National Institute on Drug Abuse Biennial Report to Congress for Years 2001-2002

EXECUTIVE SUMMARY

The National Institute on Drug Abuse (NIDA) supports over 85 percent of the world's research on the health aspects of drug abuse and addiction. NIDA-supported science addresses the most fundamental and essential questions about drug abuse, ranging from the molecule to managed care, and from DNA to community outreach research. Within this science, there is a major NIDA effort to investigate issues specific to women and to study sex/gender differences. Leadership for this effort is provided by NIDA's Women & Gender Research Coordinator and Deputy Women & Gender Research Coordinator along with NIDA's Women and Gender Research Group, which has representation from all of NIDA's program branches, offices and centers. The major goal of this effort is to infuse the study of sex/gender differences and issues specific to females in all areas of drug abuse research and to disseminate research findings in this area.

As recently as a decade ago, the National Institute on Drug Abuse (NIDA) supported virtually no gender-based research and very little research on women. Most of the research on women was from a pregnancy perspective, and in particular, the concern over the possible adverse effects on infants prenatally exposed to drugs and how to best treat drug-abusing pregnant women, topics that continue to be of great importance to NIDA today. In the early 1990's, however, NIDA began to have growing concerns about the lack of knowledge about other issues specific to women and about whether there are important, but unidentifed, differences between males and females throughout the various aspects of drug abuse. To assess these issues and to identify research gaps, in 1994 NIDA held a conference, ÒDrug Addiction Research and the Health of Women.Ó From that conference, three broad areas of gender-based drug abuse research needs were apparent: the need to study females of all ages, not just those of child-bearing age; the need to address issues specific to females in all areas of drug abuse research; and the need to study sex/gender differences in all areas of drug abuse research.

Since that meeting NIDA has been actively engaged in a number of efforts to fill these research gaps and the drug abuse research field has responded, as evidenced by a growing number of NIDA-supported research grants in this area. Today NIDA supports gender-based research in all of its major program areas. From basic research on the biological underpinnings and consequences of drug abuse, to field research on etiology and consequences of drug abuse, to research on prevention and treatment, evidence for the importance and fruitfulness of taking a gender-based research approach and analyzing data separately for males and females is growing. NIDA-supported research is repeatedly showing that gender matters in drug abuse.

The research findings summarized below, published in 2001 or 2002, are representative of NIDA's research on women and gender differences. These research findings fall into five major research areas: Biological Mechanisms and Consequences, Nicotine, Adolescents, Treatment, and HIV/AIDS. These findings strongly suggest that the identification and understanding of sex/gender differences can improve our understanding of the nature and etiology of drug abuse and have implications for tailoring prevention and treatment interventions to maximize outcomes for both males and females.

ACCOMPLISHMENTS

BIOLOGICAL MECHANISMS AND CONSEQUENCES

NIDA-supported research over the past several years has shown that the biological underpinnings and consequences of drug abuse are not always identical for males and females. Animal studies, for example, have reported for several drugs of abuse that females typically learn to self-administer drugs sooner and take in larger amounts than males, that a larger percentage of females than males acquire self-administration and that females exhibit stronger motivation to self-administer and exhibit a greater tendency to relapse following drug cessation. Other animal work has shown that estrogen plays a role in the interaction of drugs of abuse and neurotransmitter systems. Sex differences have been reported in both animal and human pharmacokinetic studies as well as studies of biological and behavioral adverse of effects of abused drugs. And, both human and animal studies have clearly shown that the menstrual/estrous cycle is a determinant of drug action, both pharmacokinetic and behavioral. NIDA-supported published research over the last two years has built on this growing body of knowledge. Animal studies have further elucidated the role of estrogen and the estrus cycle in cocaine self-administration and have shown sex differences in drug sensitivity and vulnerability as well as effectiveness of potential pharmacologic and behavioral treatments. Human studies have reported sex differences in cocaine craving and cerebral perfusion abnormalities. And menstrual cycle studies have shown that phase of the cycle is a determinant of cocaine craving and that estrogen may play a neuroprotective role in response to stimulant-induced brain injury.

Animal Research

Gender is a Stronger Determinant of Drug Self-administration than Saccharin-preference Phenotype
Prior research has shown that rats with a high preference for sweet-tasting solutions acquire self-administration of amphetamine, ethanol and morphine more rapidly than rats with a low preference. University of Minnesota researchers sought to extend this observation to cocaine and heroin and to compare males and females. Using rats selectively bred for high (HiS) or low (LoS) saccharin preference, they found that female, but not male, HiS rats acquired cocaine self-administration more rapidly than LoS rats, and a higher percentage of females of both phenotypes met the acquisition criterion, and did so more rapidly, than males. Acquisition of heroin self-administration was more rapid in females than males, but was not affected by saccharin phenotype. These findings suggest that gender is a stronger determinant of self-administration than saccharin-preference phenotype. Carroll, M.E., Morgan, A.D., Lynch, W.J., Campbell, U.C. & Dess, N.K. (2002). Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: Phenotypes and sex differences. Psychopharmacology, 161, 304-313.

The Role of Estrogen and Phase of the Estrous Cycle on Cocaine Self-administration
Two studies by these same University of Minnesota researchers report that regulation of cocaine self-administration is modulated by sex and by phase in the estrous cycle. The first study employed a two-lever drug self-administration procedure consisting of two active drug levers, one producing an increase in the dose delivered with each press and the other producing a decrease. The relationship between interdose interval and preceding dose size was used as a measure of regulation, i.e., the extent to which animals titrate cocaine intake to achieve a constant level. These researchers found that once responding stabilized, cocaine self-administration was less regulated in female rats compared with males, with the greatest variability in the spacing of individual infusions observed when females were in the estrus phase (when estrogen levels are high but decreasing). Further, when females were in the estrus phase, the highest dose of cocaine was selected almost exclusively, whereas males and females in other phases of the estrus cycle did not prefer the largest dose. In order to assess the role that estrogen might play in this sex difference, in the second study, the researchers compared acquisition of cocaine self-administration in female rats for whom estrogen was blocked, either chemically by tamoxifen or surgically by ovariectomy, with female rats for whom estrogen was not blocked. Acquisition was markedly reduced by ovariectomy and restored by estrogen replacement. These studies indicate that estrogen plays a role in the acquisition of cocaine self-administration among females and also in sex differences seen in the acquisition of cocaine self-administration. Understanding the factors that affect cocaine self-administration in the female rat may yield valuable strategies for cocaine abuse prevention in women. Lynch, W.J., Arizzi, M.N. & Carroll, M.E. (2000). Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats. Psychopharmacology, 152, 132-139. Lynch, W.J., Roth, M.E., Mickelberg, J.L. & Carroll, M.E. (2001). Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats. Pharmacology, Biochemistry and Behavior, 68, 641-646.

Maternal Separation Produces Sex-specific Changes in Sensitivity to Chronic Morphine in Neonatal Rats
Researchers at Emory University report that early post-natal stress produced by repeated separation from the dam resulted in sex-related alteration in sensitivity to morphine's antinociceptive (pain-relieving) effects. Specifically, male but not female offspring were less sensitive than non-stressed controls to morphine's antinociceptive effects, and the development of tolerance was enhanced in males, but not females. In both males and females, maternal separation was associated with an increase in the severity of withdrawal from chronic morphine, suggesting the development of a greater degree of dependence. These sex-based findings tentatively suggest that the impact of maternal separation on the opioid system is less in female than in male offspring. Whether maternal separation affects subsequent rewarding properties of morphine and perhaps differentially in males and females is yet to be determined. Kalinichev, M., Easterling, K.W. & Holtzman, S.G. (2001). Early neonatal experience of Long-Evans rats results in long-lasting changes in morphine tolerance and dependence. Psychopharmacology, 157, 305-312.

Sexual Experience Activates Neurons in the Nucleus Accumbens and Cross Sensitizes Female Hamsters to the Behavioral Effects of Amphetamine
Dopamine transmission in the nucleus accumbens can be activated by drugs of abuse, stress and motivated behaviors (e.g., sexual activity) and repeated exposure to these stimuli or events can sensitize this dopamine response. Purdue University researchers found that sexual activity elevated c-Fos induction (a measure of neuronal activity) in the core of the nucleus accumbens, but not the shell where drugs of abuse have most often been observed to activate neurons. Nevertheless, prior sexual activity made female hamsters more sensitive to the locomotor effects of amphetamine, indicating that that sexual experience can cross-sensitize neuronal responses to amphetamine. This finding raises the question of whether prior sexual activity can serve to sensitize or enhance amphetamine self-administration. Bradley, K.C. & Meisel, R.L. (2001). Sexual behavior induction of c-Fos in the nucleus accumbens and amphetamine-stimulated locomotor activity are sensitized by previous sexual experience in female Syrian hamsters. The Journal of Neuroscience, 21(6), 2123-2130.

Baclofen Reduces Cocaine Self-administration More in Female Than in Male Rats
Researchers at the University of Minnesota report that the GABA agonist baclofen reduces acquisition of cocaine self-administration in male and female rats. Specifically, baclofen reduced the percentage of both male and female rats that acquired cocaine self-administration. The effect was much more dramatic in female rats, with only 15.4% of females vs. 77.7% of male rats meeting the acquisition criterion during baclofen pretreatment compared to 100% in both male and female rats who did not receive baclofen pretreatment. Female rats that did not meet the acquisition criterion with baclofen treatment acquired self-administration within a few days after treatment termination. Campbell, U.C., Morgan, A.D. & Carroll, M.E. (2002). Sex differences in the effects of baclofen on the acquisition of intravenous cocaine self-administration in rats. Drug and Alcohol Dependence, 66, 61-69.

Ketaconazole Suppresses Food-restriction Increases in Heroin Self-administration in Female but Not Male Rats
Augmentation of drug self-administration by food restriction is well established, and given that food restriction produces an increase in the stress hormone corticosterone, it has been hypothesized that food deprivation is a stressor and thus acts as other stressors to elevate drug self-administration. Researchers at the University of Minnesota recently sought to determine whether ketaconazole, a corticosterone synthesis blocker, would suppress the increase in heroin self-administration produced by food restriction. In both male and female rats, heroin self-administration was increased approximately two-fold by food restriction. Ketaconazole suppressed the food-restriction increase in heroin self-administration in females but not in males. This outcome lends support to the hypothesis that stress mediates the effects of food restriction on increased drug self-administration, but clearly indicates that sex is a modulator of this effect. These findings also suggest that sex may be an important variable to be examined in the development for medications to treat opiate abuse. Carroll, M.E., Campbell, U.C. & Heideman, P. (2001). Ketaconazole suppresses food restriction-induced increases in heroin self-administration in rats: Sex differences. Experimental and Clinical Psychopharmacology, 9(3), 307-316.

Wheel-running Decreases Cocaine Self-administration Significantly in Female Rats Only
These same University of Minnesota researchers examined wheel-running as a nondrug alternative reinforcer form of treatment for cocaine self-administration. After steady rates of cocaine self-administration in both males and females were established, when concurrent access to the running-wheel was provided, females exhibited a 70.6% reduction in cocaine infusions, whereas in males, infusions decreased only 21.9%. Infusions increased to baseline levels when wheel access was terminated in both females and males. These results indicate that the voluntary wheel-running model in rats and possibly voluntary exercise in humans might be used as a substitutable natural reward to reduce drug abuse, especially in women. Cosgrove, K.P., Hunter, R.G. & Carroll, M.E. (2002). Wheel-running attenuates intravenous cocaine self-administration in rats: Sex differences. Pharmacology, Biochemistry and Behavior, 73, 663-671.

Human Studies

Non-treatment Seeking Women Who Use Cocaine Have Higher Cocaine Craving Scores and Greater Depressive Symptomatology Than Men
In a pilot study investigating 21 non-treatment seekers with cocaine dependence, researchers at Harvard University found that following at least 12 hours of abstinence, female subjects self-reported higher total craving scores than male subjects on a craving questionnaire. Importantly, they scored substantially higher on responsivity to drug-conditioned stimuli items, expressed a higher desire to use cocaine within the last 24 hours and a lower desire not to use cocaine in the last 24 hours. Further, females showed greater depressive symptomatology and severity of family/social problems than their male counterparts. These results suggest that gender may influence different aspects of cocaine craving, and they add to a growing body of data suggesting that symptomatology and course of cocaine dependence are not identical in men and women. Elman, I., Karlsgodt, K.H. & Gastfriend, D.R. (2001). Gender differences in cocaine craving among non-treatment-seeking individuals with cocaine dependence. American Journal of Drug and Alcohol Abuse, 27(2), 193-202.

Gender-specific Cerebral Perfusion Abnormalities in Abstinent Cocaine Abusers
Cocaine has been implicated in a variety of neuropsychiatric complications including cerebral infarcts, depression and neuropsychological abnormalities. Researchers at UCLA evaluated regional cerebral blood flow (rCBF) abnormalities both in cocaine abusers who were abstinent for at least 4 months and in healthy controls without a history of drug use. Compared to controls, abstinent cocaine abusers exhibited increased rCBF in the frontal white matter and in the globus pallidus, and decreased rCBF in the putamen and the temporal cortex. Female, but not male, cocaine abusers showed significantly reduced relative rCBF in the parietal gray matter and increased relative rCBF in the frontal and temporo-parietal white matter, whereas male, but not female, cocaine abusers showed significantly increased rCBF in the thalamus. These data demonstrate that there are regional cerebral perfusion abnormalities in abstinent cocaine users, and importantly that some of the abnormalities are gender-specific. Ernst, T., Chang, L., Oropilla, G., Gustavson, A. & Speck, O. (2000). Cerebral perfusion abnormalities in abstinent cocaine abusers: A perfusion MRI and SPECT study. Psychiatry Research: Neuroimaging, 99, 63-74.

Phase of Menstrual Cycle is a Determinant of Cocaine Craving and Subjective Response to Smoked Cocaine
In a study by researchers at the New York State Psychiatric Institute and Columbia University, eleven female research volunteers who were currently using cocaine were allowed to smoke up to six doses of cocaine in both the luteal phase which follows ovulation (levels of the hormone progesterone are at their highest) and the follicular phase which precedes ovulation (levels of estrogen are at their highest). The number of cocaine doses administered did not vary between phases; however, following cocaine administration, heart rate and several positive ratings (Ògood drug effect,Ó Òhigh,Ó ÒstimulatedÓ) were increased more during the follicular phase. Under placebo conditions, resting heart rate, reports of dysphoria and cocaine craving were greater during the luteal phase. Following cocaine administration, luteal phase dysphoric ratings were dose-dependently improved. Cocaine craving was greater during the luteal phase than during the follicular after 3mg and 25 mg cocaine, but after 12 mg cocaine, craving was higher in the follicular phase. Cocaine-produced ratings of mood states, positive drug effects and drug quality ratings were generally greater during the follicular phase. The differential subjective effects of cocaine in the luteal and follicular phases as well as the cocaine-produced amelioration of mild luteal phase dysphoria observed in this study warrant investigation of the mechanisms underlying these effects as well as an exploration of treatment implications of these findings. Evans, S.M., Haney, M. & Foltin, R.W. (2002). The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology, 159, 397-406.

Cocaine-induced Cerebral Vasoconstriction Differs as a Function of Gender and Menstrual Cycle Phase
Prior research has shown that chronic cocaine-abusing women experience fewer cerebral perfusion defects and less neuronal injury than men with comparable drug use histories. In a group of occasional cocaine users, researchers at Harvard University found that cocaine had no significant effect on cerebral blood flow during the follicular phase of a women's menstrual cycle. In the luteal phase, however, cocaine reduced blood flow by about 10%, which was not significantly different from the 20% decrease in cerebral blood flow observed in men. The insignificant effect of cocaine on women's brain blood volume prior to ovulation may be attributable to the protective effects of estrogen, which improves blood vessel elasticity and may counter the vasoconstrictive effects of cocaine. Kaufman, M.J., Levin, J.M., Maas, L.C., Kukes, T.J., Villafuerte, R.A., Dostal, K., Lukas, S.E., Mendelson, J.H., Cohen, B.M. & Renshaw, P.F. (2001). Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase. Biological Psychiatry, 49, 774-781.

A Possible Neuroprotective Role of Estrogen in Response to the Methamphetamine-induced Brain Injury
In an investigation of regional cerebral blood flow (rCBF) and cognitive function in abstinent methamphetamine users, researchers at the Brookhaven National Laboratory evaluated 20 methamphetamine-dependent participants who had been abstinent for an average of 8 months and 20 age- and gender-matched controls without a history of substance abuse. Methamphetamine users performed within normal ranges on standard neuropsychological testing, although they were slower on working memory tasks. Both male and female methamphetamine users showed similar disrupted rCBF in several brain areas, although in several brain areas, male methamphetamine users exhibited a decreased relative rCBF, whereas female users exhibited an increase. These gender differences suggest a possible neuroprotective role of estrogen in response to the methamphetamine-induced brain injury. Chang, L., Ernst, T., Speck, O., Patel, H., DeSilva, M., Leonido-Yee, M. & Miller, E.N. (2002). Perfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users. Psychiatry Research: Neuroimaging, 114(2), 65-79.

NICOTINE

The prevalence of smoking has decreased for both men and women over recent decades. Unfortunately, however, the rates have declined much more slowly for women than men and nicotine dependence rates are higher among women than men, although women smoke fewer cigarettes per day than men. Women are less successful than men at quitting smoking, have higher relapse rates after quitting and have a poorer response to nicotine replacement therapies than men, thus pointing to the need for gender-based research on nicotine addiction. Indeed, NIDA-support research, from basic laboratory studies with animals and humans to clinical studies of smoking cessation, is increasingly demonstrating that gender plays a powerful role in the nature of nicotine dependence, its etiology, its effects and how to treat it. Over the past two years NIDA-supported published research, described below, utilizing animal models has reported important sex differences in nicotine self-administration and in the patterns of CNS defects due to fetal vs. adolescent nicotine exposure. Field studies have uncovered sex differences in rates of nicotine dependence and in the predictors of smoking, and laboratory-based human studies have described sex differences associated with abstinence and in the role that sensory cues play in nicotine dependence, findings that may have implications for prevention and treatment. And clinical research has provided evidence for the efficacy new treatments for smoking cessation, especially in women.

Sex Differences in Nicotine Self-administration in Rats
University of Pittsburgh researchers compared acquisition of nicotine self-administration in male and female rats. They found that nicotine self-administration acquisition, at the lowest dose tested, was faster and more stable in female than in male rats. Females also made more bar presses to receive nicotine infusions and they displayed a shorter latency before self-administering the first nicotine infusion in a session than males. These results suggest that the motivation to obtain nicotine may be higher in females than males. Donny, E.C., Caggiula, A.R., Rowell, P.P., Gharib, M.A., Maldovan, V., Booth, S., Mielke, M.M., Hoffman, A. & McCallum, S. (2000). Nicotine self-administration in rats: Estrus cycle effects, sex differences and nicotine receptor binding. Psychopharmacology, 151, 392-405.

Gender-distinct Patterns of CNS Defects Following Adolescent Nicotine Exposure in Rats
Researchers at Duke University examined the effects of nicotine on the serotonin neurotransmitter system in both pregnant and adolescent rats using doses that replicate the plasma nicotine levels found in smokers. They found that vulnerability to nicotine's alteration of serotonin neurotransmitter systems extends from fetal life through adolescence. Following adolescent nicotine exposure, although both females and males displayed serotonergic abnormalities, the patterns of effects were gender-selective in various brain regions. This line of research is especially important given recent work showing that many adolescent smokers exhibit signs of nicotine dependence in a matter of days to weeks after initiation of occasional tobacco use, often well before the development of daily smoking. Importantly, teenage girls on average become addicted within three weeks of occasional smoking, whereas for boys, half are addicted within six months. Thus, it will be extremely useful for future research to examine whether gender-selective effects on neurochemical systems, as seen in this study, also correspond to differential early onset of nicotine dependence in males and females. Xu, Z., Seidler, F.J., Ali, S.F., Slikker Jr., W. & Slotkin, T.A. (2001). Fetal and adolescent nicotine administration: Effects on CNS serotonergic systems. Brain Research, 914, 166-178.

Nicotine Dependence Rates Higher Among Women
Using data from subjects who were last-month smokers from the National Household Survey on Drug Abuse from 1991-1993, researchers at Columbia University found that nicotine dependence rates are higher among females than males, Whites than minorities and the lowest among older adults. Dependence rates increase sharply and significantly when the quantity smoked increases from less than one cigarette a day to one to five cigarettes a day, or from one to five cigarettes a day to half a pack a day. Thereafter, the increased risk is minimal. The higher rate of dependence among women results from a greater number of dependence symptoms at the same quantity smoked, i.e., women become dependent smoking fewer cigarettes per day than men. There is also an increase in the gender gap in the rate of dependence as quantity smoked increases. These findings suggest that different thresholds of quantity and duration of smoking should be used in assessing different groups for risk for nicotine dependence. Kandel, D.B. & Chen, K. (2000). Extent of smoking and nicotine dependence in the United States: 1991-1993. Nicotine and Tobacco Research, 2, 263-274.

In a Laboratory Setting, Women Report Greater Desire to Smoke Than Men Following Both Abstinence and Ad Libitum Smoking
Researchers at the University of Minnesota examined the effects of short-term abstinence from smoking on psychophysiological activity and mood changes at both rest and in response to acute behavioral challenges. Thirty habitual smokers (15 men and 15 women) participated in two laboratory sessions conducted on two separate days following 18-21 hours of abstinence from smoking or following ad libitum smoking. Abstinence produced significant withdrawal in all participants, and women reported being less calm and less in control than men on both days. Participants showed greater systolic blood pressure responses to the behavioral challenges in the abstinence condition than in the control condition, and showed worse performance on the behavioral tasks following abstinence. Both men and women showed increased desire to smoke following the behavioral challenges. Both men and women reported stronger desire to smoke in the abstinence condition than in the ad libitum condition, and women reported a greater desire to smoke in both conditions than men. This greater desire to smoke reported by women is of special interest given that the men and women had similar levels of nicotine addiction and similar smoking histories. This finding could have implications for the design of gender-sensitive smoking cessation procedures. al'Absi, M., Amunrud, T. & Wittmers, L.E. (2002). Psychophysiological effects of nicotine abstinence and behavioral challenges in habitual smokers. Pharmacology, Biochemistry and Behavior, 72, 707-716.

Olfactory/Taste Cues Associated with Smoking Play a Greater Role in Women's Smoking Behavior Than in Men's
Aside from its delivery of nicotine, cigarette smoking behavior may also be reinforced by stimuli associated with smoking. University of Pittsburgh researchers examined the effects of smoking sensory cues (sight and smell/taste) on smoking behavior by having smokers wear opaque goggles (to block visual cues) and/or swimmers' noseclips (to block olfactory/taste) stimuli during smoking. When both visual and olfactory/taste cues were blocked, both men and women exhibited decreased liking and satisfaction from smoking, but only women decreased smoking. When only visual cues were blocked, there were no effects on the subjective effects of smoking nor on the amount smoked in either men or women. When olfactory/taste cues were blocked, however, both men and women reported decreased subjective liking and satisfaction from smoking, and this effect was stronger in women. Importantly, following the blockade of olfactory/taste cues, only women decreased their smoking. Thus, both the subjective pleasure and reinforcing effects of smoking are influenced by olfactory/taste stimuli, but not visual stimuli, particularly in women. These observations suggest that nicotine stimuli associated with smoking are more reinforcing in women than in men, and also suggest that interventions to help smokers quit may benefit from a greater focus on eliminating stimuli associated with smoking, particularly olfactory/taste stimuli, and that this approach could be particularly beneficial for females, who tend to have less success in quitting. Perkins, K.S., Gerlach, D., Vender, J., Grobe, J., Meeker, J. & Hutchison, S. (2001). Sex differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli. Nicotine and Tobacco Research, 3(2), 141-150.

Sex Differences in Adolescent Smoking Trajectories
Researchers at Rutgers University investigated developmental trajectory groups for cigarette smoking in 374 males and females who were interviewed five times from age 12 until age 31. Girls began smoking daily earlier than boys (15.7 vs. 17.4 years of age), and were more likely to belong to a smoking trajectory group than a non-smoking group, i.e., they were more likely than males to eventually begin smoking. For females, but not males, having a friend or parent who smoked was significantly related to smoking. Also for females, but not males, lower parental socioeconomic status was associated with both smoking and heavy smoking. Further, the occasional/maturing out group was made up of more females than males. These findings have implications for the development of gender-sensitive prevention efforts. Future research should examine transitions and turning points from adolescence to adulthood as well as other factors that may affect cessation and escalation differently for females and males. White, H.R., Pandina, R.J. & Chen, P.H. (2002). Developmental trajectories of cigarette use from early adolescence into young adulthood. Drug and Alcohol Dependence, 65, 167-178.

Dealing With Daily Hassles: Smoking and African American Adolescent Girls
University of Michigan researchers examined cigarette use and its relationship to daily life hassles in an urban sample of 105 African American adolescent girls. Girls who had ever smoked had a significantly greater number of daily life hassles in contrast to girls who had never smoked. Academic and family stressors were related to smoking, but peer and personal safety stressors were not. Age of smoking initiation was negatively related to the number of hassles, indicating that girls who started to smoke at a younger age reported more hassles. These findings that daily hassles are correlates of African American adolescent girls' smoking as well as the age at which they begin smoking may be useful in the design of ethnic- and gender-related smoking prevention programs for African American girls. Guthrie, B.J., Young, A.M., Boyd, C.J. & Kintner, E.K. (2001). Dealing with daily hassles: Smoking and African-American adolescent girls. Journal of Adolescent Health, 29, 109-115.

Girls May Progress Through the Stages of Smoking Earlier than Boys
Researchers at RAND investigated the relationship between emotional distress and tobacco use in 2,961 adolescents from 30 schools in California. The participants were assessed longitudinally in grade 10, grade 12 and in young adulthood. Previous research has provided support for the distress-to-use (i.e. self-medication) hypothesis, and one might expect girls, who tend to have higher rates of emotional distress, to exhibit a somewhat stronger relationship between distress and smoking than boys. Although girls did have consistently higher emotional distress scores than boys, the relationship between emotional distress in the 10th grade and smoking in the 12th grade was stronger for boys. A possible explanation for this unexpected result may be related to the timing of this measurement in relation to the stages of smoking. In the current sample, more girls than boys had tried cigarettes than boys by Grade 10 and the proportion of occasional or regular smokers was significantly higher among girls than boys in Grades 10 and 12. This difference, however, was not evident in young adulthood, at which point smoking rates appeared to even out for the two genders, thus suggesting that girls may progress through the stages of smoking earlier in their development than boys. If the impact of distress on smoking is strongest at a particular stage, for example, during the transition from experimentation to regular use, then this effect would occur earlier for many girls. Orlando, M., Ellickson, P.L. & Jinnett, K. (2001). The temporal relationship between emotional distress and cigarette smoking during adolescence and young adulthood. Journal of Consulting and Clinical Psychology, 69(6), 959-970.

Cognitive-behavioral Therapy to Reduce Weight Concerns Improves Smoking Cessation Outcome in Weight-concerned Women
Smokers concerned about weight gain are less likely to want to quit, report greater withdrawal if they do quit, are more likely to drop out of treatment, have poorer overall abstinence outcome and are more likely to be female. The average postquit weight gain of 10 pounds often sabotages early attempts at smoking cessation and may cause resistance to treatment or relapse after treatment completion. Yet, research has shown that treatment for smoking cessation that includes behavioral approaches to limiting weight gain are usually ineffective and can actually interfere with smoking cessation efforts. Researchers at the University of Pittsburgh School of Medicine have now reported the effectiveness of treatment focusing on weight gain concerns, rather than on preventing weight gain. They conducted a random controlled trial in which 219 women who were concerned about weight gain were randomly assigned to one of three treatments: 1) group smoking cessation counseling (standard group) in which weight gain was not explicitly addressed; 2) group smoking cessation counseling plus behavioral weight control to prevent weight gain (weight control group); 3) group smoking cessation counseling plus cognitive-behavioral therapy to directly reduce weight concern (CBT group). The CBT group received therapy to modify their attitude toward weight gain and to help them accept a modest weight gain in light of benefits of quitting; dieting was discouraged. Ten sessions were conducted over 7 weeks. At the end of one year, abstinence rates were significantly higher for the CBT group (21% abstinence) than the standard group (9%), but abstinence rates for the weight control group (13%) were not significantly better than the standard group. Interestingly, and unexpectedly, weight gain at the end of one year was significantly less in the CBT group (6 pounds) than the standard group (17 pounds), but weight gain in the weight control group (12 pounds) did not differ significantly from that of the standard group. Thus, CBT to reduce weight concerns, but not behavioral weight control counseling to prevent weight gain, significantly improved smoking cessation outcome in weight-concerned women and significantly decreased weight gain. Perkins, K.A., Marcus, M.D., Levine, M.D., D'Amico, D., Miller, A., Broge, M., Ashcom, J. & Shiffman, S. (2001). Cognitive-behavioral therapy to reduce weight concerns improves smoking cessation outcome in weight-concerned women. Journal of Consulting and Clinical Psychology, 69, 604-613.

The Antidepressant Buproprion May Help Smokers, Especially Females, Overcome the Effects of Genetic Predisposition on Relapse Rates
A study at the University of Pennsylvania indicates that smokers with a specific genetic variant may be more vulnerable to cigarette cravings and relapse when trying to quit smoking. The researchers found that smokers with a decreased activity variant of the CYP2B6 gene reported greater increases in cravings for cigarettes following the quit date and were about 1.5 times more likely to relapse during the treatment phase. This study also provides preliminary evidence that buproprion may help smokers, especially females, overcome the effects of genetic predisposition on relapse rates. Among women with the CYP2B6 polymorphism, 54% of those who were treated with buproprion were abstinent at the end of treatment, compared with 19% of those who received placebo. For men with the mutation, 42% who were treated with buproprion and 38% with placebo were abstinent at the end of treatment. This sex difference could be due to buproprion's effect on abstinence-induced negative mood which is more common among women. Lerman, C., Shields, P.G., Wileyto, E.P., Audrain, J., Pinto, A., Hawk, L., Kirshnan, S., Niaura, R. & Epstein, L. (2002). Pharmacogenetic investigation of smoking cessation treatment. Pharmacogenetics, 12, 627-634.

ADOLESCENTS

Early adolescence is a time when many individuals begin experimentation with various substances, and indeed many become addicted. The study of adolescents is included in virtually all areas of drug abuse research and increasingly is taking a gender-based approach. The research findings from NIDA-supported research from the past two years, highlighted below, describes findings on sex differences in use patterns, sex differences in predictors and progress to drug abuse, as well as sex differences in the clinical aspects of drug abuse in adolescents. These findings join a growing body of drug abuse research suggesting that the trajectories to drug abuse are not identical in boys and girls and that taking a gender-based approach to prevention and treatment interventions can perhaps lead to better outcomes in boys and girls.

Gender Gap in Inhalant Use is Narrowing
Researchers at Colorado State University investigated inhalant use in 35,094 adolescents from three ethnic populations from across the United States (Mexican American, American Indian and non-Latino white) who were studied over the period from 1988-1997. The data are clear that girls are equally, if not more, susceptible to inhalant use than boys. For Mexican American youths there were no gender differences in either lifetime or 30-day prevalence. For the non-Latino white youths there were no gender differences on the 30-day measure. Among American Indian youth, for both lifetime and 30-day prevalence, girls were more likely to have used inhalants than boys. Thus, the current data suggest that the historically higher rates of inhalant use for boys as compared to girls no longer prevail, indicating that girls should be included in all prevention efforts. Beauvais, F., Wayman J.C., Jumper-Thurman, P., Plested, B. & Helm, H. (2002). Inhalant abuse among American Indian, Mexican American, and Non-Latino White adolescents. American Journal of Drug and Alcohol Abuse, 28(1), 171-187.

Inner-city Girls in New York City Engage in Less Polydrug Use than Boys, Regardless of Ethnicity
Cornell University researchers assessed polydrug use in a cohort of 2,354 inner-city adolescents in 22 urban schools in New York City throughout middle school. Students completed self-report questionnaires with measures of drug use (smoking, marijuana use and drinking). In general, girls engaged in less polydrug use than boys, independent of ethnicity. This finding demonstrates that in some cases, aggregating data across gender may obscure important differences in drug use between boys and girls, and may have implications for prevention. Epstein, J.A., Botvin, G.J., Griffin, K.W. & Diaz, T. (2000). Role of ethnicity and gender in polydrug use among a longitudinal sample of inner-city adolescents. Journal of Alcohol and Drug Education, 45, 1-12.

Early Pubertal Maturation Represents a Risk Factor for Substance Abuse in Adolescent Girls
Researchers at the Pennsylvania State University have found that the timing of the onset of puberty appears to be a risk factor for substance abuse in girls. Data from 966 adolescent girls involved in the National Longitudinal Study of Adolescent Health revealed important differences between early maturing girls and their on-time and late-maturing counterparts in initiation of substance use. Twenty percent of the 7th grade girls were identified as early maturers based on body changes (increased breast size and body curviness). During 7th grade, girls in the early-maturing group were three times more likely to be in the most advanced group of substance users (involving alcohol use, drunkenness, cigarette use and marijuana use) than were those in the on-time/late groups. Between 7th and 8th grade, early developers were significantly more likely to transition out of the "No Substance Use" stage than on-time/late developers (47% vs. 22%, respectively), and were more likely to advance in substance use in general, regardless of level of use at grade 7. In a related study, researchers at the University of Kentucky administered questionnaires to 1,002 girls and boys who were followed from the 6th to the 10th grades. In girls but not boys, early pubertal onset was associated with greater cigarette use in grades 7, 8 and 9 and lower self-esteem in grade 7. In boys but not girls, early pubertal onset was associated with elevated alcohol use in grades 9 and 10. Taken together, these studies suggest that early maturing girls are at high risk for the worst substance use trajectories, and that pubertal timing could be used a marker to identify girls at high risk. Lanza, S.T. & Collins, L.M. (2002). Pubertal timing and the onset of substance use in females during early adolescence. Prevention Science, 3(1), 69-82. Martin, C., Logan, T.K., Leukefeld, C., Milich, R., Omar, H. & Clayton, R. (2001). Adolescent and young adult substance use: Association with sensation seeking, self esteem and retrospective report of early pubertal onset. A preliminary examination. International Journal of Adolescent Medicine and Health, 13(3), 211-219.

Elementary School Alcohol and Other Drug Use Increases Middle School Risk Differently in Girls and Boys
Researchers at the University of California at Berkeley found gender differences in the relationship between alcohol, tobacco and other drug (ATOD) use in elementary school and continued ATOD use in middle school in a sample of 331 ethnically and geographically diverse students from a range of low socioeconomic status backgrounds living in rural, urban or inner-city environments. Girls, but not boys, who used alcohol in elementary school were at significant increased risk for alcohol use in middle school. Elementary school use of cigarettes by boys increased their likelihood of middle school tobacco use by almost nine-fold; for girls, three-fold. There was a marginally significant increased risk of middle school marijuana use by boys who reported use during elementary school, but girls did not report marijuana use in either elementary or middle school. This gender-based association of early use of ATOD with greatly increased odds of later use has important implications for the timing of drug prevention programs. Wilson, N., Battistich, V., Syme, S.L. & Boyce, W.T. (2002). Does elementary school alcohol, tobacco, and marijuana use increase middle school risk? Journal of Adolescent Health, 30, 442-447.

Gender Differences in Psychiatric Comorbidity Among Adolescents with Substance Use Disorders
Studies suggest that different psychiatric comorbidity patterns among youths in drug treatment are associated with distinct outcomes. Research has shown that in many drug treatment programs, psychiatric comorbidity issues are not directly addressed in a systematic manner; thus, untreated comorbid psychiatric disorders may be contributing to posttreatment relapse rates wherein an estimated one in two adolescents reverts to substance abuse within 90 days of treatment. Researchers at Johns Hopkins University examined gender differences in the rates of psychiatric disorders among 135 adolescents with substance use disorders. Nearly four times as many female adolescents as male adolescents had a co-occurring major depressive disorder, and nearly three times as many male as female adolescents had a co-occurring ADHD or Conduct Disorder. Unexpectedly, rates of ADHD and Conduct Disorder were fairly high among females (23.5% and 47.1%, respectively), despite being significantly lower than for males. These findings suggest the need for adolescent drug abuse treatment programs to incorporate strategies that address these gender-based multiple comorbidity patterns. Latimer, W.W., Stone, A.L., Voight, A., Winters, K.C. & August, G.J. (2002). Gender differences in psychiatric comorbidity among adolescents with substance use disorders. Experimental and Clinical Psychopharmacology, 10, 310-315.

Past Sexual and Physical Abuse and Substance Abuse Consequences
Researchers at Boston University examined the association between past interpersonal trauma and drug and alcohol consequences in both male and female patients recruited from an urban alcohol and drug detoxification unit in Massachusetts. Substance abuse consequences included, for example, risky or illegal behavior, the impact of substance abuse on relationships, work and school problems as well as adverse physical consequences associated with substance abuse. Among the 465 patients, there was an extraordinarily high frequency of physical and sexual abuse: 72% experienced interpersonal trauma, and 75% of them first experienced it as children. Specifically, 81% of women and 69% of men reported past physical/sexual abuse, starting at a median age of 13 and 11, respectively. Further, physical and sexual abuse was significantly related to greater substance use consequences for both women and men. For men, being under the age of 17 years at first abuse was significantly associated with more substance abuse consequences than an older age at first abuse, or no abuse. For women, the association of physical and sexual abuse with substance use consequences was similar across all age groups. The mechanisms by which interpersonal violence influence substance use consequences in women and men may differ, suggesting that substance abuse prevention and treatment programs may benefit from gender-specific components. Liebschutz, J., Savetsky, J.B., Saitz, R., Horton, N.J., Lloyd-Travaglini, C. & Samet, J.H. (2002). The relationship between sexual and physical abuse and substance abuse consequences. Journal of Substance Abuse Treatment, 22, 121-128.

Female Juvenile Arrestees More Likely to Report Dependence, But Less Likely to Report Need for Treatment Than Males
Researchers at the University of Illinois at Chicago examined gender differences in drug use, self-reported dependence and perceived need for treatment in a national sample of 4,644 juvenile arrestees who were 9 to18 years old. Significantly more girls self-reported dependence than boys, but they were no more likely to report a need for treatment. Among arrestees reporting current frequent drug use, girls were significantly less likely than boys to report a need for treatment. Among the most severe drug users, girls were 7.1 times as likely as boys to say they were dependent, and were more likely than boys to report a need for treatment. These findings that juvenile arrestees' perception of their drug dependence and of their need for treatment differs by gender and by drug problem severity especially highlights the need for girls to receive treatment before their substance abuse becomes severe. Kim, J.Y.S. & Fendrich, M. (2002). Gender differences in juvenile arrestees' drug use, self-reported dependence, and perceived need for treatment. Psychiatric Services, 53(1), 70-75.

TREATMENT AND SERVICES

Over the past several years, NIDA-supported treatment and services research has increasingly been adopting a gender-based approach. This research approach is revealing widespread gender differences including treatment entry characteristics, treatment and services needs, barriers to treatment, treatment engagement and retention, treatment outcomes and relapse predictors. Such research shows, for example, that women may be less likely to enter treatment than men, have shorter lengths of stay and lower rates of treatment completion. NIDA-supported treatment and services research also is focusing on targeted groups of women including pregnant and postpartum women, women offenders, homeless women, minority women and those experiencing current and past violence and trauma. NIDA-supported published research over the last two years, highlighted below, includes research on treatment dropouts, the role of a woman's family status in her completion of treatment, treatment needs of methamphetamine-dependent women and special treatment and services issues regarding women offenders and pregnant and postpartum women. Continuing research into the specific needs of women who need treatment is necessary in order to increase success at getting women to begin treatment, and once there, to complete treatment and have successful outcomes.

Treatment Dropouts More Likely to be Female
Researchers at the University of Texas examined factors affecting treatment attrition in 165 individuals seeking treatment for cocaine dependence. Of those who initiated treatment, 65% dropped out before completing all 20-therapy sessions. Treatment dropouts were more likely to be female, to be separated from their spouses, to have poorer family/social functioning and to have fewer years of education. Individuals with higher education levels and those with poorer psychiatric functioning tended to remain in treatment longer. These findings have direct implications for identifying individuals at higher risk for attrition from outpatient substance abuse programs. Sayre, S.L., Schmitz, J.M., Stotts, A.L., Averill, P.M., Rhoades, H.M. & Grabowski, J.J. (2002). Determining predictors of attrition in an outpatient substance abuse program. American Journal of Drug and Alcohol Abuse, 28(1), 55-72.

A Women's Family Status Impacts Her Completion of Substance Abuse Treatment
The impact of a woman's family status (i.e. pregnant, living with dependent children or children in foster care) on the likelihood that she would complete drug abuse treatment was examined in 9,142 women in Illinois who completed intake for publicly funded treatment by researchers at the Piedmont Research Institute. More than half of the women failed to complete treatment. The likelihood of not completing treatment was greatest for women who were pregnant, had custody of minor children, were African American or were younger than age 21. African American women who had children in foster care, however, were more likely to complete treatment than African American women in general or women of other races. Women's needs are often overlooked and underserved in the substance abuse treatment services. In particular, pregnancy and child-care needs and their impact on women's completion of treatment must be understood and addressed in the treatment system. Scott-Lennox, J., Rose, R., Bohlig, A. & Lennox, R. (2000). The impact of women's family status on completion of substance abuse treatment. The Journal of Behavioral Health Services & Research, 27(4), 366-379.

Methamphetamine-dependent Women More Likely to Report a Syndrome of Depression and Suicidal Ideation and a Need for Psychiatric Assistance
Research has shown that psychiatric comorbidity among drug users is associated with poorer treatment outcome and a higher likelihood of relapse. In a study of 1,580 arrestees sampled from the 14 most populous counties in California, increased risk for depressive symptoms was observed for both women and men reporting methamphetamine dependence compared to those not reporting dependence. Further, women, but not men, reporting methamphetamine dependence were more likely than those not reporting methamphetamine dependence to report suicidal ideation and a need for psychiatric assistance at the time of the interview which occurred within 48 hours of arrest. These findings raise questions of whether the depression and suicidal ideation preceded or followed the onset of methamphetamine use and whether antidepressant medications would be efficacious in the treatment of methamphetamine dependence for individuals with co-occurring depression. Kalechstein, A.D., Newton, T.F., Longshore, D., Anglin, M.D., van Gorp, W.G. & Gawin, F.H. (2000). Psychiatric comorbidity of methamphetamine dependence in a forensic sample. Journal of Neuropsychiatry & Clinical Neurosciences, 12(4), 480-484.

Women Offenders
Drug-abusing women sometimes encounter treatment either within the prison system or following incarceration. Although women compose only 11% of the US jail population, the rate of incarceration is rising faster among women than among men, and female arrestees are more likely than male arrestees to be found drug positive. In fact, it is estimated that about two-thirds of female arrestees use illicit drugs. NIDA-supported published research over the last two years on women offenders, described below, has included investigation of the services needs of substance-abusing women in jail, factors that affect their retention in prison-based treatment programs and factors that affect their abstinence in the first week after treatment.

The First Week after Drug Treatment: Factors Influencing Abstinence Among Women Offenders
Researchers at the National Development and Research Institute conducted a study examining abstinence during the first week after leaving two community-based treatment programs in Portland, OR. Among 165 women offenders who were mandated to treatment, over two-thirds of the women abstained from drug use during the first week after treatment, despite their long histories of drug use and other serious problems. Women who remained abstinent during the first week after treatment, compared with those who did not, were more likely to have remained in treatment longer, received a plan to make a successful transition out of treatment, avoided associations with other drug users after leaving treatment and obtained encouragement from individuals and groups in support of abstinence. Strauss, S.M. & Falkin, G.P. (2001). The first week after drug treatment: The influence of treatment on drug use among women offenders. American Journal of Drug and Alcohol Abuse, 27(2), 241-264.

Women's Perceptions About Quality of Treatment Experience Important for Staying in a Prison-based Treatment Program
To determine why some women offenders complete prison-based drug treatment and others leave early, perceptions of various aspects of the quality of the treatment experience were compared in 101 women offenders in Portland, OR. Researchers found that the two groups differed in terms of their perceptions about the quality of treatment experience, but did not differ in their background characteristics or previous experience with drug treatment. Clients who completed the program had a more favorable perception of staff, perceiving the counselors as supportive and felt empowered by the experience in treatment. About half of the clients left prematurely, largely because of conflicts with the program's rules. Because many women drop out of treatment, programs need to consider strategies that will enhance the likelihood that these clients stay longer so that the treatment can have optimal impact. Strauss, S.M. & Falkin, G.P. (2000). The relationship between the quality of drug user treatment and program completion: Understanding the perceptions of women in a prison-based program. Substance Use & Misuse, 35(12-14), 2127-2159.

Services Needs of Substance Abusing Women in Jail
In a study of self-reported service needs of 165 women held in a large urban county jail in Ohio, researchers at the University of Akron found that 50% of the women reported a need for substance abuse services. Compared to women who did not report such a need, those women were more likely to report the need for housing, medical care, education, mental health services, family support and parenting assistance when released from jail. Housing was the need most frequently mentioned; 84% of drug abuse treatment-seeking women reported a need for housing compared to 45% of non-treatment seeking women. This study suggests that successful drug treatment of incarcerated women must consider the multidimensional needs of these women in order to break the cycle of drug use and incarceration. Alemagno, S.A. (2001). Women in jail: Is substance abuse treatment enough? American Journal of Public Health, 91(5), 798-800.

Pregnant and Postpartum Women
Drug use during pregnancy places the woman at risk for maternal complications, the infant at risk for low birth weight and small head circumference, and the baby and developing child at risk for problems with attention, emotional regulation and advanced problem solving. Thus, identification of drug use during pregnancy as well as effective drug abuse treatment are essential to the health and well being of mother and child. Self-report of drug use in pregnancy is often problematic because of the inaccuracy of recall and because of the woman's fear of losing custody of her children. A recent NIDA study, described below, has found that meconium testing, when used in conjunction with maternal self-report, results in improved accuracy for the identification of prenatal exposure. Other studies have investigated the effectiveness of incentives in enhancing both treatment attendance and abstinence in pregnant women, the identification of special treatment needs for pregnant women with PTSD, and the usefulness of buprenorphine for treatment of opioid-dependent pregnant women.

MeconiumTesting Improves Identification of Infants Prenatally Exposed to Drugs Over Maternal Self-report
Researchers at Brown Medical School evaluated maternal self-report of drug use during pregnancy and meconium assay as methods to determine exposure status to cocaine, opiates and other illicit drugs in 8,527 newborns participating the Maternal Lifestyle Study which has sites in Detroit, Memphis, Miami and Providence. Results indicate that accurate identification of exposure to illicit drugs in newborns is likely to be improved when meconium testing is used in conjunction with a maternal hospital interview. For example, 254 mothers denied use, but their infants had positive meconium confirmation for cocaine/opiates, thus allowing identification of an additional 38% of the drug-exposed infants by means of meconium testing. Many questions still remain, however, about the disposition of drugs in meconium and therefore further research is necessary. Lester, B.M., ElSohly, M., Wright, L.L., Smeriglio, V.L., Verter, J., Bauer, C.R., Shankaran, S., Bada, H.S., Walls, H.C., Huestis, M.A., Finnegan, L.P. & Maza, P.L. (2001). The Maternal Lifestyle Study: Drug use by meconium toxicology and maternal self-report. Pediatrics, 107(2), 309-317.

Drug Use During Pregnancy and Short-term Maternal Outcomes
In a separate study, Maternal Lifestyle Study researchers also found that those women who used cocaine or opiates during pregnancy had a significantly higher risk of infections, including syphilis, gonorrhea, hepatitis and HIV, psychiatric, nervous and emotional disorders and abruptio placenta. The prevalence of these risk outcomes, however, was lower than typically reported in other studies examining drug use during pregnancy, perhaps because a high percentage of the women made use of available prenatal care services: 77% of the exposed mothers and 97% of nonexposed mothers had at least one prenatal care visit. The women may also have moderated their drug use behavior during pregnancy to minimize the potential negative impact of their lifestyles on their infants. The women were largely polydrug abusers, with approximately 93% admitting to using other drugs that are known to have a negative impact on fetuses, particularly tobacco and alcohol. These results support the need for early, comprehensive prenatal care for drug-using pregnant women to prevent or treat the health hazards that accompany drug exposure, thereby optimizing maternal-infant outcome. Bauer, C.R., Shankaran, S., Bada, H.S., Lester B., Wright L.L., Krause-Steinrauf H., Smeriglio V.L., Finnegan L.P., Maza P.L. & Verter J. (2002). The Maternal Lifestyle Study: Drug exposure during pregnancy and short-term maternal outcomes. American Journal of Obstetrics and Gynecology, 186(3), 487-495.

Clinical and Psychosocial Characteristics of Substance-dependent Pregnant Women with and without PTSD
Researchers at Johns Hopkins examined clinical and psychosocial characteristics and posttraumatic stress disorder (PTSD) symptomatology in a sample of pregnant women who were severely drug-dependent. Among the 123 women, lifetime prevalence of PTSD was 19%. Compared to women without PTSD, those with PTSD had received more previous drug treatment, were more likely to report a previous suicide attempt, and reported greater need for psychiatric treatment. The most salient predictors of PTSD status were lifetime sexual abuse and family or social problems were. The results suggest that pregnant drug-dependent women with comorbid PTSD may benefit from specialized treatment services for trauma and/or abuse issues. Moylan, P.L., Jones, H.E., Haug, N.A., Kissin, W.B. & Svikis, D.S. (2001). Clinical and psychosocial characteristics of substance-dependent pregnant women with and without PTSD. Addictive Behaviors, 26, 469-474.

Incentives Enhance Treatment Attendance and Abstinence in Methadone-maintained Pregnant Women
Methadone maintenance for heroin dependence during pregnancy is associated with many benefits for both mother and baby. Methadone-maintained pregnant women, however, often use other drugs (e.g. cocaine) that may exert a detrimental effect on the fetus. Researchers at Johns Hopkins University examined the effectiveness of a short-term contingency management program designed to eliminate cocaine use in heroin-dependent pregnant women and to increase their attendance in a methadone-maintenance program. The women were randomly assigned to either an escalating voucher incentive schedule (women received a voucher exchangeable for appropriate goods and services for each day they provided a drug-free urine sample and full-day treatment attendance) or a non-incentive condition. Over the 14-day program, the escalating voucher incentive schedule significantly increased full-day treatment attendance as well as both cocaine and heroin abstinence compared to the non-incentive schedule. These findings suggest that reinforcing the co-occurrence of treatment attendance and abstinence from illicit drug use is effective and could be an important adjunct to methadone pharmacotherapy for treating pregnant heroin-dependent women. Jones, H.E., Haug, N., Silverman, K., Stitzer, M. & Svikis, D. (2001). The effectiveness of incentives in enhancing treatment attendance and drug abstinence in methadone-maintained pregnant women. Drug and Alcohol Dependence, 61, 297-306.

Buprenorphine Treatment of Pregnant Opioid-dependent Women Improves Maternal and Neonatal Outcomes
Researchers at Johns Hopkins University examined both maternal relapse as well as neonatal safety outcome measures in three pregnant opioid-dependent women who received buprenorphine for the treatment of their opioid dependence during pregnancy. The researchers found that buprenorphine, in combination with comprehensive prenatal care, was safe and effective in treating opioid dependence in these women. Prenatal exposure to buprenorphine was associated with normal birth outcomes and a mean hospitalization stay of 4.33 days (minimum possible was 4 days), and the infants exhibited only a relatively mild neonatal abstinence syndrome, requiring no pharmacological treatment. These results are promising when compared to infants born to mothers maintained on methadone during pregnancy, who experience a high incidence of neonatal abstinence syndrome, often requiring extensive treatment and hospitalization. Johnson, R.E., Jones, H.E., Jasinski, D.R., Svikis, D.S., Haug, N.A., Jansson, L.M., Kissin, W.B., Alpan, G., Lantz, M.E., Cone, E.J., Wilkins, D.G., Golden, A.S., Huggins, G.R. & Lester, B.M. (2001). Buprenorphine treatment of pregnant opioid-dependent women: Maternal and neonatal outcomes. Drug and Alcohol Dependence, 63, 97-103.

HIV/AIDS

In the United States, a greater percentage of women acquire HIV directly or indirectly from injecting drug use compared to men. According to the CDC (HIV/AIDS Surveillance Report, 2001; 13(1)), 40% of the cumulative AIDS cases in adult females were among injecting drug users (IDUs), whereas IDUs accounted for 30% of the cumulative AIDS cases in adult males. An additional 15.6% of AIDS cases among women, compared to 1.5% of AIDS cases among men, were associated with sex with injecting drug users. In all, AIDS cases among U.S. women are much more likely to be directly or indirectly (through sex with an IDU) related to injecting drug use as compared to men (56% vs. 31%). Among youth in the age range 13-19 years, females represent 61% of HIV infection. Among males aged 13 to 24 years, men who have sex with men represent 49% of reported AIDS cases, IDU represents 10%, and infection through heterosexual contact represents 9%. For females of that age range, infection through heterosexual contact represents 45% of reported AIDS cases and IDU represents 11%.

The gender differences in transmission of HIV clearly points to the needs for gender-specific approaches in understanding risk factors and in developing interventions. Recent NIDA research has examined factors associated with obtaining syringes from safer sources and factors associated needle sharing behavior among IDUs. Researchers also have investigated the role sexual risk behaviors in seroconversion among IDUs, the role played by alcohol on these risk behaviors, and the function of health and/or social service contacts as a protective factor for homeless IDU women. Recent NIDA studies among youth have examined gender differences in health and risk behavior among youth living with HIV, gender differences in sexual risk behavior in an urban minority population of African American youth, and the manner in which the use of various drugs by youth relates to sexual risk behaviors and network characteristics. A NIDA study aimed at HIV prevention characterized the attitudes of drug-involved women towards vaginal microbicides for the prevention of HIV and STDs, a preventive approach that could be use without the knowledge or cooperation of a male partner. And a study with important treatment implications found gender differences in the relationship between the initial viral load following HIV seroconversion and the risk of progression to AIDS.

Being Female Associated with Obtaining Needles From Only Safe Sources
Researchers at Johns Hopkins University examined factors associated with obtaining sterile syringes from a needle exchange program and other safe sources such as pharmacies or hospitals. Of the 741 Baltimore injectors recruited, 85% of participants obtained needles from street needle sellers, whereas only 8% of participants obtained their needles exclusively from safe sources. Participants who sold needles reported that it was easy to make used needles appear to be unused, and some admitted to selling used syringes as new. Being female, less frequent needle sharing and shooting gallery attendance were associated with obtaining needles from only safe sources. Latkin, C.A. & Forman, V.L. (2001). Patterns of needle acquisition and sociobehavioral correlates of needle exchange program attendance in Baltimore, Maryland, U.S.A. Journal of Acquired Immune Deficiency Syndrome, 27, 398-404.

Women IDUs at Particularly High Risk for Needle Sharing
Researchers at Johns Hopkins conducted interviews with 1,184 IDUs who participated in the Baltimore Needle Exchange Program from 1995-1997. Participants were asked on several occasions to give the initials of up to five of their closest friends, and asked whether they had injected drugs, shared syringes, had sex or consumed alcohol with each of these friends. Of the 17.1% of IDUs who reported using a syringe after someone else, 78.3% reported syringe sharing with close friends. Although syringe sharing occurred within integrated networks at a particular point in time, these friendship networks had considerable turnover, with less than 30% of the friends being repeated nominations as close-tie friends. Thus, while sharing tended to occur with strong ties, there was considerable change in the identity of these strong ties. This was particularly true for women, who reported higher sharing rates and higher sharing with strong-tie friends but only marginally less turnover in networks (30% repeated nominations in males vs. 26% in females). Valente, T.W. & Vlahov, D. (2001). Selective risk taking among needle exchange participants: Implications for supplemental interventions. American Journal of Public Health, 91(3), 406-411.

Social Networks of IDU Women May Facilitate HIV Risk
Another study at Johns Hopkins indicates gender differences in the social networks and syringe sharing among 508 IDUs in Baltimore. On average, women's overall social networks were significantly larger than men's. Approximately 40% of the members of women's and men's social networks were active and daily drug users. Importantly, however, women shared syringes with a significantly larger proportion of network members than men (25% vs. 17%, respectively). Women's larger networks with a high percentage of drug users and syringe sharing serves to increase their risk of HIV. Sherman, S.G., Latkin, C.A. & Gielan, A.C. (2001). Social factors related to syringe sharing among injecting partners: A focus on gender. Substance Use & Misuse, 36(14), 2113-2136.

Among Female IDUs, High-risk Sexual Activity a More Significant Predictor of HIV Seroconversion Than Needle-sharing Behaviors
Researchers at Johns Hopkins University followed a cohort of 1,874 HIV-negative IDUs from 1988 to 1998 in order to investigate drug-related and sexual risk factors for HIV. Incidence of HIV seroconversion did not significantly differ by sex; however, HIV risk factors differed markedly by gender. Whereas drug-related risk behaviors and homosexual activity were the most important predictors of HIV seroconversion among men, factors consistent with high-risk heterosexual activities were the main predictors among women. Male IDUs who had recently engaged in homosexual activity were more than twice as likely to seroconvert than those who did not. Among female IDUs, indicators of high-risk heterosexual activity were more significant than needle-sharing behaviors as independent predictors of HIV seroconversion. For example, among female IDUs, HIV incidence was more than double among those who reported recently having sex with another IDU. Further, incidence of HIV was double among women who reported a STD in the prior six months compared with those who did not. Strathdee, S.A., Galai, N., Safaiean, M., Celentano, D.D., Vlahov, D., Johnson, L. & Nelson, K.E. (2001). Sex differences in risk factors for HIV seroconversion among injection drug users. Archives of Internal Medicine, 161, 1281-1288.

Trading Sex for Money is Strongest Predictor of HIV Seroconversion in Women IDUs
Among 1,192 male and female street-recruited IDUs in San Francisco from 1986 to 1998, those 58 individuals who seroconverted between visits were compared to 1,134 controls who remained seronegative. The main risk factors for seroconversion among IDUs were sexual behaviors. The strongest predictor of seroconversion for men was having sex with men; men who had sex with men were 8.8 times as likely to seroconvert as heterosexual men. For female IDUs, the strongest predictor of HIV seroconversion was trading sex for money. Specifically, women who reported having traded sex for money in the past year were 5.1 times as likely as others to seroconvert. Further, women younger than 40 years of age were more likely to seroconvert than those 40 years or older, and women who reported having a steady sex partner who injected drugs were less likely to seroconvert than other women. Kral, A.H., Bluthenthal, R.N., Lorvick, J., Gee, L., Bacchetti, P. & Edlin, B.R. (2001). Sexual transmission of HIV-1 among injection drug users in San Francisco, USA: Risk-factor analysis. The Lancet, 357, 1397-1401.

Increased Alcohol Consumption Associated With Risky Sexual Behavior In Dependent Drug Users
In a study of 364 dependent drug users in an inpatient detoxification program, researchers at Boston University examined whether alcohol use is a modifier of HIV risk behaviors, specifically drug risk behavior and sexual risk behavior. Although there was no association between alcohol consumption and HIV drug risk behavior, alcohol use was associated with HIV sexual risk behavior in both male and female drug users, and sex-risk behaviors increased slightly with higher alcohol use levels. At the highest level of alcohol consumption, there was a significant difference in sex risk behaviors for men and women, suggesting that women who consume more alcohol on a daily basis are more likely to engage in sexual behavior placing them at higher risk for HIV infection than men. Rees, V., Saitz, R., Horton, N.J. & Samet, J. (2001). Association of alcohol consumption with HIV sex- and drug-risk behaviors among drug users. Journal of Substance Abuse Treatment, 21, 129-134.

Among Homeless Women, Substance Abuse Positively Associated with Injection Drug Use and Trading Sex
Researchers at the University of Pennsylvania and UCLA investigated whether homeless women with health and/or social service contacts were less likely to engage in HIV risk behaviors (e.g. intravenous drug use, trading sex for drugs or other commodities) than those without such contacts. Similar to previous research with homeless women, there was a high prevalence of HIV risk behavior activity in this sample of 974 women. In the previous year, 8% had injected drugs, 64% had engaged in unprotected sex and 20% had traded sex. A large proportion of the women screened positive for drug abuse or dependence (48%) and alcohol abuse or dependence (40%). Homeless women who were drug abusers were nearly ten times more likely to trade sex than were other homeless women, and those with alcohol dependence problems were five times more likely to inject drugs. Homeless women with a case manager were less likely than those without one to have injected drugs within the past year, but were no less likely to engage in unprotected sex or trade sex. Homeless women with substance abuse problems are especially vulnerable to HIV transmission, and efforts should be focused on providing access to more intense case management and drug treatment programs for this group. Kilbourne, A.M., Herndon, B., Andersen, R.M., Wenzel, S.L. & Gelberg, L. (2002). Psychiatric symptoms, health services, and HIV risk factors among homeless women. Journal of Health Care for the Poor and Underserved, 13(1), 49-65.

Adolescents

Gender Differences in Health and Risk Behavior Among Youth Living with HIV
Lifetime and current health practices and risk behaviors were examined among 350 youth living with HIV (YLH) aged 14-23 years in New York City, Los Angeles, San Francisco and Miami. Compared to females, males were more likely to use drugs and to be HIV symptomatic, had more lifetime and recent sexual partners, used condoms less in the past 3 months and were less likely to disclose their HIV status. Males, despite having more sexual partners and more drug use than females over their lifetimes, were nevertheless more likely than females to reduce their number of sexual partners and drug use since learning their HIV status. Youth who were recently sexually active (81.3%) had multiple partners. Most of the sexually active YLH used condoms consistently (81.6%). YLH who were symptomatic or had an AIDS diagnosis were likely to have recently had more seropositive sexual partners than the asymptomatic youth. Youth disclosed their serostatus to about half of their sexual partners (53.9%), although females, Latinos and YLH with AIDS were more likely to disclose their serostatus than were other groups. YLH with AIDS used fewer hard drugs than those without an AIDS diagnosis. Over half of males and about a third of females who had used hard drugs in their lifetime had stopped using them since learning of their HIV status. Rotheram-Borus, M.J., Lee, M., Zhou, S., O'Hara, P., Birnbaum, J.M., Swendeman, D., Wright, W., Pennbridge, J. & Wight, R.G. (2001). Variation in health and risk behavior among youth living with HIV. AIDS Education and Prevention, 13(1), 42-54.

Drug-using Youth at Substantially Higher Sex Risk for HIV, Especially Females
In order to determine how stigmatized drug use is related to sexual risk behaviors and network characteristics among youth in an inner city New York neighborhood, researchers conducted in-person interviews with both a sample of 363 household youths and a sample of 165 targeted street-recruited 18-24 year-olds who were cocaine, heroin, crack or injection drug users. Drug use in the preceding 12 months was categorized from lowest to highest social stigma as none, marijuana, noninjected cocaine, noninjected heroin, crack and injected drugs. Findings revealed that users of any drug were at substantially higher sex risk than those who use no drugs. For example, the proportion of male marijuana users who had concurrent partners was more than double that for those who used no illicit drugs. For females, the proportion was nearly quadruple. Further, users of the more stigmatized drugs had more sex partners. They were also more likely to report a history of concurrent sex partners, sex with someone who also had engaged in sex with a network member, commercial sex work and unprotected sex. Crack use and drug injection were more strongly associated with increased sex risk among females than among males. These data indicate that any drug use in this sample increased HIV sex risk and that the risk was greater for females than males, thus highlighting the need for gender-specific interventions. Flom, P.L., Friedman, S.R., Kottiri, B.J., Neaigus, A., Curtis, R., Des Jarlais, D.C., Sandoval, M. & Zenilman, J.A. (2001). Stigmatized drug use, sexual partner concurrency, and other sex risk network and behavior characteristics of 18- to 24-year old youth in a high-risk neighborhood. Sexually Transmitted Diseases, 28(10), 598-607.

Gender Differences in HIV-related Sexual Risk Behavior Among Urban African American Youth
Researchers at UCLA and the University of Michigan assessed alcohol and other drug (AOD) use during sexual encounters, sexual partner's age, perceived HIV risk and perceived condom effectiveness among 388 sexually active African American youth selected from the four public high schools in the second-largest school district in Michigan. Four risk groups were identified: low risk, monogamy strategy, condom strategy and high risk. The high-risk group included more males (61%) and the monogamy group included more females (75%). High-risk males reported more AOD use during sexual activity than all females, and low-risk or condom strategy males. Females had older partners, rated condoms as less effective and perceived lower HIV/AIDS risk than males. These results suggest different patterns of sexual activity and condom use among urban African American adolescent males and females, which may have implications for HIV prevention. Newman, P.A. & Zimmerman, M.A. (2000). Gender differences in HIV-related sexual risk behavior among urban African American youth: A multivariate approach. AIDS Education and Prevention,12(4), 308-325.

Prevention and Treatment Issues

Drug-involved Women as Potential Users of Vaginal Microbicides for HIV and STD Prevention
A study to obtain potential users' perspectives on vaginal microbicides was conducted among 743 women in Bridgeport, CT, Providence, RI, and San Juan, PR, who were at high risk for HIV, including IDUs and sexual partners of male IDUs. In order to be included in the study, the women had either used cocaine or heroin more than four times per month in the past six months, were not in inpatient drug treatment at the time of the study, or had a primary sexual partner in the past six months who was a drug injector. Ninety percent of the women said they would be very likely to use microbicides with paying partners (who paid for sex with money or drugs) and 78% would with primary partners. Even after potential product characteristics were rated as unacceptable, such as irritation or burning, women expressed a high likelihood of potential use. More than 80% of women said they would want their primary partners to know of their microbicide use and 42% said that they would want their paying partners to know. Women's concern about a paying partner's violent response to suggested use of risk reduction measures was inversely related to predicted likelihood of microbicide use. Hammett, T.M., Norton, G.D., Mason, T.H., Langenbahn, S., Mayer, K.H., Robles, R.R., Feudo, R. & Seage, G.R. (2000). Drug-involved women as potential users of vaginal microbicides for HIV and STD prevention: A three-city survey. Journal of Women's Health & Gender-Based Medicine, 9(10), 1071-1080.

Current Treatment Guidelines May Lead to Differences in Eligibility for HIV Treatment According to Sex
Research has shown that in men viral load after HIV seroconversion is a predictor of the risk of progression to AIDS, and this has led to the use of viral load as the basis for the current guidelines for the initiation of antiretroviral therapy, which are applied uniformly to men and women. Researchers at Johns Hopkins University have now prospectively compared the relation between the initial viral load following HIV seroconversion and the risk of progression to AIDS in a cohort of 46 female and 156 male IDUs. They found that the median viral load after seroconversion was significantly lower in women vs. men (15,103 vs. 50,766 copies per millimeter), but neither the rates of progression to AIDS nor the risk of progression to AIDS differed significantly according to sex. Further, the CD4+ lymphocyte counts did not differ by sex. While viral load had a similar qualitative predictive value for progression to AIDS in men vs. women, the same absolute viral load conferred different risks of AIDS in men vs. women. For example, an initial viral load of 17,149 copies per milliliter was associated with progression to AIDS in women but not in men, while the median viral load among men who did not progress to AIDS was 40,634 copies. Given the recommendation that treatment should be initiated when the viral load reaches 20,000 copies per milliliter, 74% of the men but only 37% of the women in this study would have been eligible for therapy at the first visit after seroconversion. Thus, treatment guidelines that are based on the viral load, rather than the CD4+ lymphocyte count, will lead to differences in eligibility for antiretroviral treatment according to sex. Sterling, T.R., Vlahov, D., Astemborski, J., Hoover, D.R., Margolick, J.B. & Quinn, T.C. (2001). Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. New England Journal of Medicine, 344(10), 720-725.