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.

Background: During the last two years, hexahydrocannabinol (HHC), the hydrogenated derivative of tetrahydrocannabinol has been freely sold by internet websites as a “legal” replacement to THC and cannabis in a range of highly attractive branded and unbranded products, some of which are sold as “legal highs”. Potentially, there could be a large demand for HHC products by individuals in Europe and internationally. Methods: Studies reporting HHC pharmacology, toxicology and analysis were identified from Pubmed and Scopus databases, and official international organizations’ websites were considered. Results: HHC showed the effects of the typical cannabinoid on the central nervous system, with lower potency than Δ9-THC. A few studies highlighted that 9(R)-HHC is more potent than 9(S)-HHC. This molecule showed an affinity for cannabinoid receptor CB1 both in vitro and in vivo, suggesting a possible therapeutic effect in several pathologies. However, the affinity for the CB1 receptor suggests a possible addiction potential, inducing the users to misuse it. Since actual intoxication cases have not yet been reported, the HHC harmful potential was not described, probably due to the lack of effective analytical methods to detect HHC in biological matrices. Conversely, different analytical assays were developed and validated to separate HHC epimers in natural and non-natural sources. Conclusion: Similarly to other NPS, the HHC represents a cheaper alternative to the controlled Δ9-THC. Its monitoring is a crucial challenge for toxicological and forensic purposes. To this concern, it is essential to further investigate HHC to support health providers in the identification of related intoxications.

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.

The aim of this study was to determine the excretion of methylone and its metabolites in sweat following the ingestion of increasing controlled doses of 50, 100, 150 and 200 mg of methylone to twelve healthy volunteers involved in a clinical trial. Methylone and its metabolites 4-hydroxy-3-methoxy-N-methylcathinone (HMMC) and 3,4-methylenedioxycathinone (MDC) were analyzed in sweat patches by liquid chromatography–tandem mass spectrometry. Methylone and MDC were detected in sweat at 2 h and reached their highest accumulation (C_max) at 24 h after the administration of 50, 100, 150 and 200 mg doses. In contrast, HMMC was not detectable at any time interval after each dose. Sweat proved to be a suitable matrix for methylone and its metabolites’ determination in clinical and toxicological studies, providing a concentration that reveals recent drug consumption.