Acute Toxicity Associated with Use of 5F-Derivations of Synthetic Cannabinoid Receptor Agonists with Analytical Confirmation

Abouchedid, Rachelle; Ho, James H; Hudson, Simon; Dines, Alison; Archer, John R. H.; Wood, David M.

doi:10.1007/s13181-016-0571-7

Cited by 33 publications

(16 citation statements)

References 27 publications

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“…Exposure to NPS can result in significant health risks as demonstrated by frequent reports on toxic effects and fatal intoxications. [3][4][5][6][7] Therefore, clinical and forensic toxicologists should be able to reliably detect an intake of NPS. Both parent compounds and metabolites can be suitable screening targets in human biosamples, which are especially important for the development of urine screening approaches.…”

Section: Introductionmentioning

confidence: 99%

Phenethylamine‐derived new psychoactive substances 2C‐E‐FLY, 2C‐EF‐FLY, and 2C‐T‐7‐FLY: Investigations on their metabolic fate including isoenzyme activities and their toxicological detectability in urine screenings

Wagmann

Hempel

Richter

et al. 2019

Drug Testing and Analysis

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Psychoactive substances of the 2C‐series are phenethylamine‐based designer drugs that can induce psychostimulant and hallucinogenic effects. The so‐called 2C‐FLY series contains rigidified methoxy groups integrated in a 2,3,6,7‐tetrahydrobenzo[1,2‐b:4,5‐b']difuran core. The aim of the presented work was to investigate the in vivo and in vitro metabolic fate including isoenzyme activities and toxicological detectability of the three new psychoactive substances (NPS) 2C‐E‐FLY, 2C‐EF‐FLY, and 2C‐T‐7‐FLY to allow clinical and forensic toxicologists the identification of these novel compounds. Rat urine, after oral administration, and pooled human liver S9 fraction (pS9) incubations were analyzed by liquid chromatography−high‐resolution tandem mass spectrometry (LC−HRMS/MS). By performing activity screenings, the human isoenzymes involved were identified and toxicological detectability in rat urine investigated using standard urine screening approaches (SUSAs) based on gas chromatography (GC)−MS, LC−MSn, and LC−HRMS/MS. In total, 32 metabolites were tentatively identified. Main metabolic steps consisted of hydroxylation and N‐acetylation. Phase I metabolic reactions were catalyzed by CYP2D6, 3A4, and FMO3 and N‐acetylation by NAT1 and NAT2. Methoxyamine was used as a trapping agent for detection of the deaminated metabolite formed by MAO‐A and B. Interindividual differences in the metabolism of the 2C‐FLY drugs could be caused by polymorphisms of enzymes involved or drug–drug interactions. All three SUSAs were shown to be suitable to detect an intake of these NPS but common metabolites of 2C‐E‐FLY and 2C‐EF‐FLY have to be considered during interpretation of analytical findings.

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Section: Introductionmentioning

confidence: 99%

Phenethylamine‐derived new psychoactive substances 2C‐E‐FLY, 2C‐EF‐FLY, and 2C‐T‐7‐FLY: Investigations on their metabolic fate including isoenzyme activities and their toxicological detectability in urine screenings

Wagmann

Hempel

Richter

et al. 2019

Drug Testing and Analysis

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“…24 Higher odds of seizures in adolescent SC exposures are consistent with previous investigations of the ToxIC Case Registry 12,18,19 and comparable to adult studies on biochemically confirmed SC-related poisonings. 25 Presentation of SC-related seizures appears to be specifically associated with acute toxicity and has not been shown to be a lasting sequela, as shown in 1 case series. 26 Analysis of the SC-only group in our study also identified an increased association with coma and/or CNS depression than in cannabis-only exposures.…”

Section: Discussionmentioning

confidence: 82%

Neuropsychiatric Sequelae in Adolescents With Acute Synthetic Cannabinoid Toxicity

Anderson¹,

Oprescu

Calello

et al. 2019

Pediatrics

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BACKGROUND AND OBJECTIVES: Adolescents represent the largest age group that presents to emergency departments (ED) for synthetic cannabinoid (SC) toxicity; however, the neurotoxic effects of acute SC exposures in this group are understudied. Our aim was to characterize the neuropsychiatric presentation of adolescents with SC-related exposure in the ED compared with those with traditional cannabis exposure. METHODS: A multicenter registry of clinical information prospectively collected by medical toxicologists (Toxicology Investigators Consortium Case Registry) was reviewed for adolescents presenting to the ED after SC or cannabis exposure from 2010 through 2018. Associations were measured between drug exposures and neuropsychiatric symptoms and/or signs. Exposures were classified into 4 groups: SC-only exposure, SC-polydrug exposures, cannabis-only exposure, and cannabis-polydrug exposures. RESULTS: Adolescents presenting to the ED with SC-only exposure (n = 107) had higher odds of coma and/or central nervous system depression (odds ratio [OR] 3.42; 95% confidence interval [CI] 1.51–7.75) and seizures (OR 3.89; 95% CI 1.39–10.94) than those with cannabisonly exposure (n = 86). SC-only drug exposure was associated with lower odds of agitation than cannabis-only exposure (OR 0.18; 95% CI 0.10–0.34). In contrast, the group with SC-polydrug exposures (n = 38) had higher odds of agitation (OR 3.11; 95% CI 1.56–7.44) and seizures (OR 4.8; 95% CI 1.80–12.74) than the cannabis-polydrug exposures group (n = 117). CONCLUSIONS: In this multisite cohort of US adolescents assessed in the ED, SC exposure was associated with higher odds of neuropsychiatric morbidity than cannabis exposure providing a distinct neurospychiatric profile of acute SC toxicity in adolescents.

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“…Though these interesting data prompted us to further investigate their effects upon chronic use, the toxicological study of these rimonabant/Fubinaca hybrids should be a primary issue. Documented side effects of Fubinaca series compounds are impaired driving, acute psychiatric distress, aggressiveness and polysubstance abuse with several SCs and alcohol [59,60,61,62,63,64]. These effects are also correlated to populations’ changes in consuming SCs, such as incarcerated persons, homeless, and their cultural heritage [65,66,67].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Orexant and Anorexant Agents with Indazole Scaffold Endowed with Peripheral Antiedema Activity

et al. 2019

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The endocannabinoid system represents an integrated neuronal network involved in the control of several organisms’ functions, such as feeding behavior. A series of hybrids of 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (mimonabant), a well-known inverse agonist of the type-1 cannabinoid receptor (CB1), once used as an antiobesity drug, and the N-(2S)-substitutes of 1-[(4-fluorophenyl)methyl]indazole-3-carboxamide with 1-amino-3-methyl-1-oxobutane (AB-Fubinaca), 1-amino-3,3-dimethyl-1-oxobutane (ADB-Fubinaca), and 3-methylbutanoate (AMB-Fubinaca), endowed with potent agonistic activity towards cannabinoid receptors CB1 and CB2 were in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied by binding assays to cannabinoid receptors and by functional receptor assays, using rat brain membranes in vitro. The most active among them as an agonist, (S)-1-(2,4-dichlorobenzyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-1H-indazole-3-carboxamide (LONI11), and an antagonist, (S)-2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoic acid (LONI4), were tested in vivo in mic, to evaluate their ability to stimulate or suppress feeding behavior after intraperitoneal (i.p.) administration. For a LONI11 formalin test and a tail flick test after an administration by the subcutaneous (s.c.) and intracerebroventricular (i.c.v.) routes, respectively, were also carried out in vivo in mice to investigate the antinociceptive property at the central and peripheral levesl. We observed a significant orexant effect for LONI11 and an intense anorexant effect for (S)-methyl 2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (LONI2) and LONI4. In zymosan-induced edema and hyperalgesia, LONI11 reduced the percent of paw volume increase and paw latency after s.c. administration, also suggesting a possible peripheral anti-inflammatory activity.

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Acute Toxicity Associated with Use of 5F-Derivations of Synthetic Cannabinoid Receptor Agonists with Analytical Confirmation

Cited by 33 publications

References 27 publications

Phenethylamine‐derived new psychoactive substances 2C‐E‐FLY, 2C‐EF‐FLY, and 2C‐T‐7‐FLY: Investigations on their metabolic fate including isoenzyme activities and their toxicological detectability in urine screenings

Phenethylamine‐derived new psychoactive substances 2C‐E‐FLY, 2C‐EF‐FLY, and 2C‐T‐7‐FLY: Investigations on their metabolic fate including isoenzyme activities and their toxicological detectability in urine screenings

Neuropsychiatric Sequelae in Adolescents With Acute Synthetic Cannabinoid Toxicity

Discovery of Orexant and Anorexant Agents with Indazole Scaffold Endowed with Peripheral Antiedema Activity

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