Exposure to Synthetic Psychoactive Substances: A Potential Cause for Increased Human Hepatotoxicity Markers.

BACKGROUND: Approximately 30 million people worldwide consume new psychoactive substances (NPS), creating a serious public health issue due to their toxicity and potency. Drug-induced liver injury is the leading cause of liver disease, responsible for 4% of global deaths each year. CONTENT: A systematic literature search revealed 64 case reports, in vitro and in vivo studies on NPS hepatotoxicity. Maximum elevated concentrations of aspartate aminotransferase (136 to 15 632 U/L), alanine transaminase (121.5 to 9162 U/L), total bilirubin (0.7 to 702 mg/dL; 0.04 to 39.03 mmol/L), direct (0.2-15.1 mg/dL; 0.01-0.84 mmol/L) and indirect (5.3 mg/dL; 0.29 mmol/L) bilirubin, alkaline phosphatase (79-260 U/L), and gamma-glutamyltransferase (260 U/L) were observed as biochemical markers of liver damage, with acute and fulminant liver failure the major toxic effects described in the NPS case reports. In vitro laboratory studies and subsequent in vivo NPS exposure studies on rats and mice provide data on potential mechanisms of toxicity. Oxidative stress, plasma membrane stability, and cellular energy changes led to apoptosis and cell death. Experimental studies of human liver microsome incubation with synthetic NPS, with and without specific cytochrome P450 inhibitors, highlighted specific enzyme inhibitions and potential drug-drug interactions leading to hepatotoxicity. SUMMARY: Mild to severe hepatotoxic effects following synthetic NPS exposure were described in case reports. In diagnosing the etiology of liver damage, synthetic NPS exposure should be considered as part of the differential diagnosis. Identification of NPS toxicity is important for educating patients on the dangers of NPS consumption and to suggest promising treatments for observed hepatotoxicity.

In vitro, in vivo metabolism and quantification of the novel synthetic opioid N-piperidinyl etonitazene (etonitazepipne).

OBJECTIVES: N-piperidinyl etonitazene (etonitazepipne) is a newly synthesized opioid related to the 2-benzylbenzimidazole analog class. Etonitazepipne has been formally notified and placed under intensive monitoring in Europe in January 2022. Nitazenes have high affinity at µ-opioid receptor (MOR). Etonitazepipne, specifically shows a EC50 of 2.49 nM, suggesting about 50 times higher potency combined with higher efficacy compared to morphine. Antinociceptive potency l ('hot plate test' with rats) was 192-fold greater than that of morphine. METHODS: Here we report on a post-mortem case involving etonitazepipne and its quantification using a standard addition method (SAM) through liquid chromatography tandem mass spectrometry (LC-MS/MS). In addition, characterization and identification of phase I human metabolites using in vitro assay based on pooled human liver microsomes (pHLM) was performed along with the analysis of authentic urine samples by means of high-performance liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). RESULTS: The concentration of etonitazepipne in post-mortem blood and urine was 8.3 and 11 ng/mL, respectively. SAM was validated by assessing the following parameters: intraday and interday repeatability, matrix effect and recovery rate in post-mortem blood. A total of 20 and 14 metabolites were identified after pHLM incubation and urine analysis, respectively. Most pronounced in vitro and in vivo transformations were O-deethylation, hydroxylation, ketone reduction, and combinations thereof. CONCLUSIONS: Considering small traces of the parent drug often found in real cases, the identification of metabolic biomarkers is crucial to identify exposure to this drug. O-deethylated, oxidated metabolites, and combination thereof are proposed as urinary biomarkers along with the parent compound.

QuEChERS Extraction and Simultaneous Quantification in GC-MS/MS of Hexahydrocannabinol Epimers and Their Metabolites in Whole Blood, Urine, and Oral Fluid.

Recently, hexahydrocannabinol (HHC) was posed under strict control in Europe due to the increasing HHC-containing material seizures. The lack of analytical methods in clinical laboratories to detect HHC and its metabolites in biological matrices may result in related intoxication underreporting. We developed and validated a comprehensive GC-MS/MS method to quantify 9(R)-HHC, 9(S)-HHC, 9αOH-HHC, 9ßOH-HHC, 8(R)OH-9(R)-HHC, 8(S)OH-9(S)HHC, 11OH-9(R)HHC, 11OH-9(S)HHC, 11nor-carboxy-9(R)-HHC, and 11nor-carboxy-9(S)-HHC in whole blood, urine, and oral fluid. A novel QuEChERS extraction protocol was optimized selecting the best extraction conditions suitable for all the three matrices. Urine and blood were incubated with ß-glucuronidase at 60 °C for 2 h. QuEChERS extraction was developed assessing different ratios of Na2SO4:NaCl (4:1, 2:1, 1:1, w/w) to be added to 200 µL of any matrix added with acetonitrile. The chromatographic separation was achieved on a 7890B GC with an HP-5ms column, (30 m, 0.25 mm × 0.25 µm) in 12.50 min. The analytes were detected with a triple-quadrupole mass spectrometer in the MRM mode. The method was fully validated following OSAC guidelines. The method showed good validation parameters in all the matrices. The method was applied to ten real samples of whole blood (n = 4), urine (n = 3), and oral fluid (n = 3). 9(R)-HHC was the prevalent epimer in all the samples (9(R)/9(S) = 2.26). As reported, hydroxylated metabolites are proposed as urinary biomarkers, while carboxylated metabolites are hematic biomarkers. Furthermore, 8(R)OH-9(R)HHC was confirmed as the most abundant metabolite in all urine samples.

Molecular Insights of New Psychoactive Substances (NPS) 2.0.

The New Psychoactive Substances (NPS) phenomenon represents an ever-changing global issue, with a number of new molecules entering the illicit market every year in response to international banning laws [...].

Sweat Testing for the Detection of Methylone after Controlled Administrations in Humans.

The aim of this study was to determine the excretion of methylone and its metabolites in sweat following the ingestion of increasing controlled doses of 50, 100, 150 and 200 mg of methylone to twelve healthy volunteers involved in a clinical trial. Methylone and its metabolites 4-hydroxy-3-methoxy-N-methylcathinone (HMMC) and 3,4-methylenedioxycathinone (MDC) were analyzed in sweat patches by liquid chromatography-tandem mass spectrometry. Methylone and MDC were detected in sweat at 2 h and reached their highest accumulation (Cmax) at 24 h after the administration of 50, 100, 150 and 200 mg doses. In contrast, HMMC was not detectable at any time interval after each dose. Sweat proved to be a suitable matrix for methylone and its metabolites' determination in clinical and toxicological studies, providing a concentration that reveals recent drug consumption.

Acute Intoxications and Fatalities Associated With Benzimidazole Opioid (Nitazene Analog) Use: A Systematic Review.

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.

Molecular Insights on New Psychoactive Substances (NPSs).

Currently, more than 1000 molecules have been classified as New Psychoactive Substances (NPSs), and it is reported that, every year, this number increases with new classes of compounds and/or newer generations of NPS families [...].

Molecular Insights and Clinical Outcomes of Drugs of Abuse Adulteration: New Trends and New Psychoactive Substances.

Adulteration is a well-known practice of drug manufacturers at different stages of drug production. The intentional addition of active ingredients to adulterate the primary drug may enhance or mask pharmacological effects or may produce more potent drugs to increase the number of available doses and the dealer's profit. Adulterants found in different drugs change over time in response to different factors. A systematic literature search in PubMed and Scopus databases and official international organizations' websites according to PRISMA guidelines was performed. A total of 724 studies were initially screened, with 145 articles from PubMed and 462 from Scopus excluded according to the criteria described in the Method Section. The remaining 117 records were further assessed for eligibility to exclude articles without sufficient data. Finally, 79 studies were classified as "non-biological" (n = 35) or "biological" (n = 35 case reports; n = 9 case series) according to the samples investigated. Although the seized samples analyses revealed the presence of well-established adulterants such as levamisole for cocaine or paracetamol/acetaminophen for heroin, the reported data disclosed new adulteration practices, such as the use of NPS as cutting agents for classic drugs of abuse and other NPS. For example, heroin adulterated with synthetic cannabinoids or cocaine adulterated with fentanyl/fentalogues raised particular concern. Notably, adulterants play a role in some adverse effects commonly associated with the primary drug, such as levamisole-adulterated cocaine that may induce vasculitis via an autoimmune process. It is essential to constantly monitor adulterants due to their changing availability that may threaten drug consumers' health.

Methylone and MDMA Pharmacokinetics Following Controlled Administration in Humans.

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50-200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d5, MDA-d5 and methylone-d3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with 0.1 mL acidified methanol and evaporated under nitrogen. Samples were reconstituted with a mobile phase and injected into the LC-MS/MS instrument. The method was fully validated according to OSAC guidelines (USA). Methylone plasma concentrations increased in a dose-proportional manner, as demonstrated by the increasing maximum concentration (Cmax) and area under the curve of concentrations (AUC). Methylone Cmax values were reported as 153, 304, 355 and 604 ng/mL, AUC0-24 values were reported as 1042.8, 2441.2, 3524.4 and 5067.9 h·ng/mL and T1/2 values as 5.8, 6.4, 6.9 and 6.4 h following the 50, 100, 150 and 200 mg doses, respectively. Methylone exhibited rapid kinetics with a Tmax of 1.5 h for the 50 mg dose and 2 h approximately after all the other doses. HMMC exhibited faster kinetics compared to methylone, with a Cmax value that was 10-14-fold lower and an AUC0-24 value that was 21-29-fold lower. Methylone pharmacokinetics was linear across 50-200 mg oral doses in humans, unlike the previously described non-linear oral MDMA pharmacokinetics. An LC-MS/MS method for the quantification of methylone, MDMA and their metabolites in human plasma was achieved. Methylone exhibited linear pharmacokinetics in humans with oral doses of 50-200 mg.

Ethical and Legal Challenges of Telemedicine in the Era of the COVID-19 Pandemic.

Background and objective: Telemedicine or telehealth services has been increasingly practiced in the recent years. During the COVID-19 pandemic, telemedicine turned into and indispensable service in order to avoid contagion between healthcare professionals and patients, involving a growing number of medical disciplines. Nevertheless, at present, several ethical and legal issues related to the practice of these services still remain unsolved and need adequate regulation. This narrative review will give a synthesis of the main ethical and legal issues of telemedicine practice during the COVID-19 pandemic. Material and Methods: A literature search was performed on PubMed using MeSH terms: Telemedicine (which includes Mobile Health or Health, Mobile, mHealth, Telehealth, and eHealth), Ethics, Legislation/Jurisprudence, and COVID-19. These terms were combined into a search string to better identify relevant articles published in the English language from March 2019 to September 2021. Results: Overall, 24 out of the initial 85 articles were considered eligible for this review. Legal and ethical issues concerned important aspects such as: informed consent (information about the risks and benefits of remote therapy) and autonomy (87%), patient privacy (78%) and confidentiality (57%), data protection and security (74%), malpractice and professional liability/integrity (70%), equity of access (30%), quality of care (30%), the professional-patient relationship (22%), and the principle of beneficence or being disposed to act for the benefit of others (13%). Conclusions: The ethical and legal issues related to the practice of telehealth or telemedicine services still need standard and specific rules of application in order to guarantee equitable access, quality of care, sustainable costs, professional liability, respect of patient privacy, data protection, and confidentiality. At present, telemedicine services could be only used as complementary or supplementary tools to the traditional healthcare services. Some indications for medical providers are suggested.

THC and CBD concentrations in blood, oral fluid and urine following a single and repeated administration of "light cannabis".

Background "Light cannabis" is a product legally sold in Europe with Δ9-tetrahydrocannabinol (THC) concentration lower than 0.2% and variable cannabidiol (CBD) content. We studied THC and CBD excretion profiles in blood, oral fluid (OF) and urine after smoking one or four light cannabis cigarettes. Methods Blood, OF and urine samples were obtained from six healthy light cannabis consumers after smoking one 1 g cigarette containing 0.16% THC and 5.8% CBD and from six others after smoking four 1 g cigarettes within 4 h. Sample collection began 0.5 and 4.5 h after smoking one or four cigarettes, respectively. Cannabinoid concentrations were quantified by gas chromatography-mass spectrometry (GC-MS). Results At the first collection, the highest THC and CBD concentrations occurred in blood (THC 7.0-10.8 ng/mL; CBD 30.2-56.1 ng/mL) and OF (THC 5.1-15.5 ng/mL; CBD 14.2-28.1 ng/mL); similar results occurred 0.5 h after the last of four cigarettes in blood (THC 14.1-18.2 ng/mL, and CBD 25.6-45.4 ng/mL) and OF (THC 11.2-24.3 ng/mL; CBD 14.4-37.0 ng/mL). The mean OF to blood ratio ranged from 0.6 to 1.2 after one and 0.6 to 1.9 after four light cannabis cigarettes. THC/CBD ratios in blood and OF were never greater than 2. Urinary 11-nor-9-carboxy-THC concentrations peaked 8 h after one and four cigarettes. Conclusions OF was a valuable alternative to blood in monitoring consumption of light cannabis. Blood and OF THC/CBD concentration ratios, never exceeded 2, possibly providing a useful biomarker to identify light cannabis vs illegal higher THC cannabis use, where THC/CBD ratios are generally greater than 10.

Development and validation of fast UHPLC-MS/MS screening method for 87 NPS and 32 other drugs of abuse in hair and nails: application to real cases.

Interest on keratinized matrix analysis for clinical and forensic purposes has been recently grown due to the wide temporary detection window for psychotropic and toxic substances entrapped after repeated consumption. The aim of this study was the development and full validation of an UHPLC-MS/MS screening method to quantify 119 molecules among most abused classic drugs and new psychoactive substances in hair and in nails, to assess the polyconsumption. Twenty-five milligrams of hair or nail samples, added with the internal standard mixture, were cut and incubated with 500 µL M3® buffer reagent at controlled temperature. After cooling, 1 µL supernatant was injected in the chromatographic system equipped with an Oasis HLB column. After the 10 min chromatographic separation through a gradient mobile phase (aqueous ammonium formate, phase A; acetonitrile, phase B), the target compounds were detected in multiple reaction monitoring mode. The method was linear (r2 always better than 0.99) in a calibration range of LOQ 20000 pg compound for milligram hair and of LOQ 1000 pg compound per milligram nail. Process efficiency of analytes under investigation was always better than 65% and no significant ion suppression due to matrix effect was observed. Intra-assay and inter-assay precision and accuracy were always better than 15%. The applicability and trueness of the method were examined by analysing real samples of hair and nail from users of psychoactive drugs in recreational contexts. Both classic drugs and new psychoactive substances could be determined as result of single or repeated use and accumulation in keratin matrices. Graphical abstract.

Intensive and pharmacological care in times of COVID-19: A "special ethics" for emergency?

BACKGROUND: The Authors have laid out an analysis of Italian COVID-19 confirmed data and fatality rates, pointing out how a dearth of health care resources in northern regions has resulted in hard, ethically challenging decisions in terms of granting patient access to intensive care units (ICU). MAIN TEXT: Having to make such decisions certainly entails substantial difficulties, and that has led many health care professional to seek ethical guidance. The Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) has attempted to meet that growing need by a set of recommendations, applying "clinical soundness" as a beacon standard; that approach tends to prioritize patients with higher life expectancy, which could be characterized as a "moderately utilitarian" approach. Yet, such a selection has engendered daunting ethical quandaries. The authors believe it can only be warranted and acceptable if rooted in a transparent decision-making process and verifiable, reviewed criteria. Moreover, the authors have stressed how clinical experimentation in a pandemic setting is a subtext of great interest from an ethical perspective. In Italy, no drug therapy and trials were undertaken for COVID-19 patients for a rather long period of time. When the epidemic was already circulating, an intervention proved necessary on the system of administrative procedures, aimed at expediting the authorization and validation of protocols, then bogged down by bureaucracy. A new system has since been instituted by a government decree that was signed about one month after the first Covid-19 case was officially recorded in the country. Such a swift implementation, which took just a few weeks, is noteworthy and proves that clinical trials can be initiated in a timely fashion, even with a pandemic unfolding. The concerted, action of supportive care and RCTs is the only way to attain effective forms of treatments for COVID-19 and any other future outbreak. CONCLUSIONS: The authors have arrived at the conclusion that the most effective and ethically sound response on the part of any national health care system would be to adequately reconfigure its organizational mechanisms, by making clinical trials and all related administrative procedures consistent with the current state of emergency.

Toxicology and Analysis of Psychoactive Tryptamines.

Our understanding of tryptamines is poor due to the lack of data globally. Tryptamines currently are not part of typical toxicology testing regimens and their contribution to drug overdoses may be underestimated. Although their prevalence was low, it is increasing. There are few published data on the many new compounds, their mechanisms of action, onset and duration of action, toxicity, signs and symptoms of intoxication and analytical methods to identify tryptamines and their metabolites. We review the published literature and worldwide databases to describe the newest tryptamines, their toxicology, chemical structures and reported overdose cases. Tryptamines are 5-HT2A receptor agonists that produce altered perceptions of reality. Currently, the most prevalent tryptamines are 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 5-methoxy-N,N- diallyltryptamine (5-MeO-DALT) and dimethyltryptamine (DMT). From 2015 to 2020, 22 new analytical methods were developed to identify/quantify tryptamines and metabolites in biological samples, primarily by liquid chromatography tandem mass spectrometry. The morbidity accompanying tryptamine intake is considerable and it is critical for clinicians and laboratorians to be informed of the latest data on this public health threat.

Determination of the Synthetic Cannabinoids JWH-122, JWH-210, UR-144 in Oral Fluid of Consumers by GC-MS and Quantification of Parent Compounds and Metabolites by UHPLC-MS/MS.

The consumption of synthetic cannabinoids (SCs) has significantly increased in the last decade and the analysis of SCs and their metabolites in human specimens is gaining interest in clinical and forensic toxicology. A pilot study has been carried out using a combination of an initial last generation gas chromatography-mass spectrometry (GC-MS) screening method for the determination of JWH-122, JWH-210, UR-144) in oral fluid (OF) of consumers and an ultra-high performance liquid chromatography high resolution mass spectrometry (UHPLC-HRMS) confirmatory method for the quantification of the parent compounds and their metabolites in the same biological matrix. OF samples were simply liquid-liquid extracted before injecting in both chromatographic systems. The developed methods have been successfully validated and were linear from limit of quantification (LOQ) to 50 ng/mL OF. Recovery of analytes was always higher than 70% and matrix effect always lower than 15% whereas intra-assay and inter-assay precision and accuracy were always better than 16%. After smoking 1 mg JWH-122 or UR-144 and 3 mg JWH-210, maximum concentration of 4.00-3.14 ng/mL JWH-122, 8.10-7.30 ng/mL JWH-210 ng/mL and 7.40 and 6.81 ng/mL UR-144 were measured by GC-MS and UHPLC-HRMS respectively at 20 min after inhalation. Metabolites of JWH 122 and 210 were quantified in OF by UHPLC-HRMS, while that of UR144 was only detectable in traces. Our results provide for the first time information about disposition of these SCs and their metabolites in consumers OF. Last generation GC-MS has proven useful tool to identify and quantify parent SCs whereas UHPLC-HRMS also confirmed the presence of SCs metabolites in the OF of SCs consumers.

Medicinal Cannabis and Synthetic Cannabinoid Use.

Cannabis products have been used for centuries by humans for recreational and medical purposes. Resent research, proposed the promising therapeutic potential of cannabis and related cannabinoids for a wide range of medical conditions, including psychiatric and neurological diseases. This Special Issue presents the latest updates on medicinal cannabis and synthetic cannabinoids pharmacology, toxicology and new analytical methods to identify and quantify these compounds in conventional and non-conventional biological matrices. Moreover, it provides current data regarding their adverse effects, safety, application for medical purposes and their harmful effects.

Herbal Preparations of Medical Cannabis: A Vademecum for Prescribing Doctors.

Cannabis has been used for centuries for therapeutic purposes. In the last century, the plant was demonized due to its high abuse liability and supposedly insufficient health benefits. However, recent decriminalization policies and new scientific evidence have increased the interest in cannabis therapeutic potential of cannabis and paved the way for the release of marketing authorizations for cannabis-based products. Although several synthetic and standardized products are currently available on the market, patients' preferences lean towards herbal preparations, because they are easy to handle and self-administer. A literature search was conducted on multidisciplinary research databases and international agencies or institutional websites. Despite the growing popularity of medical cannabis, little data is available on the chemical composition and preparation methods of medical cannabis extracts. The authors hereby report the most common cannabis preparations, presenting their medical indications, routes of administration and recommended dosages. A practical and helpful guide for prescribing doctors is provided, including suggested posology, titration strategies and cannabinoid amounts in herbal preparations obtained from different sources of medical cannabis.

Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review.

BACKGROUND AND OBJECTIVE: Changes in cannabis legalization regimes in several countries have influenced the diversification of cannabis use. There is an ever-increasing number of cannabis forms available, which are gaining popularity for both recreational and therapeutic use. From a therapeutic perspective, oral cannabis containing Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is a promising route of administration but there is still little information about its pharmacokinetics (PK) effects in humans. The purpose of this systematic review is to provide a general overview of the available PK data on cannabis and THC after oral administration. METHODS: A search of the published literature was conducted using the PubMed database to collect available articles describing the PK data of THC after oral administration in humans. RESULTS: The literature search yielded 363 results, 26 of which met our inclusion criteria. The PK of oral THC has been studied using capsules (including oil content), tablets, baked goods (brownies and cookies), and oil and tea (decoctions). Capsules and tablets, which mainly correspond to pharmaceutical forms, were found to be the oral formulations most commonly studied. Overall, the results reflect the high variability in the THC absorption of oral formulations, with delayed peak plasma concentrations compared to other routes of administration. CONCLUSIONS: Oral THC has a highly variable PK profile that differs between formulations, with seemingly higher variability in baked goods and oil forms. Overall, there is limited information available in this field. Therefore, further investigations are required to unravel the unpredictability of oral THC administration to increase the effectiveness and safety of oral formulations in medicinal use.

Cannabinoids determination in bronchoalveolar lavages of cannabis smokers with lung disease.

Background Cannabis smoke affects the lungs similarly to tobacco smoke, causing symptoms such as increased cough, sputum, hyperinflation and chronic bronchitis. Chronic use can also cause serious lung diseases and airway obstruction. We developed and validated a method for the identification and quantification of cannabinol (CBN), cannabidiol (CBD), Δ-9-tetrahydrocannabinol (THC) and its metabolites 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) in bronchoalveolar lavages (BALs) from hospitalized former or current tobacco smoking patients with lung disease and a long history of cannabis consumption and limited current tobacco use. Methods For the extraction of cannabinoids from BALs, a 1 mL sample was added with 300 µL of 0.1 N NaOH and 3 mL of hexane/ethyl acetate (9:1). The solvent was then evaporated to dryness. Trimethylsilyl derivatives were prepared and then analyzed by gas chromatography/mass spectrometry. Results The method was linear for the analytes under investigation with coefficients of determination of at least 0.99. Absolute analytical recovery was always better than 80%, imprecision and inaccuracy was always under 15%. Six cases out of 15 were positive for THC, CBN and CBD. In two BALs samples, the presence of 11-OH-THC was also measured while THC-COOH was not detected. In the six positive cases, the last cannabis smoking occurred in the previous 2-14 days. Conclusions This is the first time that cannabinoids have been detected in BALs, demonstrating the presence of a drug with its metabolites in a target organ of consumers who present with a lung disease. This occurrence let us hypothesize a role of cannabinoids in the development of the disease and prompted an investigation on possible associations between cannabis smoking and clinical outcomes in patients with lung disease and eventually evaluate a cytotoxic effect of cannabinoids themselves.

Acute Intoxications and Fatalities From Illicit Fentanyl and Analogues: An Update.

Illicit fentanyl and its analogues are very dangerous synthetic opioids, with high abuse potential and severe adverse effects including coma and death. They are used as adulterants in street heroin, cocaine, and methamphetamine, or as heroin substitutes sold to unaware users with a high risk of overdoses. Fentanyl and its analogues have also been identified in counterfeit medicinal products, such as oxycodone, hydrocodone, and alprazolam tablets, or as components of speedball mixtures together with cocaine or other stimulants. In recent years, a number of epidemics involving acute intoxications and deaths related to illicit fentanyl or its analogues have occurred in the United States, Europe, Canada, Australia, and Japan. In several cases, fatalities involved polysubstance use. A review of the most recent case reports or case series of acute intoxications and fatalities involving illicit fentanyl and its newest analogues is herein provided, together with the available information on intoxication symptoms, eventual death cause, and metabolites detected in different biological fluids and reported concentrations.