In these projects, we seek to add to the body of literature demonstrating the benefits of methadone maintenance and to enhance those benefits. Areas of research in the past year include the effects of methadone maintenance on menstrual cycle and on the rates of adverse events and the relationships between plasma and saliva levels of the enantiomers of methadone and its metabolites and treatment outcome. We have completed a study to evaluate whether menstrual cycles become more regular during methadone maintenance. While heroin's menstrual disruption has been demonstrated, there are few published data concerning methadone maintenance and menstrual function. We retrospectively examined data from 191 drug-using women from two clinical trials, lasting 25-29 weeks; each woman was maintained on 70-100 mg of methadone. Start/end dates of each menses were collected. Patterns of menstruation were classified as regular, irregular, transient amenorrhea, persistent amenorrhea, or cycle restart. Repeated-measures regression modeling was used to determine correlates of cycle length and predictors 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/predictors examined were body mass index, drug use, methadone dose, and race. In the 133 women for whom menstrual patterns could be determined, cycle-length irregularity was common; the patterns seen were: irregular, 62 (46.7%); regular, 37 (27.8%); cycle restart, 16 (12%); persistent amenorrhea, 11 (8.3%); transient amenorrhea, 7 (5.3%). Each additional week on methadone maintenance 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 while maintained on methadone. Positivity for opioids or cocaine was not significantly associated with short or long cycles. Thus, cycle length begins to normalize during methadone maintenance, and menses resumption may occur. Methadone maintenance, despite interfering with menstrual function in an absolute sense, may interfere less than illicit heroin abuse. We have also undertaken a series of analyses to characterize the prevalence and nature of adverse events (AEs) in methadone-maintained patients undergoing behavioral treatment. Our aim here is to enhance safety monitoring, which is complicated by participants? high levels of medical and psychiatric comorbidity. In the first set of analyses, now in press, we paper describe AEs reported in one of our a large (N = 286), 29-week outpatient contingency-management studies. A total of 884 AEs were reported (3.1 per patient, 0.12 per patient-week), the most common being infections (26.8%), gastrointestinal (20.5%), musculoskeletal (12.3%), and general (10%) disorders. Serious AEs were uncommon (1.6% of total). Female participants reported significantly higher rates of AEs (incidence density ratio, IDR = 1.38, p < 0.0001); lower rates of AEs were reported by African Americans (IDR = 0.73, p < 0.0001) and participants over age 40 reported lower rates of AEs (IDR = 0.84, p = 0.0095). AE incidence was not associated with the study intervention or with psychiatric comorbidity. We noted that further work is needed to adapt AE coding systems for behavioral trials for substance dependence; the standard Medical Dictionary for Regulatory Activities, International Federation of Pharmaceutical Manufacturers Associations (MedDRA) coding system does not contain a separate category for one of the most common types of AE, dental problems. Nonetheless, our data should help provide a context in which investigators and IRBs can interpret the patterns of AEs they encounter. We are currently extending this project to examine the effects of preexisting medical conditions, to characterize the use of emergency rooms for routine healthcare needs, and to determine whether methadone dose ceilings (sometimes used in our clinical trials for purposes related mostly to study design) should raise ethical concerns about compensatory intravenous heroin use and consequent AEs. Finally, we are conducting methodological studies to refine our monitoring of drug use and dose adequacy. For example, we are investigating the relationships among the concentrations of free and protein-bound enantiomers of methadone and its major metabolite EDDP in plasma and saliva. Our collaborators have developed new assays for these purposes and are now analyzing specimens from one of our completed clinical trials. We will determine associations among analyte concentrations, methadone dose, and treatment outcome. Our findings in this project may contribute to our therapeutic drug monitoring as we begin another large clinical trial in which flexible, individualized daily methadone doses are compared double-blind to fixed high doses--a comparison that has never been systematically made. A second objective of this project is to examine the roles of other psychological and physiological aspects of drug use in addiction and treatment. We are testing whether craving for cocaine and heroin predicts subsequent drug use more strongly when tested with 45-item, multifactor questionnaires than with single-item questionnaires?and, if so, whether 16-item multifactor questionnaires are an adequate substitute for the 45-item versions. In a study that represents a departure for our section, both substantively and methodologically, we are exploring the use of qualitative methods to gain insight into our patients? views on the roles of religion and spirituality in their recovery. In collaboration with outside experts on qualitative research and on the psychology of religion, we have been conducting focus groups in which our patients discuss how they reconcile their lives as drug abusers with their spiritual lives, and how (or indeed whether) issues of spirituality could be addressed in formal treatment settings. Finally, we are examining expression of the Nurr1 gene (which helps regulate expression of the dopamine-transporter gene) in peripheral blood lymphocytes of methadone-maintained patients who continue to use cocaine. Ultimately, the aim of this study is to determine whether the Nurr1 gene can be used as a biological marker of drug abuse and to determine whether treatment might reverse changes in Nurr1 gene expression.