To describe the health-related harms associated with the misuse of benzodiazepines/z-drugs, prescription opioids, gabapentinoids, and psychostimulants in Ireland by examining trends in their involvement in treatment demand, non-fatal intentional drug overdoses (IDOs), and drug related deaths (DRDs).

A repeated cross-sectional study using data from the National Drug Treatment Reporting System (NDTRS), the National Self-Harm Registry Ireland (NSHRI) and the National Drug Related Deaths Index (NDRDI) between 2010 and 2020. Trends over time (2010–2020) in treatment demand, IDOs and DRDs involving benzodiazepines/z-drugs, prescription opioids excluding opioid agonist therapy drugs, gabapentinoids, or psychostimulants (alone or concurrently), adjusting for age and gender (Negative Binomial Regression).

A total of 102,661 treatment entry cases; 51,126 people presenting with at least one IDO; and 3626 DRDs included. Benzodiazepines/z-drugs were involved in 341 per 1000 treatment entry cases; 408 per 1000 IDOs; and 546 per 1000 DRDs, followed by prescription opioids (36 per 1000 treatment entry cases; 133 per 1000 IDOs; and 207 per 1000 DRDs) and gabapentinoids (5 per 1000 treatment entry cases; 54 per 1000 IDOs; and 118 per 1000 DRDs). Benzodiazepines/z-drugs, and prescription opioid involvement was stable over time with little or no changes observed in treatment demand, IDOs and DRDs. However, NPS-Benzodiazepines (etizolam) involvement in DRDs increased by 47 % annually (Adjusted Rate Ratio (ARR) 1.47, 95 % Confidence Interval (CI) 1.30–1.65, p < 0.0001). Gabapentinoids (primarily pregabalin) associated with a large annual increase in treatment demand (+44 % annually, ARR 1.44, 95 % CI 1.36–1.52, p < 0.0001), DRDs (+35 % annually, ARR 1.35, 95 % CI 1.25–1.46, p < 0.0001), and IDOs (+9 % annually, ARR 1.09, 95 % CI 1.07–1.10, p < 0.0001). Polysubstance use harms increased with respect to treatment demand, IDOs and DRDs over study period.

While benzodiazepines account for the greatest overall harm with respect to treatment demand, IDOs and DRDs, gabapentinoids (primarily pregabalin) had the largest annual increase in harm over the study period.