Non-Fatal accidental strangulation in a stroke patient.

Non-fatal strangulation poses a significant concern in clinical forensic medicine. Indeed, surviving victims often present a diverse array of signs and symptoms. In rare instances, acute pathological events that manifest with symptoms similar to those secondary to neck compression (e.g., stroke with subsequent neurological symptoms, etc.) can lead to loss of consciousness, inadvertently resulting in strangulation. Therefore, in this context, forensic investigation plays a crucial role in interpreting the signs and symptoms presented by the victim and determining whether they are the cause or consequence of neck compression. This report presents a case of a middle-aged previously healthy woman who was found by her husband on the bathroom floor and then brought to the medical attention exhibiting signs of neck compression in combination with neurological symptoms. Since a previous episode of domestic violence involving the husband has been recorded in the hospital database, a medico-legal investigation was initiated at the behest of the prosecutor. The integration of all clinical, radiological, forensic pathological findings and circumstantial data allowed the exclusion of homicidal strangulation by ligature perpetrated by the husband, as well as suicidal hanging; instead, it classified the case as an accidental hanging, with a stroke being the underlying cause of the accident. The case provides valuable insights into the complexity of interpreting injuries associated with neck compression and emphasizes the need for comprehensive investigative approach in such cases.

Intimate partner femicide (IPF): Medico-legal investigation at the Institutes of Legal Medicine of Freiburg (Germany) and Padova (Italy).

Violence against women is a significant public health concern, with femicide as its most extreme manifestation. This crime is often perpetrated by current or former intimate partners, thus taking the name of intimate partner femicide (IPF). Although international comparisons are essential for prevention policies, cross-country comparative studies are scarce in this context. The aim of this study was to evaluate and compare clinical, epidemiological and medico-legal characteristics of IPF autopsy cases investigated at the Institutes of Legal Medicine of two Western European cities, in order to identify a potential medico-legal pattern of IPF. Autopsy and police reports of IPF cases occurred in the judicial district of Freiburg (Germany) and Padova (Italy) from 2000 to 2022 were analyzed. Data relating to victims, perpetrators, relationship context, and circumstantial and pathological-forensic characteristics of the homicide were collected. Statistical analyses were performed to explore potential relationships between the data collected. Additionally, a review of the literature dealing with autopsy-based studies on IPF was performed. Overall, 82 cases of IPF were analyzed, 39 from Freiburg and 43 from Padova. A total of 6 papers fulfilled the review inclusion criteria. Our study identified a medico-legal pattern of IPF and demonstrated that it did not vary substantially between the two European Countries considered, suggesting that certain IPF characteristics are shared at the European level. However, a significant finding emerged regarding the higher prevalence of firearm-related IPFs in Italy compared to Germany. Forensic pathology research might contribute to developing targeted prevention policies to protect women from this lethal form of violence.

The Precision, Inter-Rater Reliability, and Accuracy of a Handheld Scanner Equipped with a Light Detection and Ranging Sensor in Measuring Parts of the Body-A Preliminary Validation Study.

BACKGROUND: Anthropometric measurements play a crucial role in medico-legal practices. Actually, several scanning technologies are employed in post-mortem investigations for forensic anthropological measurements. This study aims to evaluate the precision, inter-rater reliability, and accuracy of a handheld scanner in measuring various body parts. METHODS: Three independent raters measured seven longitudinal distances using an iPad Pro equipped with a LiDAR sensor and specific software. These measurements were statistically compared to manual measurements conducted by an operator using a laser level and a meterstick (considered the gold standard). RESULTS: The Friedman test revealed minimal intra-rater variability in digital measurements. Inter-rater variability analysis yielded an ICC = 1, signifying high agreement among the three independent raters. Additionally, the accuracy of digital measurements displayed errors below 1.5%. CONCLUSIONS: Preliminary findings demonstrate that the pairing of LiDAR technology with the Polycam app (ver. 3.2.11) and subsequent digital measurements with the MeshLab software (ver. 2022.02) exhibits high precision, inter-rater agreement, and accuracy. Handheld scanners show potential in forensic anthropology due to their simplicity, affordability, and portability. However, further validation studies under real-world conditions are essential to establish the reliability and effectiveness of handheld scanners in medico-legal settings.

An unusual case of corpse concealment driven by emotional distress.

Corpse concealment involves hiding a body for criminal purposes for many different reasons, such as destroy evidence of a murder or avoid the discovery of the victim. Although defendants could argue that they did not conceal the corpse with any criminal intent, but rather to spare themselves or others from emotional distress or to honor the wishes of the deceased. However, these arguments are often challenging to substantiate, and defendants may encounter significant legal obstacles when attempting to justify their actions. Herein, we report a case involving the concealment of a woman's corpse by her father. Autopsy and histological investigations were significantly limited due to the advanced decomposition of the body. Nevertheless, by integrating these data with radiological findings obtained from total body CT and micro-CT of the larynx-hyoid complex, hanging was deemed the cause of death. Additionally, the psychological evaluation of the father indicated that the act of concealment was motivated by emotions rather than criminal intent.

Detection of butterfly fractures of long bones through multi-slice computed tomography and micro-computed tomography.

Motor-vehicle accidents often result in lower limb injuries with biosseous fractures. The present study aimed at comparing multi-slice computed tomography (MS-CT), micro-computed tomography (micro-CT) and external fractography for the analyses of experimentally produced biosseus leg fractures. Briefly, 48 human legs amputated for medical reasons were defleshed and then experimentally fractured using a 3-point dynamic bending model (70,6 J of impact energy at the middle of the anterior surface of the tibia) producing 38 biosseous and 10 mono-osseous fractures with a total of 86 fractured bones. External fractography detected 63 (73,2%) "butterfly" fractures (24 (27,9%) complete and 39 (45,3%) incomplete), 14 (16,3%) "oblique" fractures, 6 (7,0%) "comminuted" fractures and 3 (3,5%) "transverse" fractures. Forty-three (43) of the 48 included legs displayed at least one butterfly fracture located at the tibia or fibula. MS-CT correctly detected and classified 16 complete and 20 incomplete butterfly fractures, failing to properly classify 27 fractures; 19 of these misclassifications led to an interpretative error on the trauma direction (i.e., 16 incomplete butterfly fractures classified as oblique fractures and 3 incomplete butterfly fractures classified as transverse). Micro-CT correctly detected and classified 22 complete and 37 incomplete butterfly fractures, failing to properly classify 4 fractures; two of these misclassifications led to an interpretative error on the trauma direction (i.e., two incomplete butterfly fractures classified as oblique fractures). Although further studies evaluating a wider number of fractures and fracture patterns are required to drive any definitive conclusions, this preliminary experimental investigation showed that MS-CT and micro-CT represent useful tools for reconstructing the morphology of leg fractures and could be crucial for trauma analysis in the forensic context. MS-CT could be used as a screening tool, micro-CT as second level analysis and external/internal fractography as third level, confirmatory analysis.

Severe starvation and restraint in a 47-year-old woman: Clinical, autopsy and histopathological evidence of abuse and neglect.

The recognition of abuse and/or neglect still represents a challenge for both clinicians and forensic pathologists. Whereas abusive behaviors have been largely described among pediatric and elderly populations, adults' abuse and neglect is less frequently encountered, and therefore investigated. We report a case of a middle-aged woman without any known organic or psychiatric disorders who died of a multiple organ failure (MOF) due to extreme cachexia and bed-resting syndrome. The integration of all clinical, autopsy and histopathological data highlighted a picture of severe malnutrition, restraint, and widespread traumatic injuries related to abuse and neglect. We believe that the case here presented could be useful for both clinicians and forensic pathologists as it underlines once again the importance of collecting and integrating all medical evidence (both in the ante- and post-mortem settings) for reconstructing the most probable pathophysiology of disorders and injuries, comparing that reconstruction with the allegations of the caregivers, and thus identifying any potential abuse and/or neglect behaviors.

Micro-CT evaluation of morphological degenerative features of sterno-clavicular joint for age-at-death estimation in forensic anthropology - A qualitative analysis.

The analysis of the sternoclavicular joint holds significant importance in forensic anthropology, especially through the evaluation of medial clavicular ossification stage, which, however, is helpful only in subjects younger than 30 years of age. Given this limitation, the aim of the present work was to examine, through micro-CT, the surface of sternoclavicular joints of deceased individuals across various age groups, aiming to identify age-related degenerative changes applicable to age estimation in adults over 30 years old. A total of 41 deceased subjects were categorized into three age groups (20-39 years; 40-59 years; ≥60 years) for the analysis. Degenerative morphological features on both clavicular and sternal articular surfaces, including topography, porosity, and presence of osteophytes, were evaluated using a composite scoring system based on a modified "Falys-Prangle method.", which assigns to each parameter specific score ranges: 1-3 for surface topography (smooth, slightly irregular, markedly irregular), 1-6 for porosity (absent, micro- and macroporosity for <50 % or >50 % of surface, surface breakdown), 1-3 for osteophytes (absent, present, not evaluable). The findings revealed a positive correlation between degenerative morphological features and age for both clavicular (rs = 0.719) and sternal articular surfaces (rs = 0.750). Additionally, the combined assessment of the clavicle and sternum, or the evaluation of the clavicle alone, exhibited better differentiation among the three age groups. The micro-CT evaluation of degenerative alterations affecting the sternoclavicular joint proves to be a reliable and efficient method for age estimation in adults.

Syncope and Cannabis: hypervagotonia from chronic abuse? A case report and literature review.

BACKGROUND: Cannabis is the most consumed drug worldwide and number of users is increasing, particularly among youth. Moreover, cannabis potential therapeutic properties have renewed interest to make it available as a treatment for a variety of conditions. Albeit rarely, cannabis consumption has been associated with cardiovascular diseases such as arrhythmias, myocardial infarction (MI) and potentially sudden death. CASE PRESENTATION: A 24-year-old woman presented to the emergency department sent by her cardiologist because of a recent finding of a 16 seconds asystole on the implantable loop recorder (ILR) she implanted 7 months before for recurrent syncopes. She declared that she is a heavy cannabis user (at least 5 cannabis-cigarette per day, not mixed up with tobacco, for no less than 12 years) and all syncopes occurred shortly after cannabis consumption. After a collective discussion with the heart team, syncope unit, electrophysiologists and toxicologist, we decided to implant a dual chamber pacemaker with a rate response algorithm due to the high risk of trauma of the syncopal episodes. 24 months follow-up period was uneventful. CONCLUSIONS: Cannabis cardiovascular effects are not well known and, although rare, among these we find ischemic episodes, tachyarrhythmias, symptomatic sinus bradycardia, sinus arrest, ventricular asystole and possibly death. Because of cannabis growing consumption both for medical and recreational purpose, cardiovascular diseases associated with cannabis use may become more and more frequent. In the light of the poor literature, we believe that cannabis may produce opposite adverse effects depending on the duration of the habit. Acute administration increases sympathetic tone and reduces parasympathetic tone; conversely, with chronic intake an opposite effect is observed: repetitive dosing decreases sympathetic activity and increases parasympathetic activity. Clinicians should be aware of the increased risk of cardiovascular complications associated with cannabis use and should investigate its consumption especially in young patients presenting with cardiac dysrhythmias.

Phosphatidylethanol (PEth) in Blood as a Marker of Unhealthy Alcohol Use: A Systematic Review with Novel Molecular Insights.

The Alcohol Use Disorders Identification Test (AUDIT) and its short form, the AUDIT-C, the main clinical instruments used to identify unhealthy drinking behaviors, are influenced by memory bias and under-reporting. In recent years, phosphatidylethanol (PEth) in blood has emerged as a marker of unhealthy alcohol use. This systematic review aims to investigate the molecular characteristics of PEth and summarize the last ten years of published literature and its use compared to structured questionnaires. A systematic search was performed, adhering to PRISMA guidelines, through "MeSH" and "free-text" protocols in the databases PubMed, SCOPUS, and Web of Science. The inclusion criteria were as follows: PEth was used for detecting unhealthy alcohol consumption in the general population and quantified in blood through liquid chromatography coupled to mass spectrometry, with full texts in the English language. Quality assessment was performed using the JBI critical appraisal checklist. Twelve papers were included (0.79% of total retrieved records), comprising nine cross-sectional studies and three cohort studies. All studies stratified alcohol exposure and quantified PEth 16:0/18:1 through liquid chromatography coupled to mass spectrometry (LC-MS) in liquid blood or dried blood spots (DBS) with lower limits of quantitation (LLOQ) ranging from 1.7 ng/mL to 20 ng/mL. A correlation between blood PEth level and the amount of alcohol ingested in the previous two weeks was generally observed. PEth interpretative cut-offs varied greatly among the included records, ranging from 4.2 ng/mL to 250 ng/mL, with sensitivity and specificity in the ranges of 58-100% and 64-100%, respectively. Although the biomarker seems promising, further research elucidating the variability in PEth formation and degradation, as well as the molecular mechanisms behind that variability, are necessary.

Organ procurement requiring the authorization of the judicial authority. An epidemiological investigation in the Veneto region (Italy).

BACKGROUND: When death occurs through a mechanism requiring a forensic investigation, consent for organ harvesting must be sought from the Judicial Authority (JA). AIM: To perform a retrospective study of potential organ donors in the Veneto region over a six-year period (2012-2017), analysing any differences between cases in which the JA approved or denied organ harvesting. MATERIAL AND METHODS: Both non-heart beating (NHB) and heart beating (HB) donors were included. For HB cases, personal and clinical data were collected. To evaluate the correlation between the JA response and the circumstantial and clinical data a logistic multivariate analysis was performed, estimating the adjusted odds ratios (adjORs). RESULTS: Between 2012 and 2017, 17,662 organ and/or tissue donors were included, of which 16,418 were NHB donors and 1,244 HB-donors. Among the 1,244 HB-donors, JA authorization was asked in 200 cases (16.1%), approved in 154 cases (77.0%), limited in 7 cases (3.5%) and denied in 39 cases (19.5%). The JA denied the authorization for organ harvesting in 53,3% of cases with hospitalizations of less than 1 day and in 9,4% of cases with hospitalization exceeding one week [adjOR(95%CI) = 10.67 (1.92-59.22)]. The performance of an autopsy was linked to a higher chance of denied outcome from the JA [adjOR(95%CI): 3.45 (1.42-8.39)]. CONCLUSIONS: Improvements in the communication between organ procurement organizations and the JA through efficient protocols furnishing detailed information on the cause of death might lead to a better procurement process with an increase in the number of transplanted organs.

Per- and polyfluoroalkyl substances (PFAS) presence in food: Comparison among fresh, frozen and ready-to-eat vegetables.

There is a worldwide discussion to provide safety limits in food for per- and polyfluoroalkyl substances (PFAS), a group of persistent contaminants associated to human disease. Processed food is more at risk of containing increased amounts of PFAS as a consequence of intentionally or non-intentionally contamination during manipulation and packaging. Among food products, also vegetables can be submitted to industrial manipulation; therefore, a different PFAS content correlated to the level of vegetables processing is conceivable. This study assessed the amount and type of PFAS present in fresh, frozen and ready-to-eat vegetables. Differences have been observed between the three groups of samples in the average PFAS content; the difference between ready-to eat and frozen vegetables resulted statistically significative. Organic vegetables displayed a lower total amount of PFAS respect to the traditional counterpart. The impact of industrial manipulation remains to be cleared, but pesticides use during cultivation could be considered a source of PFAS contamination.

Digital Ischemia after Ultrasound-Guided Alcohol Injection for Morton's Syndrome: Case Report and Review of the Literature.

The therapeutic algorithm for symptomatic Morton's syndrome is not standardized as several managements have been proposed. Ultrasound-guided alcohol injection (USGAI) is one of the non-operative procedures described. This report presents the case of digital ischemia that occurred after alcoholization for the treatment of Morton's syndrome. This complication is described for the first time in the scientific literature, and it should not only be added to the list of sequalae of USGAI, but more importantly, it should also be explained to the patient when this alternative treatment to traditional surgery is proposed.

Phosphatidylethanol in Maternal or Neonatal Blood to Detect Alcohol Exposure during Pregnancy: A Systematic Review.

BACKGROUND: Alcohol consumption during pregnancy, even at low doses, may damage the fetus. Pregnant women tend to underreport their alcohol consumption generating the need for sensitive and specific biomarkers, among which PEth has emerged due to its high specificity and possibility to be measured in both maternal and neonatal blood. The aim of this study is to systematically review the latest 20 years of literature for depicting the state of the art, the limitations, and the prospects of PEth for estimating alcohol consumption during pregnancy. MATERIALS AND METHODS: A systematic search, adhering to PRISMA guidelines, of the latest 20 years of literature through "MeSH" and "free-text" protocols in the databases PubMed, SCOPUS, and Web of Science, with time limits 1 January 2002-1 March 2022, was performed. The inclusion criteria were as follows: PEth used for detecting alcohol consumption during pregnancy, quantified in blood through liquid chromatography coupled to mass spectrometry, and full texts in the English language. Opinion papers, editorials, and narrative reviews were excluded. RESULTS: Sixteen (16) papers were included in the present review (0.81% of total retrieved records). All the included records were original articles, of which there were seven prospective cohort/longitudinal studies, six cross-sectional studies, two observational-descriptive studies, and one retrospective study. All studies assayed PEth in at least one biological matrix; seven (7) studies quantified PEth in maternal blood, seven studies in newborn blood, and only two studies in both maternal and neonatal blood. In several included papers, PEth proved more sensitive than self-reports for identifying pregnant women with an active alcohol intake with the diagnostic efficiency improving with the increase of the maternal alcohol intake. CONCLUSIONS: Further studies, performed on wider and well-stratified populations, are needed to drive any definitive conclusion. PEth is a promising marker for monitoring alcohol use in pregnancy; however, at the present time, its use is still limited mainly by the absence of a globally agreed interpretative cut-off, the paucity of data regarding its specificity/sensitivity, and the lack of standardization on the diagnostic efficiency of the different isoforms.

Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults.

BACKGROUND: CWS/RMS-96 was an international multicenter trial with randomization between two therapy arms of the standard four-drug therapy (vincristine, ifosfamide, adriamycin, dactinomycin [VAIA]) versus an intensified six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide [CEVAIE]) for high-risk rhabdomyosarcoma (RMS), extraskeletal Ewing sarcoma (EES), and undifferentiated sarcoma (UDS) in children, adolescents, and young adults aiming to improve their survival. Intensified chemotherapy with CEVAIE did not improve outcome. METHODS: Patients younger than 21 years with a previously untreated localized HR-RMS, EES, and UDS were enrolled from Cooperative Weichteilsarkom Studiengruppe (CWS) centers in Germany, Austria, Poland, Switzerland, and from Italian Soft Tissue Sarcoma Committee (STSC) centers. Randomization (1:1) to receive either 9 × 21 days cycles of VAIA or CEVAIE was performed separately in CWS and STSC. Hyperfractionated accelerated radiotherapy (32-44.8 Gy) was added at week 9-12 according to histology and response to chemotherapy. A secondary microscopically complete nonmutilating resection was performed if possible. Primary endpoints were response to chemotherapy, event-free (EFS) and overall survival (OS). RESULTS: Five hundred fifty-seven patients (HR-RMS: n = 416, EES and UDS: n = 141) underwent randomization: VAIA (n = 273) or CEVAIE (n = 284). Radiotherapy was given to 70% of patients in both groups. A secondary resection was performed in 47% and 48% patients, respectively. The 5-year EFS and OS for the VAIA and CEVAIE treatment arms were 59.8% and 60.8% (p = .89), and 74.2% and 68.3% (p = .16), respectively. No differences in response, toxicity, or second malignancies emerged in the two groups. CONCLUSION: The use of an intensified regimen failed to show a significant improvement in tumor response and outcome of patients with localized HR-RMS, EES, and UDS.

Entrapment within an ottoman storage bed: an unusual accidental asphyxial death.

Herein, we present an uncommon forensic case of death by asphyxia. The victim was a woman whose body at death scene investigation (DSI) was discovered beside an ottoman storage bed. According to the rescue team, who had moved the body before our arrival, the body was originally found in the prone position and stuck with the neck, thorax and arms within the bed. Examination of the body showed hypostasis that was mainly distributed to the face and the lower chest while sparing the neck and the upper chest. The face was markedly swollen, and the eyes were congested with blood. Dissection and histology revealed pulmonary oedema and emphysema of both lungs. Integrating circumstantial, radiology and autopsy data, it was established that the victim, while trapped between the mattress and the edge of the ottoman storage bed, died by mechanical asphyxia due to cervical-thoracic compression and postural asphyxia acting simultaneously.

A case of lethal varicose vein rupture caused by massive leiomyoma.

Varicose veins are a common and benign disease, especially affecting the lower limbs of the elderly. This pathology can exhibit several complications, which in the majority of cases do not require medical treatment; life-threatening conditions are possible but extremely rare. We present here a suspected murder case in which a woman was found dead in her home with a large amount of blood soiling the floor and the furniture of her house. Death scene investigation (DSI) with body inspection and bloodstain pattern analysis (BPA) were not exhaustive in excluding a homicide, and the prosecutor asked for a forensic autopsy. During the dissection, a uterine neoplasia, which altered the lower limb venous system, was detected, thus allowing to reconstruct the physio-pathological mechanism of the formation and rupture of the varicose vein.

Reconstruction of the dynamic in a fatal traffic accident with prolonged dragging of the victim.

The post-mortem examination of victims of fatal road crashes and the reconstruction of the dynamic of traffic accidents are fundamental in vehicular homicides, where the degree of negligence/careless of the driver has to be established. Here we present a case in which a pedestrian was dragged along an SUV for 3.5 km, until the vehicle was parked at the house of the driver, arising the suspect of vehicular manslaughter and failure to provide assistance. On the basis of death scene investigation, analysis of video recording from a surveillance camera, post-mortem computerized tomography (PMCT) and complete post-mortem examination, including gross and microscopical findings, the accident was reconstructed as a frontal collision between the right portion of the bumper and the right side of the body of a standing pedestrian, with deformation of the bumper and production of a metal sheet hook; secondary run-over the right feet, cranio-facial trauma against the bodywork of the vehicle and hooking of the right hand of the victim to the metal sheet; prolonged dragging of the pedestrian over the road surface and severe bleeding. A multidisciplinary-multimodal methodology, including PMCT, allowed to assess the cause of death as hemorrhagic shock, suggested that the victim would have likely survived if the vehicle had stopped, and is increasingly recommendable in fatal road accidents.

Pancreatoblastoma in children: EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm that affects typically young children. Signs related to advanced upper-abdominal tumor accompanied by elevated serum α-fetoprotein levels in a young child suggest PBL, however histopathological confirmation is mandatory. The mainstay of the treatment is a complete surgical resection. Unresectable and/or metastatic PBL may become amenable to complete delayed surgery after neoadjuvant chemotherapy. This manuscript presents the international consensus recommendations for the diagnosis and treatment of children with PBL, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER (Paediatric Rare Tumors Network - European Registry) project.

Facing the challenges of very rare tumors of pediatric age: The European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) background, goals, and achievements.

It has become increasingly clear in recent years that we need to develop ad hoc strategies to combat very rare tumors (VRT) of pediatric age. In 2008, several schemes being run in different countries were pooled together to create the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) project: a cooperative study group that aimed to promote research in the relatively uncharted territory of rare tumors of pediatric age. EXPeRT members were able to activate different levels of cooperation to achieve their goals, and to obtain dedicated funding by participating in EU-financed projects. Their experiences emphasize the merits of networking, seeking new partnerships, joining forces, and pooling resources to extend the reach of research efforts, and ultimately improve the quality of patient care. Between 2018 and 2021, the EXPeRT has been active in establishing the Pediatric Rare Tumors Network - European Registry (PARTNER). This project had the main purposes of building a European common registry of pediatric VRT, but also the major task of developing diagnostic and treatment guidelines for VRT (or at least part of them). These clinical recommendations are the subject of a series of papers on Pediatric Blood and Cancer.

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications.

Novel psychoactive substances (NPS) represent a severe health risk for drug users. Even though the phenomenon has been growing since the early 2000s, the mechanisms of action of NPS at the receptors and beyond them are still scarcely understood. The aim of the present study was to provide a systematic review of the updated knowledge regarding the molecular mechanisms underlying the toxicity of synthetic opioids, cannabinoids, cathinones, and stimulants. The study was conducted on the PubMed database. Study eligibility criteria included relevance to the topic, English language, and time of publication (2010-2020). A combined Mesh and free-text protocols search was performed. Study selection was performed on the title/abstract and, in doubtful cases, on the full texts of papers. Of the 580 records identified through PubMed searching and reference checking, 307 were excluded by title/abstract and 78 additional papers were excluded after full-text reading, leaving a total of 155 included papers. Molecular mechanisms of synthetic opioids, synthetic cannabinoids, stimulants, psychedelics, and hallucinogens were reviewed and mostly involved both a receptor-mediated and non-receptor mediated cellular modulation with multiple neurotransmitters interactions. The molecular mechanisms underlying the action of NPS are more complex than expected, with a wide range of overlap among activated receptors and neurotransmitter systems. The peculiar action profile of single compounds does not necessarily reflect that of the structural class to which they belong, accounting for possible unexpected toxic reactions.