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Aims To determine trends in 3,4 methylenedioxymethamphetamine (MDMA)‐related death rates across Australia, Finland, Portugal and Turkey and to analyse the toxicology and causes of death across countries. Design Analysis of MDMA‐related deaths extracted from a national coronial database in Australia (2001–19) and national forensic toxicology databases in Finland (2001–17), Portugal (2008–19) and Turkey (2007–17). Presentation of MDMA use and seizure data (market indicators). Setting Australia, Finland, Portugal and Turkey. Cases All deaths in which MDMA was considered by the forensic pathologist to be contributory to death. Measurements Information collected on cause and circumstances of death, demographics and toxicology. Findings A total of 1400 MDMA‐related deaths were identified in Turkey, 507 in Australia, 100 in Finland and 45 in Portugal. The median age ranged from 24 to 27.5 years, and males represented between 81 and 94% of the deaths across countries. Standardized mortality rates significantly increased across all four countries from 2011 to 2017 during a period of increased purity and availability of MDMA. The underlying cause of death was predominantly due to drug toxicity in Australia (n = 309, 61%), Finland (n = 70, 70%) and Turkey (n = 840, 60%) and other causes in Portugal (n = 25, 56%). Minorities of all deaths across the countries were due to MDMA toxicity alone (13–25%). These deaths had a significantly higher blood MDMA concentration than multiple drug toxicity deaths in Australia, Finland and Turkey. Drugs other than MDMA commonly detected were stimulants (including cocaine, amphetamine and methamphetamine) (Australia 52% and Finland 61%) and alcohol (Australia 46% and Portugal 49%). In addition to MDMA toxicity, benzodiazepines (81%) and opioids (64%) were commonly identified in these deaths in Finland. In comparison, synthetic cannabinoids (15%) and cannabis (33%) were present in a minority of deaths in Turkey. Conclusions Deaths related to 3,4 methylenedioxymethamphetamine (MDMA) increased in Australia, Finland, Portugal and Turkey between 2011 and 2017. Findings show MDMA toxicity alone can be fatal, but multiple drug toxicity remains more prevalent.

The application of the design of experiments to optimize method development in the field of forensic toxicology using the urinary morphine 3-glucuronide acid hydrolysis as an example is described. Morphine and its trideuterated analogue (used as an internal standard) were extracted from urine samples by liquid-liquid extraction (ToxiTubes A) and derivatized by silylation. Chromatographic analysis was done by gas chromatography-mass spectrometry in the selected ion monitoring mode. Using the peak area ratio (morphine-to-internal standard) as the response, we investigated the independent variables that could influence the acid hydrolysis, including temperature (range 70-130 degrees C), acid volume (range 500-1,000 microL) and time (range 15-90 min). A 2(3) full factorial design for the screening and a response surface methodology, including a central composite design for optimization, were applied. The factors which influenced the response to a greater extent were temperature and its interaction both with time and acid volume. By application of a multiple regression analysis to the experimental data, a second-order polynomial equation was obtained. The optimal predicted conditions for morphine 3-glucuronide acid hydrolysis were 115 degrees C, 38 min and 500 microL for temperature, time and acid volume, respectively. Using design of experiments, instead of the one factor at a time approach, we achieved the optimum combination of all factor values, and this allowed the best results to be obtained, simultaneously optimizing resources. In addition, time and money can be saved, since other approaches are in general more time-consuming and laborious, and do not take into account the interactions between factors.

A qualitative and quantitative analytical method was developed for the simultaneous determination of 24 illicit drugs and medicines, in preserved oral fluid samples collected with the StatSure Saliva Sampler collection device. The samples were prepared by liquid-liquid extraction followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis. The chromatographic separation was performed with an Atlantis T3 (100 x 2.1 mm i.d., 3 microm) reversed-phase column using an acetonitrile/2 mM ammonium formate buffer pH 3.4 gradient and the MS/MS detection was achieved with two precursor-product ion transitions per substance. The method was fully validated, including specificity and capacity of identification, limit of detection (0.2-2.1 microg/L), limit of quantitation (0.8-6.4 microg/L), recovery (34-98%), carryover, linearity (the method was linear in the range 1-200 microg/L), intra-assay precision (coefficient of variance (CV) <20% for 20 microg/L and CV <10% for 100 microg/L) and inter-assay accuracy (mean relative error <15%) and precision (CV <20%). The method showed to be specific and sensitive. It has already been successfully used in four proficiency tests and subsequently applied to oral fluid samples collected from road traffic volunteers in the driving population of Portugal (districts of Lisbon, Coimbra and Porto), within the DRUID project.