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This thesis involves a comprehensive review of the personality, psychiatric, and genetic risk factors for alcoholism and drug abuse. Based on this review, it is hypothesised that specific risk factors cluster together to represent separate vulnerability pathways to substance abuse and that differential susceptibility to the pharmacological effects of drugs of abuse (reinforcement and intoxication) mediates the relationship between such risk characteristics and drug-taking behaviour. A series of four studies are presented indicating that groups of individuals characterized by different risk factors for alcoholism are differentially sensitive to the reinforcing properties of alcohol. Non-alcoholic young adult men presumed to be at genetic risk for alcoholism (due to high genetic loading for alcoholism) were shown to be sensitive to the effects of alcohol on resting and stress-induced physiological states hypothesized to reflect activity within a brain reward system involved in the activation of approach and avoidance behaviour. Non-alcoholic young adult males self-reporting a personality profile that has been associated with increased risk for the development of panic disorder also demonstrated idiosyncratic responses to alcohol intoxication in that they appeared particularly sensitive to the. fear-dampening effects of alcohol. Finally, a group of non-alcoholic males were identified as being particularly susceptible to elevated and problematic alcohol and drug use in early adulthood due to a disinhibited/antisocial personality profile. These findings were interpreted as reflecting separate vulnerability pathways to substance use/abuse in which differential sensitivity to drug reinforcement and disinhibited personality are thought to play an important role in determining liability to seek out behavioural reinforcement from drugs of abuse. A second set of studies tested whether these factors are implicated in the maintenance of problematic alcohol and drug consumptio

Disparities between the substance use rates of sexual or gender minority (SGM) youth and the rates of youth identifying as heterosexual (i.e., attracted to the opposite sex) and cisgender (i.e., gender identity corresponds to birth sex) have given rise to calls for 1) research to understand the specific risk and protective factors relating to substance use in SGM youth and 2) the development of corresponding intervention programming In three papers, this dissertation explores predictors for substance use among SGM youth and describes methods of targeted recruitment for a prevention intervention program tailored to SGM youth. In the first paper, comparing the contributing factors of substance use between sexual minority and heterosexual youth revealed that although many predictors were associated with use in both groups, sadness, suicidal ideation, difficulty concentrating, and forced sexual encounters were the most consistent and substantial contributors to the explanation of the difference in use rates between groups. In the second paper, risk and protective factors identified from social learning theory and minority stress theory, including perceived stress, problem-solving skills, self-esteem, self-efficacy, substance refusal skills, and peer use of substance, were generally associated with past-month substance use. Peer use of substance and substance refusal skills, in particular, were consistently and robustly associated with substance use in the sample of SGM youth, and their intersection provides insight into themes to address in future intervention development. Issues of disclosure and parental permission have made recruiting representative samples of SGM youth challenging, and the third paper offers insight into an inexpensive and time-efficient means of recruiting SGM youth for participation in such research. The specificity with which Facebook ads can be targeted to hard-to-reach populations makes it a preferred tool for researchers who seek to recruit SGM youth. Taken together, the three papers of this dissertation can serve as a guide for the development and execution of substance use prevention research that is tailored to the specific needs of SGM youth.

Certains médicaments agissant sur le système nerveux central ont comme particularité d'entraîner parfois des troubles de l'abus et de la dépendance. Ces effets indésirables sont étudiés avant la mise sur le marché du médicament, lors des essais cliniques et non cliniques. Cependant, l'abus est un phénomène plurifactoriel, influencé par des facteurs liés à la substance, individuels et environnementaux. Ces déterminants ne peuvent pas être pris en compte avant la mise sur le marché du médicament et rendent essentielle la surveillance de l'abus de médicaments après la mise sur le marché, par l'intermédiaire notamment d'études pharmacoépidémiologiques. Une surveillance efficace de l'abus de médicament implique de comprendre les déterminants de l'abus et ses mécanismes sous-jacents. L'objectif de ce travail de thèse est donc d'analyser des déterminants de l'abus en utilisant des approches pharmacoépidémiologiques. Le premier travail a été d'établir un état des lieux des systèmes de surveillance de l'abus de médicaments en France et à l'étranger (publication n°1). Nous avons par la suite utilisé une enquête en population auprès des patients fréquentant des centres de soins spécialisés pour les usagers de drogues, afin d'étudier l'impact de la mise sur le marché de génériques de la Buprénorphine Haut Dosage (BHD) sur l'abus de BHD (publication n°2). Cette étude nous a permis d'analyser l'influence de la formulation sur l'abus de médicaments. L'exploration de la localisation géographique comme déterminant de l'abus n'a jamais été réalisée en France. / Some central nervous system medications sometimes lead to abuse or dependence. These adverse effects are assessed using premarketing studies such as clinical trials and non clinical studies. However, abuse is influenced by many factors, substance-related, individual and environmental. These factors could not be taken into account in premarketing studies. Thus, postmarketing surveillance of prescription drug abuse, using in particular pharmacoepidemiologic studies is essential. An efficient postmarketing surveillance requires the comprehension of abuse-related factors and underlying mechanisms. The purpose of this work was to analyse prescription drug abuse factors using pharmacoepidemiological approaches. The first part of this work was an overview of postmarketing surveillance systems dedicated to prescription drug abuse in France and in foreign countries (publication n°1). Then, we used a survey in population of patients seen in care centres dedicated to drug users in order to assess the impact of buprenorphine maintenance generic introduction on buprenorphine maintenance abuse (publication n°2). This study allows to observe the influence of the formulation on prescription drug abuse. The factors related to geographic area have never been explored in France, at our knowledge. Therefore, we studied geographic variations of prescription opioid abuse in three regions of southern France, Provence-Alpes-Côte d'Azur-Corse, Rhône-Alpes and Midi-Pyrénées using a pharmacoepidemiologic approach based on prescription drug reimbursement database, the doctor shopping method (publication n°3).

Studies consistently find sexual orientation disparities in tobacco, alcohol and marijuana use among adolescents in the United States (Goldbach, Tanner-Smith, Bagwell, & Dunlap, 2014; Hatzenbuehler, Jun, Corliss, & Austin, 2015; Kann et al., 2018; Marshal et al., 2008; Mustanski, Van Wagenen, Birkett, Eyster, & Corliss, 2014). Having documented this elevated risk, the field has turned to identifying mediators that may explain the sexual orientation disparity in substance use behaviors. There is growing evidence that one of the mediators of sexual orientation-based health disparities is structural stigma—defined as “societal-level conditions, cultural norms, and institutional policies that constrain the opportunities, resources, and well-being of the stigmatized” (Hatzenbuehler & Link, 2014, p.2). Structural stigma can in turn lead to greater stress and subsequent negative coping behaviors among sexual minorities (Hatzenbuehler et al., 2015; Hatzenbuehler & Link, 2014; Hatzenbuehler & McLaughlin, 2014; Pachankis, Hatzenbuehler, & Starks, 2014). However, most of this work has been conducted among adults and has focused on mental health outcomes (e.g., suicide attempts, psychiatric morbidity, mental distress) as opposed to specific substance use behaviors; further, if structural factors are found to affect sexual orientation health disparities and these can be altered, the gap between sexual minority and heterosexual substance use can be narrowed through policy change. State-level substance use policy (e.g., levels of taxation of cigarettes and alcohol, policies that remove adolescent access to driving upon substance use infractions) may also explain the gap in substance use prevalence between sexual minority and heterosexual youth because tobacco, alcohol and marijuana are also stigmatized substances and restrictive substance use environments may enhance the stigma attached to sexual minority youth. However, only one study has explored this research question, and it was conducted with an adult sample (Hatzenbuehler, Keyes, Hamilton, & Hasin, 2014). This project aims to address these gaps in the literature. It uses multi-level modeling to test the association between (1) state-level sexual minority structural stigma (SMSS) and (2) state-level substance use policy environments (SUPEs) and sexual orientation disparities in recent substance use as measured in the Youth Risk Behavior Surveillance Survey (YRBSS). Analyses were also conducted to assess the size and direction of the association between SMSS and SUPE and state-level prevalence of substance use within heterosexual and sexual minority youth subpopulations. Analyses were conducted in subpopulations of female and male youth. Support was found for the structural stigma hypothesis among girls but not boys. Higher overall measures of sexual minority structural stigma were associated with larger disparities in tobacco use, alcohol use, and marijuana use among girls. Higher scores on the SMSS scale were associated with tobacco use among sexual minority girls but not heterosexual girls. Individual indicators of structural stigma (e.g., specific state-level policies) were also associated with disparities in these outcomes, as well as with the other outcomes tested (binge drinking and drunk driving). No such associations were found among male youth. Very little support was found for the hypotheses that restrictive substance use policy environments would be associated with larger sexual orientation disparities in substance use and that heterosexual but not sexual minority youth would demonstrate lower prevalence of substance use in restrictive states. Among girls, no associations were found between scales measuring the restrictiveness of substance use and sexual orientation disparities in substance use. A smaller sexual orientation disparity in recent cigarette smoking was associated with one indicator of restrictiveness: state enforcement of underage tobacco sale laws. Among boys, no associations were found between scales measuring the restrictiveness of substance use and sexual orientation disparities in substance use; two indicators of restrictiveness were associated with smaller sexual orientation disparities in binge drinking and three indicators were associated with smaller sexual orientation disparities in drunk driving. Among heterosexual but not sexual minority boys, higher tobacco taxes were associated with lower prevalence of smoking. This study raises several questions for future research on structural factors that may explain sexual orientation disparities in substance use behaviors among youth. For instance, future work is needed to understand the gender differences in response to structural stigma among sexual minorities. Sexual minority girls may have greater rejection sensitivity than sexual minority boys and thus may be more likely to use substances in response to structural stigma; however, further research is needed to test this hypothesis. In addition, the current study lacked data on the implementation of substance use policy environments, which may have masked important effects. A study of SUPE that includes measures of implementation of restrictive substance use policies is therefore needed to expand the work reported herein. Finally, a better understanding of gender identity and expression is needed; while the YRBSS measures “sex” and not gender or gender expression in these datasets, more information about these topics will help to understand how these factors may play into experiences of structural stigma and substance use policy environments.

Research on the determinants of injection drug use behavior has traditionally concentrated on factors operating at the individual level. However, more recent studies have found that behaviors surrounding injection drug use are shaped, not only by individual-level characteristics, but also by the environment in which they occur. The risk environment paradigm, proposed by Rhodes and colleagues, describes how factors exogenous to the individual influence high-risk injection behavior and blood borne virus (BBV) transmission among people who inject drugs (PWID). To date, few elements of the risk environment have been evaluated as potential determinants of high-risk injection behavior. The purpose of this dissertation was to study the influence of two elements of the risk environment on unsafe injection practices among PWID – neighborhood socioeconomic disadvantage and social discomfort surrounding the acquisition of sterile syringes from syringe exchange programs (SEPs) and pharmacies. To this end, a systematic literature review was conducted on the relation between neighborhood context and injection drug use behavior. Research gaps and methodological challenges identified in this review were used to design analyses exploring relations among neighborhood disadvantage, social discomfort, and high-risk injection behavior. These analyses were conducted using data collected from 484 PWID enrolled in the Pharmacists as Resources Making Links to Community Services (PHARM-Link) study, combined with data from the American Community Survey. Poisson regression with robust error variance was used to estimate associations between measures of neighborhood socioeconomic disadvantage and high-risk injection behavior. SEP accessibility and drug-related police activity were evaluated as potential modifiers of these relations. Similar methods were used to estimate associations between measures of social discomfort and high-risk injection behavior, including neighborhood socioeconomic disadvantage as a potential effect modifier. The systematic literature review on neighborhood context and injection drug use behavior identified few articles pertaining to this relation (n=22). Selected studies primarily investigated the influence of structural aspects of the neighborhood environment on behaviors surrounding injection drug use, while aspects of the social environment and potential modifiers of neighborhood-behavior relations were understudied. Subsequent quantitative analyses revealed that neighborhood socioeconomic disadvantage was associated with safer injection behaviors among PWID. Injectors in disadvantaged neighborhoods reported less receptive syringe sharing and less unsterile syringe use than their counterparts in relatively better off neighborhoods. Drug-related police activity attenuated associations between neighborhood disadvantage and unsterile syringe use, while the direction of associations between neighborhood disadvantage and the use of unsafe syringe sources varied with levels of SEP accessibility. In neighborhoods with high SEP accessibility, neighborhood disadvantage was associated with decreased use of unsafe syringe sources, while in neighborhoods with low SEP accessibility, neighborhood disadvantage was associated with increased use of unsafe syringe sources. Social discomfort was not associated with high-risk injection behavior, but effect modification was detected between neighborhood disadvantage and two items measuring the quality of relationships between participants and syringe staff: “Pharmacists care about my health and well-being” and “The staff at syringe exchange programs seems to care about my health and well-being.” In disadvantaged neighborhoods, participants who reported positive relationships with syringe staff were less likely to engage in receptive syringe sharing. However, in relatively better off neighborhoods, positive relationships with syringe staff were associated with increased receptive syringe sharing. Overall, the results of this dissertation support the validity of the risk environment paradigm in shaping high-risk injection behavior among PWID. Future studies should continue to investigate contextual factors as determinants of behavior surrounding injection drug use. Understanding how aspects of local-area environments influence injection risk behavior will be essential to eliminating the transmission of BBVs among PWID.