Fatal intoxication with new synthetic cannabinoids 5F-MDMB-PICA and 4F-MDMB-BINACA—parent compounds and metabolite identification in blood, urine and cerebrospinal fluid

Abstract

Synthetic cannabinoids (SCs) remain one of the largest groups of new psychoactive substances. Recently, new synthetic cannabinoids 5F-MDMB-PICA and 4F-MDMB-BINACA are increasing in popularity. A 33-year-old man lost consciousness after smoking an unknown substance. A glass pipe and two lumps of substance that turned out to contain 5F-MDMB-PICA and 4F-MDMB-BINACA were found at the scene. Blood, urine and cerebrospinal fluid were collected during the examination of the body. The synthetic cannabinoids were isolated from autopsy materials by precipitation with acetonitrile and extraction with ethyl acetate. The screening and quantitative analyses were performed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The liquid chromatography-quadrupole/time of flight mass spectrometry (LC-Q/TOF) technique was used for metabolite identification. 5F-MDMB-PICA was detected and quantified in all analysed materials, whereas 4F-MDMB-BINACA was found only in cerebrospinal fluid. The determined concentrations of 5F-MDMB-PICA were 0.9 (blood), 0.1 (urine) and 3.2 ng/mL (cerebrospinal fluid). The concentration of 4F-MDMB-BINACA in cerebrospinal fluid was 0.1 ng/mL. The main metabolites of both compounds (hydrolysis and oxidative defluorination) were found in all analysed body fluids. Cerebrospinal fluid may be important alternative material in autopsy cases. Rapid elimination of 5F-MDMB-PICA and 4F-MDMB-BINACA compounds also means that the metabolite analysis can be crucial for the investigation. Laboratories must be made aware of their presence and incorporate these SCs and their metabolites into workflows for detection and confirmation. Ester hydrolysis and oxidative defluorination products can be found in blood, urine and cerebrospinal fluid making them useful biomarkers of intake.

Synthesis and pharmacological evaluation of newly detected synthetic cannabinoid receptor agonists AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA, MDMB-4F-BUTINACA and their analogs

“…AMB-4CN-BUTINACA), respectively, were identified in Alabama, facilitated by proactive reference standard generation and toxicological screening by our laboratories ( Figure 2 ) ( 42 , 43 ). The 4-fluorobutyl compounds MDMB-4F-BUTICA (7) and MDMB-4F-BUTINACA (8) were also recently detected, with the latter involved in a suicide, as well as multiple fatal intoxications ( 7 , 31 , 44 – 49 ). With the appearance of these compounds, it is feasible that NPS manufacturers may introduce the 4-fluorobutyl or 4-cyanobutyl subunits to other amino acid-derived indole-, indazole- and 7-azaindole-3-carboxamide SCRAs in future.…”

Humanized CB1R and CB2R yeast biosensors enable facile screening of cannabinoid compounds

“…The compound 4-fluoro ADB showed the greatest sensitivity amongst compounds tested (EC 50 of 1.35 nM, Fig. 3E), is known to be highly active at cannabinoid receptors, and is implicated in at least one death from overdose 13 . nM, respectively (Fig.…”

“…The compound 4-fluoro ADB showed the greatest sensitivity amongst compounds tested (EC 50 of 1.35 nM, Fig. 3E), is known to be highly active at cannabinoid receptors, and is implicated in at least one death from overdose 13 . Similarly, the compounds A-836339 and A-834375 both have a tetramethylcyclopropylmethanone group adjacent to the carbonyl, which is known to confer CB2R bias and strong signaling 40 , while A-834735 and 5-fluoro PB22 share the indole moieties common to many synthetic cannabinoids.…”

“…Many synthetic cannabinoids are much tighter binders to cannabinoid receptors than THC, and are often sold as mixtures uncharacterized for human use 10 . Together, the high potency and lack of regulation of these compounds have led to many cases of adverse effects from recreational use, including acute psychosis, seizures, dependence and death 10–13 . Governments have attempted to regulate these compounds, but regulation remains a challenge as new compounds and analogs of existing ones are created frequently that evade restriction 10 .…”

“…Many synthetic cannabinoids are much tighter binders to cannabinoid receptors than THC, and are often sold as mixtures uncharacterized for human use 10 . Together, the high potency and lack of regulation of these compounds have led to many cases of adverse effects from recreational use, including acute psychosis, seizures, dependence and death [10][11][12][13] .…”