PLEASE READ THE INSTRUCTIONS. I PROVIDE THE 4 SCHOLARLY SOURCES, PLEASE PROVIDE THE 10 CREDIBLE SOURCES AND READ THE RUBRIC

stance use and disorder patterns for the entire sur- veyed population (aged ≥12 years), but focused our analyses on the youngest age groups (defined as youths, aged 12–17 years, and young adults, aged 18–25 years), reflecting the period when drug use and drug disorders usually begin. A special analysis of data from the Substance Abuse & Mental Health Services Administration (SAMHSA)/National Survey on Drug Use and Health (NSDUH) aggregated for the years 2002–2005 was performed to provide a sufficient sample size for statistical analyses. Design Overview The NSDUH is conducted annually and is rep- resentative of the civilian, noninstitutionalized population aged ≥12 years in each of the 50 states and the District of Columbia. In addition to the general household population, the survey uni- verse includes residents of noninstitutional group quarters (eg, shelters, rooming houses, dormito- ries, group homes) and civilians residing on mili- tary bases. Persons excluded are those with no fixed household address (eg, homeless transients not in shelters) and residents of institutional group quarters, such as jails and hospitals. The survey is conducted continuously through- out the year with face-to-face interviewing, usu- ally in the respondent’s home. Most items, in- cluding all drug use and other sensitive questions, are collected using audio computer-assisted self- interviewing (ACASI) methods. 5 The NSDUH uses a multistage clustered sampling design that begins with the selection of 7200 area segments each year with a year-to-year overlap of 50%. At the second stage of sampling, 180,000 households on average are screened annually. Within each house- hold, 0, 1, or 2 persons are selected using a sam- pling algorithm that yields equal allocations for youths, young adults, and adults (aged ≥26 years).

The sample in different years represents unique individuals, with a targeted annual sample size of 67,500. The samples achieved for the years 2002, 2003, 2004, and 2005 were 68,126; 67,784; 67,760; and 68,308 persons, respectively. In 2005, the weighted response rates for household screening and interviewing were 91.3% and 76.2%, respec- tively. Each NSDUH respondent who completes INTRODUCTION Gender is one of the obvious biological and social characteristics influencing human behavior, and much recent research has explored whether it is a risk factor in substance abuse and addiction.* Across a variety of illicit substances, when gender differ- ences are assessed, males appear at greater risk than females for substance use problems. In 2008, males comprised almost 60% of the estimated 20 million past-month illicit drug users aged ≥12 years, 1 and in 2007 they accounted for about 68% of all treat- ment admissions for alcohol, marijuana, opiates, cocaine, and other stimulants. 2 However, these findings provide only a limited perspective of gen- der differences in drug use and drug consequences.

For example, the higher incidence of males in spe- cialized substance abuse treatment facilities would seem to imply that males are more vulnerable to substance use disorders, but their greater use of treatment services may stem in part from their greater involvement with and referral from the criminal justice system. Females more typically seek help through general medical or mental health treatment services, and may not be referred to spe- cialized drug abuse treatment facilities. 3 On the other hand, when they do enter treatment, females typically do so with fewer years and smaller quanti- ties of substance use at entry than do males, and yet display generally equivalent symptom severity with more medical, psychiatric, and adverse con- sequences of their substance use disorders. Given that more males than females typically use drugs, examining rates of abuse and depen- dence among the general population may obscure differential vulnerabilities to abuse and depen- dence in those who do use drugs. Therefore, we were interested in determining whether the rates of substance use disorders among drug users dif- fered for males and females on a national scale. METHODS Recognizing that rates of use differ by gender and can be substance specific, we first analyzed sub- *Note: “Addiction” is used interchangeably with “depen- dence” as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. 4 404 Gender Medicineued to use the substance even though it was caus- ing physical problems or problems with emotions, nerves, or mental health; and (6) reduced or elim- inated involvement or participation in important activities because of the substance use.For alcohol, cocaine, heroin, pain relievers, seda- tives, and stimulants, a respondent was defined as dependent if he or she met ≥3 of 7 dependence crite- ria, including the 6 standard criteria listed previ- ously plus a seventh withdrawal symptom criterion, defined by the DSM-IV as having experienced a certain number of withdrawal symptoms that vary by substance (eg, having trouble sleeping, cramps, trembling hands). 4 For each illicit substance and for alcohol, a respondent was defined as abusing that substance if he or she met ≥1 of 4 abuse criteria and was determined not to have been dependent on the respective substance in the past year: (1) had seri- ous problems at home, work, or school caused by the substance, such as neglecting children, miss- ing work or school, doing a poor job at work or school, or losing a job or dropping out of school; (2) used the substance regularly and then did something that might have posed a physical dan- ger to self; (3) use of the substance prompted behaviors that repeatedly engendered trouble with the law; and (4) had problems with family or friends that were probably caused by using the substance, but continued to use the substance even with this knowledge.

RESULTS A total of 271,978 respondents were included in the SAMHSA/NSDUH study under analysis, with gender approximately evenly distributed and race representative of the US population.

Total Sample (Aged ≥12 Years) Significantly higher rates of use (P < 0.01) were reported by males compared with females for all but 2 drug categories (Figure 1). Alcohol, mari- juana, and psychotherapeutics used nonmedically were the most common substances reported by both males and females. Because of the low rates of use, heroin, inhal- ants, and hallucinogens were eliminated from all the interview is given an incentive payment of $30.

The findings presented in this paper are com- bined annual averages based on an analysis of NSDUH data from 2002, 2003, 2004, and 2005 (see the NSDUH Web site for more detailed meth- odology information). 6 The data reflect past-year illicit substance use (including any use of illegal substances and nonmedical use of prescription- type psychotherapeutics), use of alcohol, and past- year abuse of or dependence on the respective substances (see the Appendix for more detail on NSDUH substance classification). Comparisons of estimates for males and females were conducted using t tests (no correction for multiple tests was applied). The gender breakdown for the population aged ≥12 years was 48% male and 52% female. All standard errors and standard errors of differences were calculated using SUDAAN software (Research Triangle Institute, Research Triangle Park, North Carolina), which takes into account the survey’s complex sample design. The significance of observed differences was reported at the 0.05 and 0.01 levels. Data were also disaggregated by gender and age group for youths and young adults as the 2 populations of interest. Drug Abuse and Dependence Dependence and abuse are coded by NSDUH in such a way as to be mutually exclusive. Persons who meet criteria for dependence are coded as “dependent,” regardless of whether they also meet criteria for abuse. The NSDUH defines dependence and abuse using criteria specified in the DSM-IV. 4 As noted in the DSM-IV for marijuana, hallucino- gens, inhalants, and tranquilizers, a respondent was defined as dependent if he or she met ≥3 of 6 criteria: (1) spent a great deal of time over a period of a month getting, using, or getting over the effects of the substance; (2) used the substance more often than intended or was unable to keep set limits on the substance use; (3) needed to use the substance more than before to get desired effects or noticed that the same amount of sub- stance use had less effect than before; (4) was unable to cut down or stop using the substance every time he or she tried or wanted to; (5) contin- 405 J.H. Cotto et al.

No significant difference between the sexes was found for cocaine, and males exceeded females in their use of marijuana (P < 0.01). Among users, a significantly higher proportion of males than females met criteria for abuse of or dependence on marijuana (P < 0.01) (Figure 3B). In contrast, females exceeded males in meeting criteria for dependence on psychotherapeutics (P < 0.01). For all other measures of abuse and dependence, there were no significant gender differences. Young Adults (Aged 18 –25 Years) Males exceeded females in use of all drugs mea- sured (P < 0.01) (Figure 4A). Among users, a sig- nificantly higher proportion of males versus females met abuse criteria for all substances (P < 0.01) except cocaine, and dependence criteria for alcohol and marijuana (P < 0.01) (Figure 4B).

Females comprised a significantly higher propor- tion of those meeting dependence criteria for cocaine and psychotherapeutics (P < 0.01).

subsequent analyses. In addition, for simplifica- tion, the overall category “psychotherapeutics” was used in further analyses rather than the individual classes of medications—pain relievers, sedatives, stimulants, and tranquilizers.

Among users aged ≥12 years, the proportion of males and females that met abuse and dependence criteria varied by drug. In most cases, the propor- tion of males meeting abuse criteria exceeded that of females (P < 0.01). Cocaine was the exception, where no significant gender effects emerged. For dependence, the pattern was mixed, with female users exceeding males for dependence on cocaine (P < 0.05) and psychotherapeutics (P < 0.01), and males exceeding females for dependence on alco- hol and marijuana (both, P < 0.01) (Figure 2). Youths (Aged 12 –17 Years) Unlike the full cohort, 12- to 17-year-old females reported significantly greater use of alcohol and psychotherapeutics (both, P < 0.01) (Figure 3A). 70 20 10 50 60 0 Percent Heroin NM use of tranquilizers Hallucinogens NM use of stimulants CocaineNM use of sedatives MarijuanaNM use of pain relievers Any Illicit drug Psychotherapeutics Alcohol Inhalants Male Female * * * * * * * * * * Figure 1. Substance use in the past year by gender for those aged ≥12 years. Data are from the National Survey on Drug Use and Health, 2002–2005, combined annual averages. 26 Bars indicate the mean and standard errors of per- centages. NM = nonmedical. *P < 0.01. 406 Gender Medicinetent with previous research suggesting that females take less time to become addicted to certain sub- stances, including cocaine and opioids, after first use than do males. 7–9 This phenomenon of acceler- ated time periods between the markers of illness progression has come to be known as “telescoping,” with women advancing more rapidly from first use to regular use to first treatment episode than do men, in some cases (eg, with alcohol) at lower doses consumed less frequently. 10 Several possible explanations of this phenome- non have been put forth in the research literature.

For cocaine, women appear more sensitive than men to its reinforcing effects, initiate use earlier, and abuse cocaine more frequently. 7,8,11–13 Ado- lescent females show this same pattern of use and early initiation compared with their male counterparts. 9 Animal models bear out the clinical findings. Preclinical studies consistently have found that female rats exposed to stimulants, par- ticularly cocaine, self-administer more of the drug than do males; acquire self-administration at a faster rate than males; display elevated and less normal patterns of self-administration compared DISCUSSION Research in recent years has increasingly included a focus on sex/gender differences in response to a variety of drugs of abuse and their consequences.

Both animal and human studies are revealing a greater sensitivity among females to various drug effects as well as to adverse medical consequences, including addiction. In the present study, we found that although males generally reported more substance use than did females and were more likely to meet abuse criteria, this pattern did not hold for drugs other than marijuana in the younger group (12- to 17-year-olds). Females re- ported more use of alcohol and nonmedical use of psychotherapeutics than did males and did not significantly differ from males with regard to abuse.

Moreover, more female users also met dependence criteria for psychotherapeutics. Among the 18- to 25-year-olds, whereas more males reported use of cocaine and nonmedical use of psychotherapeutics, more female users met dependence criteria for both substances. This find- ing suggests that female users have a particular vulnerability to these substances, which is consis- 50 20 10 30 40 0 Percent Alcohol Abuse Dep Marijuana Abuse Dep Cocaine Abuse Dep Psychotherapeutics Abuse Dep Male Female * * * * * * † Figure 2. Substance abuse or dependence (Dep) in the past year by gender among users aged ≥12 years. Data are from the National Survey on Drug Use and Health, 2002–2005, combined annual averages. 26 Only the most com- monly reported categories of drugs used are shown. Bars indicate the mean and standard errors of percentages.

*P < 0.01; †P < 0.05. 407 J.H. Cotto et al.

than males; they also self-identify as having mental health and related problems (including sleep prob- lems) at higher rates than do males, which may lead to their receiving greater numbers of prescriptions. 16,17 Even so, greater access does not necessarily predict worse outcomes, as indicated by males’ greater nonmedical use of these substances and yet females’ greater likelihood of dependence.

with males; and obtain more cocaine infusions fol- lowing an abstinence period. 7,8,14 Female adolescent rats also show enhanced sensitivity to the reinforc- ing effects of cocaine. 15 In the case of nonmedical use of psychothera- peutics, a similar pattern may reflect several con- tributing factors. One is access: females are pre- scribed psychotherapeutic medications more often 40 A B 20 10 30 0 Percent Alcohol Marijuana Cocaine Psychotherapeutics Male Female * * * 40 20 10 30 0 Percent Alcohol Abuse Dep Marijuana Abuse Dep Cocaine Abuse Dep Psychotherapeutics Abuse Dep * * * Figure 3. (A) Substance use and (B) substance abuse or dependence (Dep) in t\ he past year by gender among users aged 12 to 17 years. Data are from the National Survey on Drug Use and Health, 2002–2005, combined annual averages. 26 Bars indicate the mean and standard errors of percentages. *P < 0.01. 408 Gender Medicinescription medications to effect an outcome related to performance or appearance, or to self-medicate (eg, for pain), whereas males are more likely to do so to experience a “high” from the substance. 17,18 In one study, college-aged women reported non- medical use of stimulant prescription medications to improve academic performance and to lose weight, whereas college-aged men more often Another factor is motivation to use, differences that may be key in male and female drug use pat- terns, which in turn could affect rates and patterns of abuse and dependence.

Studies of females’ nonmedical use of psycho- therapeutics indicate that they often have differ- ent reasons for use than do males. For example, young adult females are more likely to abuse pre- 100 A B 40 20 60 80 0 Percent Alcohol Marijuana Cocaine Psychotherapeutics Male Female * * * * 50 40 20 10 30 0 Percent Alcohol Abuse Dep Marijuana Abuse Dep Cocaine Abuse Dep Psychotherapeutics Abuse Dep * * * * * * * Figure 4. (A) Substance use and (B) substance abuse or dependence (Dep) in t\ he past year by gender among users aged 18 to 25 years. Data are from the National Survey on Drug Use and Health, 2002–2005, combined annual averages. 26 Bars indicate the mean and standard errors of percentages. *P < 0.01. 409 J.H. Cotto et al.

prevention efforts may be improved by develop- ing interventions that specifically target males or females. Research has already shown that some prevention programs are more effective for one gender or another, but not for both. For example, a study comparing the effects of a broad-based versus targeted prevention program on high-risk behaviors among African American youth in the 5th through 8th grades provided strong evidence that addressing multiple problematic behaviors via a single intervention prompted significant re- ductions (compared with a control group) in multi- ple health indicators, including drug abuse, violence, provocative behavior, and sexual behaviors—but only for boys; no reductions were seen for girls. 23 Conversely, a study evaluating the efficacy of a standard life skills training curriculum with rural youth reported reductions in alcohol use, mari- juana use, and binge drinking only in females, with no effect seen in males. 24 Treatments for substance abuse and addiction may also need to be targeted by gender to improve their effectiveness. Because higher rates of depen- dence on certain substances among females may reflect differing motivations for abusing them, behavioral interventions for drug abuse may need to be more gender specific. In addition, issues fre- quently cited as more problematic for women stem from contextual factors related to child care responsibilities and employability, which call for gender-specific treatment approaches that address vocational training, child care, and parenting. 25 Studies are needed to explore these and other phe- nomena that drive such gender differences. This study should be interpreted in light of sev- eral limitations. First, the NSDUH does not collect data from persons who are homeless who do not stay at shelters, active-duty military personnel, and persons housed in jails or hospitals. As a result, the prevalence of substance use, and specifically sub- stance use disorders, may be underreported overall and cannot be generalized to these subpopula- tions. Second, the data collected are self-reported and may result in recall bias, harming the validity of the findings owing to the stigma that is tied to illicit substance use and nonmedical use of pre- scription medications. This bias, however, is lim- reported using them to experiment and to coun- teract the effects of other substances. 17 These distinct motivations, as well as gender dif- ferences in the prevalence rates of certain psychi- atric conditions, may explain some of the findings reported in this article for abuse versus depen- dence. Males have higher rates of externalizing disorders (eg, antisocial personality disorder, con- duct disorder, attention deficit hyperactivity disor- der), whereas females have higher rates of inter- nalizing disorders (eg, depression, anxiety), all of which have been associated with increased risk for substance use disorders. 19 Given that externaliz- ing disorders have associated behavior patterns that frequently align with “substance abuse” crite- ria (eg, being unable to fulfill obligations at work, school, or home; recurrent substance-related legal problems; and recurrent substance use in physi- cally hazardous situations such as driving a car), males may be more likely than females to exhibit the diagnostic criteria for substance abuse. Con- versely, female users may be particularly vulnerable to behaviors associated with dependence criteria, such as the inability to stop using a substance, the development of tolerance to the effects of a sub- stance, and, in some cases, the development of with- drawal symptoms. This could result from increased sensitivity to a substance’s physiological effects 14,15,20 or because the particular comorbidities (eg, internal- izing disorders) common in females 19,21 may allow them to evade the attention of authorities or others who would intervene sooner or impose criminal charges. Notably, the distinction between abuse and dependence may ultimately become irrelevant once the fifth edition of the DSM is published in May 2013. 22 Currently in development, the DSM-5 posits a different system for diagnosing substance use disorders based on severity, removing the abuse/ dependence categories. The implications of this change for gender disparities in substance disorder diagnoses remains to be determined. The implications of potential gender differences in vulnerability to substance use, abuse, and dependence pertain to how best to prevent and treat them, taking gender (and age) into account.

If indeed males and females differ in their vulner- ability to abuse or dependence on specific drugs, 410 Gender Medicine data, and narrative writing and editing. Elisabeth Davis helped conceptualize the paper, conduct supporting research, and prepare initial drafts. Dr.

Dowling made substantial contributions to paper conceptualization, interpretation of findings, and review of drafts. Jennifer C. Elcano helped concep- tualize ideas, interpret findings, write and edit the draft and final versions, and provide primary document oversight; Anna B. Staton helped to conceptualize and interpret data. Dr. Weiss made substantial contributions to paper concept and design, data interpretation, and the writing, edit- ing, and approval of the draft and final versions.

All authors further certify that this manuscript represents valid work and that neither it nor any manuscript similar in content has been published or is being considered for publication elsewhere, including on the Internet.The authors thank James Colliver and Joseph Gfroerer of the Office of Applied Studies at the Substance Abuse and Mental Health Services Administration for providing the estimates from the NSDUH on which the study is based and for reviewing the manuscript. The authors declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity for research or professional service, and there are no relation- ships, affiliations, or personal financial holdings that could be perceived as constituting a potential conflict of interest. This study was not funded by a grant, but was conducted as a relevant work project germane to our various roles as full-time federal government employees for the National Institute on Drug Abuse.

REFERENCES 1. US Department of Health & Human Services, Substance Abuse & Mental Health Services Administration, Office of Applied Studies. National Survey on Drug Use and Health, 2007 and 2008.

Table 1.19A—illicit drug use in lifetime, past year, and past month among persons aged 12 or older, by demographic characteristics: Numbers in thou- sands, 2007 and 2008. Rockville, Md: Substance ited by NSDUH’s data collection process using ACASI. Participants listen to the question and enter their answers, which facilitates privacy and optimal data quality. Third, because these are cross-sectional epidemiologic data, it is not possi- ble to examine causality, and it is unclear whether the observations made among this age group reflect differences by age or by cohort.Follow-up studies will be critical to better under- stand whether unique gender-related vulnerabili- ties characterize younger cohorts in which females are taking substances at rates comparable to or exceeding rates in males (with the exception of marijuana). Are the differences observed here generational—that is, do they carry through as the younger group ages?—or are they more strictly age related? Directions for future studies could include examining the reasons underlying gender differ- ences in nonmedical use and dependence on psychotherapeutics—a growing problem in this country, to which females may be particularly vulnerable—or why gender differences character- ize cocaine use and dependence.

CONCLUSIONS In this national population sample of youths and young adults, these findings suggest that gender, age, and substance of abuse may all play a role in the observed patterns of drug use, abuse, and dependence. Interesting for the differences they highlight related to gender, age, and type of drug, these findings may lend themselves to follow-up multivariate analyses beyond the t tests used here, to examine the conjectures about noted differ- ences. If such subgroup differences are confirmed by further research, they raise questions about the underlying biological or sociological determinants of these patterns and, ultimately, about how we can best use this knowledge. Understanding the reasons for these differences and continuing to evaluate these patterns over time could help in the development of targeted and more effective pre- vention and treatment interventions.

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E-mail: [email protected] (continued on next page) 413 J.H. Cotto et al. Appendix. National Survey on Drug Use and Health substance classification. 6 Alcohol—Consumption of alcoholic beverages such as beer, wine, whiskey, brandy, and mixed drinks.

Any illicit drug—Includes use of hallucinogens, heroin, marijuana, cocaine, inhalants\ , opiates or nonmedical use* of sedatives, tranquilizers, stimulants, or pain relievers.

Marijuana—Includes hashish.

Cocaine—Includes crack cocaine.

Hallucinogens—Includes PCP, LSD, peyote, mescaline, psilocybin, and Ecstasy (MDMA).

Heroin—Includes inhalation, injection, smoking, and other means such as oral ingestion.

Inhalants—Includes amyl nitrite, correction fluid, degreaser, cleaning fluid, gasoline, lighter fluid, glue, shoe polish, toluene, halothane, ether or other anesthetics, paint solvents, lighter gases, nitrous oxide, spray paints, and other aerosol sprays.

Psychotherapeutics—Includes the nonmedical use of prescription-type pain relievers, stimulants, tranquilizers, and sedatives.

Pain relievers—Includes propoxyphene or codeine products, oxycodone products, hydrocodone products, tramadol products, and others.

Sedatives—Includes temazepam, flurazepam, or triazolam, and any barbiturate.

Stimulants—Includes amphetamine, dextroamphetamine, phentermine products, and m\ azindol products. Methamphetamine is also included in nonmedical stimulant use.

Tranquilizers—Includes benzodiazepines, meprobamate products, and muscle relaxants\ .

* Nonmedical use, “misuse,” or abuse are defined as use of prescription medications without a p\ rescription of the respondent’s own or simply for the experience or feeling the drug caused.