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Background: Synthetic cannabinoid receptor agonists (SCRAs) have become the largest group of new psychoactive substances monitored by the European Union Early Warning System. Despite the wide diffusion on the market, data regarding effects, toxicities, and mechanisms as well as toxic/lethal doses are still scarce. Methods: A comprehensive literature search for articles published up to January 2019 was performed in multiple electronic databases. Only cases of death in which toxicological analyses revealed the presence of SCRAs in blood or urine and at least an external examination was performed, including those occurred in emergency departments, were included. Results: Of 380 studies identified, 354 were excluded, while 8 additional manuscripts were included through the screening of relevant references cited in the selected articles. A total number of 34 manuscripts (8 case series and 26 case reports) were included. Conclusions: Typical toxic ranges for SCRAs have not been so far identified, and the results of toxicological analyses should be interpreted with caution. In death cases involving SCRAs, a thorough post-mortem examination is a prerequisite to assess the role of the substance use in the deceased and to identify a probable mechanism of death. Even after a comprehensive analysis of clinical, circumstantial, toxicological, and autoptic data, the cause and manner of death remain unclear in some cases.

BACKGROUND: Synthetic cannabinoid receptor agonists (SCRAs) have become the largest group of new psychoactive substances monitored by the European Union Early Warning System. Despite the wide diffusion on the market, data regarding effects, toxicities, and mechanisms as well as toxic/lethal doses are still scarce. METHODS: A comprehensive literature search for articles published up to January 2019 was performed in multiple electronic databases. Only cases of death in which toxicological analyses revealed the presence of SCRAs in blood or urine and at least an external examination was performed, including those occurred in emergency departments, were included. RESULTS: Of 380 studies identified, 354 were excluded, while 8 additional manuscripts were included through the screening of relevant references cited in the selected articles. A total number of 34 manuscripts (8 case series and 26 case reports) were included. CONCLUSIONS: Typical toxic ranges for SCRAs have not been so far identified, and the results of toxicological analyses should be interpreted with caution. In death cases involving SCRAs, a thorough post-mortem examination is a prerequisite to assess the role of the substance use in the deceased and to identify a probable mechanism of death. Even after a comprehensive analysis of clinical, circumstantial, toxicological, and autoptic data, the cause and manner of death remain unclear in some cases.

Synthetic cannabinoids (SCs) represent a large group of new psychoactive substances (NPS), sustaining a high prevalence on the drug market since their first detection in 2008. Cumyl‐CBMICA and Cumyl‐CBMINACA, the first representatives of a new subclass of SCs characterized by a cyclobutyl methyl (CBM) moiety, were identified in July 2019 and February 2020. This work aimed at evaluating basic pharmacological characteristics and human phase‐I‐metabolism of these compounds. Human phase‐I metabolites were tentatively identified by liquid‐chromatography–quadrupole‐time‐of‐flight‐mass‐spectrometry (LC‐QToF‐MS) of urine samples and confirmed by a pooled‐human‐liver‐microsome (pHLM) assay. The basic pharmacological evaluation was performed applying a competitive ligand binding assay and a functional activation assay (GTPγS) using cell membranes carrying the human cannabinoid receptor 1 (hCB1). Investigation of the human phase‐I‐metabolism resulted in the identification of specific urinary markers built by mono‐ or dihydroxylation. While Cumyl‐CBMICA was primarily hydroxylated at the indole ring, hydroxylation of Cumyl‐CBMINACA mainly occurred at the CBM moiety. Both substances acted as agonists at the hCB1 receptor, although substantial differences could be observed. Cumyl‐CBMINACA showed higher binding affinity (Ki = 1.32 nM vs. 29.3 nM), potency (EC50 = 55.4 nM vs. 497 nM) and efficacy (Emax = 207% vs. 168%) than its indole counterpart Cumyl‐CBMICA. This study confirms that substitution of an indole by an indazole core tends to increase in vitro potency which is potentially reflected by higher in vivo potency. The emergence and disappearance of SCs distributed via online shops carrying a CBM moiety once more demonstrates the "cat‐and‐mouse" game between manufacturers and legislation.

Since the beginning of the phenomenon of new psychoactive substances (NPS), synthetic cannabinoid receptor agonists (SCRAs) have been the largest and most prevalent subclass of these drugs in Europe. Many countries implemented specific legislation scheduling classes of substances defined on the basis of their chemical structure to reduce supply. We describe the identification and analytical characterization within the EU project ADEBAR plus of 1‐(cyclobutylmethyl)‐N‐(2‐phenylpropan‐2‐yl)‐1H‐indole‐3‐carboxamide which resulted in the formal notification through the Early Warning System of the European Monitoring Centre for Drug and Drug Addiction (EMCDDA). This is the first identification of this new SCRA worldwide and the analytical data was distributed (inter‐)nationally right after identification in 2019. First, the substance was isolated from the herbal material using preparative high‐performance liquid chromatography (HPLC). Structure elucidation and analytical characterization were performed using gas chromatography–mass spectrometry (GC–MS), gas chromatography‐solid state infrared spectroscopy (GC‐sIR), liquid chromatography‐electrospray ionization‐quadrupole time of flight‐mass spectrometry (LC‐ESI‐qToF‐MS), Raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. The new compound contains a cyclobutyl methyl group as a side chain and has not been described in any patent to our knowledge. Based on the semisystematic nomenclature of SCRAs, we propose Cumyl‐CBMICA as a short name for the compound.

The synthetic cannabinoid receptor agonist (SCRA) market is transnational, and the availability of individual SCRAs changes regularly in response to national and international legislative controls. This generates a cyclic pattern and near constant evolution of SCRA compounds. This study reports toxicology‐based and/or seized sample‐based prevalence data relating to SCRA use in prisons from Germany, the United Kingdom (UK; Scotland and Wales), and the United States (US), representing 4427 individual test results. The study examines SCRA detections in prisons from July 2018 to September 2020, and where possible, prison‐based data are compared with SCRA prevalence data in the wider population. The relative influence of Chinese, other international, and national drug legislation on the prevalence of individual SCRAs in prisons is also considered. tert‐Leucinate‐ and valinate‐indole‐ and indazole‐3‐carboxamides were the most common SCRA detections, and MDMB‐4en‐PINACA was one of the most commonly detected SCRAs in all jurisdictions by September 2020. However, despite there being a global production and supply market, there were notable regional differences. Analog controls in German and US legislation may have led to increased compound diversity that is not reflected in the UK which has both analog controls and a blanket ban on psychoactive substances. While there were regional differences, SCRA prevalence in prisons closely aligned with the SCRAs detected on the local market, demonstrating that SCRA (and possibly other NPS) monitoring programs in prisons can act as early warning systems for the wider population in that given jurisdiction.

Zusammenfassung: Ziele: Die bisherigen Empfehlungen der Deutschen Hauptstelle für Suchtfragen (DHS) zum Umgang mit Alkohol gingen von einem Grenzwert für risikoarmen Konsum aus. Ziel dieser Stellungnahme ist, diese Empfehlung zu aktualisieren. Methode: Es erfolgte eine narrative Sichtung der aktuellen Literatur hinsichtlich des Zusammenhangs von Alkoholkonsum und der Entwicklung von Morbidität und Mortalität durch eine Arbeitsgruppe des Wissenschaftlichen Kuratoriums der DHS. Die Zusammenfassung der Evidenz und die daraus abgeleiteten Empfehlungen wurden innerhalb des gesamten Kuratoriums konsentiert und vom Vorstand der DHS modifiziert beschlossen . Ergebnisse: Ein positiver Zusammenhang von Alkoholkonsum und Gesundheit, wie er in früheren Studien gefunden wurde, ist auf methodische Mängel zurückzuführen. Somit kann nicht von einer gesundheitsförderlichen Wirkung von Alkohol ausgegangen werden. Der Stand der Literatur belegt einen linearen Zusammenhang von Alkoholkonsum und der Entwicklung von Erkrankungen sowie dem vorzeitigen Versterben. Die linearen Beziehungen von Alkoholkonsummengen mit Erkrankungs- oder Sterbewahrscheinlichkeiten betreffen verbreitete Erkrankungen. Schlussfolgerung: Empfehlungen auf der Basis von risikoarmen Trinkmengen lassen sich nicht mehr aufrechterhalten. Stattdessen wird empfohlen, den Alkoholkonsum – unabhängig von der Alkoholtrinkmenge – zu reduzieren. Für die körperliche Gesundheit ist es am besten keinen Alkohol zu trinken.