National Institute on Drug Abuse Biennial Report to Congress for Years 1997-1998

EXECUTIVE SUMMARY

The mission of the National Institute on Drug Abuse (NIDA) has two critical components: first, to support and conduct drug abuse research across a broad range of disciplines; second, to ensure the rapid and effective dissemination and use of the results of that research to significantly improve drug abuse prevention, treatment, and policy. In recent years NIDA has vigorously promoted drug abuse research focusing on the study of women and gender differences, and such research is now supported in all of NIDA's major programmatic areas: Etiology, Consequences and Impact, and Prevention and Treatment./

Etiology. NIDA supports a broad base of etiological research addressing gender differences in the nature and extent of drug-using behaviors. This includes differences in drugs of abuse, patterns of abuse, routes of administration, and abuse of prescription drugs; differences in the pathways and determinants of the initiation, progression and maintenance of drug abuse; and, differences in basic behavioral and neurochemical mechanisms of drug dependence. A major initiative is a broad-based program of research on nicotine and cigarette smoking, including study of the nature of nicotine dependency, factors associated with etiology of smoking, and relationships between smoking and drug abuse.

Consequences and Impact. NIDA's approach in studying consequences and impact of drug abuse is broad-based, including epidemiologic, behavioral, psychosocial, and biomedical research. Both human and animal research is directed at identifying gender differences in the biological, behavioral, and social consequences of drug use. Studies examine gender differences in such areas as drug metabolism, endocrine functioning and reproductive biology, including the effects of drugs on the menstrual cycle. Studies also examine the impact of drug use in pregnancy and on pregnancy outcome. NIDA's program on HIV/AIDS investigates etiology and pathogenesis as they relate to women and gender differences and includes studies on drug use relative to immunology, virology, and treatment of HIV-related disease.

Prevention and Treatment. Prevention interventions that are gender-based and that address issues unique and specific to females of all ages are among NIDA's research objectives. NIDA's broad-based comprehensive drug addiction treatment research program includes pharmacological, psychotherapeutic, behavioral and psychosocial treatment modalities. Studies examine the development of and effectiveness of drug abuse treatment models that are gender sensitive and address the unique needs of women. Included are various forms of pharmacotherapy, psychotherapy, behavior therapy, cognitive therapy, skills training, counseling, and other rehabilitative therapies. In addition to treatment for drug addiction, models also address treatment for co-existing psychiatric disorder (e.g., depression, anxiety, PTSD, eating disorders).

For the FY97 and FY98, research progress on women, gender, and drug abuse falls into five major topical clusters: Genetic Factors, Biological Consequences and Mechanisms, Adolescents, HIV/AIDS, and Treatment.

GENETIC FACTORS

Considerable NIDA research effort is devoted to understanding genetic factors associated with drug abuse. Some of this research, described below, has indicated that these factors may not be identical for males and females.

Gender Differences in the Genetics of Tobacco Smoking. Two recent studies dealing with the genetics of tobacco smoking have revealed important gender differences. The first study demonstrated a role for genetically variable nicotine metabolism. Among a group of tobacco-dependent subjects, individuals having one defective and one active CYP2A6 gene copy smoked significantly fewer cigarettes per day and per week than smokers without impaired nicotine metabolism carriers of two CYP2A6 genes. This effect was stronger for males than for females. Although it appears that individuals with a defective CYP2A6 allele(s) have reduced nicotine metabolism and are therefore protected, the manner in which this protection is imparted is not yet known (Messina, Tyndale, & Sellers, 1997; Tyndale, 1998). In a second study on the genetics of tobacco smoking, twin data from large national samples from Scandinavia, Australia, and the U.S. demonstrated that, using either a genetic model-fitting approach or a logistic regression model, genetic factors play a important role in predicting which individuals who become cigarette smokers progress to being long-term persistent smokers. The association, however, was much stronger for males than for females (Heath, Madden, & Martin, 1998).

Risk for Substance Abuse and the Dopamine D5 receptor. Study of the relationship between the risk for substance abuse and the dopamine D5 receptor locus (DRD5) has revealed an increased frequency of the modal, 148 base pairs repeat length, allele of a dinucleotide polymorphism (allele 9) among substance abusing males. This finding was reproduced in females with even greater contrast between affected and nonaffected individuals. Specifically, none of the substance-abusing females had the non-9/non-9 genotype, while the frequency of this genotype among control females was 37%; among males, the respective frequencies were 25% and 47%. The greater frequency of the allele in females compared to males was statistically significant. The genotype was also found to be associated with novelty seeking in females, but not in males, for whom even a trend for such an association was absent (Vanyukov, Moss, Gioio, Hughes, Kaplan, & Tarter, 1998).

Heritability of Cannabis and Cocaine Use in a Sample of Female Twins. Two recent studies of female twin pairs (485 monozygotic and 335 dizygotic) conducted at Virginia Commonwealth University point to the role of genetic factors in female cannabis and cocaine use. Within the twin sample, prevalence of lifetime cannabis use, heavy use, abuse, and dependence (defined by DSM-IV criteria) was 47.9%, 6.7%, 7.2%, and 2.2%, respectively. Results suggested that while the twin's resemblance for cannabis use resulted from both genetic and environmental factors, their resemblance for heavy use, abuse, and dependence resulted only from genetic factors, with heritabilities ranging from 62% to 79% (Kendler, & Prescott, 1998). A previous study of male twin piars placed the heritability of cannabis use in males at 33% (ref). A study of cocaine use in a group of female twin pairs showed that the prevalence of lifetime cocaine use, abuse, and dependence was 14.0%, 3.3%, and 2.3%, respectively. As in the cannabis study, the twin's resemblance for cocaine use resulted from both genetic and environmental factors, whereas their resemblance for cocaine abuse and dependence was due only to genetic factors, with heritabilities ranging from 39% to 79% (Kendler, & Prescott, 1998). A previous study of male twin pairs places the heritability of stimulant use by male at about 50% (ref).

BIOLOGICAL CONSEQUENCES AND MECHANISMS

Accumulating NIDA-supported research is indicating that the biological impact and the biological underpinnings of drug abuse are not always identical for males and females.

Evidence for a Gender-Specific Residual Effect of Cannabis on Visuospatial Memory. A novel computerized battery of neuropsychological tests of attention and memory was used to assess residual cognitive impairment in 25 college students who were heavy smokers of marijuana, having smoked a median of 29 days in the last 30 days. These were compared with 30 light smokers, having smoked marijuana for one day in the last 30 days. Students were assessed after they had abstained from marijuana use for at least 19 hours monitored by urine toxicology. In three of the four neuropsychological tests, there were no differences in performance between the light and heavy users. In the checkerboard test, however, which measures spatial distribution of attention and spatial memory, a gender effect occurred. This test required the subject to examine a 6x6 checkerboard of squares in which certain squares were shaded. The shaded squares were then erased and the subject was required to indicate with the mouse which squares had formerly been shaded. Increasing numbers of shaded squares were presented at each trial. The heavy smoking women performed more poorly on this task than the light smoking women. They remembered significantly fewer squares and made significantly more errors than the light-smoking women. Males, however, exhibited no impairment, regardless of smoking history. These data highlight the importance of studying the residual effects of marijuana on men and women separately (Pope, Jacobs, Mialet, Yurgelun-Todd, & Gruber, 1997).

Brain Metabolites of Abstinent Male and Female Chronic Cocaine Abusers. Prior NIDA-supported research at Harvard University using single-photon emission computer tomography (SPECT) found that cocaine-dependent women exhibited fewer frontal lobe brain perfusion abnormalities than cocaine-dependent males (Levin, Holman, Mendelson, Teoh, Garada, Johnson, & Springer, 1994). Recently, researchers at UCLA using magnetic resonance imaging (MRI) and localized proton magnetic resonance spectroscopy (1H MRS) have found a gender difference in cerebral metabolite abnormalities in the frontal lobes of asymptomatic prior cocaine users who each had been abstinent for more than five months prior to testing. In the frontal gray area in both male and female cocaine users, a decrease in N-acetyl compounds and an increase in myoinositol were observed. Both changes were more pronounced in males than in females, but were non-significant. In the frontal white matter, both male and female users also had elevated myoinositol. Creatine in the frontal white matter was elevated in males, but not in females. Additionally, male users, but not female users, had higher serum creatinine. These gender differences occurred despite the lack of gender difference in lifetime cocaine use (Chang, Ernst, Strickland, & Mehringer, in press).

Neuropsychological Functioning of Abstinent Male and Female Chronic Cocaine Abusers. In a study of neuropsychological functioning in chronic cocaine abusers following sustained abstinence, both males and females exhibited impairment on measures of attention-concentration, memory, academic achievement, while visuospatial, motor, language and executive functioning measures were less consistently impaired. Although the female subjects had had a substantially greater exposure to cocaine, they were no more impaired on neuropsychological measures than men, thus suggesting a possible protective factor in women. There has been speculation by several researchers that estrogen may protect women against adverse drug-induced neurobiological effects (Stein, Strickland, Khalsa-Denniston, & Andre, 1997).

Gender Differences in Non-cognitive, Primary Sensory Activation Task. Data from a pilot study of gender differences in a non-cognitive, primary sensory activation task using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (MRI) indicated that women had a significantly lower (about 38%) mean BOLD signal response than men and that the response exhibited more hemispheric symmetry in women. Although the structural or functional basis of these differences are not known, these data demonstrate the need to consider gender differences in both the design and interpretation of functional MRI studies (Levin, Ross, Mendelson, Mello, Cohen, & Renshaw, 1998).

Cigarette Smoking and Tooth Loss. In a study of the relationship between cigarette smoking and tooth loss, cigarette smokers were found to have a higher rate of tooth loss than nonsmokers. There was, however, a dramatically greater risk of tooth loss for males. Male cigarette smokers had a 24-fold risk, while females had a 3.5-fold risk as compared with non-smokers (Krall, Dawson-Hughes, Garvey, & Garcia, 1997).

Smoking and Menstrual Cycle. Researchers at the University of Michigan reported that in healthy women smokers, the effects of nicotine administered intranasally did not vary across menstrual cycle phase. This held true for physiological, biochemical and behavioral effects ( Marks, Pomerleau, & Pomerleau, 1999). In a related study, research at the University of Minnesota examining menstrual cycle effects on tobacco cessation found no significant differences in withdrawal symptom scores across menstrual cycle phases. As expected, premenstrual symptom scores tended to be higher in the late luteal phase compared to the follicular phase. Although total withdrawal symptom scores did not differ significantly across cycle phases, these findings suggest that smoking cessation may be more difficult in the late luteal phase due to increased premenstrual symptoms (Christianson, Allen, Hatsukami, & Nelson, 1998).

Alprazolam: Abuse Liability and Effects on Premenstrual Dysphoric Disorder (PMS). Benzodiazepines are prescribed to women almost twice as frequently as to men; however, there is relatively little information regarding the effects of these medications in women, particularly with respect to their potential for misuse and/or abuse. Findings from a recent laboratory-based study at Columbia University found that acutely administered alprazolam did not have any abuse liability, nor did it appear to be a useful treatment for PMS. Double-blind testing of mood and performance changes under varying doses of alprazolam and placebo during the luteal and follicular phases of subjects with confirmed PMS indicated substantial changes in mood as a function of the cycle phase. Alprazolam, however, failed to improve negative mood, but instead increased negative mood in the follicular phase and impaired task performance following its administration. Alprazolam's failure to improve negative mood premenstrually, its increase in negative mood in the follicular phase, and its impairment of task performance in both phases argue against its clinical usefulness when administered acutely (Evans, Haney, Levin, Foltin, & Fischman, 1998).

Cocaine and Menstrual Cycle Disruption. Clinically, cocaine use has been associated with a variety of menstrual cycle disruptions including menstrual phase dysfunction, amenorrhea, and anovulation, disruptions that have also been reported in rodent models. Recently, two NIDA-supported studies have corroborated these findings in the rhesus monkey. Researchers at McLean Hospital, Harvard Medical School reported that following chronic cocaine self-administration and cocaine withdrawal, approximately 50% of the menstrual cycles were disrupted. These disruptions included amenorrhea, anovulation, and abnormally short cycles with low progesterone suggestive of luteal phase dysfunction (Mello, Mendelson, Kelly, Diaz-Migoyo, & Sholar, 1997). In a study conducted at the University of Texas Health Science Center at San Antonio, rhesus monkeys receiving daily cocaine injections exhibited anovulation, abnormal cycle lengths, and decreased levels of estradiol. These disruptions were independent of weight loss, caloric intake, or basal gonadotropin levels (Potter, Moreno, Luther, Eddy, Siler-Khodr, King, & Schenken, 1998).

THC and Pregnancy. NIDA-supported researchers have found that the mouse uterus during early pregnancy has the capacity to synthesize and degrade anandamide, an endogenous cannabinoid. This finding, coupled with earlier findings of cannabinoid receptors in the preimplantation mouse embryo and uterus, suggests that these tissues could be targets for cannabinomimetic ligands. The researchers also observed an inverse relationship between the synthase and amidase activity at the implantation or inter-implantation sites in the uterus during the peri-implantation period suggesting embryonic influence in regulating these activities. Although the physiological significance of these findings is not yet clear, it is possible that aberrant synthesis of anandamide and/or expression of the cannabinoid receptors in the uterus and/or embryo could contribute to early pregnancy (Paria, Deutsch, & Dey, 1996).

Females and Anabolic Steroid Use. In the rat model, study of six commonly used anabolic-androgenic steroids, stanozolol, oxymetholone, testosterone cypionate, 17 alpha-methyltestosterone, methandrostenolone and nandrolone decanoate, has shown that short-term administration of high doses of all of these drugs except methandrostenolone produces alterations in vaginal estrus and interferes with the display of sexual receptivity (Clark, Blasberg, & Brandling-Bennett, 1998; Blasberg, & Clark, 1997). These findings illustrate that short-term administration of AAS compounds do elicit measurable and distinct effects on the estrous cycle as well as on female sexual behavior.

Gender-related Differences in the Antinociceptive Effect of Morphine. Results from a rodent model of gender-related differences in the antinociceptive activity of morphine in rats has indicated that male rats were uniformly more sensitive to the antinociceptive properties of morphine than were females in three different assays: the hot-plate, tail-flick, and abdominal-constriction tests. These gender-related differences in antinociceptive activity appear to reflect markedly enhanced central nervous system sensitivity in males, compared with females, as serum levels of morphine during peak antinociception did not differ by gender. Further, it is hypothesized that these gender-related sensitivities are reflected in antinociception mediated by both spinal and supraspinal mechanisms. Additionally, the results of this study suggest that the acute effects of steroids play little role in the gender-related differences observed because short-term castration did not alter the observed gender-related differences. Rather, it appears more probable that the organizational effects of steroids during critical periods in development, which determine gender-related distinctions, may be significant in producing the male-female differences (Cicero, Nock, & Meyer, 1996).

Gender Difference in Up-Regulation of Nicotinic Acetylcholine Receptors in Rat Brain. Recent declines in tobacco smoking have been less pronounced in women than in men. This prompted an evaluation of gender differences in the effects of chronic nicotine administration on nicotinic acetylcholine receptor (nAChR) binding in the rat. Results indicate that for males, but not females, chronic nicotine produced an increase in receptor density. These findings underscore the importance of exploring gender differences in pharmacological responses (Koylu, Demirgoren, London, & Pogun, 1997).

ADOLESCENTS

Study of adolescents is included in many areas of NIDA-supported research including etiology, epidemiology, prevention, treatment, and HIV/AIDS. Increasing research effort is devoted to the study of females and gender differences.

Gender Differences in Drug Use Among 8th, 10th and 12th Graders. Data from NIDA's 1998 Monitoring the Future Survey indicated that younger girls are more likely than boys to use illicit drugs other than marijuana: 12.1% of 8th-grade girls and 9.6% of boys reported using drugs other than marijuana; in 10th grade, 17.5 percent of girls and 15.6% of boys reported similar drug use. Among 12th-graders, 21.7 percent of boys and 18.0% of girls reported using drugs other than marijuana (Johnston, O'Malley, & Bachmen, in press).

Gender Differences in Rates of Dependency. A recent study conducted at Columbia University found that adolescent females have a higher rate of cocaine dependence than adolescent males. They are also significantly more at risk for dependence on marijuana than are females in any other age group. Among adults, however, dependence on marijuana is higher among males than females (Kandel, Chen, Warner, Kessler, & Grant, 1997).

Adolescent Conduct Disorder Predictive of HIV Risk Taking Behaviors. Typically, conduct disorder (externalizing disorder) and ADHD are more frequently diagnosed in drug abusing boys, whereas affective disturbances (internalizing disorders) are more frequently identified in drug abusing girls. This male-female difference in conduct disorder, however, was not found in a recent study of runaway and homeless adolescents that sought to assess the prevalence of conduct disorder among those adolescents and to investigate associations between conduct disorder and HIV risk behaviors. The Diagnostic Interview Schedule for Children and a standardized HIV risk assessment questionnaire were administered to 219 runaway and homeless adolescents recruited from a drop-in center serving high risk youth. Conduct disorder was diagnosed in 50% of the males and 60% of the females and was the strongest predictor of lifetime use of heroin and/or cocaine and exchanging sex for money, drugs, food or shelter, as well as the number of drugs used and the number of sex partners in the last 3 months. The high rate of conduct disorder in this population of runaway and homeless adolescents, and the association between conduct disorder and both drug and sex-related HIV risk behaviors, indicate a need for interventions that consider the influence of psychiatric diagnosis on high risk behaviors (Booth, & Zhang, 1997).

Maternal Smoking in Pregnancy, Child Behavior Problems, and Adolescent Smoking. A longitudinal sample of mother-child dyads was used to examine the possible role of child behavior problems in explaining the effect of maternal prenatal smoking on adolescent daughter's smoking. Maternal smoking during pregnancy is associated with higher levels of child behavior problems, particularly among girls. Childhood behavior problems were found to increase the likelihood of lifetime smoking among daughters but were not found to explain the effect of prenatal maternal smoking on their current smoking. Maternal smoking in pregnancy, especially heavy use of a pack or more a day, retained a unique effect on girls' current smoking after controlling for current maternal smoking, child behavior problems, and maternal monitoring of the child. The effect of maternal prenatal smoking is suggestive of a biological component, which may have direct or indirect influences on adolescent smoking (Griesler, Kandel, & Davies, 1998).

Maternal Factors Related to Initial and Increased Levels of Adolescent Drug Involvement. The impact of maternal and adolescent factors on initial and increased levels of drug use by adolescents was examined in two age groups, 12-14 years and 15-18 years. Lack of maternal attachment was associated with initial levels of drug use for both groups. However, the mother-child relationship and models of the mother's unconventionality had a greater impact on the older than on the younger group's increased involvement (Brook, Cohen & Jaeger, 1998).

Marijuana Use and Academic Achievement in Mexican-American Students. The relationship between academic achievement (as measured by standardized achievement scores), substance use, and related psychosocial factors was examined in 2,165 middle school students who identified themselves as Mexican-American. Survey items queried use of marijuana in the last year and indices of student characteristics including susceptibility to peer influence, dysphoria, school satisfaction, self-esteem, and academic achievement. Results indicated that peer susceptibility distinguished marijuana users from non-users, regardless of level of academic achievement for both males and females. In addition, a higher percentage of males than females were found to smoke marijuana, suggesting that, even among students who were academically talented, males were more susceptible to marijuana use than females (Codina, Yin, Katims, & Zapata, 1998). These findings suggest that prevention and mediation programs should focus their efforts both on risk factors that may be applicable for all students (such as peer susceptibility) in addition to targeting risk factors that are more significant for identified subgroups, such as males and females. In this way, the complex issue of substance use and abuse among our young can be addressed more effectively.

Gender, Ethnicity, and School Attendance as Factors in Inhalant Use among Youth. Level and intensity of volatile solvent use was assessed via self report among American Indian, Mexican-American, and White American youth according to three school enrollment statuses: dropout, academically at-risk (enrolled), and control. A higher proportion of the dropout cohort reported use of volatile solvents, regular use, and more intense use than either the academically at-risk group or the control group. There was an interaction between gender and ethnicity: American Indian females reported higher lifetime and 30-day prevalence than did American Indian males, whereas male use was higher than female use among the Mexican Americans and White Americans (Bates, Plemons, Jumper-Thurman, & Beauvais, 1997).

Middle school Versus High School Drug Use and Eating Disorders. Comparison of 2,000 middle-school and high school females indicated no significant differences in their use of tobacco, alcohol, cocaine, diet pills supplements, vitamins, self-induced vomiting or intent to use any of these in the future. However, younger females displayed less knowledge of the adverse consequences of these behaviors, they perceived less prevalence of these behaviors among their peers, and expressed less belief in the media. While prevention programs for high school girls may be too late to deter experimentation, the results underscore the need for intervention at an earlier age, at a time when critical knowledge items and attitudes are not yet firmly established (Clarke, Elliott, Goldberg, Moe, Poole, & Witherrite, 1997).

Drug Use in Adolescent Mothers. Researchers at the University of Washington conducted longitudinal analyses of 241 adolescent mothers' use of marijuana, alcohol, and tobacco from the time of pregnancy through one year post-partum. Substance use increased dramatically after delivery to 6 months post-partum, leveling off between 6 and 12 months post-partum. As substance use increased after pregnancy so did intentions to use, favorable attitudes toward use, perceived norms regarding use, and beliefs favorable to use. Changes in specific outcome and normative beliefs were observed over time with the young mothers seeing bad outcomes (such as negative effects on their health) as less likely, and positive outcomes (such as helping them forget their problems) as more likely. They also perceived less disapproval from their families, friends, and doctors after their babies were born (Morrison, Spencer, & Gillmore, 1998). These findings suggest that young mothers are heeding warnings about the danger to their babies of using substances during pregnancy, but are less convinced that substance use has negative effects on parenting or on their own health. The contrast between the abundance of messages warning about substance use during pregnancy and the very few messages aimed at reducing substance use among parents may reinforce a notion that substance use is not very harmful when one is not pregnant.

Treatment of Adolescents. Several NIDA-supported research projects are beginning to study gender differences in the treatment of adolescents. A study of the effectiveness of a 12-Step approach to treatment of adolescent drug abusers indicated a tendency for girls to have better post-treatment outcomes despite their being equivalent with boys on pretreatment problems, severity and length of time in therapy (Winters, Stinchfield, Opland, Weller, & Latimer, in press). In another study, the efficacy of lithium treatment for adolescents (age 12-18) with bipolar disorders and secondary substance dependency was examined. Lithium was found for both boys and girls to be an efficacious treatment for both disorders in terms of concurrently reducing symptoms of psychopathology (e.g., improved mood) and the use of illicit substances (Geller, Cooper, Sun, Zimerman, Frazier, Williams, & Heath, 1998).

HIV/AIDS

Drug use plays a major role in the spread of AIDS: up to 46% of women's AIDS cases have been directly attributed to injection drug use and as much as 18% to women's heterosexual contacts with injection drug users. Therefore considerable research effort by NIDA has been devoted to the study of women, gender, drug abuse, and HIV/AIDS.

Gender Differences in the Relationship between HIV-I Viral Load and Progression to AIDS. Significant differences have been found in the quantity of virus (viral load) between men and women infected with HIV. A study of HIV viral load in injecting drug users found that women had a significantly lower viral load than men even though men and women had statistically similar time to developing AIDS. An HIV-infected woman with half the viral load (or amount of virus circulating in the bloodstream) as an infected man, had a similar rate of progression to AIDS. Women with the same viral load as men had a 1.6-fold higher risk of AIDS. These data suggest that while women and men have a similar time to developing AIDS, they differ in the relationship between the amount of virus and the disease process. Hormonal differences, especially estrogen levels, may account for the disparity, but further research is needed to determine the biological mechanism (Farzadagen, Hoover, Astermborski, Lyles, Margolik, Markham, Quinn, & Vlahov, 1998; Sterling, Lyle, Quinn, Astermborski, Margolik, Macalino, & Vlahov, 1998). Given that women are typically diagnosed later in the course of the disease and have poorer access to treatment, these findings have implications for recommendations about when doctors should begin treatment with drugs that combat AIDS, relative to viral load thresholds in women.

Gender Differences in HIV Prevention. Considerable NIDA research effort is being devoted to HIV prevention among drug users. A recent study demonstrated that effectiveness of HIV prevention interventions can differ by gender. Researchers found that sexual risks of HIV infections were more likely to decrease for drug-dependent men if the risk reduction information was provided on the street as opposed to an office setting, whereas for drug-dependent women, an office setting with counseling was more conducive to risk reduction than was street counseling (Trotter, Bowen, Baldwin, & Prie, 1996).

AIDS Education Programs for African-American Women. Changes in cognitive, psychological, and risky behavior were assessed two years after completion of either a traditional or specialized AIDS education program in a sample of impoverished at-risk African American women. The traditional group watched an AIDS videotape and received a 1-hour basic AIDS education program. In addition to the videotape, the specialized group received a 2-hour program in which they received a demonstration of risk-reducing behaviors, discussion of problem-focused coping, and techniques to enhance self-esteem. Also, they received individualized responses to their concerns such as referrals to drug rehabilitation programs or shelters. Both groups reported significant improvement at two years in their self-esteem and social resources. They also reported less threat perception, avoidant coping, emotional disturbance, HIV risk behavior, and drug use behavior. When compared with the traditional group, however, women in the specialized group reported more social resources, more reduced emotional distress, less use of an avoidant coping style, and less drug use (Nyamathi, & Stein, 1997). This work highlights the advantages of culturally-sensitive HIV risk reduction programs and the importance of connecting women with social services available in their communities. Sexual Risk Behaviors among Native American Drug Users. Patterns of sexual behavior and condom use were examined in a sample of 114 Native American drug-using men and women. Data were collected on self-reported sexual behaviors in the past 30 days, including descriptions of the most recent sex partners (up to five partners). There were 157 sex partner pairs of which at least one partner was a drug user. Native American women (55%) were more likely than Native American men (23%) to report never using condoms for vaginal and anal sex in the last 30 days. Compared with other ethnic pair combinations, sex partner pairs composed of Native American women and white men (n=18) were least likely to use condoms (6% of pairs) and the most likely to report an injection drug user sex partner (33% of pairs) (Fenaughty, Fisher, Cagle, Stevens, Baldwin, & Booth, 1998). These results suggest a potential vector of HIV and other STDS between white male IDUs and Native American women and highlight the need for further qualitative and quantitative research to examine the factors underlying this pattern of sexual risk behavior.

Drug-Involved Women Prefer Female-Controlled Protection from HIV and Other STDs. As part of NIDA's multi-site Cooperative Agreement for AIDS Community-Based Outreach/Intervention Research Program, in 1996 six sites initiated a study to examine the acceptability of the female condom among women at high risk for HIV and other STDs and to determine its potential utility as an additional risk-reduction tool for drug-involved women. The six participating sites were San Antonio, St. Louis, Washington, DC, Rio de Janeiro, Lexington/Louisville, and Raleigh/Durham. Outcome data available from three of the six sites indicated that a sizable proportion of the women who were followed up after initial educational training sessions reported use of the female condom on one or more occasions of heterosexual contact (41.5% in San Antonio, 75.4% in St. Louis, and 77.5% in Rio de Janeiro). Most women preferred the female condom to the male condom in terms of overall satisfaction, thus suggesting a viable role for this device in the HIV prevention field (Surratt, Wechsberg, Cottler, Leukefeld, Klein, & Desmond, 1998).

Psychosocial Risk Factors for HIV Transmission in Female Drug Abusers. A cross-sectional study examined the influences of domains of psychosocial risk factors on needle sharing with familiar people and with strangers in a cohort of 119 female injecting drug users (IDUs), 46% of whom were HIV+. Data from individually administered questionnaire interviews indicated that personality, family, and peer attributes related to needle sharing in women were similar to those found in men, with certain exceptions. Specifically, in males, the family was more distal in its effect on needle-sharing behavior. The role of the family, particularly the significant other, was more important and proximal in its effect on needle-sharing behavior in women than in men (Brook, Brook, Whiteman, Win, Gordon-Maloul, Roberto, Amundsen, Masci, & de Catalogne, 1997). The data suggest that women's resilience and resistance to self-destructive behavior are closely related to ties with others. In women, there was a main effect as well as mediating effects of protective family factors buffering the risk factors leading to needle sharing.

High Prevalence of Sexual and Drug Use Risks Found in Drug-Using Women Who Have Sex With Women. Researchers examined the HIV-related risks of women IDUs and crack cocaine users who have sex with women. Between 1992-1994, 3,856 women were recruited from street settings in 19 U.S. cities participating as sites in NIDA's Cooperative Agreement for AIDS Community-Based Outreach/Intervention Research Program. An analysis of data from 231 women who reported female sex partners in the 30 days before interview indicated that 53% of the women had shared syringes and 66% had shared injection supplies. Only 11 women (6%) always used barrier protection while giving oral sex to women and 5 (3%) while receiving oral sex from women in the 30 days before interview. Fifty percent of the women reported sex with men as well as women in the previous 30 days, but only 26%-30% of the women who had sex with men used barrier methods to protect themselves from acquiring or transmitting HIV or other STDs . Having sex with men was predicted by commercial sex work, but not by self-identifying as a "lesbian." This high prevalence of risky sex and drug behaviors among drug using women who have sex with women, indicates a need to increase prevention efforts aimed toward this risk group (Kral, Lorvick, Bluthenthal, & Watters, 1997).

Increased Transmission of Vertical Hepatitis C Virus (HCV) Infection to HIV-infected Infants of HIV and HCV Co-infected Women. Considerable NIDA research effort is devoted to the study of vertical transmission of Hepititis C Virus and HIV to infants of HIV-infected pregnant women and the role of drug use. Recent findings include the following: (a) Maternal infection with HCV is associated with increased HIV maternal-infant transmission. Drug use during pregnancy is highly correlated with HCV infection (53% vs. 16% in non-drug users) and with HIV perinatal transmission (24% vs. 16% in non-drug users) (Hershow, Riester, Lew, Quinn, Mofenson, Davenny, Landesman, Cotton, Hanson, Hillyer, Tang, & Thomas, 1997). (b) The rate of HCV is higher in HIV+ infants vs. HIV- infants born to mothers co-infected with HIV & HCV (40% vs. 5%). In HIV- infants born to HCV & HIV co-infected mothers, the rate of HCV is similar to the rate in infants born to HIV-uninfected mothers (Papaevangelou, Pollack, Rochford, Kokka, Hou, Chernoff, Hanna, Krasinski, & Borkowsky, 1998). (c) A mother infected with HIV & HCV is more likely to transmit HCV when maternal HCV plasma viral load is elevated. HIV+ infants have a 3.2 fold higher risk of HCV infection. HCV transmission risk is lowest when maternal HCV viral load is low or undetectable (Thomas, Villano, Riester, Hershow, Mofenson, Landesman, Hollinger, Davenny, Riley, Diaz, Tang, & Quinn, 1998).

TREATMENT

NIDA continues its longstanding commitment to research on treatment of and services for pregnant and postpartum women. In addition, NIDA is increasing its treatment and services research efforts that focus on women independently of their reproductive status and that focus on gender differences. Some of the recent progress made in these areas is described below.

Gender Differences in Psychiatric and Substance Use Comorbidity among Opioid Abusers Seeking Treatment. Psychiatric and substance use comorbidity was assessed in 716 opioid abusers (47.2% women) seeking methadone maintenance during a 5-year period. Rates of co-occurring mental disorders and personality traits were compared by gender. Although comorbidity rates were similar in women and men (47% vs 48%), women were less likely than men to have a DSM-III-R personality disorder (28.4% vs 40.5%) or an antisocial personality (15.4% vs 33.9%) but more likely to have a mood disorder (27.5 % vs 11.4%) and 7 times more likely to have a borderline personality (9.5% vs 1.3%). Although all patients had at least one substance use diagnosis beyond opioid dependence, most often cocaine dependence, women were less likely than men to have a life-time cannabis, alcohol, or hallucinogen disorder or a current cannabis (12.1% vs 19.8%) or alcohol dependence (19.5% vs 29.4%) (Brooner, King, Kidorf, Schmidt, & Bigelow 1997).

Physical and Sexual Abuse, Psychopathology, and Drug Treatment Outcomes. Numerous studies have reported that women in drug abuse treatment report high levels of physical and sexual abuse, levels much higher than males in drug abuse treatment. In a recent study, relationships among history of physical or sexual abuse, psychopathology, and drug treatment outcomes were examined in a longitudinal study of 330 patients in 26 outpatient programs. Sexual abuse was reported by 61% of the women and 13% of the men. Physical abuse was reported by 62% of the women and 45% of the men. Both forms of abuse were found to be associated with greater psychopathology in both males and females but with significant gender differences. For women, sexual abuse was associated with more psychopathology than was physical abuse. The inverse relationship was found for men: physical abuse was associated with more psychopathology than was sexual abuse. Treatment outcome was related to physical and sexual abuse and to psychopathology in a complex manner and differed for men and women (Gil-Rivas, Fiorentine, Anglin, & Taylor, 1997). The study points to the need to assess histories of sexual and physical abuse and co-occurring psychopathology in the treatment of drug abuse.

Childhood Physical and Sexual Abuse, PTSD, and Drug Treatment. In recent years, numerous studies have reported high rates of childhood physical and sexual abuse by women receiving drug abuse treatment with estimates ranging from 50% to 90%. Clinically this information often comes to light when female drug abusers in treatment are also diagnosed with posttraumatic stress disorder (PTSD). Studies have shown that 30%-59% of females in drug abuse treatment have comorbid PTSD. This rate is two to three times higher than for males in drug abuse treatment. PTSD is often associated with poorer treatment outcomes if not recognized and treated (Najavits, Weiss, & Shaw, 1997). NIDA is currently supporting several studies to determine the most efficacious treatment approach. Based on what is known to date, all patients should be carefully screened and evaluated for trauma and PTSD, and drug dependency and PTSD should be treated concurrently.

Differences in Characteristics of Males and Females Entering Treatment. Recent research has shown that compared to men entering treatment, women report more daily cocaine use and report more physical and mental health problems (Wechsberg, Craddock, & Hubbard, 1998). Reasons for entering treatment also differ between males and females. Men enter drug abuse treatment largely because of pressure from family, employers, and the criminal justice system, whereas, women are more likely to enter treatment through a referral from a medical provider or social worker (Grella, & Joshi, in press).

Drug Abuse Treatment of Pregnant and Post-Partum Women. Recently several studies have shown that voucher reinforcement programs, which have been shown to be effective in several other populations, are also effective in improving treatment retention and reducing drug use in pregnant drug-dependent women (Svikis, lee, Haug, & Stitzer, 1997). Ongoing research is examining the effectiveness of voucher reinforcement for maintaining drug abstinence while teaching job skills in post-partum drug dependent women (Silverman, K. JHU).

Gender Differences in Drug Abuse Relapse. Recent research has shown that gender is a factor in drug abuse relapse. In one study, women in drug abuse treatment relapsed less frequently than men, possibly because they were more likely than men to engage in group counseling (Fiorentine, Anglin, Gil-Rivas, & Taylor, 1997). In a study investigating the antecedents of relapse, researchers reported that women were more likely to report negative emotions and interpersonal problems prior to relapse, whereas men were more likely to report positive experiences, to engage in self-justification, and to rationalize afterward. Women's return to drug use was reported to be more impulsive than men's (McKay, Rutherford, Cacciola, Kabasakalian-McKay, & Alterman, 1996).

Smoking Relapse Rates Higher for Women than for Men. Several NIDA-supported researchers are investigating the basis for the higher smoking relapse rates observed in women compared to men. In a recently completed study, 135 smokers who made an unaided attempt at quitting were interviewed before quitting and were followed for one year after cessation. Relapse rates were extremely high both for men and women with 62% of participants returning to regular smoking within 15 days after cessation. Women and men were equally likely to maintain short-term abstinence (through 15 days), but women were more than three times as likely to relapse subsequently. Gender differences were observed for several variables related to smoking history, demographics, social support, perceived stress, and motivational factors, but these differences did not explain the increased risk of relapse for women (Ward, Klesges, Zbikowski, Bliss, & Garvey, 1997).

DATOS. NIDA's national study of individuals in drug abuse treatment programs between 1991-93, (the Drug Abuse Treatment Outcome Study or DATOS) indicated that women constituted 39% of admissions to outpatient methadone programs, 33% of admissions to long-term residential programs, 33% admissions to outpatient drug-free programs, and 33% of admissions to short-term inpatient programs (Anglin, Hser, & Grella, 1997). In one of the DATOS studies of treatment outcomes in short-term and long-term treatment programs, women who had at least 28 days of treatment (with at least 14 days in short-term inpatient) had sharp reductions in their use of illicit drugs, HIV risk behavior, and illegal activities. For instance, at intake 84 % of the women who were admitted to long-term residential treatment programs admitted at intake using illegal drugs every day or at least once a week. Twelve months after treatment, only 28% continued to abuse drugs. Short-term inpatient treatment women also showed significant reductions in illegal drug use a year after their treatment with 86% admitting use at intake and 32% reporting use after one year.

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