducted an extensive review of the literature published from 1975 to 2005 on substance abuse treatment in women. They found a tremendous increase in attention to gender differences in the literature during the past 15 years; 90% of the articles discussing gender had been published since 1990.

This increase in awareness of gender-specific issues is also seen in the clinical sector, with about 40% of substance abuse treatment facilities now providing special programs or groups for women.2 In this article, we summarize and discuss the findings of various studies that have looked at the epidemiology; relationship of comorbidity and victimization; diagnostic and screening issues; course of illness; psychosocial and biologic influences; and treatment of substance abuse in terms of the influence of female gender.

Epidemiology
A number of epidemiologic survey studies have demonstrated that the prevalence rates of drug and alcohol use disorders are consistently higher among men than among women.3,4 The most recent of these studies, the National Institute on Alcohol Abuse and Alcoholism’s National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), surveyed more than 40,000 adults and found that men are twice as likely as women to meet lifetime DSM-IV criteria for any drug use disorder (13.8% of men vs 7.1% of women).5 Twelve-month prevalence rates of alcohol abuse are almost 3 times as high among men as they are among women (6.9% of men vs 2.6% of women).6 These ratios are consistent with the findings of other past epidemiologic surveys, showing that the gender differential for alcohol use disorders is higher than that for drug use disorders.3,7

In contrast, prescription drug abuse in women closely approaches that of men. The National Survey on Drug Use and Health reported 12-month prevalence rates of abuse or dependence for nonmedical use of pain relievers to be 1.4% for men and 1.1% for women 18 to 25 years old, and 0.5% for men and 0.4% for woman 26 years and older.8 The differential for tobacco use and dependence is substantially less than for any other drug of abuse; only slightly more men than women report tobacco use (13.5% men vs 10.2% women) and meet criteria for tobacco dependence (31% men vs 27% women).3,9

Psychiatric comorbidity and victimization
One area that has received considerable attention is gender differences in psychiatric comorbidity. Both epidemiologic studies and studies of treatment-seeking patients indicate that gender differences in the patterns of comorbid psychiatric disorders in substance users follow the same patterns seen in the general population, with women more likely to meet criteria for anxiety, depression, eating disorders, and borderline personality disorder and men more likely to meet criteria for antisocial personality disorder.10,11 However, a number of studies indicate that for women, the onset of the psychiatric disorder is more likely to antedate the onset of the substance use disorder. This suggests gender differences in the relationship between psychiatric and substance use disorders.12

One study exploring gender differences in the onset of major depression episode (MDE) and alcohol dependence using the Epidemiologic Catchment Area data set found that women with MDE were more than 7 times as likely as women without MDE to have alcohol dependence at a 2-year follow-up point. However, men with MDE were not at any enhanced risk for the development of alcohol dependence.13

Gender differences in comorbidity are also particularly important in nicotine dependence. A number of studies have demonstrated that persons with depression are more likely to smoke cigarettes and are less successful in smoking cessation attempts. This relationship appears to be particularly strong for women. Indeed, a recent study demonstrated that women with a history of MDE were twice as likely to relapse to smoking at 1-year follow-up as women without MDE.14

Converging lines of evidence suggest that a relationship between trauma, posttraumatic stress disorder, and substance use disorders also may be particularly important for women. Early life stress, particularly sexual abuse, is more common in girls than in boys and is associated with a risk of substance use disorders.15 Women exposed to violence in adulthood also demonstrate a higher risk for drug and alcohol dependence. Moreover, alcohol and drug abuse place women at risk for repeated victimization, thus perpetuating the cycle of victimization and substance use.16 Animal studies have demonstrated that uncontrollable stress increases drug self-administration and that neurobiologic correlates of stress appear to mediate this response.17 Gender differences in the neurobiologic response to stress may be especially important in understanding the relationship between trauma and substance use disorders for women.

Diagnostic and screening issues
Even though general awareness of addiction in women has increased, limitations in the identification and treatment of substance use disorders in women still remain. Women tend to seek treatment at mental health or primary care clinics, rather than addiction treatment programs.18 Thus, it is important to screen for substance abuse among women in those settings.

Several studies have examined the use of brief surveys or single items that can be embedded within other health surveys at primary care and obstetrics clinics to screen for substance use problems.19-21 These studies have demonstrated that substance abuse and psychiatric conditions are typically undetected and untreated in substantial numbers of women (19% of women with substance abuse problems and 26% with psychiatric conditions).21 Studies show that the addition of a single question about the last episode of drinking can help increase detection of problematic use among men and women in primary care settings.19 As such, brief surveys or screening items may be useful to prompt more in-depth assessment of patients‘ treatment needs.

Course of illness
One of the most reproducible findings in studies of women with substance use disorders is an increased vulnerability to adverse consequences of substance use, abuse, and dependence.22-26 In general, females advance more rapidly than males from use to regular use to first treatment episode.25,27-29 In addition, when they enter treatment, in spite of fewer years of use and smaller quantities of substances used, their substance abuse symptom severity is generally equivalent to that of males; and females average more medical, psychiatric, and adverse social consequences of substance use than do males.25,26,28,29 This phenomenon has been called the „telescoping“ of substance use disorders in women, and it is likely that both biologic and psychosocial factors contribute to this phenomenon.

Psychosocial influences
Social factors—primarily family environment—also appear to influence women’s substance use. Women with alcohol dependence are more likely than men with alcohol dependence to have role models in their nuclear families and/or spouses who are also alcohol-dependent.30,31 A study by Cavallo and colleagues32 in adolescent smokers indicated a positive relationship between female smokers and perception of smoking as a weight control strategy as well as concerns about gaining weight on quitting. In addition, women are more likely to cite stressful life experiences and interpersonal stressors as reasons for substance use and relapse, while men are more likely to report external temptation situations as precursors to relapse.

Biologic influences
There are a number of biologic factors that are likely to contribute to the telescoping of substance use disorders in women as described above. Women become intoxicated after drinking smaller amounts of alcohol than men. Women also achieve higher blood alcohol concentrations after drinking equivalent amounts of alcohol, mainly because they have less total body water30,33 and a lower concentration of gastric dehydrogenase, an enzyme responsible for alcohol metabolism.34 These findings provide a biologic basis for the increased vulnerability of women to the physiologic and psychological consequences of drinking. Recent neuroimaging studies have confirmed this finding by demonstrating equivalent brain atrophy in men and women despite less consumption by women.26

There also is accumulating evidence from preclinical and clinical studies indicating that hormonal fluctuation during the menstrual cycle can impact response to and craving for drugs. For example, estrogen augments behavioral responses to cocaine in female rats by modulating the mesocorticolimbic dopamine system.35-37 In humans, this may explain increased responsiveness to cocaine cues or more severe use of cocaine at intake in women.38,39 The most recent study by Evans and Foltin40 has shown that administration of progesterone to women during the follicular phase of the menstrual cycle attenuated the positive subjective effects of cocaine, indicating that progesterone may reduce the response to cocaine in women.41

In a study by Sofuoglu and coinvestigators,42 women reported lower ratings of „feeling high“ on cocaine during the luteal phase than women in the follicular phase or men. Thus, ovulating women may be more vulnerable to relapse during the follicular phase, when progesterone levels are lower, than in the luteal phase.43 This is an area of active investigation that could have important implications for treatment.

Neuroimaging techniques have provided important information about the neural processes underlying gender differences in the area of substance abuse. During a stress imaging task, female cocaine users showed greater brain activation than males.44 Using positron emission tomography to compare men and women during cue-induced cocaine craving, Kilts and coauthors45 found greater activation in women than in men in the dorsal striatum and anterior cingulate cortices and lower activity in the amygdala, which assesses the pleasure of an experience and connects it with its consequences. The gender differential in brain activation by stress and drug cues provides important information about gender differences in reasons for drug use, with clear implications for treatment.44

Gender differences in treatment
A number of studies indicate that women are less likely than men to enter treatment.1 Reasons for lower rates of treatment entry may include sociocultural factors (eg, stigma, lack of partner/family support to enter treatment), socioeconomic factors (eg, child care), pregnancy, fears concerning child custody issues, and complexities associated with increased rates of co-occurring psychiatric disorders and the availability of appropriate dual-diagnosis treatments.1,30,46 Furthermore, as previously stated, many women seek treatment at settings or clinics other than substance abuse clinics (eg, primary care, mental health).18

Those women who do enter substance abuse treatment receive similar benefits to those received by men. There are few, if any, consistent gender differences in treatment outcome, retention rates, or relapse rates across various types of substances, treatment settings, and types of treatment.1,47,48 In studies that have found gender differences, women typically have better outcomes than men. For example, women have been found to have higher rates of abstinence at 6-month follow-up (79.3% of women vs 54% of men) and at 5 years (odds ratio, 1.9).24,49,50 Women also demonstrate greater improvement in other domains (eg, medical problems51), have shorter relapse episodes,52 and are more likely to seek help following a relapse.52,53

It is still unclear whether women-focused or gender-specific treatments are more effective than standard substance abuse treatments.1,54-56 Some data suggest that women-focused outpatient or residential treatments produce higher rates of treatment completion than traditional programs.57,58 Data also suggest that residential programs that allow women to be accompanied by their children result in higher rates of retention, an important factor in predicting treatment outcome.59,60

In summary, the converging data suggest that women are less likely to enter substance abuse treatment, but once they do they are at least as likely as men to complete and benefit from treatment. There is a paucity of research—in particular randomized clinical trials—addressing issues of gender-specific treatment. However, programs that address barriers to treatment that are specific to women (eg, child care) and provide careful psychiatric assessment and treatment are likely to be more effective. More research is needed to determine the benefits of such treatments and to identify potential subgroups of women (eg, pregnant women, women with comorbid eating disorders) for whom women-focused treatments may be especially useful.

Conclusions
There are important gender differences in substance use disorders that are meaningful for screening, diagnosis, and course of illness, as well as treatment. Fortunately, gender differences have been a focus of increased attention in recent studies. This line of investigation will be important in helping shape prevention and treatment efforts for both men and women.

Dr Back is assistant professor, Dr Contini is a postdoctoral fellow, and Dr Brady is professor and director, division of clinical neuroscience, Medical University of South Carolina, Charleston. The authors report no conflicts of interest regarding the subject matter of this article.

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