Drug-facilitated crime (DFC) is a criminal act (e.g., assault, robbery, or sexual assault) in which the perpetrator uses drugs to impair the victim's ability to resist, remember, or recognize the crime being committed. Ethanol is commonly implicated in DFC casework, but limited data are published on other substances currently implicated in these crimes. DFC cases submitted to a large forensic reference laboratory between 2019 and 2023 were analyzed. Analytes and combinations were evaluated based on effect class. In total, 2371 blood samples and 5,041 urine samples were tested for common alcohols, GHB, and a variety of illicit and prescription medications. The most prevalent drug classes were cannabinoids (delta-9-THC/delta-9-THCCOOH), ethanol, and stimulants, with delta-9 THC/metabolites being most prevalent in both matrices, followed closely by ethanol. The stimulant drug class's most prevalent analytes include methamphetamine, cocaine/cocaine metabolites, and amphetamine. Gamma-hydroxybutyric acid (GHB) and flunitrazepam were infrequently detected. Polydrug combination data showed similar trends to when substances were identified alone, specifically that ethanol, cannabinoids, or a stimulant were often found in combination. Sedating substances were more prevalent than stimulating substances, specifically benzodiazepines and antihistamines. Polydrug data support urine collection in DFC cases, as they identified analytes in 22% of cases with negative blood toxicology. Recent literature notes novel psychoactive substances, including designer benzodiazepines, being detected in DFC cases globally, and recommends their inclusion in comprehensive DFC scopes. It is imperative that the appropriate matrix, scope, and limitations be evaluated to accurately determine trends, and scopes are continuously updated to capture the ever-changing drug market.