Unregulated Drug Research Articles

Randomised clinical trial of a 16 mg vs 24 mg maintenance daily dose of buprenorphine to increase retention in treatment among people with an opioid use disorder in Rhode Island: study protocol paper

IntroductionBuprenorphine is a highly effective treatment for opioid use disorder (OUD). However, provider observations and preliminary research suggest that the current standard maintenance dose may be insufficient for suppressing withdrawal...

Differences in heroin overdose risk associated with the unregulated drug market: Insights from a supervised injecting facility in Melbourne, Australia.

To determine the contribution that variation in the unregulated drug market has on the risk of heroin overdose across individuals with different levels of personal overdose risk. A retrospective cohort study of heroin injecting episodes and overdose cases were examined over a 12-month period between 30 June 2022 and 30 June 2023. The Medically Supervised Injecting Room in Melbourne, Australia. 1474 witnessed heroin overdose cases were examined amongst a cohort of 337 individuals who were predominantly male (n = 276, 81.7%) with a median age of 43.5years (interquartile range 37.25-49.00 years, range 20-75 years). The daily overdose rate was used to differentiate High and Low daily overdose risk categories. The number of overdose events that an individual experienced during the study period was used to differentiate people into Standard, Moderate and High personal overdose risk categories. Each overdose case was differentiated by the personal overdose risk of the individual who experienced the overdose, as well as the overdose risk of the day that overdose occurred. A stratified overdose risk profile was then derived across the nine different daily overdose risk and personal overdose risk categories. The rate of overdose approximately doubled on High overdose risk days compared with Standard overdose risk days, increasing by a factor of 2.11, 2.41 and 2.03 times for individuals in the Standard, Moderate and High personal overdose risk groups. Conversely, the rate of overdose was also substantially reduced on Low overdose risk days to a factor of 0.17, 0.28 and 0.20, respectively. Among heroin users in Melbourne, Australia, there is an approximately 10-times difference in the risk of overdose on some days compared with others, which appears to be attributable to the effects of the unregulated drug market and not the effects of variation in personal overdose risk of individuals.

Impacts of the COVID-19 pandemic on the availability and retail price of unregulated drugs in Vancouver, Canada: An interrupted time-series analysis, 2018-2022

BackgroundImpacts of the COVID-19 pandemic on unregulated drug markets in North America have not been well characterized. We sought to estimate potential changes in the availability and retail price of unregulated drugs in Vancouver, Canada pre- vs. post-emergence of the COVID-19 pandemic. MethodsWe used self-report data from two prospective cohorts of people who use drugs in Vancouver. We employed interrupted time series analyses to identify changes in the monthly prevalence of immediate availability (i.e., within 10 minutes vs. any longer) and median retail price of crystal methamphetamine, powder cocaine, crack cocaine, and ‘down’ (the local term for unregulated opioids, e.g., heroin, fentanyl, etc), post-pandemic emergence (i.e. post-July 2020). ResultsBetween 2018 and 2022 among 739 participants, the monthly prevalence of immediate availability significantly decreased for all drugs immediately post- emergence of the pandemic (all p<0.05). The monthly prevalence of immediate availability of cocaine declined most (-18.1%, 95% confidence interval [CI]: -25.9, -10.4) and the immediate availability of ‘down’ declined least (-13.0%, 95% CI:-18.8, -7.3). In analyses of median price, the only significant change was in the price of cocaine, which increased by $3.46 per 0.5 grams (95% CI:1.0, 5.9) immediately post-emergence of the pandemic. ConclusionWhile more research is needed to investigate reasons for the observed trends, the stagnant price amidst decreased availability for all drugs examined in this study (save cocaine) may reflect decreased purity/increased contamination of unregulated drugs following the beginning of the pandemic in our study setting. These findings may have implications for drug policy and practice approaches, particularly in regions where synthetic psychoactive substances are increasingly dominating the unregulated drug supply.

Unpacking the Effects of Decriminalization: Understanding Drug Use Experiences and Risks among Individuals Who Use Drugs in British Columbia

ObjectivesOn January 31, 2023, a three-year exemption from the Controlled Drugs and Substances Act was granted to the Canadian province British Columbia (BC), allowing the cumulative possession of 2.5 g of specific unregulated drugs amongst adults. The goals of the policy are to reduce health, social, and economic harms associated with criminalization, stigma, drug overdose deaths, as well as drug seizures, arrests, and associated enforcement and court costs. As the inaugural year has passed, we aimed to assess people who use drugs’ awareness and knowledge of the, as well as the policy’s impact on their drug use patterns and overdose risk.MethodsWe conducted 100 telephone-based semi-structured interviews with people who use drugs from across BC, exploring changes in drug use experiences and perceived overdose risk since the implementation of the policy. Participants also completed an interviewer-administered survey assessing socio-demographics and substance use patterns. We utilized a qualitative content analysis approach to analyze the interview data.ResultsOur findings indicate a general awareness of the policy among participants, although some policy details were often misunderstood, and participants expressed the need for more widespread dissemination of policy information. While the majority of participants reported that their drug use patterns remained unchanged after decriminalization, some made subtle adjustments, such as carrying under the 2.5 g threshold to minimize the risk of criminalization. Participants highlighted several policy benefits and concerns, including its potential to reduce criminalization and stigmatization, but also increase public drug consumption. Participants offered suggestions for policy improvement.ConclusionThese findings underscore the need for ongoing monitoring of the impacts of decriminalization regarding its potential impact on people who use drugs’ drug use patterns and related risks. Reevaluation of the possession threshold and efforts to enhance education and awareness about the policy could help achieve the policy’s goals.

Implementation of a community-based LC-UV drug checking service: promising preliminary findings on feasibility and validity

BackgroundThe increasing diversity of psychoactive substances on the unregulated drug market poses significant health, psychological, and social risks to people who use drugs (PWUD). To address these risks, various harm reduction (HR) policies have been implemented, including drug checking services (DCS). Many analytical methods are used for DCS. While qualitative methods (e.g., thin layer chromatography, spectroscopy) are easier to implement, they are not as accurate as quantitative methods (e.g., LC-UV, LC-MS). Some HR programmes have implemented high-performance liquid chromatography coupled with UV detection (LC-UV). This article presents the cross-validation of this quantitative method with a reference liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) method.MethodsDrug samples were provided by PWUD to a DCS called DrugLab in Marseille, France. The samples were weighed and prepared through dissolution in methanol, followed by ultrasonic bathing. Samples were analysed onsite using LC-UV analysis. They were then subsequently analysed with the reference LC-HRMS method. The LC-UV instrument in DrugLab was calibrated after being purchased; analysis of standard solutions was routinely performed once a month and after maintenance operations. For the LC-HRMS instrument, calibration and quality control procedures followed European Medicines Agency (EMA) guidelines. Statistical analyses were conducted including Spearman correlation tests using IBM® SPSS® Statistics version 20.ResultsA total of 102 samples representing different product classes and cutting agents were cross-validated. Differences between both analyses methods for each molecule analysed were ≤ 20%, with significant correlations between both methods’ results for most substances. Notably, LC-HRMS provided lower concentration values for cocaine and acetaminophen, whereas it provided higher values for other substances. Correlations were significant for cocaine, ketamine, MDMA, heroin, amphetamine, caffeine, acetaminophen, and levamisole.ConclusionsThis study demonstrates that the results provided by DrugLab were accurate and reliable, making LC-UV an adaptable, stable, and suitable analytical method for simple matrices like drugs in a DCS context. However, this cross validation does not guarantee accuracy over time. A proficiency test project in HR laboratories across France is currently under development in order to address potential drifts in LC-UV accuracy.

Quantitation and Abundance of Xylazine and Xylazine Metabolites in Human Urine and Plasma by LC-MS/MS

Abstract The most common cause of drug overdose fatality in the US involves synthetic opioids such as fentanyl. Recently the Director of the White House Office of National Drug Control Policy designated fentanyl adulterated or associated with xylazine as an emerging threat to the US, and a national response plan will include xylazine testing. Xylazine is a clonidine analog and is not FDA-approved for use in humans but has been increasingly detected in unregulated illicit drugs supplies. Our understanding of xylazine detection, metabolism, and clinical impact on patients, however, is limited. The objectives of this study are to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect xylazine and xylazine metabolites in urine and plasma, and to investigate the presence and abundance of xylazine metabolites in remnant urine and plasma samples submitted for clinical testing. This is achieved by first collecting paired urine and serial plasma samples when urine tests positive for xylazine during routine clinical testing. Plasma samples were prepared for LC-MS/MS analysis by protein precipitation with methanol and xylazine-D6 internal standard. Urines were prepared by dilution with xylazine-D6, followed by a hydrolysis with beta-glucuronidase. All experiments were performed using an Aquity HPLC coupled to a Waters TQS-micro triple quadrupole mass spectrometer. LC separation utilized a C18 column with a 4-minute gradient from 2% to 98% mobile phase B (0.1% formic acid and 2mM ammonium acetate in A: water; B: methanol) with a flow rate of 400 μl/min at 50°C. Multiple reaction monitoring for xylazine and 4-OH-xylazine was optimized with commercial standards. Calibration curves for both analytes were prepared from 0.5 – 2,000 ng/mL in plasma, and 5 – 5,000 ng/mL in urine. Product ion scanning was used to detect four additional xylazine metabolites by spectral matching with previously published full scan tandem mass spectra. The highest intensity fragment ions observed in the product ion spectra were used to develop multiple reaction monitoring experiments for four additional xylazine metabolites, previously described as: sulfone-xylazine, oxo-xylazine, OH-sulfone-xylazine, and OH-oxo-xylazine, in 50 remnant urines and 70 individual plasmas. In remnant urines, xylazine concentrations ranged from less than 5 to greater than 5,000 ng/mL. In remnant plasmas, xylazine ranged from less than 0.5 to 158 ng/mL. Previously reported xylazine metabolites were detected in both urine and plasma, and relative peak area ratios were calculated as metabolite-to-xylazine in both matrices. In urine, the highest average peak area ratio (3.1) was observed for sulfone xylazine, after hydrolysis. In plasma, the highest average peak area ratio (1.4) was observed for oxo-xylazine. We were unable to absolutely quantitate either metabolite due to lack of available standards. Future studies include investigation on the association of xylazine exposure and plasma concentrations with clinical presentation and patient outcomes.

Oral fentanyl consumption and withdrawal impairs fear extinction learning and enhances basolateral amygdala principal neuron excitatory-inhibitory balance in male and female mice

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having increased withdrawal symptoms as compared to females, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.

Overdose as a complex contagion: modelling the community spread of overdose events following law enforcement efforts to disrupt the drug market

BackgroundThe opioid overdose mortality crisis in the USA is an ongoing public health epidemic. Ongoing law enforcement strategies to disrupt local unregulated drug markets can have an iatrogenic effect of...

B-298 Quantitation and Abundance of Xylazine and Xylazine Metabolites in Human Urine by LC-MS/MS

Abstract Background The most common cause of drug overdose fatality in the US involves synthetic opioids such as fentanyl. Recently the Director of the White House Office of National Drug Control Policy designated fentanyl associated with xylazine as an emerging threat to the US, and a national response plan will include xylazine testing. Xylazine, a clonidine analog is not FDA-approved for use in humans but has been increasingly detected in unregulated illicit drugs supplies. Our understanding of xylazine detection, metabolism, and clinical impact on patients, however, is limited. The objectives of this study are to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to investigate the presence and abundance of xylazine metabolites in remnant urine samples submitted for clinical testing. Methods Remnant urine samples were identified when tested positive for xylazine during routine clinical LC-MS/MS testing. All experiments were performed using an Acquity HPLC coupled to a Waters TQS-micro triple quadrupole mass spectrometer. Urines were diluted with xylazine-D6 internal standard, hydrolyzed using β-glucuronidase and separated on a 100mm x 2.1mm, 2.6μm Kinetex C18 column (Phenomenex) with a 4 minute step gradient from 2% to 98% mobile phase B (0.1% formic acid and 2mM ammonium acetate in A: water; B: methanol) with a flow rate of 400 μl/min at 50°C. Xylazine and 4-OH-xylazine were detected in positive mode using multiple reaction monitoring, with transitions optimized from standards (Cayman Chemical and/or Sigma Aldrich), resulting in the following transitions: xylazine: 221&amp;gt;90, 221&amp;gt;164; 4-OH xylazine: 237&amp;gt;90, 237&amp;gt;137. Xylazine and 4-OH-xylazine were quantified using calibration curves prepared from 1 - 5,000 ng/mL in negative urine. Product ion scanning (PIS) was used to detect four additional xylazine metabolites, based on spectral matching to previously published full scan high resolution product ion spectra. The highest abundance fragment ions and identified retention times from PIS experiments were used to perform targeted detection for sulfone-xylazine (253&amp;gt;181, 253&amp;gt;147), oxo-xylazine (235&amp;gt;122, 235&amp;gt;114), OH-sulfone-xylazine (269&amp;gt;197, 269&amp;gt;163), and OH-oxo-xylazine (251&amp;gt;197, 251&amp;gt;148). Results Xylazine was detected at &amp;gt;=1 ng/mL in 38% (54/138) of fentanyl positive urines. A subset (n= 362) of urines that screened positive for opiates, amphetamines, or cocaine metabolite, were also tested but xylazine was detected in only 1 urine that did not contain fentanyl.Xylazine concentrations quantified in 61 remnant urines ranged from &amp;lt;1 to &amp;gt;5,000 ng/mL. 4-OH-xylazine concentrations ranged from &amp;lt;1 to 509 ng/mL. We observed five previously reported xylazine metabolites: 4-OH-xylazine, oxo-xylazine, sulfone-xylazine, OH-oxo-xylazine, OH-sulfone-xylazine. The mean concentration ratio of 4-OH-xylazine-to-xylazine was 0.11. The mean peak area ratios (metabolite-to-xylazine) for sulfone-xylazine, OH-oxo-xylazine, OH-sulfone-xylazine, and oxo-xylazine were 3.5, 3.8, 2.1, and &amp;lt;0.1, respectively. The proposed sulfone-xylazine and OH-oxo-xylazine metabolites were observed to have the most abundant signal of all detected metabolites, although there is currently no commercially available standard to facilitate quantification. Conclusions Xylazine and 4-OH-xylazine were quantitated in 61 patient urines. Four additional xylazine metabolites were observed and relative abundance to xylazine was estimated using peak areas. Future studies include quantitation of xylazine and xylazine metabolites in plasma and association of xylazine detection with clinical presentation and patient outcomes.

Access and barriers to safer supply prescribing during a toxic drug emergency: a mixed methods study of implementation in British Columbia, Canada

BackgroundIn March 2020, British Columbia, Canada, introduced prescribed safer supply involving the distribution of pharmaceutical grade alternatives to the unregulated toxic drug supply. Prior research has demonstrated positive impacts on overdose mortality, but with limited reach to people who use substances. Objectives of this study were to (1) identify barriers to accessing safer supply prescribing among people who use substances; and (2) determine whether and how barriers differed between people with and without prescriptions, and between urban and rural settings.MethodsWe conducted a participatory mixed-methods study guided by the Consolidated Framework for Implementation Research. Participants (≥ 19 years old) had received a safer supply prescription or were seeking one (survey n = 353; interviews n = 54).ResultsParticipants who had a prescription were more likely to be living in a large urban centre, compared to medium/smaller centres and rural areas (78.5% vs. 65.8%, standardized mean difference = 0.286). Participants who did not have a prescription were more likely to report an array of structural, interpersonal, and health-related barriers (compared to those who had a prescription). In interviews, participants linked experiences of barriers to stigma and criminalization, low availability of services, lack of information and prescribers, not being able to get what they need, and anxieties, worries and doubts stemming from personal circumstances. There were no notable differences between large urban centres and medium/smaller centres and rural areas in the presence of specific types of barriers.ConclusionsFindings demonstrate restricted access to safer supply prescribing outside of large urban centres and provide future targets for enhancing implementation. Attention is needed to promote equity and counter systemic barriers in the implementation of responses to the ongoing toxic drug emergency.

Correlates of fentanyl preference among people who use drugs in Rhode Island

BackgroundFentanyl is increasingly pervasive in the unregulated drug supply and is a driver of drug overdose deaths in the United States. The aims of this study were to characterize and identify correlates of fentanyl preference among people who use drugs (PWUD) in Rhode Island (RI).MethodsUsing bivariate analysis, we examined associations between fentanyl preference and sociodemographic and psychosocial characteristics at baseline among participants enrolled in the RI Prescription Drug and Illicit Drug Study from August 2020-February 2023. Fentanyl preference was operationalized based on responses to a five-point Likert scale: “I prefer using fentanyl or drugs that have fentanyl in them.” Participants who responded that they “strongly disagree,” “disagree,” or were “neutral” with respect to this statement were classified as not preferring fentanyl, whereas participants who responded that they “agree” or “strongly agree” were classified as preferring fentanyl.ResultsAmong 506 PWUD eligible for inclusion in this analysis, 15% expressed a preference for fentanyl or drugs containing fentanyl as their drug of choice. In bivariate analyses, preference for fentanyl was positively associated with younger age, white race, lifetime history of overdose, history of injection drug use, past month enrollment in a substance use treatment program, past month treatment with medications for opioid use disorder, and preferences for heroin and crystal methamphetamine (all p < 0.05). Descriptive data yielded further insight into reasons for fentanyl preference, the predominant having to do with perceived effects of the drug and desire to avoid withdrawal symptoms.ConclusionsOnly a relatively small subset of study participants preferred drugs containing fentanyl. Given the increased prevalence of fentanyl contamination across substances within the unregulated drug market, the result for PWUD is increasingly less agency with respect to choice of drug; for example, people may be forced to use fentanyl due to restricted supply and the need to mitigate withdrawal symptoms, or may be using fentanyl without intending to do so. Novel and more effective interventions for PWUD, including increased access to age-appropriate harm reduction programs such as fentanyl test strips and overdose prevention centers, are needed to mitigate fentanyl-related harms.

Syringe services program staff and participant perspectives on changing drug consumption behaviors in response to xylazine adulteration

BackgroundXylazine is an increasingly common adulterant in the North American unregulated drug supply that is associated with adverse health outcomes (e.g., skin infections, overdose). However, there are significant knowledge gaps regarding how xylazine was initially identified and how syringe services program (SSP) staff and clients (people who use drugs) responded to its emergence.MethodsFrom June–July 2023, we conducted qualitative interviews with medical (e.g., clinicians) and frontline SSP staff (e.g., outreach workers) and adult clients with a history of injection drug use at a Miami-based SSP. Inductive memos identified emergent codes; thematic analysis involving team consensus established final themes.ResultsFrom interviews with SSP staff (n = 8) and clients (n = 17), xylazine emergence was identified at different times, in various ways. Initially, during summer 2022, clients identified a “tranquilizer-like substance” that worsened sedation and withdrawal and caused wounds. SSP medical staff later identified this adulterant as xylazine by treating new medical cases and through diverse information-sharing networks that included professional societies and news sources; however, frontline SSP staff and clients needed additional educational resources about xylazine and its side effects. With limited guidance on how to reduce harm from xylazine, SSP clients altered their drug consumption routes, reduced drug use, and relied on peers’ experiences with the drug supply to protect themselves. Some individuals also reported preferring xylazine-adulterated opioids and increasing their drug use, including the use of stimulants to avoid over sedation.ConclusionsXylazine’s emergence characterizes the current era of unprecedented shifts in the unregulated drug supply. We found that xylazine spurred important behavioral changes among people who use drugs (e.g., transitioning from injecting to smoking). Incorporating these experiences into early drug warning surveillance systems and scaling up drug-checking services and safer smoking supply distribution could help mitigate significant health harms caused by xylazine and other emergent adulterants.

Beyond individual factors: a critical ethnographic account of urban residential fire risks, experiences, and responses in single-room occupancy (SRO) housing

BackgroundBurn injuries are a significant public health concern, closely linked to housing conditions and socioeconomic status. Residents in socioeconomically deprived neighbourhoods are at increased risk of exposure to hazards due to older and poorer housing conditions and limited access to fire protection measures. Individual behaviours such as substance use, smoking, and hoarding are often highlighted as primary causes of residential fires, overshadowing the broader socioeconomic and structural factors that also play a significant role in housing safety. This paper explores the correlation between inadequate housing conditions and heightened fire risks leading to burn injuries, focusing on the contextual factors shaping everyday urban fire risks, experiences, and responses of residents living in Single-Room Occupancy (SRO) housing in Vancouver’s Downtown East Side (DTES) and staff working in the fire, health, housing (social and private), and non-profit sectors.MethodsAs part of an ongoing ethnographic study, we partnered with the Vancouver Fire Rescue Services (VFRS) to conduct participant observations in private, non-profit, and government-owned SROs, modular homes, and a temporary shelter. This paper synthesizes insights from participant observations from the first author’s self-reflexive journals, including informal conversations with approximately fifty-nine individuals such as SRO tenants, SRO managers/caretakers, health workers, burn survivors, municipal staff, not-for-profit staff, and firefighters.ResultsUrgent housing-related issues contributing to inequitable everyday urban fire risks were identified, such as structural deficiencies in SRO buildings and systems, inadequate waste management and storage, and inequitable approaches to addressing hoarding. Additionally, disparities in access to information and the interaction between interpersonal and structural stigmas were significant factors, underscoring the pressing need for intervention.ConclusionCommunities like DTES, facing precarious housing conditions, disadvantaged neighbourhoods, and complex health and social challenges, necessitate a comprehensive and holistic approach to fire prevention and safety. Recognizing the interplay between housing instability, mental and physical health issues, unregulated toxic drug supply, drug criminalization, and structural inequities allows practitioners from various sectors to develop contextually driven fire prevention strategies. This multifaceted approach transcends individual-level behaviour change and is crucial for addressing the complex issues contributing to fire risks in underserved communities.

Increases in housing rules and surveillance during COVID-19: impacts on overdose and overdose response in a community-based cohort of sex workers who use drugs in Vancouver, BC

IntroductionSince the beginning of the COVID-19 pandemic, COVID-19 risk mitigation measures have expanded to include increased rules and surveillance in supportive housing. Yet, in the context of the dual public health emergencies of COVID-19 and the unregulated drug toxicity crisis, we have not evaluated the unintended health and social consequences of such measures, especially on criminalized women. In order to address this dearth of evidence, our aim was to assess the association between increased housing rules and surveillance during COVID-19 and (a) nonfatal overdose, and (b) administration of naloxone for overdose reversal among women sex workers who use drugs in Vancouver, BC.MethodsThis study is nested within An Evaluation of Sex Workers Health Access (AESHA), a community-based prospective cohort of women sex workers in Metro Vancouver (2010–present). Using cross-sectional data collected during the first year of COVID-19 (April 2020–2021), we developed separate multivariable logistic regression confounder models to examine the independent associations between experiencing increased housing rules and surveillance during COVID-19 on (a) nonfatal overdose, and (b) administration of naloxone for overdose reversal in the last 6 months.ResultsAmongst 166 participants, 10.8% reported experiencing a recent non-fatal overdose and 31.3% recently administered naloxone for overdose reversal. 56.6% reported experiencing increased rules and surveillance within their housing during COVID-19. The prevalence of non-fatal overdose and administering naloxone was significantly elevated among those exposed to increased housing rules and surveillance during COVID-19 versus those who were unexposed (83.3% vs. 52.1%; 75.0% vs. 48.2%, respectively). In separate multivariate confounder models, exposure to increased housing rules and surveillance during COVID-19 was independently associated with increased odds of administering naloxone [AOR: 3.66, CI: 1.63–8.21], and marginally associated with non-fatal overdose [AOR: 3.49, CI: 0.92–13.27].ConclusionEfforts to prioritize the right to safe, adequate and affordable housing must avoid reinforcing an overly coercive reliance on surveillance measures which, while often well-intended, can negatively shape residents’ well-being. Furthermore, public health responses to pandemics must include criminalized populations so that measures do not exacerbate overdose risk. Implementation of a regulated drug supply is recommended, alongside housing policies that promote residents' rights, safety, and health.

A qualitative evaluation of a fentanyl patch safer supply program in Vancouver, Canada

BackgroundThe ongoing overdose crisis in Canada has prompted efforts to increase access to a “safer supply” of prescribed alternatives to the unregulated drug supply. While safer supply programs predominantly distribute hydromorphone tablets, the Safer Alternatives for Emergency Response (SAFER) program in Vancouver, Canada offers a range of prescribed alternatives, including fentanyl patches. However, little is known about the effectiveness of fentanyl patches as safer supply. Drawing on the perspectives and experiences of program participants, we sought to qualitatively evaluate the effectiveness of the SAFER fentanyl patch program in meeting its intended aims, including reducing risk of overdose by decreasing reliance on the unregulated drug supply. MethodsAs part of a larger mixed-methods evaluation of SAFER, semi-structured qualitative interviews were conducted with 17 fentanyl patch program participants between February 2022 and April 2023. Thematic analysis of interview data focused on program engagement, experiences, impacts, and challenges. ResultsThe flexible program structure, including lack of need for daily dispensation, the extended missed dose protocol, and community pharmacy patch distribution fostered engagement and enhanced autonomy. Improved management of withdrawal symptoms and cravings due to steady transdermal dosing led to reduced unregulated drug use and overdose risk. Participants also experienced economic benefits and improvements in overall health and quality of life. However, skin irritation and patch adhesion issues were key barriers to program retention. ConclusionOur findings demonstrate the value of including fentanyl patch safer supply in the substance use continuum of care and offer insights for innovations in delivery of this intervention.

Providers’ knowledge and perception of xylazine in the unregulated drug supply: a sequential explanatory mixed-methods study

BackgroundXylazine is increasingly prevalent in the unregulated opioid supply in the United States. Exposure to this adulterant can lead to significant harm, including prolonged sedation and necrotic wounds. In the absence of literature describing healthcare providers’ experiences with treating patients who have been exposed to xylazine, we aimed to explore what gaps must be addressed to improve healthcare education and best practices.MethodsFrom October 2023 to February 2024, we conducted a sequential explanatory mixed-methods study, with (1) a quantitative survey phase utilizing convenience sampling of healthcare providers treating patients in Connecticut and (2) a qualitative semi-structured interview phase utilizing purposive sampling of providers with experience treating patients with xylazine exposure. Summary statistics from the survey were tabulated; interview transcripts were analyzed using thematic analysis.ResultsSeventy-eight eligible healthcare providers participated in our survey. Most participants had heard of xylazine (n = 69, 95.8%) and had some knowledge about this adulterant; however, fewer reported seeing one or more patients exposed to xylazine (n = 46, 59.8%). After sampling from this subgroup, we conducted fifteen in-depth interviews. This qualitative phase revealed five themes: (1) while xylazine is novel and of concern, this is not necessarily exceptional (i.e., there are other emerging issues for patients who use drugs); (2) participants perceived that xylazine was increasingly prevalent in the drug supply, even if they were not necessarily seeing more patients with xylazine-related outcomes (XROs); (3) patients primarily presented with non-XROs, making it difficult to know when conversations about xylazine were appropriate; (4) patients with XROs may experience issues accessing healthcare; (5) providers and their patients are learning together about how to minimize XROs and reduce the sense of helplessness in the face of a novel adulterant.ConclusionsXylazine-specific education for healthcare providers is currently insufficient. Improving this education, as well as resources (e.g., drug checking technologies) and data (e.g., research on prevention and treatment of XROs), is crucial to improve care for patients who use drugs.

Xylazine in the Unregulated Drug Market: An Integrative Review of Its Prevalence, Health Impacts, and Detection and Intervention Challenges in the United States.

Xylazine, a veterinary sedative, has emerged as a concerning element in the landscape of substance use in the United States. This integrative review synthesizes evidence from a systematic examination of 14 selected studies conducted between 2008 and 2023. The primary objective is to comprehensively understand the epidemiology and prevalence of xylazine use, particularly its involvement in drug-related deaths, regional variations, national impact, co-occurrence with opioids, and challenges associated with detection and intervention. The results underscore stark regional disparities in xylazine prevalence. West Virginia and Miami-Dade County have experienced alarming surges in xylazine-involved drug-related deaths. Nationally, its influence extends beyond regional boundaries, predominantly affecting white males in the Northeast. The co-occurrence of xylazine with opioids, especially fentanyl and heroin, significantly amplifies the risks of fatal overdoses. Detecting xylazine presents formidable challenges due to its frequent presence alongside other substances, necessitating enhanced surveillance and more effective detection methods. User perspectives emerge as pivotal, emphasizing the importance of user-informed harm reduction strategies. In conclusion, this review has significant policy implications. Tailored, region-specific strategies are imperative to address the diverse prevalence of xylazine use. A nationwide response is indispensable, prioritizing harm reduction initiatives, enhanced detection methods, and active user engagement. The multifaceted nature of the xylazine issue requires comprehensive approaches to mitigate its profound risks effectively. Policymakers are urged to consider regional disparities and the co-occurrence of xylazine with opioids when crafting targeted interventions. Immediate, user-informed harm reduction is vital to address the evolving landscape of xylazine use in the United States.

Protective or potentially harmful? Altering drug consumption behaviors in response to xylazine adulteration.

Xylazine is an increasingly common adulterant in the North American unregulated drug supply that is associated with adverse health outcomes (e.g., skin infections, overdose). However, there are significant knowledge gaps regarding how xylazine was initially identified and how syringe services program (SSP) staff and clients (people who use drugs) responded to its emergence. From June-July 2023, we conducted qualitative interviews with medical (e.g., clinicians) and frontline SSP staff (e.g., outreach workers) and adult clients with a history of injection drug use at a Miami-based SSP. Inductive memos identified emergent codes; thematic analysis involving team consensus established final themes. From interviews with SSP staff (n = 8) and clients (n = 17), xylazine emergence was identified at different times, in various ways. Initially, during summer 2022, clients identified a "tranquilizer-like substance" that worsened sedation and withdrawal and caused wounds. SSP medical staff later identified this adulterant as xylazine by treating new medical cases and through diverse information-sharing networks that included professional societies and news sources; however, frontline SSP staff and clients needed additional educational resources about xylazine and its side effects. With limited guidance on how to reduce harm from xylazine, SSP clients altered their drug consumption routes, reduced drug use, and relied on peers' experiences with the drug supply to protect themselves. Some individuals also reported preferring xylazine-adulterated opioids and increasing their drug use, including the use of stimulants to avoid over sedation. Xylazine's emergence characterizes the current era of unprecedented shifts in the unregulated drug supply. We found that xylazine spurred important behavioral changes among people who use drugs (e.g., transitioning from injecting to smoking). Incorporating these experiences into early drug warning surveillance systems and scaling up drug-checking services and safer smoking supply distribution could help mitigate significant health harms caused by xylazine and other emergent adulterants.

A polylysine/hyaluronan-based core-shell nanoparticle triggers drug delivery by ATP/hyaluronidase dual stimuli for inducing apoptosis of breast cancer cells

The limitations of self-assembled polymeric nanoparticles for cancer therapy, including instability in the bloodstream, non-specific targeting of cancer cells, and unregulated intracellular drug delivery, were effectively addressed by the development of core-shell SNX@PLL-FPBA/mHA NPs. The core was SNX@PLL-FPBA NPs prepared from polylysine conjugated 3-fluoro-4-carboxyphenylboronic acid (PLL-FPBA) self-assembly and SNX encapsulation, while the shell was methacrylate-modified hyaluronic acid (mHA) adhering to the core by electrostatic interactions and subsequently stabilized by photo-crosslinking, without the use of any organic solvent. SNX@PLL-FPBA/mHA NPs exhibited good stability in varying ionic strengths (0–0.30 M NaCl), pH levels (6.8 and 7.4), and plasma environments mimicking the blood, ensuring their efficacy in systemic circulation. The drug delivery from the nanoparticles was highly sensitive to ATP/Hyals stimuli (82 % within 48 h), closely mimicking the intracellular environment of breast cancer cells. The nanoparticles demonstrated good hemocompatibility and non-toxicity towards human skin fibroblasts. Efficient internalization of SNX@PLL-FPBA/mHA NPs by MCF-7 and MDA-MB-231 breast cancer cells was observed by CLSM and flow cytometry. The intracellular ATP/Hyals stimuli triggered the rapid drug delivery and induced cellular apoptosis. Thus, SNX@PLL-FPBA/mHA NPs were a promising drug nanocarrier for breast cancer therapy, offering improved stability, targeted delivery, and controlled drug release to enhance treatment outcomes.

Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice.

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having more withdrawal symptoms, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.