Maintained anxiolytic effects of cannabidiol after treatment discontinuation in healthcare workers during the COVID-19 pandemic.

Objective: To assess whether the effects of oral administration of 300 mg of Cannabidiol (CBD) for 28 days on mental health are maintained for a period after the medication discontinuation. Methods: This is a 3-month follow-up observational and clinical trial study. The data were obtained from two studies performed simultaneously by the same team in the same period and region with Brazilian frontline healthcare workers during the COVID-19 pandemic. Scales to assess emotional symptoms were applied weekly, in the first month, and at weeks eight and 12. Results: The primary outcome was that, compared to the control group, a significant reduction in General Anxiety Disorder-7 Questionnaire (GAD-7) from baseline values was observed in the CBD group on weeks two, four, and eight (Within-Subjects Contrasts, time-group interactions: F1-125 = 7.67; p = 0.006; ηp 2 = 0.06; F1-125 = 6.58; p = 0.01; ηp 2 = 0.05; F1-125 = 4.28; p = 0.04; ηp 2 = 0.03, respectively) after the end of the treatment. Conclusions: The anxiolytic effects of CBD in frontline health care professionals during the COVID-19 pandemic were maintained up to 1 month after the treatment discontinuation, suggesting a persistent decrease in anxiety in this group in the real world. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings and weigh the benefits of CBD therapy against potential undesired or adverse effects.

Analysis of opiates in urine using microextraction by packed sorbent and gas Chromatography- Tandem mass spectrometry.

Opiates recreational consumption has always been a concern in society, public health, and in clinical toxicology analysis. The aim of this study was to develop and fully validate an analytical method, which was simple and rapid for the determination of tramadol, codeine, morphine, 6- acetylcodeine, 6-monoacetylmorphine and fentanyl using gas chromatography coupled to tandem mass spectrometry. The procedure includes the use of microextraction by packed sorbent for sample clean-up. A mixed mode sorbent was used, allowing the minimal use of solvents. The method was validated in urine samples, with the ability to detect and quantify all analytes with satisfactory linearity (in the range of 1 - 1000 ng/mL for all analytes, except for fentanyl (10-1000 ng/mL)). Extraction efficiency varied from 17 to 107%, which did not impair sensitivity, taking into account the low LLOQs obtained (1 ng/ mL for all analytes; and 10 ng/mL for fentanyl). The developed procedure proved to be fast, selective, and accurate for use in routine analysis, with a low volume of sample (250 µL).

An Update on the Implications of New Psychoactive Substances in Public Health.

The emergence of new psychoactive substances has earned a great deal of attention, and several reports of acute poisoning and deaths have been issued involving, for instance, synthetic opiates. In recent years, there have been profound alterations in the legislation concerning consumption, marketing, and synthesis of these compounds; rapid alert systems have also been subject to changes, and new substances and new markets, mainly through the internet, have appeared. Their effects and how they originate in consumers are still mostly unknown, primarily in what concerns chronic toxicity. This review intends to provide a detailed description of these substances from the point of view of consumption, toxicokinetics, and health consequences, including case reports on intoxications in order to help researchers and public health agents working daily in this area.

Cannabidiol for COVID-19 Patients with Mild to Moderate Symptoms (CANDIDATE Study): A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Importance: Owing to its anti-inflammatory properties and antiviral "in vitro" effect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cannabidiol (CBD) has been proposed as a potential treatment for coronavirus disease 2019 (COVID-19). Objective: To investigate the safety and efficacy of CBD for treating patients with mild to moderate COVID-19. Design: Randomized, parallel-group, double-blind, placebo-controlled clinical trial conducted between July 7 and October 16, 2020, in two sites in Brazil. Setting: Patients were recruited in an emergency room. Participants: Block randomized patients (1:1 allocation ratio-by a researcher not directly involved in data collection) with mild and moderate COVID-19 living in Ribeirão Preto, Brazil, seeking medical consultation, and those who voluntarily agreed to participate in the study. Interventions: Patients received 300 mg of CBD or placebo added to standard symptomatic care during 14 days. Main Outcome and Measure: The primary outcome was reduction or prevention of the deterioration in clinical status from mild/moderate to severe/critical measured with the COVID-19 Scale or the natural course of the resolution of typical clinical symptoms. Primary study outcome was assessed on days 14, 21, and 28 after enrollment. Results: A total of 321 patients were recruited and assessed for eligibility, and 105 were randomly allocated either in CBD (n=49) or in placebo (n=42) group. Ninety-one participants were included in the analysis of efficacy. There were no baseline between-group differences regarding disease severity (χ2=0.025, p=0.988) and median time to symptom resolution (12 days [95% confidence interval, CI, 6.5-17.5] in the CBD group, 9 days [95% CI, 4.8-13.2] in the placebo group [χ2=1.6, p=0.205 by log-rank test]). By day 28, 83.3% in the CBD group and 90.2% in the placebo group had resolved symptoms. There were no between-group differences on secondary measures. CBD was well tolerated, producing mostly mild and transient side effects (e.g., somnolence, fatigue, changes in appetite, lethargy, nausea, diarrhea, and fever), with no significant differences between CBD and placebo treatment groups. Conclusions and Relevance: Daily administration of 300 mg CBD for 14 days failed to alter the clinical evolution of COVID-19. Further trials should explore the therapeutic effect of CBD in patients with severe COVID-19, possibly trying higher doses than the used in our study. Trial Registration: ClinicalTrials.gov identifier NCT04467918 (date of registration: July 13, 2020).

Efficacy and Safety of Cannabidiol Plus Standard Care vs Standard Care Alone for the Treatment of Emotional Exhaustion and Burnout Among Frontline Health Care Workers During the COVID-19 Pandemic: A Randomized Clinical Trial.

Importance: Frontline health care professionals who work with patients with COVID-19 have an increased incidence of burnout symptoms. Cannabidiol (CBD) has anxiolytic and antidepressant properties and may be capable of reducing emotional exhaustion and burnout symptoms. Objective: To investigate the safety and efficacy of CBD therapy for the reduction of emotional exhaustion and burnout symptoms among frontline health care professionals working with patients with COVID-19. Design, Setting, and Participants: This prospective open-label single-site randomized clinical trial used a 1:1 block randomization design to examine emotional exhaustion and burnout symptoms among frontline health care professionals (physicians, nurses, and physical therapists) working with patients with COVID-19 at the Ribeirão Preto Medical School University Hospital in São Paulo, Brazil. Participants were enrolled between June 12 and November 12, 2020. A total of 214 health care professionals were recruited and assessed for eligibility, and 120 participants were randomized in a 1:1 ratio by a researcher who was not directly involved with data collection. Interventions: Cannabidiol, 300 mg (150 mg twice per day), plus standard care or standard care alone for 28 days. Main Outcomes and Measures: The primary outcome was emotional exhaustion and burnout symptoms, which were assessed for 28 days using the emotional exhaustion subscale of the Brazilian version of the Maslach Burnout Inventory-Human Services Survey for Medical Personnel. Results: A total of 120 participants were randomized to receive either CBD, 300 mg, plus standard care (treatment arm; n = 61) or standard care alone (control arm; n = 59) for 28 days. Of those, 118 participants (59 participants in each arm; 79 women [66.9%]; mean age, 33.6 years [95% CI, 32.3-34.9 years]) received the intervention and were included in the efficacy analysis. In the treatment arm, scores on the emotional exhaustion subscale of the Maslach Burnout Inventory significantly decreased at day 14 (mean difference, 4.14 points; 95% CI, 1.47-6.80 points; partial eta squared [ηp2] = 0.08), day 21 (mean difference, 4.34 points; 95% CI, 0.94-7.73 points; ηp2 = 0.05), and day 28 (mean difference, 4.01 points; 95% CI, 0.43-7.59 points; ηp2 = 0.04). However, 5 participants, all of whom were in the treatment group, experienced serious adverse events: 4 cases of elevated liver enzymes (1 critical and 3 mild, with the mild elevations reported at the final 28-day assessment) and 1 case of severe pharmacodermia. In 2 of those cases (1 with critical elevation of liver enzymes and 1 with severe pharmacodermia), CBD therapy was discontinued, and the participants had a full recovery. Conclusions and Relevance: In this study, CBD therapy reduced symptoms of burnout and emotional exhaustion among health care professionals working with patients during the COVID-19 pandemic. However, it is necessary to balance the benefits of CBD therapy with potential undesired or adverse effects. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04504877.

Recent bionalytical methods for the determination of new psychoactive substances in biological specimens.

One of the problems associated with the consumption of new psychoactive substances is that in most scenarios of acute toxicity the possibility of quick clinical action may be impaired because many screening methods are not responsive to them, and laboratories are not able to keep pace with the appearance of new substances. For these reasons, developing and validating new analytical methods is mandatory in order to efficiently face those problems, allowing laboratories to be one step ahead. The goal of this work is to perform a critical review regarding bionalytical methods that can be used for the determination of new psychoactive substances (phenylethylamines, cathinones, synthetic cannabinoids, opioids, benzodiazepines, etc), particularly concerning sample preparation techniques and associated analytical methods.

Adulterants in crack cocaine in Brazil.

INTRODUCTION: Brazil is the world's biggest consumer of crack cocaine, and dependence is a major public health issue. This is the first study to investigate the prevalence of potentially harmful adulterants present in hair samples from Brazilian patients with crack cocaine dependence. METHOD: We evaluated adulterants in hair samples extracted by convenience from 100 patients admitted at the 48 hour-observation unit of Centro de Referência de Álcool, Tabaco e Outras Drogas (CRATOD), Brazil's largest center for addiction treatment. A cross-sectional analysis was performed with the data obtained. RESULTS: Adulterants were found in 97% of the analyzed hair samples. The most prevalent adulterant was lidocaine (92%), followed by phenacetin (69%) and levamisole (31%). CONCLUSION: Adulterants were widely prevalent in hair samples from crack users treated at CRATOD: at least one adulterant was present in virtually all the hair samples collected. This points to a need to monitor adverse effects in the clinical setting in order to provide this high-risk group of patients with prompt and effective care related to the acute and chronic complications associated with these adulterants.

Adulterants in crack cocaine in Brazil / Adulterantes no crack vendido na "Cracolândia"

Abstract Introduction Brazil is the world's biggest consumer of crack cocaine, and dependence is a major public health issue. This is the first study to investigate the prevalence of potentially harmful adulterants present in hair samples from Brazilian patients with crack cocaine dependence. Method We evaluated adulterants in hair samples extracted by convenience from 100 patients admitted at the 48 hour-observation unit of Centro de Referência de Álcool, Tabaco e Outras Drogas (CRATOD), Brazil's largest center for addiction treatment. A cross-sectional analysis was performed with the data obtained. Results Adulterants were found in 97% of the analyzed hair samples. The most prevalent adulterant was lidocaine (92%), followed by phenacetin (69%) and levamisole (31%). Conclusion Adulterants were widely prevalent in hair samples from crack users treated at CRATOD: at least one adulterant was present in virtually all the hair samples collected. This points to a need to monitor adverse effects in the clinical setting in order to provide this high-risk group of patients with prompt and effective care related to the acute and chronic complications associated with these adulterants.

Resumo Introdução O Brasil é o maior consumidor mundial de crack, e a dependência é um grande problema de saúde pública. Este é o primeiro estudo a investigar a prevalência de adulterantes potencialmente nocivos presentes em amostras de cabelo de pacientes brasileiros com dependência de crack. Métodos Foram avaliados adulterantes em amostras de cabelos extraídos por conveniência de 100 pacientes internados na unidade de observação de 48 horas do Centro de Referência de Álcool, Tabaco e Outras Drogas (CRATOD), o maior centro de tratamento de dependência do Brasil. Uma análise transversal foi realizada com os dados obtidos. Resultados Foram encontrados adulterantes em 97% das amostras de cabelo analisadas. O adulterante mais prevalente foi a lidocaína (92%), seguida da fenacetina (69%) e levamisol (31%). Conclusão Os adulterantes foram amplamente prevalentes em amostras de cabelo de usuários de crack tratados no CRATOD: pelo menos um adulterante estava presente em praticamente todas as amostras de cabelo coletadas. Isso aponta para a necessidade de monitorar os efeitos adversos no ambiente clínico, a fim de proporcionar a esse grupo de pacientes de alto risco cuidados imediatos e efetivos relacionados às complicações agudas e crônicas associadas a esses adulterantes.

Hair analysis when external contamination is in question: A review of practical approach for the interpretation of results.

Despite having been extensively discussed over the last decade, the differentiation between systemic exposure and external contamination still continues to be one of the limitations of hair testing for drugs. For this reason, we consider it worthwhile to re-state some basic principles in this short review. Various studies investigating a diversity of wash protocols, most using artificially contaminated hair with cocaine, have been valuable in evaluating wash efficacy and in understanding the incorporation of drugs in hair. However, assessments of wash efficacy made with real hair samples, as opposed to artificially contaminated samples, provide a different perspective, and demonstrate how rarely external contamination affects the interpretation of results. Data from a large number of hair samples from crack cocaine users, confirmed the usefulness of our protocol to remove most of the externally deposited cocaine. The data showed that hair levels of cocaine and benzoylecgonine in crack cocaine users were overall high with ratio of benzoylecgonine to cocaine in all samples above 0.1. The wash residue concentrations of cocaine ranged from not detected to 21ng/mg with a median of 0.5ng/mg. Cocaine was detected in the wash residue in 105 out of 138 samples. The wash to hair cocaine ratio ranged from not detected to 0.36 with a median of 0.02. The wash to hair cocaine ratios were below 0.07 in 133 cases. The five cases that produced wash to hair ratios above 0.1, one sample was at 0.11, three at 0.13 and one at 0.36, possibly because these cases were at the lower end of cocaine levels, however, we could not rule out that the hair was contaminated. Whilst it is not possible to differentiate between the drug extracted from the hair and the drug attached to the outside of the hair, we can compare levels of drug in the wash residue with levels detected in the hair sample. In addition, further diagnostic criteria must be applied to minimise potential misdiagnosis of external contamination. When drugs are detected in hair, individuals have clearly been in an environment where drugs are present, but it is only on rare occasions that it is unclear whether this is the result of drug use or of external contamination, and, in those cases, the results of testing need to be interpreted in the light of corroborating evidence from clinical data or social context.

Small molecule specific run acceptance, specific assay operation, and chromatographic run quality assessment: recommendation for best practices and harmonization from the global bioanalysis consortium harmonization teams.

Consensus practices and regulatory guidance for liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assays of small molecules are more aligned globally than for any of the other bioanalytical techniques addressed by the Global Bioanalysis Consortium. The three Global Bioanalysis Consortium Harmonization Teams provide recommendations and best practices for areas not yet addressed fully by guidances and consensus for small molecule bioanalysis. Recommendations from all three teams are combined in this report for chromatographic run quality, validation, and sample analysis run acceptance.

Simultaneous determination of losartan and hydrochlorothiazide in human plasma by LC/MS/MS with electrospray ionization and its application to pharmacokinetics.

A method based on a simple liquid-liquid extraction (LLE) followed by high-performance liquid chromatography with negative ion electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) detection was developed for the simultaneous determination of losartan (LOS) and hydrochlorothiazide (HCTZ) in human plasma, using valsartan (VAL) and chlorthalidone (CHTD) as an internal standard, respectively. The acquisition was performed in multiple reactions monitoring (MRM) and the limit of quantification was 4 ng/mL for both LOS and HCTZ. The method was linear in the studied range (4-800 ng/mL for LOS and 4-500 ng/mL for HCTZ). The intra-assay precisions ranged from 2.6-11.9% for LOS and 1.4-8.2% for HCTZ, while the inter-assay precisions ranged from 1.0-8.0% for LOS and 2.5-7.7% for HCTZ. The intra-assay accuracies ranged from 91.3 to 107.6% for LOS and 91.5 to 105.8% for HCTZ, while the inter-assay accuracies ranged from 99.9 to 106.4% for LOS and 97.4 to 101.4% for HCTZ. The analytical method was applied to a bioequivalence study, in which 28 healthy adult volunteers (14 men) received single oral doses (100 mg LOS + 25 mg HCTZ) of reference and test formulations, in an open, two-period, balanced randomized, crossover protocol. Based on the 90% confidence interval of the individual ratios for Cmax and AUC0-inf, it was concluded that the test formulation is bioequivalent to the reference Hyzaar formulation with respect to the rate and extent of absorption of both LOS and HCTZ.

Determination of bromazepam in human plasma by high-performance liquid chromatography with electrospray ionization tandem mass spectrometric detection: application to a bioequivalence study.

A simple method using a one-step liquid-liquid extraction (LLE) followed by high-performance liquid chromatography (HPLC) with positive ion electrospray ionization tandem mass spectrometric (ESI-MS/MS) detection was developed for the determination of bromazepam in human plasma, using lorazepam as internal standard. The acquisition was performed in the multiple reaction monitoring mode, monitoring the transitions: m/z 316 > 182 for bromazepam and m/z 321 > 275 for lorazepam. The method was linear over the studied range (1-100 ng ml(-1)), with r(2) > 0.98, and the run time was 2.5 min. The intra- and inter-assay precisions were 2.7-14.6 and 4.1-17.3%, respectively and the intra- and inter-assay accuracies were 87-111 and 75.8-109.5%, respectively. The mean recovery was 73.7%, ranging from 64.5 to 79.7%. The limit of quantification was 1 ng ml(-1). At this concentration the mean intra- and inter-assay precisions were 14.6 and 7.1%, respectively, and the mean intra- and inter-assay accuracies were 102.5 and 104%, respectively. Bromazepam stability was evaluated and the results showed that the drug is stable in standard solution and in plasma samples under typical storage and processing conditions. The method was applied to a bioequivalence study in which 27 healthy adult volunteers (14 men) received single oral doses (6 mg) of reference and test bromazepam formulations, in an open, two-period, randomized, crossover protocol. The 90% confidence interval of the individual ratios (test formulation/reference formulation) for C(max) (peak plasma concentration), AUC(0-96) and AUC(0-inf) (area under the plasma concentration versus time curve from time zero to 96 h and to infinity, respectively) were within the range 80-125%, which supports the conclusion that the test formulation is bioequivalent to the reference formulation regarding the rate and extent of bromazepam absorption.

Combined chromatographic methodology for antidoping control in horse urine

A combination of chromatographic techniques is described for the screening of drugs in horse urine for antidoping control purposes. The procedure consists of liquid-liquid base extraction with analysis by HPTLC and GC-NPD and liquid-liquid acidic extraction followed by HPTLC and HPLC. The results of 86 drugs analyzed by these procedures, as well as limits of detection of the drugs in each technique are presented, The use of ELISA tests are recommended for the screening of drugs which would not be detected by the chromatographic proposed procedure. The results show that the proposed combination of techniques enables an efficient antidoping control of racing horses.