Despite their high comorbidity, the effects of brief interventions (BI) to reduce cannabis use, alcohol use and anxiety symptoms have received little empirical attention. The aims of this study were to examine whether a therapist-delivered BI (TBI) or computer-guided BI (CBI) to address drug use, alcohol consumption (when relevant) and HIV risk behaviors, relative to enhanced usual care (EUC), was associated with reductions in parallel trajectories of alcohol use, cannabis use and anxiety symptoms, and whether demographic characteristics moderated reductions over time. Latent growth curve modeling was used to examine joint trajectories of alcohol use, cannabis use and anxiety symptoms assessed at 3, 6 and 12 months after baseline enrollment. Hurley Medical Center Emergency Department (ED) in Flint, MI, USA. The sample was 780 drug-using adults (aged 18-60 years; 44% male; 52% black) randomly assigned to receive either a TBI, CBI or EUC through the HealthiER You study. ED-delivered TBI and CBIs involved touchscreen-delivered and audio-assisted content. The TBI was administered by a Master's-level therapist, whereas the CBI was self-administered using a virtual health counselor. EUC included a review of health resources brochures in the ED. Assessments of alcohol use (10-item Alcohol Use Disorders Identification Test), cannabis use (past 30-day frequency) and anxiety symptoms (Brief Symptom Inventory-18) occurred at baseline and 3-, 6- and 12-month follow-up. TBI, relative to EUC, was associated with significant reductions in cannabis use [B = -0.49, standard error (SE) = 0.20, P < 0.05) and anxiety (B = -0.04, SE = 0.02, P < 0.05), but no main effect for alcohol use. Two of 18 moderation tests were significant: TBI significantly reduced alcohol use among males (B = -0.60, SE = 0.19, P < 0.01) and patients aged 18-25 years in the TBI condition showed significantly greater reductions in cannabis use relative to older patients (B = -0.78, SE = 0.31, P < 0.05). Results for CBI were non-significant. Emergency department-based therapist-delivered brief interventions to address drug use, alcohol consumption (when relevant) and HIV risk behaviors may also reduce alcohol use, cannabis use and anxiety over time, accounting for the overlap of these processes. © 2019 Society for the Study of Addiction.