Has GBL replaced GHB in recreational settings?

Has GBL replaced GHB in recreational setting

Cannabidiol, ∆9 -Tetrahydrocannabinol, and Metabolites in Human Blood by Volumetric Absorptive Microsampling and LC-MS/MS Following Controlled Administration in Epilepsy Patients

Cannabidiol (CBD) exhibits anti-inflammatory, anxiolytic, antiseizure, and neuroprotective proprieties without addictive or psychotropic side effects, as opposed to Δ9-tetrahydrocannabinol (THC). While recreational cannabis contains higher THC and lower CBD concentrations, medical cannabis contains THC and CBD in different ratios, along with minor phytocannabinoids, terpenes, flavonoids and other chemicals. A volumetric absorptive microsampling (VAMS) method combined with ultra-high-performance liquid chromatography coupled with mass spectrometry in tandem for quantification of CBD, THC and their respective metabolites: cannabidiol-7-oic acid (7-COOH-CBD); 7-hydroxy-cannabidiol (7-OH-CBD); 6-alpha-hydroxy-cannabidiol (6-α-OH-CBD); and 6-beta-hydroxycannabidiol (6-β-OH-CBD); 11- Hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH). After overnight enzymatic glucuronide hydrolysis at 37°C, samples underwent acidic along with basic liquid-liquid extraction with hexane: ethyl acetate (9:1, v/v). Chromatographic separation was carried out on a C18 column, with the mass spectrometer operated in multiple reaction monitoring mode and negative electrospray ionization. Seven patients with intractable epilepsy were dosed with various CBD-containing formulations and blood collected just before their daily morning administration. The method was validated following international guidelines in toxicology. Linear ranges were (ng/ml) 0.5-25 THC, 11-OH-THC, THCCOOH, 6-α-OH-CBD and 6-β-OH-CBD; 10-500 CBD and 7-OH-CBD; and 20-5000 7-COOH-CBD. 7-COOH-CBD was present in the highest concentrations, followed by 7-OH-CBD and CBD. This analytical method is useful for investigating CBD, THC and their major metabolites in epilepsy patients treated with CBD preparations employing a minimally invasive microsampling technique requiring only 30 µL blood

Is the right to abortion at risk in times of COVID-19? The italian state of Affairs within the european context

The COVID-19 health emergency has thrown the health systems of most European countries into a deep crisis, forcing them to call off and postpone all interventions deemed not essential or life-saving in order to focus most resources on the treatment of COVID-19 patients. To facilitate women who are experiencing difficulties in terminating their pregnancies in Italy, the Ministry of Health has adapted to the regulations in force in most European countries and issued new guidelines that allow medical abortion up to 63 days, i.e., 9 weeks of gestational age, without mandatory hospitalization. This decision was met with some controversy, based on the assumption that the abortion pill could “incentivize” women to resort to abortion more easily. In fact, statistical data show that in countries that have been using medical abortion for some time, the number of abortions has not increased. The authors expect that even in Italy, as is the case in other European countries, the use of telemedicine is likely to gradually increase as a safe and valuable option in the third phase of the health emergency. The authors argue that there is a need to favor pharmacological abortion by setting up adequately equipped counseling centers, as is the case in other European countries, limiting hospitalization to only a few particularly complex case

Is the Right to Abortion at Risk in Times of COVID-19? The Italian State of Affairs within the European Context

The COVID-19 health emergency has thrown the health systems of most European countries into a deep crisis, forcing them to call off and postpone all interventions deemed not essential or life-saving in order to focus most resources on the treatment of COVID-19 patients. To facilitate women who are experiencing difficulties in terminating their pregnancies in Italy, the Ministry of Health has adapted to the regulations in force in most European countries and issued new guidelines that allow medical abortion up to 63 days, i.e., 9 weeks of gestational age, without mandatory hospitalization. This decision was met with some controversy, based on the assumption that the abortion pill could “incentivize” women to resort to abortion more easily. In fact, statistical data show that in countries that have been using medical abortion for some time, the number of abortions has not increased. The authors expect that even in Italy, as is the case in other European countries, the use of telemedicine is likely to gradually increase as a safe and valuable option in the third phase of the health emergency. The authors argue that there is a need to favor pharmacological abortion by setting up adequately equipped counseling centers, as is the case in other European countries, limiting hospitalization to only a few particularly complex cases

In silico and in vitro human metabolism of IOX2, a performance-enhancing doping agent

IOX2 is a potent inhibitor of prolyl hydroxylase 2, a key enzyme in the regulation of hypoxia-inducible factor (HIF) and oxygen homeostasis. As such, it can be used to enhance athletic performance and is currently banned by the World Anti-Doping Agency (WADA). Detection of metabolites is critical to demonstrate drug use in doping. However, there is currently little data on IOX2 human metabolism. Our aim was to identify relevant biomarkers of IOX2 use in humans. For this purpose, IOX2 was incubated with 10-donor-pooled human hepatocytes for 3 h, incubates were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), and LC-HRMS/MS data were screened with Compound Discoverer (Thermo Scientific) for a comprehensive identification of IOX2 metabolites. Additionally, IOX2 human metabolites were predicted with GLORYx open-access software (University of Hamburg, Germany) to assist in the LC-HRMS/MS analysis and data mining. Thirteen metabolites were identified, oxidation at the quinolinyl group, O-glucuronidation, and combinations being predominant biotransformations. The results were consistent with previous animal studies and a single case of oral microdose administration. We suggest hydroxyquinolinyl-IOX2 as major biomarker of IOX2 use in biological samples, glucuronide hydrolysis being critical to increase IOX2 and hydroxyquinolinyl-IOX2 detectability in urine

Biomarkers of 4-hydroxy-N,N-methylpropyltryptamine (4-OH-MPT) intake identified from human hepatocyte incubations

Background: 4-Hydroxy-N,N-methylpropyltryptamine (4-OH-MPT) is a psychedelic tryptamine whose use is regulated in several countries. Due to unspecific effects, consumption can be ascertained only through toxicological analyses. However, the trace amounts of tryptamines are usually challenging to detect in biological samples. 4-OH-MPT metabolism was characterized to identify optimal metabolite markers of intake in clinical/forensic toxicology. Research design and methods: 4-OH-MPT was incubated with 10-donor-pooled human hepatocytes to simulate in vivo conditions; samples were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), and data were processed with Compound Discoverer from Thermo Scientific. LC-HRMS/MS and data mining were supported by in silico metabolite predictions (GLORYx). Results: Three phase I and four phase II metabolites were identified, including N-oxidation and N-demethylation at the alkylamine chain, and O-glucuronidation and sulfation at the hydroxylindole core. Conclusions: 4-OH-MPT metabolic fate was consistent with the human metabolism of tryptamine analogues: we suggest 4-OH-MPT-N-oxide and 4-hydroxy-N,N-propyltryptamine (4-OH-PT) as metabolite biomarkers of 4-OH-MPT consumption after glucuronide/sulfate hydrolysis in biological samples to improve detection of 4-OH-MPT and phase I metabolites; 4-OH-MPT-glucuronide is suggested as an additional biomarker when hydrolysis is not performed. Further research on the metabolism of structural analogues is necessary to evaluate the specificity of 4-OH-MPT metabolite biomarkers

Replacing GHB with GBL in Recreational Settings: A New Trend in Chemsex

Abstract: Background: Recently, Gamma-hydroxybutyrate (GHB) consumption in the recreational setting has been replaced by that of its prodrug Gamma-butyrolactone (GBL), cheaper and easier to obtain due to several legal industrial applications. Objective: The aim of the present paper was to report the most authoritative literature on the pharmacology and toxicology of GBL, dependence and abuse potential and the related public health issues together with the results of the analyses of several illicit liquid preparations containing GHB/GBL generally sold as “G”. Method: International literature concerning “Gamma-butyrolactone”, “GBL” “toxicology”, “pharmacology”, “abuse”, “dependence” and “GHB has been reviewed and liquid preparations containing GHB/GBL analysed by ultra-high performance liquid chromatography coupled to the tandem mass spectrometry validated methodology. Results: GBL for recreational purposes is orally administered in liquid form and rapidly transformed into GHB by lactonase enzymes present in the blood. As GBL shows a higher lipophilicity than GHB, it is absorbed more quickly, its bioavailability is higher and its effects are faster than those of GHB. Studies on rodents have shown that GBL has a low acute toxicity and only central nervous system depression has been highlighted. GBL abuse potential broadly mimics that of GHB, taking into account that it exerts its effects on the only after conversion into GHB. The analysis of 30 illicit preparations generally sold as “G” highlighted the presence of GBL in all of them at a mean concentration of 760.7 ±91.46 mg/mL (range: 588.5 - 899.3 mg/mL). Conclusion: GBL currently represents a growing public health issue since the substance is relatively cheaper and easier to obtain than GHB. Improvement and implementation of laws and policies to place GBL under control are needed to limit its diffusion, the eventual health threat for users and its non -negligible abuse liability and dependence risk

UHPLC-MS-MS Determination of THC, CBD and Their Metabolites in Whole Blood of Light Cannabis Smokers

"Light cannabis" is a product legally sold in Europe with Delta(9)-tetrahydrocannabinol (THC) concentration <0.2% and variable cannabidiol (CBD) content. In this study, we aimed to assess the time courses of THC and metabolites (11-nor-9-carboxy-THC and 11-hydroxy-THC) and CBD and metabolites (CBD-7-oic acid, 7-hydroxy-CBD, 6 alpha-hydroxy-CBD and 6 beta-hydroxy-CBD) in whole blood of 10 healthy participants after smoking one or four light cannabis cigarettes (0.16% THC and 5.8% CBD). Blood samples were collected 0.5-4 h after administration. Blood analysis was performed by reversed-phase ultra-performance liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode after glucuronide hydrolysis and liquid-liquid extraction in basic and acidic conditions. The method was validated following the most recent guidelines in toxicology: the method was linear, accurate, precise and sensitive (lower limits of quantification ranged from 0.005 to 0.01 ng/mL); carryover, matrix effect, recovery, process efficiency and dilution integrity were also assessed. As previously reported, the main metabolites of THC were THC-COOH and then 11-OH-THC, and the main metabolites of CBD were 7-OH-CBD and then 7-COOH-CBD. The time of the first collection, which likely occurred after the maximal concentration of most of the analytes, and the short monitoring time, up to 4 h after smoking, limited the evaluation of the pharmacokinetic parameters

Development of enantioselective high-performance liquid chromatography-tandem mass spectrometry method for quantitative determination of methylone and some of its metabolites in oral fluid

In the present study an enantioselective high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the first time for quantitative determination of the recreational drug of abuse methylone and its major metabolites in oral fluid. The simultaneous chemo- and enantioseparation of methylone and its major metabolites was performed on a polysaccharide-based chiral column based on amylose tris(5-chloro-3-methylphenylcarbamate) as chiral selector (Lux i-Amylose-3) with methanol containing 0.4 % (v/ v) aqueous ammonium hydroxide as mobile phase. The time required for enantioselective analysis of methylone and its 2 major metabolites was 15 min.This method was fully validated following the Organization of Scientific Area Committees (OSAC) for Forensic Science guidelines. This method was applied for the enantioselective determination of methylone and its metabolites in oral fluid and enantioselectivity in metabolism and pharmacokinetic of the parent compound and metabolites was observed.While the first enantiomer of methylone was found at higher concentration, both metabolites shown greater concentration for the second enantiomer. The results revealed that MET undergoes an enantioselective biotransformation to its metabolites HMMC and MDC, with S-(-)-MET more rapidly metabolized and eliminated from the body

Usefulness of Oral Fluid for Measurement of Methylone and Its Metabolites: Correlation with Plasma Drug Concentrations and the Effect of Oral Fluid pH

The aim of this study was to investigate methylone and its metabolites concentration in oral fluid following controlled increasing doses, focusing on the effect of oral fluid pH. Samples were obtained from a clinical trial where twelve healthy volunteers participated after ingestion of 50, 100, 150 and 200 mg of methylone. Concentration of methylone and its metabolites 4-hydroxy-3-methoxy-N-methylcathinone (HMMC) and 3,4-methylenedioxycathinone in oral fluid were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were estimated, and the oral fluid-to-plasma ratio (OF/P) at each time interval was calculated and correlated with the oral fluid pH using data from our previous study in plasma. Methylone was detected at all time intervals after each dose; MDC and HMMC were not detectable after the lowest dose. Oral fluid concentrations of methylone ranged between 88.3-503.8, 85.5-5002.3, 182.8-13,201.8 and 214.6-22,684.6 ng/mL following 50, 100, 150 and 200 mg doses, respectively, peaked between 1.5 and 2.0 h, and were followed by a progressive decrease. Oral fluid pH was demonstrated to be affected by methylone administration. Oral fluid is a valid alternative to plasma for methylone determination for clinical and toxicological studies, allowing for a simple, easy and non-invasive sample collection