The increase in benzodiazepine-laced drugs and related risks in Canada: The urgent need for effective and sustainable solutions.

The overdose crisis in Canada has continuously evolved and is increasingly challenging to contain, while efforts from governments and policymakers to address it have often fallen short and resulted in unintended consequences. One of the main repercussions has been an unprecedented rise in adulterants in the illegal drug supply, including a wide array of pharmacological and psychoactive compounds and chemicals, which has resulted in a progressively toxic drug supply. Most recently, there has been a stark increase in synthetic benzodiazepine-laced opioids (i.e., 'benzodope') in some Canadian jurisdictions. This unique combination carries distinct and amplified risks for people who use drugs including fatal and non-fatal overdoses, increased dependence and withdrawal symptoms, and places them in extremely vulnerable positions. The emergence of benzodiazepines within the illicit drug supply has substantially contributed to drug-related morbidity and mortality in Canada, and has further complicated current public health initiatives and overdose prevention efforts. This reality underscores the need for effective and sustainable policy solutions to address the evolving overdose epidemic including increased knowledge and education on the specific harms of opioid and benzodiazepine co-use (especially in regards to the complexity of opioid/benzodiazepine overdoses), scaling-up harm reduction measures, and eliminating the toxic drug supply altogether.

A Case of Phenibut Directed Detoxification Leading to Toxicity During the COVID-19 Pandemic.

BACKGROUND: Phenibut is a non-Food and Drug Administration-approved gamma-aminobutyric acid analog marketed in the United States as an anxiolytic, cognitive enhancer, and alcohol withdrawal treatment through online supplement vendors. In this case report, we describe a woman's self-directed detoxification with phenibut used to manage withdrawal symptoms from fentanyl and benzodiazepines in March 2020 during the height of the COVID-19 pandemic. CASE: A 38-year-old woman with severe opioid, benzodiazepine, gabapentin, stimulant use disorders developed altered mental status after oral phenibut ingestion intended to help self-manage opioid and benzodiazepine withdrawal. She chose self-directed detoxification as she feared COVID-19 exposure in detoxification facilities. Her altered mental status drove her to jump out a third-story window causing multiple spinal fractures. After a long hospitalization, she self-directed her discharge home due to concerns about COVID-19. Her premature discharge disrupted opioid and benzodiazepine use disorder treatment plans. CONCLUSION: This case highlights the risks of phenibut use for selfdirected detoxification. With COVID-19 related changes in the drug supply, people may be more likely to use online pharmaceuticals, therefore, substance use assessments should inquire about the online acquisition of new psychoactive drugs. Public health messaging regarding the risks of infectious disease transmission in addiction care settings is needed to guide addiction treatment choices among people who use substances.

A nationwide cohort study of the association of benzodiazepines with SARS-CoV-2 infection and clinical outcomes.

The evidence for the impact of benzodiazepine (BZD) use on infection or clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is limited. We evaluated the association of BZD use with SARS-CoV-2 infection and the clinical outcomes of coronavirus disease 2019 (COVID-19) using a nationwide COVID-19 database from South Korea. This nationwide cohort study was performed using the COVID-19 database from the Health Insurance Review and Assessment Service of Korea, and SARS-CoV-2 positivity was investigated according to BZD use. SARS-CoV-2-positive adult patients were assessed in three groups, those who needed hospitalization, those with severe symptoms requiring intensive care, and those who died. A multivariate logistic regression model was used for all the analyses. After adjusting for potential confounding factors, there was no association between BZD use and SARS-CoV-2 positivity. SARS-CoV-2-positive patients with BZD use showed an increased risk of need for hospitalization from COVID-19 compared to those without BZD use (odds ratio [OR]: 1.33, 95% confidence interval [CI] 1.07-1.65). In addition, there was a higher risk for long-term users (OR: 2.64, 95% CI 1.08-6.47). Chronic BZD use contributed to a higher risk of the need for hospitalization among COVID-19 patients, whereas BZD use did not increase the risk of SARS-CoV-2 test positivity, severe outcomes, or mortality.

Use of sedative-hypnotic medications and risk of dementia: A systematic review and meta-analysis.

AIMS: Growing evidence suggests an association between the use of sedative-hypnotic medications and risk of dementia. The aim of this study is to examine this association using a meta-analysis approach. METHODS: MEDLINE (PubMed) and Scopus were systematically searched for studies published in English only. The quality of studies was evaluated using the Newcastle-Ottawa scale, and an overall odds ratio was pooled using a random-effects model. RESULTS: A total of 35 articles were included in the analysis. Pooled odds ratios (ORs) for dementia from all records were (OR; 1.33, 95% CI 1.19-1.49) for benzodiazepine (BZD) combined use (Subgroup-1), (OR: 1.46, 95% CI 1.23-1.73) for short-acting BZD use (Subgroup-2), (OR: 1.72, 95% CI 1.48-1.99) for long-acting BZD use (Subgroup-3), (OR: 1.13, 95% CI 0.97-1.32) for BZDs without specification of duration of action (Subgroup-4), (OR: 1.64, 95% CI 1.13-2.38) for the combined BZDs and Z-drugs, (OR: 1.43, 95% CI 1.17-1.74) for Z-drugs only, (OR: 1.14, 95% CI 0.88-1.46) for antidepressant use, (OR: 0.97, 95% CI 0.68-1.39) for antipsychotic use and (OR: 0.98, 95% CI 0.85-1.13) for anticonvulsant use. When sensitivity analysis was performed, association between overall use of BZDs and short-acting BZDs with the increased risk of dementia disappeared after exclusion of studies that were not adjusted for age covariate (OR: 1.2, 95% CI 1.0-1.44) and (OR: 1.22, 95% CI 0.75-2.01), respectively. Adjustment for protopathic bias by introduction of a lag period showed no evidence of increased risk of dementia with the use of BZDs (Subgroup-1) (OR: 1.14, 95% CI 0.82-1.58), Z-drugs (OR: 1.29, 95% CI 0.78-2.13), and combined BZDs and Z-drugs (OR: 1.51, 95% CI 0.91-2.53). Combined use of BZDs and Z-drugs showed more positive association when only studies of non-user design were analysed (OR: 2.75, 95% CI 2.23-3.39). CONCLUSIONS: All the investigated sedative-hypnotics showed no association with increased risk of dementia except for BZDs. However, the observed association with BZDs did not persist after exclusion of studies with potential reverse causation and confounding by indication. Therefore, this association needs to be assessed carefully in future research.

Efficacy and safety of balovaptan for socialisation and communication difficulties in autistic adults in North America and Europe: a phase 3, randomised, placebo-controlled trial.

BACKGROUND: There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults. METHODS: V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917). FINDINGS: Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred. INTERPRETATION: Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures. FUNDING: F Hoffmann-La Roche.

[Effect of treatment with benzodiazepines on the hospital prognosis of Coronavirus disease 2019]. / Efecto del tratamiento con benzodiacepinas en el pronóstico hospitalario de la enfermedad por coronavirus 2019.

INTRODUCTION: The consequences of the use of of benzodiazepines in coronavirus disease 2019 have not yet been studied. We compared the hospital prognosis of patients hospitalized for coronavirus disease 2019 in benzodiazepine users and non-users. PATIENTS AND METHODS: Observational study with a retrospective cohort design. All consecutive patients admitted with a confirmed diagnosis of coronavirus disease 2019 were included. The patients under chronic treatment with benzodiazepines at the time of admission were studied and compared with non-users. The primary objective was to analyze the mortality of patients who used chronic benzodiazepines at the time of admission and compare them with those who did not use them. The secondary objective was to analyze the risk of severe disease due to coronavirus 2019, acute respiratory distress syndrome and admission to the Intensive Care Unit in both groups of patients. RESULTS: We included 576 patients, 138 (24.0%) used benzodiazepines. After adjusting for sex, age, baseline situation and all the different variables between both groups, benzodiazepine users did not show a higher odds of mortality (OR: 1,1, IC 95%: 0,7-1,9, p = 0,682) or higher risk of severe disease due to coronavirus 2019 (OR: 1.2, 95% CI: 0.7-1.8, p = 0.523). They also did not have a higher risk of acute respiratory distress syndrome (OR: 1.2, IC 95%: 0.8-1.9, p = 0.315) or more admission to the Intensive Care Unit (OR: 0.8, 95% CI: 0.4-1.4, p = 0.433). CONCLUSION: In our sample, treatment with benzodiazepines at the time of admission was not associated with a worse hospital prognosis in patients with coronavirus disease 2019.

TITLE: Efecto del tratamiento con benzodiacepinas en el pronóstico hospitalario de la enfermedad por coronavirus 2019.Introducción. Las consecuencias del consumo de benzodiacepinas en el marco de la la enfermedad por coronavirus 2019 (COVID-19) no se habían estudiado hasta ahora. En el presente estudio se comparó el pronóstico hospitalario de pacientes ingresados por COVID-19 que tomaban benzodiacepinas con el de otros ingresados por idéntico motivo que no las tomaban. Pacientes y métodos. Estudio observacional de cohortes retrospectivo. En el estudio se admitió a todos los pacientes consecutivos ingresados con un diagnóstico confirmado de COVID-19. Se estudió a los pacientes que en el momento del ingreso estaban en tratamiento crónico con benzodiacepinas en comparación con otros que no las tomaban. El objetivo principal fue analizar la mortalidad de dichos pacientes con uso crónico de benzodiacepinas y compararla con la mortalidad de los que no tomaban. El objetivo secundario fue analizar en ambos grupos de pacientes el riesgo de padecer un cuadro grave por COVID-19, el síndrome de dificultad respiratoria aguda o el ingreso en la unidad de cuidados intensivos. Resultados. Se admitieron 576 pacientes, 138 (24,0%) de los cuales tomaban benzodiacepinas. Después del ajuste por sexo, edad, situación inicial y todas las variables diferentes entre ambos grupos, los pacientes que tomaban benzodiacepinas no mostraron una probabilidad mayor de muerte (odds ratio: 1,1; IC 95%: 0,7-1,9; p = 0,682) ni un riesgo más acusado de COVID-19 grave (odds ratio: 1,2; IC 95%: 0,7-1,8; p = 0,523). Tampoco presentaron un riesgo mayor de síndrome de dificultad respiratoria aguda (odds ratio: 1,2; IC 95%: 0,8-1,9; p = 0,315) ni de ingreso en la unidad de cuidados intensivos (odds ratio: 0,8; IC 95%: 0,4-1,4; p = 0,433). Conclusión. En esta muestra de pacientes con COVID-2019, el tratamiento con benzodiacepinas en el momento del ingreso no apareció asociado con un empeoramiento del pronóstico hospitalario.

New Psychoactive Substances consumption and their monito- ring during Covid-19 pandemic.

ABSTRACT: Currently, the world is facing an unprecedent change of everyday life, due to the Covid-19 pandemic that has been affecting all the nations for more than one year. The public health systems were restructured in all the countries as a response to the constant emergency status, ne-glecting some services like toxicological analyses. In this scenario, the current spread of the New Psychoactive Substances is less controlled than before and the data on its expected mutation come from seizures analyses. Where the global distribution of drugs of abuse was affected by the restriction, fentanyl seizures did not drop during the pandemic. Moreover, new synthesis of fentanyl analogues resulted in new toxic adulterants as by products. Furthermore, diversion of benzodiazepines and new designer benzodiazepines were reported during the pandemic period. In this scenario, the scientific community and the international agencies should tighten their collaboration in order to monitor the emerging of new unknown substances.

Increasing diversion of prescribed benzodiazepines and Z-drugs to new psychoactive substances.

ABSTRACT: Over the last few years reports have indicated an increase in the number, type and availability of new psychoactive substances belonging to the benzodiazepine class. These molecules may pose high risks to users, since the majority have never undergone clinical trials or tests so their pharmacology and toxicology is largely unknown. However the new drug scenario emerging from the COVID-19 global pandemic seems to play a role in increasing the diversion of prescribed benzodiazepines and Z-drug. A brief presentation of this phenomenon is hereby presented. The awareness and response activities at national and international levels related to this issue should be enforced.