Exploring trajectories of drug use, violence, and suicidality among marginalized women : avenues of intervention and the therapeutic potential of psychedelics

Background: Women who are marginalized due to social and/or economic disadvantage, including street-involved women, sex workers, and women who use drugs, experience numerous health and social inequities that disproportionately elevate risk of violence and suicidality. However, research and intervention programs to prevent violence and address systemic drivers of suicidality have been largely absent for this population and the socio-structural determinants remain poorly understood and under investigated. This dissertation therefore sought to explore trajectories of drug use, violence and suicidality among marginalized sex workers and aimed to identify avenues of intervention with a special focus on the therapeutic utility of psychedelics. Methods: This dissertation drew on data collected from AESHA (An Evaluation of Sex Workers’ Health Access), a community-based open prospective cohort of women sex workers across Metro Vancouver, Canada. Bivariate and multivariable logistic regression analyses using generalized estimating equations were employed to examine associations between various intersecting socio-structural factors and suicidality. Cox regression analyses were used to examine the impact of individual and socio-structural factors on incidence of crystal methamphetamine injection and suicidality, and assessed the independent effect of naturalistic psychedelic use on suicidality. Results: This dissertation identified that sex workers experience elevated risk and rates of suicidality influenced by dynamic, interrelated socio-structural factors. Experiences of interpersonal violence, homelessness, trauma/mental illness and physical/sexual childhood abuse were among the strongest determinants shaping drug use trajectories and risk of suicidality. Importantly, the study findings demonstrated that increased social cohesion had an independent protective effect on suicidality, as did psychedelic use, which was associated with a 60% reduced hazard of suicidality. Conclusion: Socio-structural factors play a critical role in potentiating and mitigating risk of suicide. Strengthening social cohesion among sex workers may be an important protective strategy, and this dissertation provides some of the first empirical evidence of the potential benefits of psychedelic use for preventing suicidality. The collective findings of this dissertation offer critical insights into how integrated, trauma-informed, community-led structural interventions may mitigate risk of suicide, and underscore the need to advance research on the therapeutic utility of psychedelics alongside broader interventions that facilitate social cohesion and connectedness.Graduate and Postdoctoral StudiesGraduat

Neutrophil-mediated mechanisms of damage and in vitro protective effect of colchicine in non-vascular Behçet's syndrome

Behçet’s syndrome (BS) is a systemic vasculitis with several clinical manifestations. Neutrophil hyperactivation mediates vascular BS pathogenesis, via both a massive reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) release. Here, we investigated neutrophil‐mediated mechanisms of damage in non‐vascular BS manifestations and explored the in‐vitro effects of colchicine in counteracting these mechanisms. NETs and intracellular ROS production was assessed in blood samples from 80 BS patients (46 with active non‐vascular BS, 34 with inactive disease) and 80 healthy controls. Moreover, isolated neutrophils were incubated for 1 h with an oxidating agent [2,2′‐azobis (2‐amidinopropane) dihydrochloride; 250 nM] and the ability of pure colchicine pretreatment (100 ng/ml) to counteract oxidation‐induced damage was assessed. Patients with active non‐vascular BS showed remarkably increased NET levels [21.2, interquartile range (IQR) = 18.3–25.9 mU/ml] compared to patients with inactive disease (16.8, IQR = 13.3–20.2 mU/ml) and to controls (7.1, IQR = 5.1–8.7 mU/ml, p < 0.001]. Also, intracellular ROS tended to increase in active BS, although not significantly. In active non‐vascular BS, NETs correlated with neutrophil ROS production (p < 0.001) and were particularly increased in patients with active mucosal (p < 0.001), articular (p = 0.004) and gastrointestinal symptoms (p = 0.006). In isolated neutrophils, colchicine significantly reduced oxidation‐induced NET production and cell apoptosis, although not via an anti‐oxidant activity. Neutrophil‐mediated mechanisms might be directly involved in non‐vascular BS, and NETs, more than ROS, might drive the pathogenesis of mucosal, articular and intestinal manifestations. Colchicine might be effective in counteracting neutrophils‐mediated damage in BS, although further studies are needed