Background: Currently, there is a great interest in the potential medical use of cannabidiol (CBD), a non-intoxicating cannabinoid. Productive pharmacological research on CBD occurred in the 1970s and intensified recently with many discoveries about the endocannabinoid system. Multiple preclinical and clinical studies led to FDA-approval of Epidiolex®, a purified CBD medicine formulated for oral administration for the treatment of infantile refractory epileptic syndromes, by the US Food and Drug Administration in 2018. The World Health Organization considers rescheduling cannabis and cannabinoids. CBD use around the world is expanding for diseases that lack scientific evidence of the drug’s efficacy. Preclinical and clinical studies also report adverse effects (AEs) and toxicity following CBD intake. Methods: Relevant studies reporting CBD’s AEs or toxicity were identified from PubMed, Cochrane Central, and EMBASE through January 2019. Studies defining CBD’s beneficial effects were included to provide balance in estimating risk/benefit. Results: CBD is not risk-free. In animals, CBD AEs included developmental toxicity, embryo-fetal mortality, central nervous system inhibition and neurotoxicity, hepatocellular injuries, spermatogenesis reduction, organ weight alterations, male reproductive system alterations, and hypotension, although at doses higher than recommended for human pharmacotherapies. Human CBD studies for epilepsy and psychiatric disorders reported CBD-induced drug-drug interactions, hepatic abnormalities, diarrhea, fatigue, vomiting, and somnolence. Conclusion: CBD has proven therapeutic efficacy for serious conditions such as Dravet and Lennox-Gastaut syndromes and is likely to be recommended off label by physicians for other conditions. However, AEs and potential drug-drug interactions must be taken into consideration by clinicians prior to recommending off-label CBD.

Background: Synthetic benzimidazole opioids (BOs) are highly potent µ-opioid receptor agonists with heroin-like effects. Isotonitazene was first available in 2019 in the drug market, although new analogs have multiplied recently. The authors aimed to identify BO use trends and gather toxicological data from BO-related cases to assist in clinical and forensic investigations. Methods: A systematic literature search was conducted according to the PRISMA guidelines. PubMed and Scopus databases were accessed in October 2021 to identify scientific reports of BO-related intoxication and fatalities. Publication dates, case descriptions, symptoms, autopsy findings, and concentrations of BOs and metabolites in biological matrices were compiled. Results: Data from 8 case reports with 93 fatalities involving isotonitazene (n = 65), metonitazene (n = 20), etonitazepyne (N-pyrrolidino etonitazene) (n = 8), flunitazene (n = 4), and/or butonitazene (n = 1), and 1 acute intoxication involving etonitazepyne were collected. Autopsy findings included pulmonary congestion/high lung weight (66%), cardiomegaly/high cardiac weight (39%), cerebral edema (22%), gastric contents in the airways (22%), and organ congestion (22%). Median peripheral blood concentrations were 1.7 ng/mL for isotonitazene (0.4–9.5 ng/mL, n = 13), 5.4 ng/mL for metonitazene (0.52–33 ng/mL, n = 17), 5.4 ng/mL for etonitazepyne (2.4–8.3 ng/mL, n = 2), 1.3 ng/mL for flunitazene (0.58–2.1 ng/mL, n = 2), and 3.2 ng/mL for butonitazene (n = 1). Central nervous system depressants were almost always coadministered. Conclusions: Isotonitazene was predominant in cases from 2019 to mid-2020 and was replaced by metonitazene after scheduling in the United States. Typical findings on opioid overdoses have been reported. Peripheral blood concentrations were consistent with a potency similar to that of fentanyl. These results must be interpreted carefully, considering the scarcity of reports on BO-related cases and drug co-exposures.

Recently, synthetic opioid-related overdose fatalities, led by illicitly manufactured fentanyl and analogs, increased at an alarming rate, posing a global public health threat. New synthetic fentanyl analogs have been constantly emerging onto the drug marked for the last few years, to circumvent the laws and avoid analytical detection. Analytical methods need to be regularly updated to keep up with the new trends. In this study, we aimed to develop a new method for detecting the newest fentanyl analogs with a high sensitivity, in whole blood, urine, and hair. The method is intended to provide to clinical and forensic toxicologists a tool for documenting consumption. We developed a comprehensive ultra-high-performance liquid chromatography-tandem mass spectrometry method for quantifying fentanyl and 22 analogs and metabolites. Urine samples were simply diluted before injection; a liquid-liquid extraction was performed for blood testing; and a solid phase extraction was performed in hair. The chromatographic separation was short (8 min). The method was validated with a high sensitivity; limits of quantifications ranged from 2 to 6 ng/L in blood and urine, and from 11 to 21 pg/g in hair. The suitability of the method was tested with 42 postmortem blood, urine, or hair specimens from 27 fatalities in which fentanyl analogs were involved. Average blood concentrations (±SD) were 7.84 ± 7.21 and 30.0 ± 18.0 μg/L for cyclopropylfentanyl and cyclopropyl norfentanyl, respectively (n = 8), 4.08 ± 2.30 μg/L for methoxyacetylfentanyl, (n = 4), 40.2 ± 38.6 and 44.5 ± 21.1 μg/L for acetylfentanyl and acetyl norfentanyl, respectively (n = 3), 33.7 and 7.17 μg/L for fentanyl and norfentanyl, respectively (n = 1), 3.60 and 0.90 μg/L for furanylfentanyl and furanyl norfentanyl, respectively (n = 1), 0.67 μg/L for sufentanil (n = 1), and 3.13 ± 2.37 μg/L for 4-ANPP (n = 9). Average urine concentrations were 47.7 ± 39.3 and 417 ± 296 μg/L for cyclopropylfentanyl and cyclopropyl norfentanyl, respectively (n = 11), 995 ± 908 μg/L for methoxyacetylfentanyl, (n = 3), 1,874 ± 1,710 and 6,582 ± 3,252 μg/L for acetylfentanyl and acetyl norfentanyl, respectively (n = 5), 146 ± 318 and 300 ± 710 μg/L for fentanyl (n = 5) and norfentanyl (n = 6), respectively, 84.0 and 23.0 μg/L for furanylfentanyl and furanyl norfentanyl, respectively (n = 1), and 50.5 ± 50.9 μg/L for 4-ANPP (n = 10). Average hair concentrations were 2,670 ± 184 and 82.1 ± 94.7 ng/g for fentanyl and norfentanyl, respectively (n = 2), and 10.8 ± 0.57 ng/g for 4-ANPP (n = 2).

BACKGROUND: ADB-PINACA and its 5-fluoropentyl analog 5F-ADB-PINACA are among the most potent synthetic cannabinoids tested to date, with several severe intoxication cases. ADB-PINACA and 5F-ADB-PINACA have a different legal status, depending on the country. Synthetic cannabinoid metabolites predominate in urine, making detection of specific metabolites the most reliable way for proving intake in clinical and forensic specimens. However, there are currently no data on ADB-PINACA and 5F-PINACA metabolism. The substitution of a single fluorine atom distinguishes the 2 molecules, which may share common major metabolites. For some legal applications, distinguishing between ADB-PINACA and 5F-PINACA intake is critical. For this reason, we determined the human metabolic fate of the 2 analogs.METHODS: ADB-PINACA and 5F-PINACA were incubated for 3 h with pooled cryopreserved human hepatocytes, followed by liquid chromatography—high-resolution mass spectrometry analysis. Data were processed with Compound Discoverer.RESULTS: We identified 19 and 12 major ADB-PINACA and 5F-ADB-PINACA metabolites, respectively. Major metabolic reactions included pentyl hydroxylation, hydroxylation followed by oxidation (ketone formation), and glucuronidation of ADB-PINACA, and oxidative defluorination followed by carboxylation of 5F-ADB-PINACA.CONCLUSIONS: We recommend ADB-PINACA ketopentyl and hydroxypentyl, and ADB-PINACA 5-hydroxypentyl and pentanoic acid, as optimal markers for ADB-PINACA and 5F-ADB-PINACA intake, respectively. Since the 2 compounds present positional isomers as the primary metabolites, monitoring unique product ions and optimized chromatographic conditions are required for a clear distinction between ADB-PINACA and 5F-ADB-PINACA intake.