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.

The internet and social networking sites play a significant role in the marketing, sale and the distribution of drugs. The internet is being used both as a source of information and communication but also as a tool to disseminate drug-related websites and sell controlled substances without prescriptions. Our review aims to obtain knowledge concerning the profile of the online drug consumer and the determinants of internet preference. PubMed, Google Scholar and Scopus databases were searched without any language limitations by using a set of keywords. For each set of keywords we evaluated all articles providing socio-demographic characteristics of online drug consumers; reasons for purchasing online drugs; risks related to the online shopping of medicaments and features of illicit/legitimate commercial sites. All data has been analysed and compared for these specified clusters. Results report a majority of Caucasian males in their twenties, both in internet users and drug user/abusers. Several studies reported that the men usually perceive less risks, are more likely to turn to the internet as a source of prescription drugs and, subsequently, more likely to buy drugs and illegal substances online. On the other hand, women were noted as more likely to search for health information. The protection of identity by screen pseudonyms, variety and quality of product listings, selection of vendors based on review feedbacks, reduced personal risks, forum activity and the availability of a service for prescriptiononly drugs stimulate the growth and development of both OPs and drug marketplaces.

Synthetic cannabinoids (SCs) remain one of the largest groups of new psychoactive substances (NPS) on the European drug market. Although the number of new derivatives occurring on the market has dropped in the last two years, newly emerging NPS still represent a challenge for laboratories performing forensic drug analysis in biological matrices. The newly emerged SC 4F‐MDMB‐BINACA has been reported by several law enforcement agencies in Europe and the USA since November 2018. This work aimed at revealing urinary markers to prove uptake of 4F‐MDMB‐BINACA and differentiate from the use of structurally similar SCs. Phase‐I metabolites detected in human urine specimens were confirmed by phase‐I metabolites generated in vitro using a pooled human liver microsomes (pHLM) assay. Seized materials and test‐purchased “legal high” products were analyzed by gas chromatography–mass spectrometry (GC–MS) and liquid chromatography−quadrupole‐time‐of‐flight−mass spectrometry (LC−qToF−MS). Human urine specimens and pHLM assay extracts were measured with liquid chromatography−electrospray ionization−tandem mass spectrometry (LC−ESI−MS/MS) and confirmed by LC−qToF−MS. In January 2019, the Institute of Legal Medicine in Erlangen (Germany) identified 4F‐MDMB‐BINACA in three herbal blends. During the same time period, the described SC was identified in a research chemical purchased online. Investigation of phase‐I metabolism led to the metabolites M10 (ester hydrolysis) and M11 (ester hydrolysis and dehydrogenation) as reliable urinary markers. Widespread distribution on the German drug market was proven by analysis of urine samples from abstinence control programs and by frequent detection of 4F‐MDMB‐BINACA in “herbal blends” and “‘research chemicals” purchased via the Internet.

Purpose Cumyl-PEGACLONE was the first synthetic cannabinoid (SC) with a γ-carbolinone core structure detected in forensic casework and, since then, it has dominated the German SC-market. Here the first four cases of death involving its fluorinated analog, 5F-Cumyl-PEGACLONE, a recently emerged γ-carbolinone derived SC, are reported. Methods Complete postmortem examinations were performed. Postmortem samples were screened by immunoassay, gas chromatography mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry. For quantification of SCs, the standard addition method was employed. Herbal blends were analyzed by GC-MS. In each case of death, the Toxicological Significance Score (TSS) was assigned to the compound. Results 5F-Cumyl-PEGACLONE was identified at concentrations ranging 0.09-0.45 ng/mL in postmortem femoral blood. In case 1, signs of hypothermia and kidney bleedings were noted. Despite a possible tolerance due to long term SC use, a TSS of 3 was assigned. In case 2, an acute heroin intoxication occurred and a contributory role (TSS = 1) of 5F-Cumyl-PEGACLONE was suggested. In case 3, a prisoner was found dead. GC-MS analysis of herbal blends, retrieved in his cell together with paraphernalia, confirmed the presence of 5F-Cumyl-PEGACLONE and a causative role was deemed probable (TSS = 2). In case 4, the aspiration of gastric content due to a SC-induced coma was observed (TSS = 3). Conclusions 5F-Cumyl-PEGACLONE is an emerging and extremely potent SC which raises serious public health concerns. A comprehensive analysis of circumstantial, clinical, and postmortem findings, as well as an in-depth toxicological analysis is necessary for a valid interpretation and for the assessment of the toxicological significance.

Synthetic cannabinoids (SC) remain one of the largest groups of new psychoactive substances (NPS) on the European drug market. In December 2018, Cumyl-CH-MEGACLONE, a novel SC based on a γ-carboline-1-one core structure was firstly identified in Hungary, and later also other European countries. This work aims to reveal the pharmacological characteristics and phase-I metabolism of Cumyl-CH-MEGACLONE and compare the data to its analogs Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE. The purified substance was characterized by means of gas chromatography–mass spectrometry (GC–MS), liquid chromatophraphy–quadrupole-time-of-flight-mass-spectrometry (LC–QToF-MS), attenuated-total-reflection-infrared-spectroscopy (ATR-FTIR) and nuclear-magnetic-resonance-spectroscopy (NMR). Phase-I metabolites were identified by LC–QToF-MS analysis combined with a scheduled precursor ion list of authentic urine samples and confirmed by comparison with metabolites built in vitro by pooled human liver microsome assays (pHLM). Pharmacological data was obtained in a competitive ligand binding assay and a receptor activation assay at the human cannabinoid receptor 1 (hCB1). The structure of 5-cyclohexylmethyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (semisystematic name: Cumyl-CH-MEGACLONE) was identified in a herbal blend as the main active ingredient. Investigation of phase-I biotransformation of Cumyl-CH-MEGACLONE led to three monohydroxylated metabolites (M08, M10 and M13) as reliable urinary markers for proof of consumption. At the hCB1, Cumyl-CH-MEGACLONE shows high binding affinity with Ki = 1.01 nM (2.5-fold higher than JWH-018), an EC50 of 1.22 nM and high efficacy with EMAX = 143.4% above constitutive activity of the receptor (1.13-fold higher than JWH-018). Comparison to the analogs 5F-Cumyl-PEGACLONE and Cumyl-PEGACLONE (both are hCB1 full agonists carrying a 5-fluoropentyl or pentyl chain instead of the cyclohexylmethyl (CHM) moiety) suggests that Cumyl-CH-MEGACLONE is more likely to resemble the pharmacologic profile of the latter one.

In June 2018, a 'research chemica'l labeled 'AB‐FUB7AICA' was purchased online and analytically identified as 5F‐AB‐P7AICA, the 7‐azaindole analog of 5F‐AB‐PINACA. Here we present data on structural characterization, suitable urinary consumption markers, and preliminary pharmacokinetic data. Structure characterization was performed by nuclear magnetic resonance spectroscopy, gas chromatography–mass spectrometry, infrared and Raman spectroscopy. Phase I metabolites were generated by applying a pooled human liver microsome assay (pHLM) to confirm the analysis results of authentic urine samples collected after oral self‐administration of 2.5 mg 5F‐AB‐P7AICA. Analyses of pHLM and urine samples were performed by liquid chromatography−time‐of‐flight mass spectrometry and liquid chromatography–tandem mass spectrometry (LC–MS/MS). An LC–MS/MS method for the quantification of 5F‐AB‐P7AICA in serum was validated. Ten phase I metabolites were detected in human urine samples and confirmed in vitro. The main metabolites were formed by hydroxylation, amide hydrolysis, and hydrolytic defluorination, though – in contrast with most other synthetic cannabinoids – the parent compound showed the highest signals in most urine samples. The compound detection window was more than 45 hours in serum. The concentration‐time profile was best explained by a two‐phase pharmacokinetic model. 5F‐AB‐P7AICA was detected in urine samples until 65 hours post ingestion. Monitoring of metabolite M07, hydroxylated at the alkyl chain, next to parent 5F‐AB‐P7AICA, is recommended to confirm the uptake of 5F‐AB‐P7AICA in urinalysis. It seems plausible that the shift of the nitrogen atom from position 2 to 7 (e.g. 5F‐AB‐PINACA to 5F‐AB‐P7AICA) leads to a lower metabolic reactivity, which might be of general interest in medicinal chemistry.

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GHB causes cognitive and psychomotor impairment and risky driving behavior. Multiple aspects and variables are still waiting clarification, such as the harmful potential of illicit preparations, the effect of precursors and impairing dosages. GHB (and its precursors) must be considered a substantial personal and public risk even in the absence of a clear dose-effects correlation.