Director's Report to Council - Research Findings Excerpts

September, 2005

Basic Neurosciences Research

Cocaine and Development

Cocaine use during pregnancy is associated with neurobehavioral problems in school-aged children that implicate alterations in attentional processes, potentially due to impairments in the noradrenergic system. In a recent study, NIDA supported researchers report a direct, disruptive effect of cocaine on noradrenergic neurons that may provide a neurobiological basis for changes in attentional function observed, in clinical and pre-clinical investigations, in offspring exposed to cocaine in utero. In this study, rats were administered cocaine in a physiologically relevant dose during critical phases of gestation. The locus coeruleus, a brain region, was analyzed for neurite outgrowth characteristics. Results showed that cocaine inhibited locus coeruleus neurite outgrowth and development and female offspring appeared most vulnerable to such effects. Snow, D.S., Carman, H.M., Smith, J.D., Booze, R.M., Welch, M.A. and Mactutus, C.F. Cocaine-induced Inhibition of Process Outgrowth in Locus Coeruleus Neurons: Role of Gestational Exposure Period and Offspring Sex. International Journal of Developmental Neuroscience, 22(5), pp. 297-308, 2004.

Basic Behavioral Research

Inhibition of Dopaminergic and Serotonergic Reuptake during Gestation Has a Variety of Effects on Maternal Behavior in the Rat

Psychostimulants, antidepressants, anti-anxiety medications, and some antipsychotics all inhibit reuptake of one or more of the catecholmine neurotransmitters. Dr. Josephine Johns previously showed that gestational exposure to cocaine alters several aspects of maternal behavior and oxytocin levels in the rat, but it was not known whether this effect was mediated by cocaine-induced inhibition of catecholamine reuptake, or which neurotransmitters were involved. In this study, she systematically tested specific reuptake blockers of dopamine and serotonin during gestation, alone or in combination, to determine the effect of long-term reuptake inhibition on maternal behavior, postpartum aggression towards an intruder ("maternal aggression"), and oxytocin levels. Rat dams were treated throughout gestation with amfonelic acid, fluoxetine, or a combination of both at various doses, to investigate effects of reuptake inhibition of dopamine and serotonin systems, respectively. The more appetitive aspects of maternal behavior (nesting, licking, touching), and general activity of the dams, were increased by a low dose of amfonelic acid, a high dose of fluoxetine, or the high dose combination, more than other treatments. Maternal aggression was decreased by amfonelic acid and somewhat increased by fluoxetine. The results for crouching behavior were complex, but overall suggested both dopaminergic and serotonergic involvement. Dopamine uptake inhibition had a strong effect on hippocampal oxytocin levels, while receptor dynamics appeared to be more strongly affected by serotonin uptake inhibition. Dr. Johns is continuing her examination of oxytocin levels and receptor expression, which as recent studies suggest, may have a greater role in maternal care in humans than previously thought. Since pregnant women frequently take drugs (e.g. antidepressants, cocaine) that induce long-term reuptake inhibition of dopamine and/or serotonin, it is important to understand the effects of such drugs on behavior and biochemistry. The quantitative measures in this study indicate that long-term reuptake inhibition of dopamine or serotonin, or both, has specific and complex effects on different aspects of maternal behavior. The overall conclusion is that these treatments do not impair maternal behavior per se, but they alter it in a variety of ways that can further our understanding of alterations in human maternal behavior after perinatal exposure to drugs with the same mechanism of action. Johns, J.M., Joyner, P.W., McMurray, M.S., Elliott, D.L., Hofler, V.E., Middleton, C.L., Knupp, K., Greenhill, K.W., Lomas, L.M. and Walker, C.H. The Effects of Dopaminergic/serotonergic Reuptake Inhibition on Maternal Behavior, Maternal Aggression, and Oxytocin in the Rat. Pharmacology, Biochemistry and Behavior, 81, pp. 769-785, 2005.

Preclinical "Binge" Model of Inhalant Abuse for Studying Prenatal Exposure Effects

Dr. Scott Bowen at Wayne State University has developed a binge model for exposing animals to abused inhalants. In his static exposure chambers, animals receive high concentrations of solvents over relatively brief exposure periods, mimicking the typical pattern of solvent abuse in humans. Previous exposure paradigms have employed long-term, relatively low levels of inhalant treatment, but with this model, the investigator attempts to produce repeated and rapidly resolved high-peak blood solvent concentrations. Recently he has used this procedure to study the teratogenic impact of toluene exposure during gestational days eight through 20 in the rat. Solvent abuse in adolescent females of childbearing age is a concern because rates of first-time solvent use among young people between 18 and 25 rose 243% during the 1990s and toluene-related embryopathy and malformations have been reported, with high levels of exposure linked to gross morphological teratogenicity. Moreover, follow-up evaluations reveal developmental delays and language impairment, among other neurological pathologies, and retardation in physical growth. In the present study, timed-pregnant females were exposed twice per day for 15 min to either 8000 (L) or 12,000 (H) ppm toluene. There was also an "air-only" control group (C) that was placed in the chambers twice daily for an equal amount of time. Pups were assessed on measures of early neonatal growth, perinatal outcome, and neurobehavioral development. From whole litter assessments of reflex development, strength and motor coordination, the investigators note a greater number of weaker pups in the highest dose group on post-natal (PN) day 16 (i.e., close to half the animals from the H group were at or below the 25th percentile of the C group). There were also significant effects of solvent exposure on negative geotaxis, with longer latencies for both concentration groups on PN days 6-8. On PN1, H litters weighed significantly less than the other two groups. However, between PN12-21, H pups gained relatively more weight than control animals, showing "catch up" growth. The authors also observed a dose relationship for gross malformations, external soft tissue malformations, number of pups classified as "runts", and neonatal mortality: The percentage of litters affected by these three kinds of outcomes was 12.5, 29.4 and 52.9 for the CF, L and H exposure conditions, respectively. These differences were seen with similar maternal weights and maternal weight gains across the three groups. There were also no significant between group differences in total litter size or mean gestational length. It appears that this procedure, using high dose, binge exposure conditions, may better reproduce the key pharmacodynamic features of inhalant abuse in humans and provide a more valid characterization of toluene embryopathy than studies employing longer, lower dose exposure. Bowen, S.E., Batis, J.C., Mohammadi, M.H. and Hannigan, J.H. Abuse Pattern of Gestational Toluene Exposure and Early Postnatal Development in Rats. Neurotoxicology and Teratology, 27, pp. 105-116, 2005.

Decreased Motivation to Obtain Cocaine Following Extended Access: Effects of Sex and Ovarian Hormones

As described in the September 2004 Director's Report to Council, Drs. Wendy Lynch and Jane Taylor reported sex differences in cocaine self-administration (1.5 mg/kg/infusion) under a 24-hour access procedure in which rats received four 10-min discrete trials per hour for seven days -- a procedure which produces escalation of cocaine intake in a binge-abstinence pattern. Drs. Lynch and Taylor found that compared to males, females self-administered more cocaine, self-administered for longer periods of time, and exhibited greater disruption in the diurnal control over cocaine intake. In an assessment of long-term changes in cocaine motivation, conducted following a 10-day forced abstinence period, females exhibited an increase in motivation for cocaine as measured by behavior under a progressive ratio schedule, whereas males did not. (Lynch, W.J. and Tavlor, J.R. Sex Differences in the Behavioral Effects of 24-hr Access to Cocaine Under a Discrete Trial Procedure. Neuropsychopharmacology, 29, pp. 943-951, 2004). In a recent follow-up study, these researchers examined more immediate changes in cocaine motivation by testing 1, 2, and 3 days following the 7-day discrete trial procedure. Whereas males showed no change in cocaine motivation over the three test days, as assessed by progressive ratio performance, females exhibited a marked reduction in motivation. By comparing ovariectomized females with and without estrogen replacement, the researchers found that estrogen modulated the motivation for cocaine. Taken together, these two studies indicate that at 1, 2, 3, and 10 days following seven days of high access to cocaine, males exhibit no change in cocaine motivation, whereas females exhibit a reduction at 1, 2, and 3 days, and an increase at 10 days. These outcomes, along with earlier research using variations of the 24-hr discrete trials procedure with only male rats, illustrate male-female differences in the development and time course of cocaine motivation during and following extended access to cocaine. These data add to a growing body of human and animal literature indicating sex differences in cocaine addiction. Lynch, W.J. and Taylor, J.R. Decreased Motivation Following Cocaine Self-administration Under Extended Access Conditions: Effects of Sex and Ovarian Hormones. Neuropsychopharmacology, 30, pp. 927-935, 2005.

Behavioral and Brain Development Research

Prenatal Tobacco Exposure and Offspring Smoking in Early Adolescence

In this prospective study of a birth cohort of 567 14-year-olds, investigators at the University of Pittsburgh examined relationships among trimester-specific prenatal tobacco exposure (PTE), offspring smoking, and other correlates of adolescent smoking. Average age of the adolescents was 14.8 years (range: 13.9-16.6 years). Approximately half of the sample was female, and about half was African-American. Data on maternal tobacco and other substance use were collected both prenatally and postnatally. Fifty-one percent of the mothers were prenatal smokers and 53% smoked when their children were 14 years old. PTE in the third trimester significantly predicted offspring smoking (ever/never, smoking level, age of onset) when demographic and other prenatal substances were included in the analyses. PTE remained a significant predictor of the level of adolescent smoking when maternal and child psychological characteristics were added to the model. When more proximal measures of the child's smoking were included in the model, including mother's current smoking and friends' smoking, PTE was no longer significant. Significant predictors of adolescent smoking at age 14 were female gender, Caucasian race, child externalizing behavior, maternal anxiety, and child depressive symptoms. The authors conclude that although direct effects of PTE on offspring smoking behavior have previously been reported from this study and by others, by early-adolescence, this association was not significant in this sample after controlling for the more proximal covariates of adolescent smoking such as mother's current smoking and peer smoking. They also note that many of the reports in the literature that indicate a relationship between PTE and offspring smoking have been retrospective or have not included important variables such as other prenatal substance exposures, maternal and child psycho-social characteristics, mother's current smoking, and friends' smoking. Cornelius, M.D., Leech, S.L., Goldschmidt, L. and Day, N.L. Is Prenatal Tobacco Exposure a Risk Factor for Early Adolescent Smoking? Neurotoxicology and Teratology, 27, pp. 667-676, 2005.

School Performance of Children with Gestational Cocaine Exposure

Researchers from the University of Pennsylvania have reported results on school performance in a sample of children exposed to cocaine in utero. At the completion of fourth grade, a total of 135 children (62 with gestational cocaine exposure and 73 without) who were enrolled at birth and followed prospectively, were evaluated using report card data, standardized test results, teacher and parent report, and natal and early childhood data. Successful grade progression was defined as completing grades 1 through 4 without being retained. Cocaine-exposed and control children were similar in school performance (all p>=0.10): successful grade progression (71% cocaine-exposed vs. 84% control), Grade Point Average (2.4+/-0.8 vs. 2.6+/-0.7), reading below grade level (30% vs. 28%), and standardized test scores below average (reading [32% vs. 35%], math [57% vs. 44%], science [39% vs. 36%]). Children with successful progression, regardless of cocaine exposure, had higher Full Scale IQ and better home environments. The researchers conclude that in this inner-city cohort, cocaine-exposed and control children had similar poor school performance, with better home environment and higher Intelligence Quotient associated with an advantage for successful grade progression, regardless of gestational cocaine exposure. Hurt, H., Brodsky, N.L., Roth, H., et al. School Performance of Children with Gestational Cocaine Exposure. Neurotoxicology and Teratology, 27, pp. 23-211, 2005.

Prenatal Drug Exposure and Selective Attention in Preschoolers

Based on research conducted at Case Western Reserve University, a recent report focused on selective attention in a large, polysubstance cocaine-exposed cohort of 4-year-olds and their at-risk comparison group. Maternal pregnancy use of cocaine and use of cigarettes were both associated with increased commission errors, interpreted as indicative of inferior selective attention. Severity of maternal use of marijuana during pregnancy was positively correlated with omission errors, suggesting impaired sustained attention. Substance exposure effects were independent of maternal postpartum psychological distress, birth mother cognitive functioning, current caregiver functioning, other substance exposures, and child concurrent verbal IQ. Noland, J.S., Singer, L.T., Short, E.J., et al. Prenatal Drug Exposure and Selective Attention in Preschoolers. Neurotoxicology and Teratology, 27, pp. 429-438, 2005.

Relative Ability of Biologic Specimens and Interviews to Detect Prenatal Cocaine Exposure

University of Florida researchers recruited women in a labor and delivery service, enrolling all consenting patients with a history of prenatal cocaine use and the next admission with no recorded use. During the immediate postpartum period, private, structured interviews were carried out to obtain details of prenatal cocaine use and to identify a priori exclusion criteria (other illicit drug use, high alcohol use and chronic illnesses and medications). Amniotic fluid, cord blood, infant urine, meconium, and maternal hair were also collected. All specimens were blindly analyzed with respect to exposure, using gas chromatography/mass spectrometry. Of 115 subjects, 46 had one or more biologic specimens positive for cocaine metabolites and five admitted prenatal use, but had negative specimens. Of these 51 identified as users by any method, 38 admitted, 32 were positive for urine, 28 for hair, and 25 for meconium. Of the 38 admitters, 87% had positive specimens. Of the 77 denying use, 17% were positive. Urine was most frequently positive in identified users, 67% overall and 62% of users who denied. Hair was next, positive in 65% of all users and 50% of users who denied. Of the 13 subjects who denied use but were positive on at least one specimen, four were identified solely by urine, two only by hair and one only by meconium. Self-report identified five users with all negative specimens. The authors conclude that although no one method identified all users, the single method that maximally identified users was detailed history taken by experienced interviewers. Eyler, F.D., Behnke, M., Wobie, K., Garvan, C.W. and Tebbett, I. Relative Ability of Biologic Specimens and Interviews to Detect Prenatal Cocaine Use. Neurotoxicology and Teratology, 27, pp. 677-687, 2005.

Clinical Neuroscience Research

Enlarged Striatum in Abstinent Methamphetamine Abusers: A Possible Compensatory Response

Since so little is known about structural brain abnormalities associated with methamphetamine (METH) abuse, Dr. Linda Chang and colleagues at University of Hawaii evaluated METH-dependent subjects for possible morphometric changes. They focused on the striatum of recently abstinent METH abusers, to determine whether morphometric changes, if any, were related to cognitive performance, and to evaluate if there might be sex-by-METH interactions on morphometry. Structural MRI was performed in 50 METH and 50 comparison subjects with age range and gender controlled. Quantitative morphometric analyses were performed in the subcortical gray matter, cerebellum and corpus callosum (CC). Neuropsychological tests were also performed in 44 METH and 28 comparison subjects. All METH users, regardless of gender, showed an enlarged putamen and GP when compared to controls. Additionally, female METH users displayed a larger mid-posterior CC. Although METH users had normal cognitive function, those with smaller striatal structures reported greater cumulative METH usage and had poorer cognitive performance. Since METH subjects with less cumulative METH usage had larger striatal structures and had relatively normal cognitive performance, the enlarged putamen and GP might represent a compensatory response to maintain function. Possible mechanisms for the striatal enlargement include glial activation and inflammatory changes associated with METH-induced injury. Chang, L., Cloak, C., Patterson, K., Grob, C., Miller, E.N. and Ernst, T. Biol Psychiatry, 157, pp. 967-974, 2005.

Significant Association of the 4 Subunit of the Nicotine Acetylcholine Receptor with Nicotine Dependence

M.D. Li and colleagues studied over 2000 subjects from more than 600 families with three measures of smoking severity (heaviness, quantity, and dependence) and demonstrated association with at least two (of six studied) single nucleotide polymorphisms (SNPs). However, different SNPs were associated in different ethnic groups (African Americans and European Americans). Furthermore, in female African Americans on SNP was significantly associated with all three nicotine dependence measures. The 2 subunit of the nACHR gene was also examined but no association was found. This study is believed to be the first to confirm a genetic role of the CHRNA4 gene, separately in African and European American samples as well as indicate that such an association may be sex-specific as well. Li, M.D., Beuten, J., Ma, J.Z., Payne, T.J., Lou, X.-Y., Garcia, V., Duenes, A.S., Crews, K.M. and Elston, R.C. Human Molecular Genetics, 14, pp. 1211-1219, 2005.

Body Mass Predicts Orbitofrontal Activity during Visual Presentations of High-Calorie Foods

Yurgelun-Todd and colleagues at McLean Hospital used BOLD fMRI to investigate the relationship between weight status and reward-related brain activity in normal weight humans. Orbitofrontal and anterior cingulate cortex activity as measured by fMRI in 13 healthy, normal-weight adult women as they viewed images of high-calorie and low-calorie foods, and dining-related utensils. Body mass index correlated negatively with both cingulate and orbitofrontal activity during high-calorie viewing, negatively with orbitofrontal activity during low-calorie viewing, and positively with orbitofrontal activity during presentations of nonedible utensils. With greater body mass, activity was reduced in brain regions important for evaluating and modifying learned stimulus-reward associations, suggesting a relationship between weight status and responsiveness of the orbitofrontal cortex to rewarding food images. Killgore, W.D.S. and Yurgelun-Todd, D.A. Neuroreport, 16, pp. 859-863, 2005.

Epidemiological Risk Estimates of Cocaine Dependence for the United States, 2000-2001

This paper presents new estimates for the risk of becoming cocaine dependent within 24 months after first use of the drug, and study subgroup variation in this risk. The study estimates are based on the National Household Survey on Drug Abuse conducted during 2000-2001, with a representative sample of U.S. residents aged 12 years and older (n = 114,241). A total of 1081 respondents were found to have used cocaine for the first time within 24 months prior to assessment. Between 5 and 6% of these recent-onset users had become cocaine dependent since onset of use. Excess risk of recent cocaine dependence soon after onset of cocaine use was found for female subjects, young adults aged 21-25 years, and non-Hispanic Black/African-Americans. The use of crack-cocaine and taking cocaine by injection was associated with having become cocaine dependent soon after onset of use. These epidemiologic findings help to quantify the continuing public health burden associated with new onsets of cocaine use in the 21st century. O'Brien, M.S. and Anthony, J.C. Risk of Becoming Cocaine Dependent, Epidemiological Estimates for the United States, 2000-2001. Neuropsychopharmacology, 30, pp. 1006-1018, 2005.

Early Violent Death among Delinquent Youth

This study compared mortality rates for delinquent youth with those for the general population, controlling for differences in gender, race/ethnicity, and age. This prospective longitudinal study examined mortality rates among 1829 youth (1172 male and 657 female) enrolled in the Northwestern Juvenile Project, a study of health needs and outcomes of delinquent youth. Participants, 10 to 18 years of age, were sampled randomly from intake at the Cook County Juvenile Temporary Detention Center in Chicago, Illinois, between 1995 and 1998. The sample was stratified according to gender, race/ethnicity (African American, non-Hispanic white, Hispanic, or other), age (10-13 or >= 14 years), and legal status (processed as a juvenile or as an adult), to obtain enough participants for examination of key subgroups. The sample included 1005 African American (54.9%), 296 non-Hispanic white (16.2%), 524 Hispanic (28.17%), and 4 other-race/ethnicity (0.2%) subjects. Data on deaths and causes of death were obtained from family reports or records and were then verified by the local medical examiner or the National Death Index. For comparisons of mortality rates for delinquents and the general population, all data were weighted according to the racial/ethnic, gender, and age characteristics of the detention center, these weighted standardized populations were used to calculate reported percentages and mortality ratios. Mortality ratios were calculated by comparing the sample's mortality rates with those for the general population of Cook County, controlling for differences in gender, race/ethnicity, and age. Results indicated that sixty-five youth died during the follow-up period. All deaths were from external causes. As determined by using the weighted percentages to estimate causes of death, 95.5% of deaths were homicides or legal interventions (90.1% homicides and 5.4% legal interventions), 1.1% of all deaths were suicides, 1.3% were from motor vehicle accidents, 0.5% were from other accidents, and 1.6% were from other external causes. Among homicides, 93.0% were from gunshot wounds. The overall mortality rate was greater than 4 times the general-population rate. The mortality rate among female youth was nearly 8 times the general-population rate. African American male youth had the highest mortality rate (887 deaths per 100 000 person-years). These findings indicate that early violent death among delinquent and general-population youth affects racial/ethnic minorities disproportionately and should be addressed, as are other health disparities. Future studies should identify the most promising modifiable risk factors and preventive interventions, explore the causes of death among delinquent female youth, and examine whether minority youth express suicidal intent by putting themselves at risk for homicide. Teplin, L.A., McClelland, G.M., Abram, K.M., and Mileusnic, D. Early Violent Death among Delinquent Youth: A Prospective Longitudinal Study. Pediatrics, 115, pp. 1586-1593, 2005.

Gender/Racial Differences in "Jock" Identity, Dating, and Adolescent Sexual Risk

Despite recent declines in overall sexual activity, sexual risk-taking remains a substantial danger to US youth. Existing research points to athletic participation as a promising venue for reducing these risks. Linear regressions and multiple analyses of covariance were performed on a longitudinal sample of nearly 600 Western New York adolescents in order to examine gender- and race-specific relationships between "jock" identity and adolescent sexual risk-taking, including age of sexual onset, past-year and lifetime frequency of sexual intercourse, and number of sexual partners. After controlling for age, race, socioeconomic status, and family cohesion, male jocks reported more frequent dating than nonjocks but female jocks did not. For both genders, athletic activity was associated with lower levels of sexual risk-taking, however, jock identity was associated with higher levels of sexual risk-taking, particularly among African American adolescents. Future research should distinguish between subjective and objective dimensions of athletic involvement as factors in adolescent sexual risk. Miller, K.E., Farrell, M.P., Barnes, G.M., Melnick, M.J. and Sabo, D. Gender/racial Differences in Jock Identity, Dating, and Adolescent Sexual Risk. Journal of Youth and Adolescence, 34, pp. 123-136, 2005.

Nicotine Phenotypes based on Withdrawal Discomfort, Response to Smoking, and Ability to Abstain

Smoking is often viewed as a comprehensive phenotype rather than a complex set of traits involving intermediate phenotypes. To explore this issue in a laboratory setting, researchers tested 69 smokers stratified on depression, nicotine dependence, and gender. On the third day of an initial withdrawal period, participants were tested for differences in uncued and cued craving and withdrawal. On the fourth day, participants were exposed to a controlled dose of smoke and assessed for physiological and hedonic effects and reduction of craving and withdrawal. Following resumption of smoking for at least a week, participants were then tested on their ability to abstain for an 11-day interval. During the withdrawal test, high-depressed smokers and men exhibited elevated craving and withdrawal scores overall, whereas no differences emerged for dependence. Cue exposure produced significant increases in craving but not withdrawal. During the smoke-exposure test, men were significantly more likely than women, and high-depressed smokers more likely than low-depressed smokers, to show evidence of experiencing pleasurable "buzzes." High-dependent smokers showed significant increases in diastolic blood pressure, possibly suggestive of greater sensitivity to nicotine. During the quit test, high-dependent smokers had more difficulty abstaining than low-dependent smokers, and women more than men, no differences emerged based on depression. Independently of group membership, inability to abstain was predicted by increased anxiety, depression, and difficulty concentrating in response to cue exposure. These findings provide support for the existence of phenotypes that can be distinguished by withdrawal symptomatology (primarily driven by depression) and ability to remain abstinent (primarily driven by dependence). Pomerleau, O.F., Pomerleau, C.S., Mehringer, A.M., Snedecor, S.M., Ninowski, R. and Sen, A. Nicotine Dependence, Depression, and Gender: Characterizing Phenotypes Based On Withdrawal Discomfort, Response to Smoking and Ability to Abstain. Nicotine & Tobacco Research, 7, pp. 91-102, 2005.

Timing of Entry into Fatherhood in Young, At-Risk Men

The timing of first fatherhood was examined in a sample of 206 at-risk, predominantly White men, followed prospectively for 17 years. An event history analysis was used to test a model wherein antisocial behavior, the contextual and familial factors that may contribute to the development of antisocial behavior, and common correlates of such behavior, including academic failure, substance use, and early initiation of sexual behaviors, lead both directly and indirectly to an early transition to fatherhood. Having a mother who was younger at first birth, low family socioeconomic status, poor academic skills, failure to use condoms, and being in a cohabitating or marital relationship predicted entry into fatherhood. Pears, K.C., Pierce, S.L., Kim, H.K., Capaldi, D.M. and Owen, L.D. The Timing of Entry into Fatherhood in Young, At-risk Men. Journal of Marriage and the Family, 67, pp. 429-447, 2005.

Personality Factors Contributing to Comorbidity

The authors investigated the role of personality traits in accounting for comorbidity in common psychiatric and substance use disorders. 7588 participants in a population-based twin registry in Virginia were interviewed with the SCID to determine lifetime diagnoses of common psychiatric and substance use disorders, and completed self-report questionnaires to determine dimensions of neuroticism, extraversion, and novelty seeking. Of note, neuroticism accounted for the highest proportion of comorbidity within internalizing (mood and anxiety) disorders (20-45%) and between internalizing and externalizing (antisocial and substance use) disorders (19-88%). Variation in neuroticism and novelty seeking each accounted for a modest proportion (10-12% and 7-14%, respectively) of the comorbidity within externalizing disorders. Extraversion contributed negligibly. Although rates of disorders differed among the genders, the patterns of comorbidity accounted for by personality were similar in males and females. These findings extend previous research on personality and psychiatric disorder by using a population-based sample and by quantifying the proportion of comorbidity explained by personality dimension. Given that comorbidity among psychiatric and substance use disorders is extremely common, these findings can help refine our understanding of those underlying traits that put individuals at risk for multiple later disorders, regardless of gender, particularly the role of neuroticism. Khan, A.A., Jacobson, K.C., Gardner, C.O., Prescott, C.A. and Kendler, K.S. Personality and Comorbidity of Common Psychiatric Disorders. British Journal of Psychiatry, 186, pp. 190-196, 2005.

Association of Early Adolescent Problem Behavior with Adult Psychopathology

The authors investigated whether the association between adolescent problem behavior and adult substance use and mental health disorders was general, such that adolescent problem behavior elevates the risk for a variety of adult disorders, or outcome-specific, such that each problem behavior is associated specifically with an increased risk for disorders clinically linked to that behavior (e.g., early alcohol use with adult alcohol abuse). A population-based group of 578 male and 674 female twins reported whether they had ever engaged in, and the age of initiation of, five adolescent problem behaviors: smoking, alcohol use, illicit drug use, police trouble, and sexual intercourse. Participants also completed a structured clinical interview at both ages 17 and 20 covering substance use disorders, major depressive disorder, and antisocial personality disorder. Each problem behavior was significantly related with each clinical diagnosis. The association was especially marked for those who had engaged in multiple problem behaviors before age 15. Among those with four or more problem behaviors before age 15, the lifetime rates of substance use disorders, antisocial personality disorder, and major depressive disorder exceeded 90%, 90%, and 30% in males and 60%, 35%, and 55% in females, respectively. The association between the clinical diagnoses and adolescent problem behavior was largely accounted for by two highly correlated factors. This study suggests that early adolescent problem behavior identifies a subset of youth who are at an especially high and generalized risk for developing adult psychopathology. McGue, M. and Iacono, W.G. The Association Of Early Adolescent Problem Behavior With Adult Psychopathology. American Journal of Psychiatry, 162(6), pp. 1118-1124, 2005.

Child Psychopathology and Early Substance Use

This study examined the relationships between childhood externalizing and internalizing disorders and early substance use and abuse, in a large community-based sample of twins of both genders, at ages 11 and 14. The sample was composed of twins participating in the Minnesota Twin Family Study, an epidemiological sample of twins and their families representative of the largely-Caucasian population of Minnesota. A total of 699 twin girls and 665 twin boys participated at both time-points. Twins participated in in-person, life-time diagnostic assessments of the following childhood DSM III-R externalizing and internalizing disorders at age 11: conduct disorder, oppositional defiant disorder, attention deficit hyperactivity disorder, major depressive disorder and in addition, for girls only, overanxious disorder and separation anxiety disorder. At ages 11 and 14, substance use and abuse were assessed. Consistent with the literature, externalizing disorders at age 11, particularly conduct and oppositional disorders, were related to substance use and abuse in both boys and girls, at ages 11 and 14. Among the internalizing disorders, only major depression among girls at age 11 showed a relationship to substance use and abuse at age 14. These findings can help refine populations that may benefit from interventions for early substance abuse. King, S.M., Iacono, W.G. and McGue, M. Childhood Externalizing and Internalizing Psychopathology in the Prediction of Early Substance Use. Addiction, 99, pp. 1548-1559, 2004.

Heritability of Cigarette Smoking and Family Dysfunction in Women

Previous studies using adoption samples have found that the impact of genetic risk factors on alcoholism in women have a stronger influence when there is a history of conflict in the family. The authors of this study investigated a similar impact on cigarette smoking in a population-based twin sample. A sample of 1676 female twins from a population-based registry provided data on maximum lifetime cigarette smoking and family dysfunction assessed as the mean report of up to four informants (twin, co-twin, mother, father). Using a variety of statistical approaches and models, the hypothesis was not confirmed; on the contrary, the heritability (proportion of variance due to genetic factors) of cigarette smoking was reduced at higher levels of family dysfunction, and unique environmental factors became more significant. Further work, with different populations and substances, is needed; in the meantime, the authors caution against a broad assumption that adverse childhood environments always increase heritability. Kendler, K.S., Aggen, S.H., Prescott, C.A., Jacobson, K.C. and Neale, M.C. Level of Family Dysfunction and Genetic Influences on Smoking in Women. Psychological Medicine, 34, pp. 1263-1269, 2004.

Partitioning Common and Specific Influences on Drug Use and Abuse

Previous studies of the genetic epidemiology of drug abuse have generally modeled drug use and drug abuse and dependence separately. However, the authors of this paper note that drug use disorders are contingent on drug use (one cannot develop the disorder without first using the drug) and so they apply a model that can partition the genetic and environmental influences into those that are common to both stages and those that are stage-specific. Using the SCID, data on use and abuse/dependence of cannabis, cocaine, sedatives, stimulants and any illicit drug were obtained from 1191 male and 934 female Caucasian twin pairs in the Mid-Atlantic Twin Registry. Results provide evidence for both genetic, shared environmental and unique environmental influences that are common to illicit drug use and abuse/dependence, and factors that are specific to abuse/dependence. Similarities among different types of drugs and between both sexes were noted in the patterns of risk influences. Thus, it is likely that there are some genetic and environmental factors that influence both drug use and abuse/dependence regardless of the drugs used or gender of the user, and that there are other factors that operate specifically to predispose to abuse and dependence once use has onset. Agrawal, A., Neale, M.C., Jacobson, K.C., Prescott, C.A. and Kendler, KS. Illicit Drug Use and Abuse/Dependence: Modeling of Two-Stage Variables Using the CCC Approach. Addictive Behaviors, 30(5), pp. 1043-1048, 2005.

Attitudes of Emergency Medical Service Providers Towards Naloxone Distribution Programs

Training and distributing naloxone to drug users is a promising method for reducing deaths associated with heroin overdose. Emergency Medical Service (EMS) providers have experience responding to overdose, administering naloxone, and performing clinical management of the patient. Little is known about the attitudes of EMS providers toward training drug users to use naloxone. An anonymous survey was conducted of 327 EMS providers to assess their attitudes toward a pilot naloxone program. Of 176 who completed the survey, the majority were male (79%) and Caucasian (75%). The average number of years working as an EMS provider was 7 (SD = 6). Overall attitudes toward training drug users to administer naloxone were negative, with 56% responding that this training would not be effective in reducing overdose deaths. Differences in attitudes did not vary by gender, level of training, or age. Providers with greater number of years working in EMS were more likely to view naloxone trainings as effective in reducing overdose death. Provider concerns included drug users' inability to properly administer the drug, program condoning and promoting drug use, and unsafe disposal of used needles. The study concludes that incorporating information about substance abuse and harm reduction approaches in continuing education classes may improve the attitudes of providers toward naloxone training programs. Tobin, K., Gaasch, W., Clarke, C., MacKenzie, E. and Latkin, C. Attitudes of Emergency Medical Service Providers Towards Naloxone Distribution Programs. J Urban Health, 82(2), pp. 296-302, 2005.

The Effect of Serostatus on HIV Risk Behavior Change Among Women Sex Workers in Miami, Florida

HIV prevention and risk reduction are especially salient and timely issues for women, particularly among those who are drug-involved or who exchange sex for drugs or money. Studies suggest that HIV-prevention measures can be effective with highly vulnerable women, and have the potential to produce significant reductions in risk behaviors among both HIV-negative and HIV-positive women. Within this context, this paper examines risk behaviors and HIV serostatus among 407 drug-involved women sex workers in Miami, Florida, and investigates the effects of participation in HIV testing, counseling, and a risk-reduction intervention on subsequent behavioral change among this population. Overall, at follow-up, the HIV-positive women were 2.4 times more likely than the HIV-negative women to have entered residential treatment for drug abuse, 2.2 times more likely to have decreased the number of their sex partners, 1.9 times more likely to have decreased the frequency of unprotected sex, 1.9 times more likely to have reduced their levels of alcohol use, and 2.3 time more likely to have decreased their crack use. These data support the importance of HIV testing and risk-reduction programs for drug-involved women sex workers. Inciardi, J., Surratt, H., Kurtz, S. and Weaver, J. The Effect of Serostatus on HIV Risk Behavior Change Among Women Sex Workers in Miami, Florida. AIDS Care, 17 (Supplement 1): S88-S101, June 2005.

Predictors of High Rates of Suicidal Ideation Among Drug Users

Several studies have attempted to understand the link among substance abuse, depression, and suicidal ideation (SI). Assessment of this link is important to develop specific interventions for persons in substance abuse treatment. This association was tested among 990 drug users in and out of treatment with significant criminal justice histories from two NIDA-sponsored studies. The Diagnostic Interview Schedule and Substance Abuse Module assessed DSM-III-R depression, number of depression criteria met, antisocial personality disorder (ASPD), and substance use disorders. Compared with men, women were twice as likely to report depression (24% vs. 12%), whereas men were nearly twice as likely to report ASPD (42% vs. 24%). High rates of SI were found, with women more likely than men to report thoughts of death (50% vs. 31%), wanting to die (39% vs. 21%), thoughts of committing suicide (47% vs. 33%), or attempting suicide (33% vs. 11%); 63% of women and 47% of men reported at least one of these suicidal thoughts or behaviors. Male and female ideators were more likely than nonideators to report depressed mood and to meet criteria for depression, ASPD, and alcohol use disorders. Male ideators were more likely than male nonideators to meet criteria for cocaine use disorders. Using logistic regression, SI among men was predicted by alcohol use disorder (OR - 1.60), ASPD (OR - 1.59), and number of depression criteria (OR _ 9.38 for five criteria). Among women, SI was predicted by older age, marital status, alcohol use disorder (OR - 2.77), and number of depression criteria (OR - 9.12 for five criteria). These original findings point out the need to discuss suicidal thoughts among depressed drug users for early treatment and prevention. Cottler, L., Campbell, W., Krishna, V., Cunningham-Williams, R. and Abdallah, A. Predictors of High Rates of Suicidal Ideation Among Drug Users. J Nerv Ment Dis,193, pp. 431-437, 2005.

Barriers to Health and Social Services for Street-Based Sex Workers

Homelessness, poverty, drug abuse and violent victimization faced by street-based women sex workers create needs for a variety of health and social services, yet simultaneously serve as barriers to accessing these very services. Researchers utilized interview (n = 586) and focus group (n = 25) data to examine the service needs and associated barriers to access among women sex workers in Miami, Florida. Women most often reported acute service needs for shelter, fresh water, transportation, crisis intervention, and drug detoxification, as well as long-term needs for mental and physical health care, drug treatment, and legal and employment services. Barriers included both structural (e.g., program target population, travel costs, office hours, and social stigma) and individual (e.g., drug use, mental stability, and fear) factors. Bridging these gaps is tremendously important from a public health perspective given the disease burden among this population. The findings support additional efforts to improve service staff training and outreach and to reduce marginalization and stigma in this population through peer education, empowerment, and accessing care and treatment. Kurtz, S., Surratt, H., Kiley, M. and Inciardi, J. Barriers to Health and Social Services for Street-Based Sex Workers. J Health Care for the Poor and Underserved, 16, pp. 345-361, 2005.

The Social Structural Production of HIV Risk among IDUs

In this paper, researchers discuss the increasing appreciation for and need to understand how social and structural factors shape HIV risk. Drawing on a review of recently published literature, they describe the social structural production of HIV risk associated with injecting drug use. They use an inclusive definition of the HIV 'risk environment' as the space, whether social or physical, in which a variety of factors exogenous to the individual interact to increase vulnerability to HIV. Factors identified as critical in the social structural production of HIV risk associated with drug injecting include cross-border trade and transport links; population movement and mixing; urban or neighborhood deprivation and disadvantage; specific injecting environments (including shooting galleries and prisons); the role of peer groups and social networks; the relevance of 'social capital' at the level of networks, communities and neighborhoods; the role of macro-social change and political or economic transition; political, social and economic inequities in relation to ethnicity, gender and sexuality; the role of social stigma and discrimination in reproducing inequity and vulnerability; the role of policies, laws and policing; and the role of complex emergencies such as armed conflict and natural disasters. The researchers argue that the HIV risk environment is a product of interplay in which social and structural factors intermingle but where political-economic factors may play a predominant role; moreover, 'structural HIV prevention' implies community actions and structural changes within a broad framework concerned to alleviate inequity in health, welfare and human rights. Rhodes, T., Singer, M., Bourgois, P., Friedman, S. and Strathdee, S. The Social Structural Production of HIV Risk among IDUs. Social Science and Medicine, 61, pp. 1026-1044, 2005.

Herpes Simplex Virus 2 and Syphilis Among Young Drug Users in Baltimore, Maryland

To examine the sex specific seroprevalence and correlates of herpes simplex virus 2 (HSV-2) and syphilis among a cohort of young drug users, researchers recruited drug users aged 15-30 years old who used heroin, cocaine, or crack between October 1999 and August 2002. Baseline interviews gathered information on socio-demographics, drug use and sexual behaviors. Serum was tested at baseline for HSV-2 and syphilis seroreactivity. For each sexually transmitted infection (STI), infected and non-infected participants were stratified by sex and compared using x2, Mann-Whitney tests, and logistic regression. The study found that, of the 543 participants recruited, 42.4% were female and 39.3% were African-American. The seroprevalence of STIs among females and males, respectively, were HSV-2: 58.7% and 22.0%; syphilis: 4.3% and 0.3%. In multivariate models, older age, African-American race, having over 30 lifetime sex partners, current HIV infection and previous incarceration were independently associated with HSV-2 infection among males. For females, older age, African-American race, sex trade, and daily heroin use were independently associated with HSV-2. For females, only a self reported previous syphilis diagnosis was associated with current syphilis seroreactivity in multivariate analyses. Examination of this cohort revealed a particularly high seroprevalence of HSV-2 and syphilis, especially among female drug users. Few infected participants had been previously diagnosed with these infections. Plitt, S., Sherman, S., Strathdee, S. and Taha, T. Herpes Simplex Virus 2 and Syphilis Among Young Drug Users in Baltimore, Maryland. Sex Transm Inf., 81, pp. 248-253, 2005.

The Relationship Between College Fraternity/Sorority Membership and Substance Use

Nationally representative probability samples of US high school seniors (modal age 18 years) were followed longitudinally across two follow-up waves during college (modal ages 19/20 and 21/22). The longitudinal sample consisted of 10 cohorts (senior years of 1988 97) made up of 5883 full-time undergraduate students, of whom 58% were women and 17% were active members of fraternities or sororities. Analysis of the longitudinal data revealed that active members of fraternities and sororities had higher levels of heavy episodic drinking, annual marijuana use and current cigarette smoking than non-members at all three waves. Although members of fraternities reported higher levels than non-members of annual illicit drug use other than marijuana, no such differences existed between sorority members and non-members. Heavy episodic drinking and annual marijuana use increased significantly with age among members of fraternities or sororities relative to non-members, but there were no such differential changes for current cigarette use or annual illicit drug use other than marijuana. These findings indicate that the higher rates of substance use among US college students who join fraternities and sororities predate their college attendance, and that membership in a fraternity or sorority is associated with considerably greater than average increases in heavy episodic drinking and annual marijuana use during college. These findings have important implications for prevention and intervention efforts aimed toward college students, especially members of fraternities and sororities. McCabe, S.E., Schulenberg, J.E., Johnston, L.D., O'Malley, P.M., Backman, J.G. and Kloska, D.D. Selection and Socialization Effects of Fraternities and Sororities on US College Student Substance Use: A Multi-cohort National Longitudinal Study, Addiction, 100, pp. 512-524, 2005.

Prevention Research

Parents' Beliefs Synergistically Affect Children's Drinking

This research examined whether mother's and father's beliefs about their children's alcohol use had cumulative self-fulfilling effects on their children's future drinking behavior. Researchers analyzed longitudinal data from 115 seventh-grade children and their mothers and fathers. Questionnaire data were collected at two points in time 12 months apart. At the first time point, researchers measured parents' beliefs about their child's alcohol use, the child's alcohol use and intentions to use and other risk and protective factors for substance use. At the second time point, child's recent alcohol use was measured. Findings suggest that the inaccurate portion (e.g., overestimation or underestimation) of parent's beliefs about their children's behavior at time 1 uniquely accounted for variance in a model predicting alcohol use at time 2. Mothers' beliefs that overestimated children's alcohol use more strongly predicted time 2 alcohol use when father's beliefs also overestimated time 2 use, a process the authors call synergistic accumulation. However, synergistic accumulation did not occur when parents' beliefs underestimated children's alcohol use. Madon, S., Guyll, M., Spoth, R. and Willard, J. Self-Fulfilling Prophecies: The Synergistic Accumulative Effect of Parents' Beliefs on Children's Drinking Behavior. Psychological Science, 15(12), pp. 837-845, 2004.

Higher Impulsivity Related to Fewer Negative Expectancies and More Marijuana Use

The current study evaluated a model of marijuana use by examining the relationship between a distal risk factor (impulsivity) and a proximal risk factor (marijuana use expectancies) and marijuana use. An impulsive personality style has been identified as both a risk factor and a predictor of substance use and abuse. Marijuana expectancies, or evaluations of marijuana's expected effects (positive, negative, or neutral) have emerged as a strong predictor of marijuana use. Estimated probabilities and subjective evaluations of personally expected marijuana effects, along with impulsivity and frequency of marijuana use, were assessed in a sample of 337 college undergraduates (248 females, 89 males, average age of 20.84 years). Tests of mediation indicated that negative expectancies were a significant mediator for both males and females. That is, participants who were higher on impulsivity had fewer negative expectancies and in turn used more marijuana. Vangsness, L., Bry, B.H. and LaBouvie, E.W. Impulsivity, Negative Expectancies, and Marijuana Use: A Test of the Acquired Preparedness Model. Addictive Behaviors, 30, pp. 1071-1076, 2005.

Research on Behavioral & Combined Treatments For Drug Abuse

Anxiety Disorders among Patients with Co-occurring Bipolar and Substance Use Disorders

Dr. Kolodziej and colleagues at Harvard and Boston University examined the prevalence and nature of anxiety disorder among treatment seeking patients diagnosed with current bipolar and substance use disorders, and investigated the association between anxiety disorders and substance use. Among 90 participants diagnosed with bipolar disorder I ( n=75, 78%) or II ( n=15, 22%), 43 ( 48%) had a lifetime anxiety disorder, with posttraumatic stress disorder (PTSD) occurring most frequently (n=21, 23%). They found that those with PTSD, but not with the other anxiety disorders assessed, began using drugs at an earlier age and had more lifetime substance use disorders, particularly cocaine and amphetamine use disorders, than those without PTSD. Most participants with PTSD were women, sexual abuse was the most frequently reported index trauma, and the mean age of the earliest index trauma occurred before the mean age of initiation of drug use. These findings highlight the heterogeneity of dually diagnosed patients, and the importance of further investigating the ramifications of a trauma history among those who are diagnosed with bipolar and substance use disorders. Kolodziej, M.E., Griffin, M.L., Najavits, L.M., Otto, M.W., Greenfield, S.F. and Weiss, R.D. Anxiety Disorders among Patients with Co-Occurring Bipolar and Substance Use Disorders. Drug and Alcohol Dependence, 80, pp. 251-257, 2005.

Research on Pharmacotherapies For Drug Abuse

Effect of Nicotine Replacement Therapy on Post-cessation Weight Gain and Nutrient Intake: A Randomized Controlled Trial of Postmenopausal Female Smokers

This study of 94 postmenopausal female smokers evaluated the effect of nicotine replacement therapy (NRT) and hormone therapy (HT) on change in weight, energy intake, and physical activity during 2 weeks of smoking abstinence. Women, stratified by current use of HT, were randomized to nicotine or placebo patch. After 2 weeks of abstinence, women on nicotine patch had significantly larger increases in total caloric and fat intake than women on placebo patch and a trend toward larger increases in carbohydrates (total and sweet). Conversely, the nicotine group had less weight gain, 0.47 kg, than the placebo group, 1.02 kg (F=10.31, p=0.002). No effects were observed for hormone therapy. It appears that in short-term smoking abstinence, postmenopausal women on NRT gain less weight than do women on placebo, in spite of consuming more calories. This may be beneficial in the critical first 1-2 weeks of tobacco cessation, especially in light of postmenopausal weight gain. Allen, S.S., Hatsukami, D., Brintnell, D.M. and Bade, T. Effect of Nicotine Replacement Therapy on Post-cessation Weight Gain and Nutrient Intake: A Randomized Controlled Trial of Postmenopausal Female Smokers. Addict. Behav., 30, pp. 1273-1280, 2005.

Spontaneous Smoking Cessation During Pregnancy Among Ethnic Minority Women: A Preliminary Investigation

This study examined the postpartum relapse rates and characteristics of pregnant women who stopped smoking without professional intervention. Baseline characteristics of women who spontaneously quit were compared to women who continued to smoke. Women who spontaneously quit were also randomized to a psychotherapy relapse prevention treatment, or to usual care. The sample was ethnically diverse, containing 141 low-income women who were predominantly Hispanic, 23% (n=33) of whom spontaneously quit smoking. The variables that significantly differentiated between "spontaneous quitters" and ongoing smokers were entered into a regression analysis, which revealed that higher self-confidence, smoking fewer cigarettes per day, and younger age accounted for 25% of the variance in spontaneous cessation. Adding the psychotherapy intervention conferred no additional protection against relapse in this subgroup of spontaneous quitters. The six-month abstinence rate of 36% is similar to that found in Caucasian and higher-income populations. These results extend research with pregnant smokers to a new population and may have implications for healthcare providers and policy makers. Morasco, B.J., Dornelas, E.A., Fischer, E.H., Oncken, C. and Lando, H.A. Spontaneous Smoking Cessation During Pregnancy Among Ethnic Minority Women: A Preliminary Investigation. Addict. Behav., 31, pp. 203-210.

Research on Medical Consequences of Drug Abuse

Disorders of Glucose Metabolism Among HIV-infected Women

Abnormal glucose metabolism in HIV-infected patients has largely been attributed to the use of protease inhibitors. However, most studies of glucose metabolism in HIV-infected patients have focused on men or have lacked appropriate control groups. Authors assessed the factors associated with previously diagnosed diabetes among 620 middle-aged women with or at risk for HIV infection. For a subset of 221 women without previously diagnosed diabetes, we performed an oral glucose tolerance test (OGTT) to measure glucose and insulin levels, and we assessed factors associated with abnormal glucose tolerance, insulin resistance, and insulin secretion. Thirteen percent of the women in the present study had previously diagnosed diabetes. Among women without previously diagnosed diabetes who underwent an OGTT, 6% had previously undiagnosed diabetes, and 12% had impaired glucose tolerance (IGT). According to multivariate analysis, factors that were associated with previously diagnosed diabetes included current methadone treatment, body mass index of >or =25, family history of diabetes, and physical inactivity. Factors that were independently associated with an abnormal result of an OGTT (i.e., a result consistent with IGT or diabetes) included age >or =50 years, family history of diabetes, physical inactivity, and a high number of pack-years of smoking. Factors independently associated with insulin resistance included waist circumference, Hispanic ethnicity, physical inactivity, and, among HIV-infected women, use of HAART that did not include protease inhibitors. Factors associated with lower levels of insulin secretion included current opiate use (i.e., methadone or heroin) and older age. The authors conclude that abnormal glucose metabolism is highly prevalent among middle-aged women with or at risk for HIV infection, particularly women who use opiates. Screening for diabetes in the HIV primary care setting should occur for women who have classic risk factors for diabetes, rather than solely for women who are taking PIs. Interventions that target modifiable risk factors, including obesity and physical inactivity, are also warranted. Howard, A.A., Floris-Moore, M., Arnsten, J.H., Santoro, N., Fleischer, N., Lo, Y. and Schoenbaum, E.E. Disorders of Glucose Metabolism Among HIV-infected Women. Clin Infect Dis., 40(10), pp. 1492-1499, 2005.

Depressive Symptoms, Quality of Life, and Neuropsychological Performance in HIV/AIDS: The Impact of Gender and Injection Drug Use

Limited attention has been paid to the potential impact of gender and injection drug use (IDU) on mood, quality of life, and neuropsychological performance in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Several studies that describe the natural history of HIV/AIDS in terms of mental health and neuropsychological ability have focused solely on men or have excluded injection drug users. Women and injection drug users are two groups for whom the incidence of HIV infection is increasing. Additionally, the National Academy of Sciences recently recommended that studies concerned with health-related research include males and females, and that researchers analyze their data for gender differences. The goals of the current study were to investigate possible relationships between HIV and IDU status and depressive symptoms, quality of life, and neuropsychological performance in women and men matched for age, race, and education. Overall, women reported more depressive symptoms than men, and this gender difference was most evident in women who were both infected with HIV and who were also injection drug users. Women and HIV-infected individuals reported the poorest quality of life scores. Women outperformed men on a measure of verbal memory and HIV(-) participants outperformed HIV(+) participants on a measure of perceptual speed. Finally, gender and HIV status interacted such that uninfected women performed the best, and infected men performed the worst, on a test of verbal memory. A better understanding of how men and women with different drug use profiles respond to HIV/AIDS may substantially improve survival, as well as aspects of daily functioning, of affected individuals. Thus, further study and development of treatment protocols targeted at including women and IDU are needed. Wisniewski, A.B., Apel, S., Selnes, O.A., Nath, A., McArthur, J.C., Dobs, A.S. Depressive Symptoms, Quality of Life, and Neuropsychological Performance in HIV/AIDS: The Impact of Gender and Injection Drug Use. J Neurovirol., 11(2), pp. 138-143, 2005.

Gender Effects Following Repeated Administration of Cocaine and Alcohol in Humans

Use of cocaine, alcohol, and the two drugs simultaneously is common and the risk of morbidity and mortality associated with these drugs is widely reported. This double-blind, placebo-controlled, randomized study examined gender differences in response to administration of these drugs alone and in combination. Current users of cocaine and alcohol (n = 17) who met diagnostic criteria (DSM-IV) for cocaine dependence and alcohol abuse or dependence (not physiologically dependent on alcohol) and who were not seeking treatment for substance use disorders gave voluntary, written, informed consent to participate in three drug administration sessions:1) four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg following the initial cocaine dose and a second drink at +60 min (120 mg/kg) calculated to maintain a plasma alcohol concentration of approximately 100 mg/dL; 2)four doses of cocaine and alcohol placebo; 3) cocaine placebo and alcohol. Pharmacokinetics were obtained by serial blood sampling, physiological measurements (heart rate and blood pressure) were obtained with automated equipment, and subjective effects were assessed using visual analog scales over 480 min. Responses to cocaine, alcohol, and cocaine-alcohol were equivalent by gender for most measurements. Women had higher heart rates following alcohol administration (p = .02). Women consistently reported higher ratings for "Feel Good", a measure of overall mental/physical well-being, for all study conditions, reaching statistical significance for cocaine (p = .05) and approaching significance for alcohol administration (p = .1). Women showed equivalent responses to drug administration with the exception of perception of well-being, which was significantly increased for women. These findings may have implications for differential risk for acute and chronic toxicity in women. McCance-Katz, E.F., Hart, C.L., Boyarsky, B., Kosten, T. and Jatlow, P. Gender Effects Following Repeated Administration of Cocaine and Alcohol in Humans. Subst Use Misuse, 40(4), pp. 511-528, 2005.

Services Research

Chemically Dependent Youth Benefit from Psychiatric Services

Many adolescents with alcohol and drug problems have mental health co-morbidities. The literature suggests that patients entering chemical dependency (CD) treatment with co-occurring problems have less successful outcomes, including treatment dropout and relapse. Researchers examine the impact of psychiatric services on treatment initiation, retention, and alcohol and drug abstinence outcomes for adolescents in CD treatment. Participants were 419 adolescents aged 12-18 years who were seeking treatment at four CD programs of a nonprofit, managed care, group model health system. A parent or guardian for each adolescent also participated. Participants were surveyed at intake and at 6 months and the researchers were exposed to clinical and administrative data pertaining to their diagnoses for CD and psychiatric utilization. Six-month response rates were 91% for adolescents and 93% for parents. Fifty-five percent of the patients with treatment intakes had at least one psychiatric diagnosis in addition to a substance use disorder. Compared with matched controls, patients with CD intakes had higher rates of depression, anxiety, eating disorders, attention deficit hyperactivity disorder, conduct disorder, and conduct disorder including oppositional defiant disorder. Thirty-one percent of the full sample had psychiatric visits in the 6 months after intake; among those with a psychiatric diagnosis, 54% had a psychiatric visit. Girls and those with higher Youth Self-Report internalizing scores were more likely to have a psychiatric visit (OR = 2.27, p < 0.001 and OR = 1.05, p < 0.0001, respectively). Adolescents receiving psychiatric services were more likely to be abstinent from both alcohol and drugs than those not receiving these services (OR = 1.57, 95% CI = 0.98-2.5) and more likely to be alcohol abstinent (OR = 1.68, 95% CI = 1.00-2.85). Those adolescents at co-located clinics had higher odds of abstinence from both alcohol and drugs (OR = 1.57, 95% CI = 1.03-2.39) and drugs (OR = 1.84, 95% CI = 1.87-2.85) and of returning after intake to initiate CD treatment (OR = 2.28, 95% CI = 1.44-3.61, p < 0.001) than others. The results demonstrate the need for psychiatric treatment of adolescents in CD treatment and highlight the importance of their receiving such services. Sterling, S. and Weisner, C. Chemical Dependency and Psychiatric Services for Adolescents in Private Managed Care: Implications for Outcomes. Alcoholism: Clinical and Experimental Research, 25(5), pp. 801-809, 2005.

Juvenile Offenders at Increased Risk for HIV Infection

The purpose of this study was to examine the prevalence, multiple correlates, and gender differences in chlamydia and gonorrhea infections among adolescents incarcerated in a youth detention center in the southern region of the United States. STD screening was conducted on 1816 youth, ages 10-18, as they entered the facility. Rates of undiagnosed chlamydia were 24.7% for incarcerated girls and 8.1% for boys. Gonorrhea was detected in 7.3% of the girls and 1.5% of the boys. Only youth 13 years or older were asked to complete a survey: 763 assented to participate, and 690 gave permission to link their STD test results to their survey responses. The majority of the juveniles who participated in the study were African American (89%) and male (67%). Predictors of STD positivity differed for boys and girls. Demographic characteristics (gender, race, and age) account for 52% of the total variance in STD infections; youths' behavior (alcohol use, sex under the influence of alcohol, history of STD and sexual risk reduction strategy) accounts for about one-third of the total variance, psychological (sexual abuse, alcohol and drug expectancies) and family variables (family structure/living arrangements, supervision and monitoring, parental involvement, family communication) account for 8.6% (boys) and 7.2% (girls) of the total variance. An approach that considers psychological and social influences on adolescent sexual behavior is useful for identifying potential risk and protective factors of adolescent STD/HIV risk that are amenable to intervention. Robertson, A.A., Baird-Thomas, C., St. Lawrence, J.S. and Pack, R. Predictors of Infection with Chlamydia or Gonorrhea in Incarcerated Adolescents. Sexually Transmitted Diseases, 32(2), pp. 115-122, 2005.

Effectiveness of Highly Regarded Adolescent Substance Abuse Treatment Programs

This study conducted the first systematic evaluation of the quality of highly regarded adolescent substance abuse treatment programs in the United States. An advisory panel of 22 experts defined 9 key elements of effective treatment for adolescent substance abuse based on a review of the literature. In-depth telephone and written surveys were conducted with 144 highly regarded adolescent substance abuse treatment programs identified by panel members and by public and private agencies. There was a 100% response rate to the initial interviews, and a 65% response rate to the follow-up surveys. The open-ended survey responses were coded by defining 5 components deemed to be crucial in addressing each of the 9 key elements, and quality scores were calculated overall and for each of the 9 key elements. Out of a possible total score of 45, the mean score was 23.8 and the median was 23. Top-quartile programs were not more likely to be accredited. The majority of programs scored at least 4 of a possible 5 on only 1 of the 9 key elements (qualified staff). The elements with the poorest-quality performance were assessment and treatment matching, engaging and retaining teens in treatment, gender and cultural competence, and treatment outcomes. Most of the highly regarded programs surveyed are not adequately addressing the key elements of effective adolescent substance abuse treatment. Expanded use of standardized assessment instruments, improved ability to engage and retain youths, greater attention to gender and cultural competence, and greater investment in scientific evaluation of treatment outcomes are among the most critical needs. Expanding awareness of effective elements in treating adolescents will lead the way to program improvement. Brannigan, R., Schackman, B.R., Falco, M. and Millman, R.B. The Quality of Highly Regarded Adolescent Substance Abuse Treatment Programs: Results of an In-depth National Survey. Archives of Pediatric Adolescence Medicine, 158, pp. 904-909, 2004.

Quality of Social Support Affects Employment Outcomes

This study examined social support and its association with employment, income, and drug use in a sample of 534 low-income women. Social support was operationalized as two distinct categories. Functional support was defined as the perceived quality of one's interactions with others, considered as either actual or perceived assistance from others. Structural support was defined as the number of individuals within a network as well as the social ties or links within the network. Such networks as social, employment, drug, and emergency are characterized by size and density. Over the two-year study period, significant increases attributable to the quality of these relationships were observed in hours-worked, income from work, income from other sources, and total income. There was also a significant decrease in welfare income. Results suggest that the perceived quality of support received is an important factor in achieving positive employment outcomes. Simply using a quantitative measure of social support was not sufficient in this analysis. For welfare populations a beneficial change in the quality of functional support could lead to improvements in work hours. Brown, V.L. and Riley, M.A. Social Support, Drug Use, and Employment Among Low-Income Women. American Journal of Drug and Alcohol Abuse, 31, pp. 203-223, 2005.

Intramural Research

Treatment Section, Clinical Pharmacology and Therapeutics Research Branch

Menstrual Cycle Length during Methadone Maintenance

While heroin's menstrual disruption has been demonstrated, there are few published data concerning methadone maintenance (MM) and menstrual function. This study was conducted to evaluate whether cycles were more regular during MM. Start/end dates of each menses were collected from 191 drug-using women from two clinical trials, lasting 25-29 weeks, while on 70-100 mg of methadone. Participants were classified as regular, irregular, transient amenorrhea, persistent amenorrhea, or cycle restarters. Repeated-measures regression modeling was used to determine correlates of cycle length, probability of long cycles (>40 days), and short cycles (<20 days). Bleeding episodes (days from "start" to "stop") were defined as one or more bleeding days, bound by at least two non-bleeding days. Correlates of cycle length, body mass index, drug use, methadone dose, and race were calculated. Women had a high prevalence of cycle length irregularity; 133 participants: regular 37 (27.8%); irregular 62 (46.7%); transient amenorrhea 7 (5.3%); persistent amenorrhea 11 (8.3%); cycle restarters 16 (12%). Each additional week on MM was associated with decreased risk of long (OR=0.96, p=0.001 and short (OR=0.92, p=0.001) cycles. Of 27 women with secondary amenorrhea pre-study, 16 (59%) restarted menses. Positivity for opioids or cocaine was not significantly associated with short or long cycles. Cycle length begins to normalize during MM. Menses resumption may occur. MM, despite interfering with menstrual function in an absolute sense, may interfere less than illicit heroin abuse. Schmittner, J., Schroeder, J.R., Epstein, D.H., and Preston, K.L. Addiction, 100(6), pp. 829-836, 2005.

Clinical Pharmacology Section, Clinical Pharmacology and Therapeutics Research Branch

Calorie Restriction Increases Cigarette Use In Adult Smokers

Cigarette smokers weigh less than nonsmokers, and smokers often gain weight when they quit. This is a major barrier to smoking cessation, especially among women. However, strict dieting is not recommended during smoking cessation out of concern that it might promote relapse. One reason is that calorie restriction increases self-administration of drugs of abuse in animals. This relationship has never been experimentally demonstrated in humans. This study evaluated whether calorie restriction increases cigarette smoking in humans. Seventeen (9M, 8F) healthy, normal-weight smokers not attempting to quit were cycled in partially counterbalanced order, double-blind, through four diets: normal calorie (2000-2800 kcal/day), low calorie (700 kcal/day deficit), low carbohydrate (CHO)-normal calorie, and low CHO-low calorie, for six days per diet on an inpatient research ward. Smoking was assessed by cigarette counts, breath carbon monoxide (CO) levels, and cigarette craving. Compared with the normal calorie diet, while on the low calorie diet, subjects smoked 8% more cigarettes (p<0.02) and had 11% higher breath CO levels (p<0.01). The low CHO- normal calorie diet showed no significant effect on either variable, but there was a 15% increase in breath CO levels (p<0.05) on the low CHO-low calorie diet. There were no changes in self-reported cigarette craving or mood. Consistent with animal studies, moderate calorie restriction was associated with a small but statistically significant increase in cigarette smoking, with no independent effect of carbohydrate deprivation. These findings suggest that dieting may increase smoking behavior, and could impede smoking cessation attempts. Cheskin, L.J., Hess, J.M., Henningfield, J., and Gorelick, D.A. Psychopharmacology 179, pp. 430-436, 2005.