High-risk polysubstance use among LGBTQ+ people who use drugs in the United States: An application of syndemic theory

•Among LGBTQ+ who use drugs, one fifth reported lifetime problems with 10 drugs.•Psychosocial and structural burdens predict high-risk polysubstance use.•Binary transgender people experienced highest rates of high-risk polysubstance use.•Binary transgender people experienced highest rates of homelessness, discrimination.•Syndemic conditions explain the prevalence of polysubstance use among LGBTQ+ people. Compared to heterosexual and cisgender people, lesbian, gay, bisexual, transgender, queer, and other sexual and gender minority (LGBTQ+) people are more likely to develop problems with high-risk polysubstance use. According to syndemic theory, this disparity in high-risk polysubstance use is produced by the LGBTQ+ community's increased vulnerability to experiencing psychosocial (e.g., discrimination, unwanted sex) and structural (e.g., food insecurity, homelessness) conditions, greater likelihood of coping with concurrent health problems (e.g., human immunodeficiency virus [HIV]), and decreased opportunities to develop protective factors (e.g., social support, resilience). Data from 306 LGBTQ+ participants living in the United States (U.S.) with a lifetime history of alcohol and drug use were analyzed; 21.2% reported lifetime problems with 10 different drugs. Bootstrapped hierarchical multiple regression was used to test demographic correlates and syndemic predictors of high-risk polysubstance use. One-way ANOVA and post-hoc comparison tests were used to test subgroup differences by gender. Results indicated that income, food insecurity, sexual orientation-based discrimination, and social support were associated with high-risk polysubstance use, explaining 43.9% of the variance of high-risk polysubstance use. Age, race, unwanted sex, gender identity-based discrimination, and resilience were not significant. Group comparison tests revealed that, compared to nonbinary people and cisgender sexual minority men and women, transgender individuals experienced significantly higher levels of high-risk polysubstance use and sexual orientation-based discrimination but significantly lower levels of homelessness and social support. This study provided further evidence for conceptualizing polysubstance use as an adverse outcome of syndemic conditions. Harm reduction strategies, anti-discrimination laws, and gender-affirming residential treatment options should be considered in U.S. drug policy. Clinical implications include targeting syndemic conditions to reduce high-r