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Abstract: Discovered in the United States of America (USA) in the 1960s, ketamine was introduced as an anaesthetic drug to specifically replace phencyclidine. Briefly, the substance moved from the medical world to recreational users, since it was discovered that intense psychedelic experiences were obtained with dosages lower than those prescribed for anesthesia. At the end of the 90’s, circulated in London nightclubs as a drug itself and as counterfeit 3,4-methylenedioxymethamphetamine tablets. In 1997, the Drug Enforcement Administration (DEA) alerted the United States (US) government to the increasing diffusion of ketamine in American 'clubs', and in 1999, the substance was added to Schedule III of drugs controlled by federal authorities. In 2002, ketamine epidemics moved to Europe, and the European Monitoring Centre for Drugs and Drug Addiction carried out a risk assessment monitoring of the phenomenon. An estimated ninety-nine percent of all global ketamine seizures occurred in Asia. Its growing popularity is due to the fact that this new psychoactive substance is cheaper than other stimulants such as MDMA that the amount used for recreational purposes does not cause respiratory depression and its legal use as a drug makes it widely available for a diversion towards illicit markets. Nevertheless, acute intoxication and several deaths have been related to exclusive ketamine use both in Europe and internationally. Since 2015, there has been and increasing rise of the illicit ketamine market and currently the drug is being used with unprecedented peaks and a consequent significant increase in seizures and clinical cases worldwide.

At the end of the 90s in Europe, the new psychoactive substances (NPS) phenomenon was limited to a small number of molecules created to mimic the actions and psychoactive effects of licensed medicines and existing drugs that are controlled by the United Nations drug conventions and therefore traded as their "legal" replacements. NPS were mostly circulating in rave parties and electronic music festivals. The globalization, the evolution of e-commerce and the growing popularity of NPS, facilitated the development of a wide illegal market in constant expansion. The dynamic nature of this phenomenon has led to an evolution in the prevention and monitoring of NPS trafficking within the European Union. The European legislative system has been amended with the aim of creating a faster and more effective regulatory system to tackle NPS diffusion and ban their sale and circulation. At the end of 2008, in compliance with the European Council Decision 2005/387/JHA, the Anti-Drug Policies Department of the Presidency of the Council of Ministers activated the National Early Warning System to promote a rapid exchange of information on NPS between Italy and the EU.

In the late 2019, an epidemic of cases with severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has spread from China to the rest of the world, resulting in a global pandemic (COronaVIrus Disease 19, COVID-19 pandemic). Starting from the first months of 2020, several restrictions have been imposed by governments to face the public health threat, impacting the usual patterns of drug abuse throughout the world (1). The temporary border closure affected the usual illicit drug route of shipping from country to country, resulting in scarcity of classic street drugs (2). Moreover, restrictive measures internationally adopted by several countries made necessary to close all the usual recreational settings in which stimulants drugs are commonly abused. On the contrary, since in house drugs abuse became the most feasible option, other private encounters might have caught on, such as chemsex (3). In particular this phenomenon, which originated mainly in the large cities of Northern Europe, has gradually spread across the continent and is now a worrying reality in western European countries. Other rising trends of substance abuse include cognitive enhancers and new psychoactive substances (4, 5). Furthermore, the consequent social isolation and the likely limited access to detoxification centers caused additional psychological distress, pushing drug addicts toward alternative psychotropic drugs, possibly through illegal online marketplaces. An international overview of the new trends of drug abuse during the current COVID-19 pandemic and the related health risks are hereby discussed, taking into consideration different points of view. Can New Trends of Substance Abuse Be Identified During COVID-19 Pandemic? As we write this opinion paper, the social and economic restrictions due to the coronavirus pandemic have already seriously impacted health and social fields. COVID-19 outbreak has led to the implementation of social distancing to contain the spread of the disease, changing people’s lifestyle. People have been going through a moment of anxiety and fear for their health and their jobs, and they are forced to live an unfamiliar lifestyle, deprived of relationships. Furthermore, the condition of people with psychological troubles may have worsened during the pandemic as a result of the unconsciously mirroring of others feelings (6). This peculiar situation may have pushed more people toward a deviant behavior linked to licit or illicit substance use, and it may have been a good opportunity for drug dealers to attract new customers. However, global issues have not favored the usual trade business. Indeed, social distancing has substantially reduced drug trafficking on the streets, pushing consumers toward illegal markets on the dark web or through messaging applications (7). Furthermore, the paucity of classic drugs, together with the impossibility to go out to look for those, might have induced addicts to misuse psychoactive prescription drugs such as benzodiazepines (8–10). In this concern, although there is limited scientific evidence, the impact of the COVID-19 pandemic could lead to substantial modifications in substance use patterns, and an increased risk of substitution, adulteration, contamination, and dilution with a potentially harmful substance. As such, reports from forensic science and toxicology laboratories are crucial for the early detection and response to such events (11, 12). Moreover, in this period of home confinement, users might no longer be looking for “socializing” substances to be used in recreational settings, but for psychotropic drugs to be consumed in solitude. Even short periods of isolation and loneliness can have negative consequences on physical and mental well-being. The feeling of isolation can lead to anxiety and anger, and even sleep disorders, depression, and post-traumatic stress disorders, which may be underestimated due to the lack of specific screening tools (13, 14). Moreover, psychiatric assistance from health professionals is not assured due to the temporary monopolization of psychiatric facilities for COVID-19 treatment (15). In addition to drug addicts using prescription sedatives available at home, some may have shifted to narcotics such as new synthetic opioids or designer benzodiazepines, available online. Indeed, these two classes of new psychoactive substances showed the highest consumption increase in 2019 (16–19).

Background and Aims Sustained-Low Efficiency Dialysis (SLED) is a hybrid Renal Replacement Therapy (RRT) increasingly used in critically ill patients with Acute Kidney Injury (AKI). Usually lasting 8-12 hours, this modality combines several advantages of both intermittent and continuous RRT (CRRT). Regional citrate anticoagulation (RCA) represents the most adequate anticoagulation strategy to avoid the extracorporeal circuit clotting. Hypophosphatemia (serum phosphorus, s-P, levels ≤ 2.5 mg/dl) is a common electrolyte disorder in critically ills, with an increased incidence in course of prolonged RRTs, especially when standard dialysis/replacement solutions and highly intensive modalities are employed. Given the potentially negative impact of hypophosphatemia on patients’ outcomes, strategies aimed at preventing its onset should be appropriately implemented. This pilot study is aimed at evaluation of safety and efficacy of a simplified RCA protocol for SLED, based on the combination of a low-concentrated citrate solution with a phosphate-containing solution. Methods a prospective observational study was conducted on critically ill patients with AKI requiring RRT or End Stage Renal Disease (ESRD) previously on RRT admitted to our renal Intensive Care Unit (ICU). SLED was performed by the Prismax system (Baxter) and polyacrylonitrile AN69 haemofilters (ST 150, 1.5 m2, Baxter). 8-hours SLED sessions were prescribed, in the SLED-f variant, by using a 18 mmol/l pre-dilution trisodium citrate solution (Regiocit 18/0, Baxter) combined with a phosphate-containing solution acting as dialysate (Ca2+ 0, HPO42- 1, Mg2+ 0.75, HCO3- 22 mmol/l; Biphozyl, Baxter) and a standard RRT solution acting as post-dilution replacement fluid (Prismasol 4, Baxter). Calcium chloride (CaCl 10%) was infused in a separate central venous line to maintain the systemic Ca2+ (s-Ca2+) within a normal range. Each patient underwent three consecutive daily SLED sessions. The activated coagulation time (ACT), acid–base parameters, s-Ca2+ and potassium were measured at SLED start and every 2 h. Phosphorus and magnesium losses with RRT were replaced, when needed, with sodium glycerophosphate pentahydrate (GlycophosTM 20 mmol/20 ml, Fresenius Kabi Norge AS, Halden, Norvegia) and magnesium sulphate. Results a total of 60 SLED-f sessions were performed in 20 ICU patients. At ICU admission, the average APACHE II score was 21.8 and half of patients were mechanically ventilated. Many of them showed hemodynamic instability and AKI was oliguric in 90% of cases. No premature interruptions for irreversible filter clotting occurred and the prescribed dialysis dose was delivered in 95% of cases. No statistically significant differences were observed between systemic ACT at SLED start and during RRT sessions, and no major hemorrhagic events were observed. Regarding RCA, no clinically relevant episode of hypo or hypercalcemia was observed, and calcium infusion rate remained constant in course of treatments. Acid-base status was effectively maintained during the entire period of treatment and no episodes of clinically relevant metabolic acidosis or alkalosis were registered. The analysis of the main laboratory variables at SLED start, in course and after 24 h of treatment did not show statistically significant differences. Regardless of starting values, s-P and s-Mg were progressively corrected and maintained within the normality range, limiting the need for exogenous supplementations. Conclusions These preliminary data suggest that our simplified RCA protocol for SLED, combining a low-citrate solution with a phosphate-containing solution, is safe and efficacious allowing to optimizing acid-base balance and to preventing RRT-related hypophosphatemia.

The penalty system implemented by Italian law still represents a barrier against psychoactive drugs and drug addiction, especially at a time when the age of first consumption has considerably dropped. Presidential Decree n. 309 of October 9, 1990 entitled "Consolidation of the laws governing drugs and psychotropic substances, the prevention, treatment and rehabilitation of drug addicts", and referred to as Presidential Decree 309/90, is the reference text for the cultivation, production, trade and use of narcotics and other psychoactive substances in Italy. The Presidential Decree has its origins in the now-forgotten law of December 22, 1975, n. 685, amended by law 162/90, which provided a draft of the current Presidential Decree 309/90. The current text has been amended numerous times over the years.

At the end of 2019, the European Monitoring Centre for Drugs and Drug Addiction was monitoring around 790 new psychoactive substances, more than twice the total number of controlled substances under the United Nations Conventions. These substances, which are not subject to international drug controls, include a wide range of molecules, including the assortment of drugs such as synthetic cannabinoids, stimulants, opiates, and benzodiazepines. Most of them are sold as “legal” substitutes for illicit drugs, while others are intended for small groups willing to experiment with them in order to know their possible new effects. At the national level, various measures have been taken to control new substances and many European countries have responded with specific legislation in favor of consumer safety and by extending or adapting existing drug laws to incorporate the new psychoactive substances. Moreover, since 1997, an early warning system has been created in Europe for identifying and responding quickly to the risks of new psychoactive substances. In order to establish a quicker and more effective system to address the criminal activities associated with new dangerous psychoactive substances, the European legal framework has considerably changed over the years.

Nail analysis can be performed as a substitute or complement to hair analysis for the retrospective determination of psychotropic drugs consumption in forensic contexts. The application of nail analysis in a "chemsex" context is reported herein. An ultra-performance liquid chromatography-tandem mass spectrometry method was developed to quantify the most common drugs of abuse, synthetic cannabinoids, synthetic cathinones and GHB in fingernails and toenails of individuals presumptively using these drugs in music and sex settings. Results were compared to the concentrations measured in hair. Nail and hair keratin matrices were digested with VMA-TM3® buffer reagent and underwent a solid phase extraction before chromatographic separation with reversed phase columns and a linear gradient elution with 5 mM ammonium formate and acetonitrile, for detecting classic drugs of abuse, or 0.1% formic acid and methanol, for detecting synthetic cathinones, synthetic cannabinoids, and GHB. Analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode after positive electrospray ionization. Nails of individuals practicing "chemsex" contained at least three different psychoactive drugs, and up to eight drugs simultaneously. Identified drugs included cocaine, benzoylecgonine, cocaethylene, delta-9-tetrahydrocannabinol, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, ketamine, norketamine, mephedrone, methylone, 4-methyletcathinone, methcathinone, γ-hydroxybutyric acid (GHB) and γ-butyrolactone. Most used drugs were MDMA and GHB followed by cocaine and ketamine. Drugs concentrations ranged from 0.1 to 690 ng/mg in fingernails. In the two individuals who also provided toenails, concentrations were always higher in fingernails than in toenails, while in two other individuals who donated also hair, concentrations in this latter matrix were either higher or lower than those measured in fingernails. This study demonstrated that nails may well represent an appropriate non-conventional biological matrix to provide additional information in forensic toxicology.

Aldehydes are widespread environmental and industrial compounds, able to stimulate a range of adverse health effects (e.g., general toxicity, allergenic reactions, mutagenicity, and carcinogenicity). We have previously presented quantitative structure-activity relationships (QSARs) for the genotoxicity of simple and alpha,beta-unsaturated aliphatic aldehydes. In this study, we show that the QSAR models are able to correctly predict--based only on the knowledge of the chemical structure--the genotoxicity of other aldehydes, not considered in the development phase of the models. This adds confidence to the reliability of our QSAR models as tools for the theoretical assessment of the genotoxic hazard posed by aldehydes. The analysis of SOS Chromotest induction ability and the ease of formation of DNA adducts by the aldehydes provided further mechanistic insights.

A versatile new method has been developed as a continuous symmetry measure for chiral compounds. The application of principal component analysis (PCA) to the complete N x N pairwise similarity matrices (electrostatic potential and shape indices) of a series of dihydropyridine calcium channel antagonists allowed to single out a chirality component and to compute a chirality score in terms of the between-enantiomers difference on the component value. The possibility to have chirality defined continuously at the series level could be of importance in eudismic analyses where the relative potency of two enantiomers is studied as well as in QSAR studies dealing with chiral molecules in order to improve the power of the generated models.