In recent years, the marked increase in the abuse of fentanyl and its analogues has emphasized the importance of developing highly sensitive and selective analytical methods for their detection in biological matrices. Oral fluid (OF) has emerged as a useful alternative to blood in forensic toxicology, offering a non-invasive and easily accessible matrix for the identification of a recent drug intake. However, its composition requires rigorous sample preparation and robust analytical techniques. A gas chromatography–tandem mass spectrometry (GC-MS/MS) method was developed and validated for the quantification of four opioids and seven fentanyl analogues. A fast and simple solid-phase extraction (SPE) procedure was optimized, enabling the identification and quantification of all analytes in 11 min. The method was validated according to international guidelines, showing a satisfactory degree of linearity (R² ≥ 0.993), precision, accuracy, and sensitivity, with limit of detections (LODs) ranging from 0.10 to 0.20 ng/mL. The method was then successfully applied to n = 10 real OF samples collected during traffic stops set up by police forces which tested negative at the screening tests. Two samples tested positive for codeine and morphine, and one was positive for fentanyl and norfentanyl. The small number of samples currently limits the interpretation of the results. However, our study represents a good starting point for further application of this method to a wider population of real samples.

Background/Objectives: Antidepressants are widely prescribed medications that may affect psychomotor performance and driving ability depending on their pharmacological profile. This study investigated the prevalence and patterns of antidepressant use among drivers undergoing forensic toxicological evaluation and explored their potential implications for road safety. Methods: An observational study was conducted on n = 6316 drivers undergoing forensic toxicological assessment following licence suspension for driving under the influence (DUI) of alcohol and/or drugs between January 2023 and December 2025. Reported antidepressants were classified into selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), serotonin antagonist and reuptake inhibitors (SARIs), tricyclic antidepressants (TCAs), norepinephrine–dopamine reuptake inhibitors (NDRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), and monoamine oxidase inhibitors (MAOIs). Distribution patterns were analysed descriptively and discussed considering the available literature. Results: Antidepressant use was reported by n = 132 participants (2.1%). SSRIs were the most common class (44.0%), followed by SNRIs (26.5%) and SARIs (17.4%). TCAs (6.1%), NDRIs (3.7%), and NaSSAs (2.3%) were less common, while no MAOI use was reported. Among antidepressant users, n = 28 individuals (21.2%) tested positive for other psychoactive substances, including benzodiazepines, cocaine, and cannabinoids. Conclusions: The use of antidepressants was relatively uncommon in the study population. However, clinical evaluation remains important, particularly at the start of treatment and during dose adjustments to determine the potential for an increased risk while driving. Further studies integrating toxicological analyses and clinical data are needed to better define the relationship between antidepressant exposure, polysubstance use, and road safety.